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Traditional recruitment strategies, such as research information leaflets and advertisements in newspapers, appear ineffective in recruiting ethnic minority groups for research purposes. The use of FB proved to be a more successful method. Future research should examine the factors that account for the potential effectiveness of FB as a recruitment method for hard-to-reach populations.
Clinical trials are research studies that test how well new medical approaches work in people. Each study answers ... prevent, screen for, diagnose, or treat a disease. Clinical trials may also compare a new treatment to a ...
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Full Text Available ... trial is to find out if an experimental drug, therapy, medical device, lifestyle change, or test will ... disease. Phases of Clinical Trials Clinical trials of drugs are usually described based on their phase. The ...
... Eye Health Information > Clinical Trials in Vision Research Clinical Trials in Vision Research Clinical studies depend on people ... vision research in the United States. Basics of Clinical Trials What is a clinical trial? Clinical trials are ...
... and her initial results. Nueva Esperanza Para Las Enfermedades Del Corazón 09/23/2014 Milena tuvo un ... Story 09/23/2014 Nueva Esperanza Para Las Enfermedades Del Corazón 09/23/2014 Children and Clinical ...
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Information about NCI programs and initiatives that sponsor, conduct, develop, or support clinical trials, including NCI’s Clinical Trial Network (NCTN) and NCI Community Oncology Research Program (NCORP) initiatives.
... to This Site Terms and Conditions Disclaimer ClinicalTrials.gov is a registry and results database of publicly ... of human participants conducted around the world. ClinicalTrials.gov is a registry and results database of publicly ...
Friedman, Lawrence M; DeMets, David L; Reboussin, David M; Granger, Christopher B
This is the fifth edition of a very successful textbook on clinical trials methodology, written by recognized leaders who have long and extensive experience in all areas of clinical trials. The three authors of the first four editions have been joined by two others who add great expertise. Most chapters have been revised considerably from the fourth edition. A chapter on regulatory issues has been included and the chapter on data monitoring has been split into two and expanded. Many contemporary clinical trial examples have been added. There is much new material on adverse events, adherence, issues in analysis, electronic data, data sharing, and international trials. This book is intended for the clinical researcher who is interested in designing a clinical trial and developing a protocol. It is also of value to researchers and practitioners who must critically evaluate the literature of published clinical trials and assess the merits of each trial and the implications for the care and treatment of ...
Full Text Available ... a disease. A clinical trial may compare experimental products or tests to those already available or may ... Institutes of Health | U.S. Department of Health & Human Services Customer Support | Accessibility | Copyright | Privacy | Viewers and Players
U.S. Department of Health & Human Services — Provides patients, family members, health care professionals, and members of the public easy access to information on clinical trials for a wide range of diseases...
Full Text Available ... experimental drug, therapy, medical device, lifestyle change, or test will help treat, find, or prevent a disease. A clinical trial may compare experimental products or tests to those already available or may compare existing ...
Senn, S J
The relevance of the philosophy of Sir Karl Popper to the planning, conduct and analysis of clinical trials is examined. It is shown that blinding and randomization can only be regarded as valuable for the purpose of refuting universal hypotheses. The purpose of inclusion criteria is also examined. It is concluded that a misplaced belief in induction is responsible for many false notions regarding clinical trials.
... How Am I Protected? Mark Bowden / iStock Ethical guidelines The goal of clinical research is to develop knowledge that improves human ... data and decide whether the results have medical importance. Results from clinical trials are often published in peer-reviewed scientific ...
Kraus, V B; Blanco, F J; Englund, M
The objective of this work was to describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from...... of reasons but in particular, to determine whether biomarkers are useful in identifying those individuals most likely to receive clinically important benefits from an intervention; and to determine whether biomarkers are useful for identifying individuals at earlier stages of OA in order to institute...... both academia and industry, convened to discuss issues related to soluble biomarkers and to make recommendations for their use in OA clinical trials based on current knowledge and anticipated benefits. This document summarizes current guidance on use of biomarkers in OA clinical trials...
McAlindon, T. E.; Driban, J. B.; Henrotin, Y.;
The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct...... and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials...... that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA....
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... will not know if you are taking the medicine or the placebo until the clinical trial is over. How do ... can already get by prescription ) or sugar pills ( placebos ) with the new medicine may last longer than Phases I and II ...
Chassany, O; Duracinský, M
The current reference guideline about ethics in clinical trials is the Declaration of Helsinki of human rights in medical research. Three major principles are emphasised: respect of the patient to accept or not to participate in a trial, the constraints and the presumed risks must be acceptable for patients included in a study, and vulnerable subjects should not participate in studies. The investigator is responsible for obtaining a free and well-informed consent from patients before their inclusion in a study. Where possible, a new drug should always first be compared to placebo in order to prove its superiority. Else, a small-sized trial comparing a new drug versus a reference treatment can lead to an erroneous conclusion of absence of difference. Moreover, good results or improvement are obtained in at least 30% of cases with placebo, whatever the disease. The use of placebo is unethical in life-threatening diseases and when an effective proved drug exists. The use of placebo is ethical in severe diseases with no efficient drug, in some severe diseases even when an active reference treatment is available, and in all moderate and functional diseases. In order to detect flawed studies, most journals now ask for any manuscript submitted and reporting results of a randomised clinical trial to join a checklist in order to verify the quality of the trial. Finally, it remains the responsibility of the doctor to decide whether or not a protocol is ethical, to participate or not and to include patients or not.
Full Text Available ... Trials Insurance Coverage and Clinical Trials How to Work With Your Health Insurance Plan Federal Government Programs Patient Safety Informed Consent Children's Assent Scientific Review Ending Trials Early Deciding to Take Part ...
Bayés, M; Rabasseda, X; Prous, J R
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: 4'-Thio-ara-C, 5-methyltetrahydrofolate; ABT-089, AD-237, AF-37702, alvocidib hydrochloride, apricitabine, armodafinil, atrasentan, AVE-5883, avian influenza vaccine, azimilide hydrochloride; Banoxantrone, BIBF-1120; CD34+ cells, certolizumab pegol, CHIR-258, cilansetron, CoFactor, CX-3543, cystemustine; D-003, dexloxiglumide, DMXB-anabaseine; Ecogramostim, elcometrine, elcometrine/ethinylestradiol, etravirine; Fenretinide, fingolimod hydrochloride, fospropofol disodium; Gaboxadol, gestodene, glutamine; Human insulin, hyaluronic acid; Incyclinide, indacaterol, ispronicline, istradefylline; Labradimil, lamifiban, lapatinib, L-arginine hydrochloride, liposomal cisplatin, liposome encapsulated paclitaxel, LY-517717; Manidipine hydrochloride/delapril hydrochloride, maraviroc, MBP(82-98), MD-0727, MDX-214, melanotan I, MMR vaccine; Nacystelyn, nalfurafine hydrochloride, nibentan, nilotinib, NK-105; OBI-1, oblimersen sodium, olmesartan medoxomil, olmesartan medoxomil/hydrochlorothiazide, oregovomab; Pexelizumab, PG-116800, PG-CPT, PHA-794428, prasugrel; RC-3095, rDNA insulin, RFB4(dsFv)-PE38, rhEndostatin, rhenium Re-186 etidronate, rhGM-CSF, roflumilast, romidepsin; Sarcosine, SGLU1, SGN-40, succinobucol; TAU, teduglutide, telatinib, tesofensine, tipifarnib, tirapazamine, TKA-731, tolvaptan, trabectedin; Vaccimel, vatalanib succinate, velafermin, vildagliptin, vinflunine; XP-19986; YM-155.
Full Text Available ... treatment, screening, diagnostic, prevention, and supportive care trials. Treatment Trials In treatment trials, researchers may gather information about experimental treatments, ...
Pienciak-Siewert, Alison; Horan, Dylan P; Ahmed, Alaa A
Classical theories of motor learning hypothesize that adaptation is driven by sensorimotor error; this is supported by studies of arm and eye movements that have shown that trial-to-trial adaptation increases with error. Studies of postural control have shown that anticipatory postural adjustments increase with the magnitude of a perturbation. However, differences in adaptation have been observed between the two modalities, possibly due to either the inherent instability or sensory uncertainty in standing posture. Therefore, we hypothesized that trial-to-trial adaptation in posture should be driven by error, similar to what is observed in arm reaching, but the nature of the relationship between error and adaptation may differ. Here we investigated trial-to-trial adaptation of arm reaching and postural control concurrently; subjects made reaching movements in a novel dynamic environment of varying strengths, while standing and holding the handle of a force-generating robotic arm. We found that error and adaptation increased with perturbation strength in both arm and posture. Furthermore, in both modalities, adaptation showed a significant correlation with error magnitude. Our results indicate that adaptation scales proportionally with error in the arm and near proportionally in posture. In posture only, adaptation was not sensitive to small error sizes, which were similar in size to errors experienced in unperturbed baseline movements due to inherent variability. This finding may be explained as an effect of uncertainty about the source of small errors. Our findings suggest that in rehabilitation, postural error size should be considered relative to the magnitude of inherent movement variability.
Full Text Available ... Usually, trial participants must show signs of the disease or condition before they can join this type of trial. Prevention Trials Click for more information In prevention trials, ...
Bayés, M; Rabasseda, X; Prous, J R
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort
Full Text Available ... Trials Information A to Z List of Cancer Drugs Complementary & Alternative Medicine (CAM) Questions to Ask about ... Types of Treatment Side Effects Clinical Trials Cancer Drugs Complementary & Alternative Medicine Coping Feelings & Cancer Adjusting to ...
Full Text Available ... Unusual Cancers of Childhood Treatment Childhood Cancer Genomics Study Findings Metastatic Cancer Metastatic Cancer Research Common Cancer ... Trials Insurance Coverage and Clinical Trials How to Work With Your Health Insurance Plan Federal Government Programs ...
Full Text Available ... Trials Information A to Z List of Cancer Drugs Complementary & Alternative Medicine (CAM) Questions to Ask about ... Types of Treatment Side Effects Clinical Trials Cancer Drugs Complementary & Alternative Medicine Coping Feelings & Cancer Adjusting to ...
Full Text Available ... trial. Prevention Trials Click for more information In prevention trials, researchers study ways to reduce the risk of getting a disease or a specific medical problem. These trials find out if lifestyle changes, such as exercising more, getting more sleep, ...
Smallwood, Rachel F.; Cusumano, Joseph P.
If humans exploit task redundancies as a general strategy, they should do so even if the redundancy is decoupled from the physical implementation of the task itself. Here, we derived a family of goal functions that explicitly defined infinite possible redundancies between distance (D) and time (T) for unidirectional reaching. All [T, D] combinations satisfying any specific goal function defined a goal-equivalent manifold (GEM). We tested how humans learned two such functions, D/T = c (constant speed) and D·T = c, that were very different but could both be achieved by neurophysiologically and biomechanically similar reaching movements. Subjects were never explicitly shown either relationship, but only instructed to minimize their errors. Subjects exhibited significant learning and consolidation of learning for both tasks. Initial error magnitudes were higher, but learning rates were faster, for the D·T task than for the D/T task. Learning the D/T task first facilitated subsequent learning of the D·T task. Conversely, learning the D·T task first interfered with subsequent learning of the D/T task. Analyses of trial-to-trial dynamics demonstrated that subjects actively corrected deviations perpendicular to each GEM faster than deviations along each GEM to the same degree for both tasks, despite exhibiting significantly greater variance ratios for the D/T task. Variance measures alone failed to capture critical features of trial-to-trial control. Humans actively exploited these abstract task redundancies, even though they did not have to. They did not use readily available alternative strategies that could have achieved the same performance. PMID:23054607
Aptel, F; Cucherat, M; Blumen-Ohana, E; Denis, P
Clinical trials are playing an increasingly crucial role in modern evidence based medicine, allowing for rigorous scientific evaluation of treatment strategies and validation of patient care. The results of clinical trials often form the rational basis from which physicians draw information used to adapt their therapeutic practices. Critical reading and analysis of trials involves the assessment of whether the available data provide enough credible evidence that the treatment will result in a clinically significant and relevant improvement. Evaluating the quality of a clinical trial is a process that draws upon sometimes complex methodological and statistical concepts, with which the reader should nonetheless be familiar in order to come to impartial conclusions regarding the raw data presented in the clinical trials. The goal of the current article is to review the methodological and statistical concepts required for the design and interpretation of clinical trials, so as to allow for a critical analysis of publications or presentations of clinical trials. The first section describes the major methodological principles of clinical trial design required for a rigorous evaluation of the treatment benefit, as well as the various pitfalls or biases that could lead to erroneous conclusions. The second section briefly describes the main statistical tests used in clinical trials, as well as certain situations that may increase the risk of false positive findings (type 1 error), such as multiple, subgroup, intermediate and non-inferiority analysis. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
Full Text Available ... Phases of Clinical Trials Cancer Treatment Types of Cancer Treatment Surgery Radiation Therapy Chemotherapy Immunotherapy Targeted Therapy Hormone Therapy Stem Cell Transplant Precision ...
... this page: //medlineplus.gov/ency/patientinstructions/000823.htm A guide to clinical trials for cancer To use ... trial and where to find one. What is a Clinical Trial for Cancer? Clinical trials for cancer ...
Full Text Available ... Institutes of Health funds much of this basic research. Screening Trials In screening trials, researchers study ways of finding a disease before symptoms occur. These methods, often called screening tests, can include imaging tests ...
Cihoric, Nikola; Tsikkinis, Alexandros; Minniti, Giuseppe; Lagerwaard, Frank J; Herrlinger, Ulrich; Mathier, Etienne; Soldatovic, Ivan; Jeremic, Branislav; Ghadjar, Pirus; Elicin, Olgun; Lössl, Kristina; Aebersold, Daniel M; Belka, Claus; Herrmann, Evelyn; Niyazi, Maximilian
The records of 208.777 (100%) clinical trials registered at ClinicalTrials.gov were downloaded on the 19th of February 2016. Phase II and III trials including patients with glioblastoma were selected for further classification and analysis. Based on the disease settings, trials were classified into three groups: newly diagnosed glioblastoma, recurrent disease and trials with no differentiation according to disease setting. Furthermore, we categorized trials according to the experimental interventions, the primary sponsor, the source of financial support and trial design elements. Trends were evaluated using the autoregressive integrated moving average model. Two hundred sixteen (0.1%) trials were selected for further analysis. Academic centers (investigator initiated trials) were recorded as primary sponsors in 56.9% of trials, followed by industry 25.9%. Industry was the leading source of monetary support for the selected trials in 44.4%, followed by 25% of trials with primarily academic financial support. The number of newly initiated trials between 2005 and 2015 shows a positive trend, mainly through an increase in phase II trials, whereas phase III trials show a negative trend. The vast majority of trials evaluate forms of different systemic treatments (91.2%). In total, one hundred different molecular entities or biologicals were identified. Of those, 60% were involving drugs specifically designed for central nervous system malignancies. Trials that specifically address radiotherapy, surgery, imaging and other therapeutic or diagnostic methods appear to be rare. Current research in glioblastoma is mainly driven or sponsored by industry, academic medical oncologists and neuro-oncologists, with the majority of trials evaluating forms of systemic therapies. Few trials reach phase III. Imaging, radiation therapy and surgical procedures are underrepresented in current trials portfolios. Optimization in research portfolio for glioblastoma is needed.
Ayres, Thomas R.
The Dynamo Clinical Trial evaluates long-term stellar magnetic health through periodic X-ray examinations (by the Chandra Observatory). So far, there are only three subjects enrolled in the DTC: Alpha Centauri A (a solar-like G dwarf), Alpha Cen B (an early K dwarf, more active than the Sun), and Alpha Canis Majoris A (Procyon, a mid-F subgiant similar in activity to the Sun). Of these, Procyon is a new candidate, so it is too early to judge how it will fare. Of the other two, Alpha Cen B has responded well, with a steady magnetic heartbeat of about 8 years duration. The sickest of the bunch, Alpha Cen A, was in magnetic cardiac arrest during 2005-2010, but has begun responding to treatment in recent years, and seems to be successfully cycling again, perhaps achieving a new peak of magnetic health in the 2016 time frame. If this is the case, it has been 20 years since A's last healthful peak, significantly longer than the middle-aged Sun's 11-year magnetic heartbeat, but perhaps in line with Alpha Cen A's more senescent state (in terms of "relative evolutionary age," apparently an important driver of activity). (By the way, don't miss the exciting movie of the Alpha Cen stars' 20-year X-ray dance.)
Full Text Available ... disease or prevent a disease from returning. Supportive Care Trials In supportive care trials, researchers look for ways to make life ... groups, and various types of social interventions. Supportive care interventions are not intended to treat or cure ...
Thompson, Michael A
Social media has potential in clinical trials for pointing out trial issues, addressing barriers, educating, and engaging multiple groups involved in cancer clinical research. Social media is being used in clinical trials to highlight issues such as poor accrual and barriers; educate potential participants and physicians about clinical trial options; and is a potential indirect or direct method to improve accrual. We are moving from a passive "push" of information to patients to a "pull" of patients requesting information. Patients and advocates are often driving an otherwise reluctant health care system into communication. Online patient communities are creating new information repositories. Potential clinical trial participants are using the Twittersphere and other sources to learn about potential clinical trial options. We are seeing more organized patient-centric and patient-engaged forums with the potential to crowd source to improve clinical trial accrual and design. This is an evolving process that will meet many individual, institutional, and regulatory obstacles as we move forward in a changed research landscape.
The inclusion of a partial meal replacement with or without inulin to a calorie restricted diet contributes to reach recommended intakes of micronutrients and decrease plasma triglycerides: A randomized clinical trial in obese Mexican women.
Full Text Available Abstract Background Obesity is a major public health problem in many poor countries where micronutrient deficiencies are prevalent. A partial meal replacement may be an effective strategy to decrease obesity and increase micronutrient intake in such populations. The objective was to evaluate the efficacy of a partial meal replacement with and without inulin on weight reduction, blood lipids and micronutrients intake in obese Mexican women. Methods In a randomized controlled clinical trial 144 women (18–50 y with BMI ≥ 25 kg/m2, were allocated into one of the following treatments during 3 months: 1 Two doses/d of a partial meal replacement (PMR, 2 Two doses/d of PMR with inulin (PMR + I , 3 Two doses/d of 5 g of inulin (INU and 4 Control group (CON. All groups received a low calorie diet (LCD. Weight, height, hip and waist circumference were measured every 2 weeks and body composition, lipids and glucose concentration and nutrient intake were assessed at baseline and after 3 months. Results All groups significantly reduced weight, BMI, waist and hip circumference. Differences between groups were only observed in BMI and weight adjusted changes: At 45 days PMR group lost more weight than INU and CON groups by 0.9 and 1.2Kg, respectively. At 60 days, PMR + I and PMR groups lost more weight than in INU by 0.7 and 1Kg, respectively. Subjects in PMR, PMR + I and INU significantly decreased triglycerides. Energy intake was reduced in all groups. Fiber intake increased in PMR + I and INU groups. Some minerals and vitamins intakes were higher in PMR and PMR + I compared with INU and CON groups. Conclusion Inclusion of PMR with and without inulin to a LCD had no additional effect on weight reduction than a LCD alone but reduced triglycerides and improved intake of micronutrients during caloric restriction. PMR could be a good alternative for obese populations with micronutrient deficiencies. ClinicalTrials.Gov ID
Holmes, Jonathan M
Randomized clinical trial (RCT) study design leads to one of the highest levels of evidence, and is a preferred study design over cohort studies, because randomization reduces bias and maximizes the chance that even unknown confounding factors will be balanced between treatment groups. Recent randomized clinical trials and observational studies in amblyopia can be taken together to formulate an evidence-based approach to amblyopia treatment, which is presented in this review. When designing future clinical studies of amblyopia treatment, issues such as regression to the mean, sample size and trial duration must be considered, since each may impact study results and conclusions. Copyright © 2015 Elsevier Ltd. All rights reserved.
George, Stephen L; Buyse, Marc
Highly publicized cases of fabrication or falsification of data in clinical trials have occurred in recent years and it is likely that there are additional undetected or unreported cases. We review the available evidence on the incidence of data fraud in clinical trials, describe several prominent cases, present information on motivation and contributing factors and discuss cost-effective ways of early detection of data fraud as part of routine central statistical monitoring of data quality. Adoption of these clinical trial monitoring procedures can identify potential data fraud not detected by conventional on-site monitoring and can improve overall data quality. PMID:25729561
Full Text Available ... to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase ...
Full Text Available ... out if an experimental drug, therapy, medical device, lifestyle change, or test will help treat, find, or ... specific medical problem. These trials find out if lifestyle changes, such as exercising more, getting more sleep, ...
Katz, J N; Losina, E; Lohmander, L S
To highlight methodological challenges in the design and conduct of randomized trials of surgical interventions and to propose strategies for addressing these challenges. This paper focuses on three broad areas: enrollment; intervention; and assessment including implications for analysis. For eac...
Full Text Available ... new tests that could identify a disease in its early stages. Usually, trial participants must show signs ... often healthy people (20 to 80), to judge its safety and side effects, and to find the ...
... and effective in people. What is an HIV/AIDS clinical trial? HIV/AIDS clinical trials help researchers ... to HIV Can anyone participate in an HIV/AIDS clinical trial? It depends on the study. Some ...
N V Ramamurthy
Full Text Available The Indian media in general, with the exception of a few domain expert journalists, have failed to comprehend the complexities involved in the clinical trial process. In the run up to the deadline-based coverage of a story, a majority of them fall short in conveying the right perspective to readers, but nevertheless they have been successful in sensationalizing an event in this arena. Possibly by unintended misrepresentation, or mostly out of ignorance of the nuances involved in the clinical trials process, the media has done more harm than good, and got away with it. On the other side, the industry has been reluctant to engage with the media in a meaningful dialog for too long now. It bears not only the consequences of damage to its professional reputation following such reportage, but also the repercussions of unnecessary clampdowns by the regulators. Science journalism in India has yet to rise as a profession.
Full Text Available ... Resources Conducting Clinical Trials Statistical Tools and Data Terminology Resources NCI Data Catalog Cryo-EM NCI's Role ... Contacts Other Funding Find NCI funding for small business innovation, technology transfer, and contracts Training Cancer Training ...
Full Text Available ... Cancer Research and Discovery Stories of Discovery R&D Resources Conducting Clinical Trials Statistical Tools and Data ... about some of NCI's major research initiatives R&D Resources Tools and data sets for researchers Research ...
Full Text Available ... Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Lung Cancer Lymphoma Pancreatic Cancer ... Therapy Chemotherapy Immunotherapy Targeted Therapy Hormone Therapy Stem Cell Transplant Precision Medicine Side Effects Clinical Trials Information ...
Full Text Available ... Resources Conducting Clinical Trials Statistical Tools and Data Terminology Resources NCI Data Catalog Cryo-EM NCI's Role ... Report (RPPR) Grant Closeout Grant Resources NCI Grants Management Legal Requirements NCI Grant Policies Grants Management Contacts ...
... Resources Conducting Clinical Trials Statistical Tools and Data Terminology Resources NCI Data Catalog Cryo-EM NCI's Role ... Report (RPPR) Grant Closeout Grant Resources NCI Grants Management Legal Requirements NCI Grant Policies Grants Management Contacts ...
Stewart, J.; Beyer, B. K.; Chadwick, K.; De Schaepdrijver, L.; Desai, M.; Enright, B.; Foster, W.; Hui, J. Y.; Moffat, G. J.; Tornesi, B.; Van Malderen, K.; Wiesner, L.; Chen, C. L.
The Health and Environmental Sciences Institute (HESI) Developmental and Reproductive Toxicology Technical Committee sponsored a pharmaceutical industry survey on current industry practices for contraception use during clinical trials. The objectives of the survey were to improve our understanding of the current industry practices for contraception requirements in clinical trials, the governance processes set up to promote consistency and/or compliance with contraception requirements, and the effectiveness of current contraception practices in preventing pregnancies during clinical trials. Opportunities for improvements in current practices were also considered. The survey results from 12 pharmaceutical companies identified significant variability among companies with regard to contraception practices and governance during clinical trials. This variability was due primarily to differences in definitions, areas of scientific uncertainty or misunderstanding, and differences in company approaches to enrollment in clinical trials. The survey also revealed that few companies collected data in a manner that would allow a retrospective understanding of the reasons for failure of birth control during clinical trials. In this article, suggestions are made for topics where regulatory guidance or scientific publications could facilitate best practice. These include provisions for a pragmatic definition of women of childbearing potential, guidance on how animal data can influence the requirements for male and female birth control, evidence-based guidance on birth control and pregnancy testing regimes suitable for low- and high-risk situations, plus practical methods to ascertain the risk of drug-drug interactions with hormonal contraceptives. PMID:27042398
Schöler, M; Frietsch, T; Jambor, C; Knels, R
Formerly developed resuscitation fluids solely imitated the main function of the blood -oxygen transport. A research driven by the army requested an oxygen carrier that does not need cross typing and cooled storage. Artificial oxygen carriers (AOC) use either the molecular oxygen bondage to hemoglobin: HBOC- "hemoglobin based oxygen carriers" or the physical dissolution of oxygen in the blood plasma compartment by hyperbaric pressure in perfluorocarbon emulsions (PFC). Decades of preclinical and clinical research did pass but the results were disappointing- in Russia, a not well designed PFC is available locally and the only approved HBOC in South Africa is not being used much. Other products, just prior to filing for FDA approval, did not achieve convincing study results and research and production was stopped. Some trials have been stopped by the FDA for safety reasons, half of trials with the primary endpoint reduction of allogeneic transfusion requirement were unsuccessful or offset by an increased blood requirement later. However, some ventures currently are trying to use the knowledge gained so far and are investigating third and fourth generation products of artificial blood components. These imitate the cellular structure of red cells as micells, nanocapsules, (ABC- artificial blood cells) or gas bubbles (microbubbles), admixture of volume substitutes such as starches, gelatin or albumin or use hyperbaric oxygenation . Artificial platelets are in clinical phase IIa, recombinant albumin in phase III. In this article, a short overview about the current situation on artificial blood products is given. The critical point for the break through for artificial blood products did not come yet but could be ahead-
Emery, C. A.; Roos, Ewa M.; Verhagen, E.;
The risk of post-traumatic osteoarthritis (PTOA) substantially increases following joint injury. Research efforts should focus on investigating the efficacy of preventative strategies in high quality randomized controlled trials (RCT). The objective of these OARSI RCT recommendations is to inform...
Rosa, Carmen; Campbell, Aimee N C; Miele, Gloria M; Brunner, Meg; Winstanley, Erin L
Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices or the Internet) into the design and execution of studies. In the meantime, individuals and corporations are relying more on electronic platforms and most have incorporated such technology into their daily lives. This paper provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for treatment of substance use disorders is presented. Using e-technologies to design and implement clinical trials has the potential to reach a wide audience, making trials more efficient while also reducing costs; however, researchers should be cautious when adopting these tools given the many challenges in using new technologies, as well as threats to participant privacy/confidentiality. Challenges of using e-technologies can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored.
The Conducting Clinical Trials in Europe meeting, held in London, included topics covering new developments in the field of clinical trials and recommendations on how to best conduct a trial. This conference report highlights selected presentations on the state of affairs of trials in Europe, conducting trials in emerging markets, strategies for improving trials, trial design options, peri-approval and pediatric trials, and the role of key players, such as physicians. Company perspectives from Pfizer Inc and Nycomed are also included.
Information about actively enrolling, ongoing, and completed clinical trials of cancer prevention, early detection, and supportive care, including phase I, II, and III agent and action trials and clinical trials management. |
... Care Apply Online Application Process Veteran Eligibility Active Duty Families of Veterans Women Veterans Determine Costs Copays ... VHA Forms & Publications Quality & Safety Quality of Care Ethics VA/DOD Clinical Practice Guidelines Access and Quality ...
Gil-Extremera, B; Jiménez-López, P; Mediavilla-García, J D
Clinical trials are essential tools for the progress of clinical medicine in its diagnostic and therapeutic aspects. Since the first trial in 1948, which related tobacco use with lung cancer, there have been more than 150,000 clinical trials to date in various areas (paediatrics, cardiology, oncology, endocrinology, etc.). This article highlights the importance for all physicians to participate, over the course of their professional career, in a clinical trial, due to the inherent benefits for patients, the progress of medicine and for curricular prestige. The authors have created a synthesis of their experience with clinical trials on hypertension, diabetes, dyslipidaemia and ischaemic heart disease over the course of almost 3 decades. Furthermore, a brief reference has been made to the characteristics of a phase I unit, as well as to a number of research studies currently underway. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.
Reimer, C; Lødrup, A B; Smith, G;
BACKGROUND: Many reflux patients remain symptomatic on a standard dose of proton pump inhibitor (PPI). Alginates decrease the number of reflux events by forming a raft on top of the stomach content and thus offer a supplemental mechanism of action to acid suppression. AIM: To assess the efficacy...... of an alginate (Gaviscon Advance, Reckitt Benckiser, Slough, UK) on reflux symptoms in patients with persistent symptoms despite once daily PPI. METHODS: This was a multicentre, randomised, placebo-controlled, 7-day double-blind trial preceded by a 7-day run-in period. Reflux symptoms were assessed using......: In patients with residual reflux symptoms despite PPI treatment, adding an alginate offers additional decrease in the burden of reflux symptoms (EudraCT/IND Number: 2011-005486-21)....
Full Text Available Data generated in all clinical trial are recorded on the data collection instrument Case report Form / Electronic Case Report Form by investigators located at various sites in various countries. In multicentric clinical trials since different investigator or medically qualified experts are from different sites / centers recording the medical term(s uniformly is a big challenge. Medical coders from clinical data management team process these terms and perform medical coding. Medical coding is performed to categorize the medical terms reported appropriately so that they can be analyzed/reviewed. This article describes process which is used for medical coding in clinical data management and two most commonly used medical dictionaries MedDRA and WHO-DDE in brief. It is expected to help medical coders to understand the process of medical coding in clinical data management. Few common issues which the medical coder faces while performing medical coding, are also highlighted.
Bergmann, J F; Chassany, O
To improve medical knowledge by reading clinical trial reports it is necessary to check for the respect of the methodological rules, and to analyze and criticize the results. A control group and a randomisation are always necessary. Double blind assessment, sample size calculation, intention to treat analysis, a unique primary end point are also important. The conclusions of the trial are valid only for the population included and the clinical signification of the results, depending on the control treatment, has to be evaluated. Respect of the reading rules is necessary to assess the reliability of the conclusions, in order to promote evidence-based practice.
Summers, Ron; Vyas, Hiten; Dudhal, Nilesh; Doherty, Neil F; Coombs, Crispin R; Hepworth, Mark
This paper will investigate innovations in information management for use in clinical trials. The application typifies a complex, adaptive, distributed and information-rich environment for which continuous innovation is necessary. Organisational innovation is highlighted as well as the technical innovations in workflow processes and their representation as an integrated set of web services. Benefits realization uncovers further innovations in the business strand of the work undertaken. Following the description of the development of this information management system, the semantic web is postulated as a possible solution to tame the complexity related to information management issues found within clinical trials support systems.
Lubaroff, David M
This review presents important information about the current state of the art for vaccine immunotherapy of prostate cancer. It includes important preclinical research for each of the important prostate cancer vaccines to have reached clinical trials. To date, the only prostate cancer vaccine that has completed Phase III trials and has been approved and licensed by the US FDA is Sipuleucel-T, which immunizes patients against the prostate-associated antigen prostatic acid phosphatase. The benefits and concerns associated with the vaccine are presented. A current Phase III trial is currently underway using the vaccinia-based prostate-specific antigen vaccine Prostvac-TRICOM. Other immunotherapeutic vaccines in trials include the Ad/prostate-specific antigen vaccine Ad5-prostate-specific antigen and the DNA/prostatic acid phosphatase vaccine. A cellular vaccine, GVAX, has been in clinical trials but has not seen continuous study. This review also delves into the multiple immune regulatory elements that must be overcome in order to obtain strong antitumor-associated antigen immune responses capable of effectively destroying prostate tumor cells.
The NCI Community Oncology Research Program (NCORP) is a national network of investigators, cancer care providers, academic institutions, and other organizations. NCORP conducts multi-site cancer clinical trials and studies in diverse populations in community-based healthcare systems across the United States and Puerto Rico.
... National Institutes of Health grant numbers. (See also Secondary IDs data element on ClinicalTrials.gov.) OUTCOME MEASURE A planned ... and Secondary Outcome Measure . (See also Primary and Secondary Outcome Measures data element and Outcome Measure results data element on ...
Full Text Available ... Questions to Ask about Your Diagnosis Research Cancer Treatment Types of Cancer Treatment Side Effects Clinical Trials Information A to Z ... Alternative Medicine (CAM) Questions to Ask about Your Treatment Research Coping with Cancer Feelings and Cancer Adjusting ...
Full Text Available ... Questions to Ask about Your Diagnosis Research Cancer Treatment Types of Cancer Treatment Side Effects Clinical Trials Information A to Z ... Alternative Medicine (CAM) Questions to Ask about Your Treatment Research Coping with Cancer Feelings and Cancer Adjusting ...
A 6-month clinical trial in the Philippines sought to determine the efficacy of coconut oil and of "monolaurin," a coconut oil byproduct, in killing HIV by breaking down its coating. This research is based on the theory that medium-chain fatty acids, like monolaurin, can have this effect on certain viruses. The trial involves 12 women and 3 men in the early stage of HIV infection. 10 patients will take different doses of monolaurin, and 5 will consume coconut oil. It is hypothesized that the regimen will lead to higher CD4 counts and a lower viral load. The trial was almost abandoned because it received only lukewarm approval from the Health Secretary.
Kim, Jane S.; Knickelbein, Jared E.; Nussenblatt, Robert B.; Sen, H. Nida
The treatment of noninfectious uveitis continues to remain a challenge for many ophthalmologists. Historically, clinical trials in uveitis have been sparse, and thus, most treatment decisions have largely been based on clinical experience and consensus guidelines. The current treatment paradigm favors initiation then tapering of corticosteroids with addition of steroid-sparing immunosuppressive agents for persistence or recurrence of disease. Unfortunately, in spite of a multitude of highly unfavorable systemic effects, corticosteroids are still regarded as the mainstay of treatment for many patients with chronic and refractory noninfectious uveitis. However, with the success of other conventional and biologic immunomodulatory agents in treating systemic inflammatory and autoimmune conditions, interest in targeted treatment strategies for uveitis has been renewed. Multiple clinical trials on steroid-sparing immunosuppressive agents, biologic agents, intraocular corticosteroid implants, and topical ophthalmic solutions have already been completed, and many more are ongoing. This review discusses the results and implications of these clinical trials investigating both alternative and novel treatment options for noninfectious uveitis. PMID:26035763
Over the past decades, randomised controlled trials (RCTs) have prevailed over clinical judgement, case reports, and observational studies and became the gold evidential standard in medicine. Furthermore, during the same time frame, RCTs became a crucial part of the regulatory process whereby a new therapeutic can gain access to the drug market. Today, clinical trials are large and tightly regulated enterprises that have to comply with ethical requirements while maintaining high epistemic standards, a balance that becomes increasingly difficult as the research questions become more sophisticated. In this review, the author will discuss some of the most important ethical issues surrounding RCTs, with an eye to the most recent debates and the context of oncological research in particular. PMID:24482672
.... Clinical Trials in Neurology aims to improve the efficiency of clinical trials and the development of interventions in order to enhance the development of new treatments for neurologic diseases...
Whicher, Danielle M; Miller, Jennifer E; Dunham, Kelly M; Joffe, Steven
To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g. clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers' decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers' decisions, including protection from harm and maximization of benefits; (2) advancement of organizational mission and values; and (3) stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers' actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding
Information for researchers about developing, reporting, and managing NCI-funded cancer prevention clinical trials. Protocol Information Office The central clearinghouse for clinical trials management within the Division of Cancer Prevention.Read more about the Protocol Information Office. | Information for researchers about developing, reporting, and managing NCI-funded cancer prevention clinical trials.
Gustafsson, Finn; Atar, Dan; Pitt, Bertram;
Trialists have an ethical and financial responsibility to plan and conduct clinical trials in a manner that will maximize the scientific knowledge gained from the trial. However, the amount of scientific information generated by randomized clinical trials in cardiovascular medicine is highly...... variable. Generation of trial databases and/or biobanks originating in large randomized clinical trials has successfully increased the knowledge obtained from those trials. At the 10th Cardiovascular Trialist Workshop, possibilities and pitfalls in designing and accessing clinical trial databases were......, in particular with respect to collaboration with the trial sponsor and to analytic pitfalls. The advantages of creating screening databases in conjunction with a given clinical trial are described; and finally, the potential for posttrial database studies to become a platform for training young scientists...
Accrual to cancer clinical trials (CCT) is imperative to safeguard continued improvement in cancer outcomes. A retrospective chart review was performed of patients (n=140) starting a new anti-cancer agent in a north Dublin cancer centre. This review was performed over a four-month period, beginning in November 2015. Only 29% (n=41) had a CCT option. The overall accrual rate to CCT was 5% (n=7), which is comparable to internationally reported figures. The main reasons for failure to recruit to CCT included the lack of a CCT option for cancer type (n=30, 23%), stage (n=25, 19%), and line of treatment (n=23, 17%). Over the last decade, the rate of accrual to CCTs has in fact doubled and the number of trials open to recruitment has tripled. Ongoing governmental and philanthropic support is necessary to continue this trend to further expand CCT patient options with a target accrual rate of 10%.
In this study we aimed to evaluate the effectiveness of Iyengar yoga in chronic neck pain by means of a randomized clinical trial. 77 with chronic neck pain who scored > 40 mm on a 100-mm visual analog scale (VAS) were randomized to a nine week Iyengar yoga program with weekly 90-minute classes or to a self-care/exercise program. The primary outcome measure was change of mean pain at rest (VAS) from baseline to week ten. Secondary outcomes included pain at motion, functional disabilit...
Full Text Available Women use more medicines than men because they fall ill more often and suffer more from chronic diseases, but also because women pay more attention to their health and have more consciousness and care about themselves. Although medicines can have different effects on women and men, women still represent a small percentage in the first phases of trials (22% which are essential to verify drugs dosage, side effects, and safety. Even though women are more present in trials, studies results are not presented with a gender approach. This situation is due to educational, social, ethical and economical factors. The scientific research must increase feminine presence in clinical trials in order to be equal and correct, and all the key stakeholder should be involved in this process. We still have a long way to cover and it doesn't concern only women but also children and old people. The aim is to have a medicine not only illness-focused but patient-focused: a medicine able to take into consideration all the patient characteristics and so to produce a really personalized therapy. What above described is part of the reasons why in 2005 was founded the National Observatory for Women's Health (Osservatorio Nazionale sulla Salute della Donna, ONDa which promotes a gender health awareness and culture in Italy, at all the levels of the civil and scientific society.
Gustafsson, Finn; Atar, Dan; Pitt, Bertram
Trialists have an ethical and financial responsibility to plan and conduct clinical trials in a manner that will maximize the scientific knowledge gained from the trial. However, the amount of scientific information generated by randomized clinical trials in cardiovascular medicine is highly...
Full Text Available Greg S MartinDepartment of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, Georgia, USAThe Open Access Journal of Clinical Trials began in 2009 with the goal of being an authoritative, open access source for international, peer-reviewed publications in the field of human research and clinical trials. Since then, the Open Access Journal of Clinical Trials has published approximately 30 high-quality articles on original research, innovative reviews, and critical commentaries. These articles have spanned many aspects of clinical trials wonderfully, including trial design and management; legal, ethical and regulatory issues of clinical trials; subject participation and retention in clinical trials; and data collection and data management.
Berry, Scott M; Muller, Peter
Already popular in the analysis of medical device trials, adaptive Bayesian designs are increasingly being used in drug development for a wide variety of diseases and conditions, from Alzheimer's disease and multiple sclerosis to obesity, diabetes, hepatitis C, and HIV. Written by leading pioneers of Bayesian clinical trial designs, Bayesian Adaptive Methods for Clinical Trials explores the growing role of Bayesian thinking in the rapidly changing world of clinical trial analysis. The book first summarizes the current state of clinical trial design and analysis and introduces the main ideas and potential benefits of a Bayesian alternative. It then gives an overview of basic Bayesian methodological and computational tools needed for Bayesian clinical trials. With a focus on Bayesian designs that achieve good power and Type I error, the next chapters present Bayesian tools useful in early (Phase I) and middle (Phase II) clinical trials as well as two recent Bayesian adaptive Phase II studies: the BATTLE and ISP...
Full Text Available Abstract Background The purpose of this study was to demonstrate how formative program process evaluation was used to improve dose and fidelity of implementation, as well as reach of the intervention into the target population, in the "Active by Choice Today" (ACT randomized school-based trial from years 1 to 3 of implementation. Methods The intervention integrated constructs from Self-Determination Theory and Social Cognitive Theory to enhance intrinsic motivation and behavioral skills for increasing long-term physical activity (PA behavior in underserved adolescents (low income, minorities. ACT formative process data were examined at the end of each year to provide timely, corrective feedback to keep the intervention "on track". Results Between years 1 and 2 and years 2 and 3, three significant changes were made to attempt to increase dose and fidelity rates in the program delivery and participant attendance (reach. These changes included expanding the staff training, reformatting the intervention manual, and developing a tracking system for contacting parents of students who were not attending the after-school programs regularly. Process outcomes suggest that these efforts resulted in notable improvements in attendance, dose, and fidelity of intervention implementation from years 1 to 2 and 2 to 3 of the ACT trial. Conclusion Process evaluation methods, particularly implementation monitoring, are useful tools to ensure fidelity in intervention trials and for identifying key best practices for intervention delivery.
Goswami, Neela D; Pfeiffer, Christopher D; Horton, John R; Chiswell, Karen; Tasneem, Asba; Tsalik, Ephraim L
There is a paucity of clinical trials informing specific questions faced by infectious diseases (ID) specialists. The ClinicalTrials.gov registry offers an opportunity to evaluate the ID clinical trials portfolio. We examined 40,970 interventional trials registered with ClinicalTrials.gov from 2007-2010, focusing on study conditions and interventions to identify ID-related trials. Relevance to ID was manually confirmed for each programmatically identified trial, yielding 3570 ID trials and 37,400 non-ID trials for analysis. The number of ID trials was similar to the number of trials identified as belonging to cardiovascular medicine (n = 3437) or mental health (n = 3695) specialties. Slightly over half of ID trials were treatment-oriented trials (53%, vs. 77% for non-ID trials) followed by prevention (38%, vs. 8% in non-ID trials). ID trials tended to be larger than those of other specialties, with a median enrollment of 125 subjects (interquartile range [IQR], 45-400) vs. 60 (IQR, 30-160) for non-ID trials. Most ID studies are randomized (73%) but nonblinded (56%). Industry was the funding source in 51% of ID trials vs. 10% that were primarily NIH-funded. HIV-AIDS trials constitute the largest subset of ID trials (n = 815 [23%]), followed by influenza vaccine (n = 375 [11%]), and hepatitis C (n = 339 [9%]) trials. Relative to U.S. and global mortality rates, HIV-AIDS and hepatitis C virus trials are over-represented, whereas lower respiratory tract infection trials are under-represented in this large sample of ID clinical trials. This work is the first to characterize ID clinical trials registered in ClinicalTrials.gov, providing a framework to discuss prioritization, methodology, and policy.
Vieira, Jean Mendes de Lucena; Lima, Elisangela da Costa; Land, Marcelo Gerardin Poirot; Ventura, Miriam; Coelho, Helena Lutescia Luna
This study aimed to characterize the clinical trials with medicines enrolling Brazilian children and adolescents, registered in the databases of Clinical Trials and the Brazilian Clinical Trials Network (ReBEC) from 1994 to 2014. Only 462 clinical trials enrolled Brazilian children and adolescents. There was an increase in registrations beginning in 2003, with an important drop in 2011. Among these trials, 35.5% were hosted in Brazil. The international clinical trials were mostly conducted by North American companies. In both cases, multinational industry was the principal source of funding. The clinical trials were predominantly phase III with injectable and solid oral pharmaceutical forms of antiviral drugs. Domestic clinical trials showed wider variation in the pharmaceutical forms and higher percentage of liquid formulations, when compared to the international trials. In addition to heavy external dependence for conducting clinical trials, the study emphasized the challenge for pediatric care in Brazil, which presents epidemiological peculiarities in an environment prone to the use of unlicensed medicines for children.
Hansson, Sven Ove
A probabilistic explication is offered of equipoise and uncertainty in clinical trials. In order to be useful in the justification of clinical trials, equipoise has to be interpreted in terms of overlapping probability distributions of possible treatment outcomes, rather than point estimates representing expectation values. Uncertainty about treatment outcomes is shown to be a necessary but insufficient condition for the ethical defensibility of clinical trials. Additional requirements are proposed for the nature of that uncertainty. The indecisiveness of our criteria for cautious decision-making under uncertainty creates the leeway that makes clinical trials defensible.
Chen, Yin-Ying; Wu, Ping; Wang, Jie
Drug clinical trial is an important link in the chain of new drug research and development. The results of drug discovery and development directly depend on the extent of standardization of clinical trials. Therefore, improving the quality of drug clinical trials is of great importance, and drug clinical trial institutions play a crucial role in the quality management of drug clinical trials. After years of development, the overall level of drug clinical trials has advanced rapidly in China, and a large number of clinical trials of traditional Chinese medicine have also been carried out. However, there is still a big gap between our country and developed countries. Therefore, for the construction and management of Chinese drug clinical trial institutions, there is still a long way to go. This study aims to analyze the current development of drug clinical trial institutions in China and explore the existing problems from three aspects, including current situations of institutional organization and management, regional and professional distributions, and quality control. And some suggestions are put forward finally, including support of traditional Chinese medicine, introduction of drug-risk management system, and construction of information management.
Cihoric, Nikola; Tsikkinis, Alexandros; Miguelez, Cristina Gutierrez; Strnad, Vratislav; Soldatovic, Ivan; Ghadjar, Pirus; Jeremic, Branislav; Dal Pra, Alan; Aebersold, Daniel M; Lössl, Kristina
Background To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. Methods The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, p...
Cihoric, Nikola; Tsikkinis, Alexandros; Gutierrez Miguelez, Cristina; Strnad, Vratislav; Soldatovic, Ivan; Ghadjar, Pirus; Jeremic, Branislav; Dal Pra, Alan; Aebersold, Daniel M; Lössl, Kristina
Background To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. Methods The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type,...
Bose, Anindya; Das, Suman
Prolonged timelines and large expenses associated with clinical trials have prompted a new focus on improving the operational efficiency of clinical trials by use of Clinical Trial Management Systems (CTMS) in order to improve managerial control in trial conduct. However, current CTMS systems are not able to meet the expectations due to various shortcomings like inability of timely reporting and trend visualization within/beyond an organization. To overcome these shortcomings of CTMS, clinical researchers can apply a business intelligence (BI) framework to create Clinical Research Intelligence (CLRI) for optimization of data collection and analytics. This paper proposes the usage of an innovative and collaborative visualization tool (CTA) as CTMS "add-on" to help overwhelm these deficiencies of traditional CTMS, with suitable examples.
Levin, Mindy F; Snir, Osnat; Liebermann, Dario G; Weingarden, Harold; Weiss, Patrice L
The objective of this study was to evaluate the potential of exercises performed in a 2D video-capture virtual reality (VR) training environment to improve upper limb motor ability in stroke patients compared to those performed in conventional therapy. A small sample randomized control trial, in an outpatient rehabilitation center with 12 patients with chronic stroke, aged 33-80 years, who were randomly allocated to video-capture VR therapy and conventional therapy groups. All patients participated in four clinical evaluation sessions (pre-test 1, pre-test 2, post-test, follow-up) and nine 45-minute intervention sessions over a 3-week period. Main outcomes assessed were Body Structure and Function (impairment: Fugl-Meyer Assessment [FMA]; Composite Spasticity Index [CSI]; Reaching Performance Scale for Stroke), Activity (Box and Blocks; Wolf Motor Function Test [WMFT]), and Participation (Motor Activity Log) levels of the International Classification of Functioning. Improvements occurred in both groups, but more patients in the VR group improved upper limb clinical impairment (FMA, CSI) and activity scores (WMFT) and improvements occurred earlier. Patients in the VR group also reported satisfaction with the novel treatment. The modest advantage of VR over conventional training supports further investigation of the effect of video-capture VR or VR combined with conventional therapy in larger-scale randomized, more intense controlled studies.
Ellenberg, Susan S; Culbertson, Richard; Gillen, Daniel L; Goodman, Steven; Schrandt, Suzanne; Zirkle, Maryan
In any clinical trial, it is essential to monitor the accumulating data to be sure that the trial continues to be safe for participants and that the trial is being conducted properly. Data monitoring committees, independent expert panels who undertake regular reviews of the data as the trial progresses, serve an important role in safeguarding the interests of research participants and ensuring trial integrity in many trials. Many pragmatic clinical trials, which aim to inform healthcare decisions by comparing alternate interventions in heterogeneous healthcare delivery settings, will warrant review by an independent data monitoring committee due to their potential impact on clinical practice. However, the very features that make a trial "pragmatic" may pose challenges in terms of which aspects of a trial to monitor and when it is appropriate for a data monitoring committee to intervene. Using the Pragmatic-Explanatory Continuum Indicator Summary tool that draws distinctions between pragmatic and explanatory clinical trials, we review characteristics of pragmatic clinical trials that may have implications for data monitoring committees and interim monitoring plans. These include broad eligibility criteria, a focus on subjective patient-centered outcomes, and in some cases a lack of standardized follow-up procedures across study sites. Additionally, protocol adherence is often purposefully not addressed in pragmatic trials in order to accurately represent the clinical practice setting and maintain practicability of implementation; there are differing viewpoints as to whether adherence should be assessed and acted upon by data monitoring committees in these trials. Some other issues not specifically related to the Pragmatic-Explanatory Continuum Indicator Summary criteria may also merit special consideration in pragmatic trials. Thresholds for early termination of a pragmatic clinical trial might be controversial. The distinguishing features of pragmatic clinical
Anand, Vibha; Cahan, Amos; Ghosh, Soumya
ClinicalTrials.gov was established as a web-based registry for clinical trials of human participants in 2000. Mandatory registration started in 2008. Given more than a decade of registered trials, it's important to understand the "topic" areas and their evolution over time from this resource. This information may help in identifying current knowledge gaps. We use dynamic topic model (DTM) methods to discover topics and their evolution over last 17 years. Our model suggests that there are disease or organ specific trials such as 'Cardiovascular disorders', Heart & Brain conditions', or 'Breast & Prostate cancer' as well as trials registered for general health. General health trials are less likely to be FDA regulated, but both health and pain management, as well as surgical, heart, and brain trials have upward trend in recent years while advanced cancer trials have downward trended. Our model derives unique insights from metadata associated with each topic area.
Full Text Available Clinical trials are emerging as an important activity in India as it is an essential component of the drug discovery and development program to which India is committed. The only robust way to evaluate a new medicine is by doing properly designed clinical trials. In addition to advancing science, clinical trials offer myriad benefits to the participants. The recent hue that created in India about clinical trials is probably an exaggeration of facts. However, these points to the need for ensuring proper compliance with the regulatory norms and proper training of concerned personnel in good clinical practice (GCP. This will ensure that India continues to reap the benefits of clinical trials and also become a world leader in this field.
Patrick I Okonta
Full Text Available The conduct of clinical trials for the development and licensing of drugs is a very important aspect of healthcare. Drug research, development and promotion have grown to a multi-billion dollar global business. Like all areas of human endeavour involving generation and control of huge financial resources, it could be subject to deviant behaviour, sharp business practices and unethical practices. The main objective of this review is to highlight potential ethical challenges in the conduct of clinical trials in Nigeria and outline ways in which these can be avoided. Current international and national regulatory and ethical guidelines are reviewed to illustrate the requirements for ethical conduct of clinical trials. Past experiences of unethical conduct of clinical trials especially in developing countries along with the increasing globalisation of research makes it imperative that all players should be aware of the ethical challenges in clinical trials and the benchmarks for ethical conduct of clinical research in Nigeria.
Okonta, Patrick I
The conduct of clinical trials for the development and licensing of drugs is a very important aspect of healthcare. Drug research, development and promotion have grown to a multi-billion dollar global business. Like all areas of human endeavour involving generation and control of huge financial resources, it could be subject to deviant behaviour, sharp business practices and unethical practices. The main objective of this review is to highlight potential ethical challenges in the conduct of clinical trials in Nigeria and outline ways in which these can be avoided. Current international and national regulatory and ethical guidelines are reviewed to illustrate the requirements for ethical conduct of clinical trials. Past experiences of unethical conduct of clinical trials especially in developing countries along with the increasing globalisation of research makes it imperative that all players should be aware of the ethical challenges in clinical trials and the benchmarks for ethical conduct of clinical research in Nigeria.
Research misconduct and fraud in clinical research is an increasing problem facing the scientific community. This problem is expected to increase due to discoveries in central statistical monitoring and with the increase in first-time clinical trial investigators in the increasingly global reach of oncology clinical trials. This paper explores the most common forms of fraud in clinical trials in order to develop offensive and defensive strategies to deal with fraud. The offensive strategies are used when fraud is detected during a trial and the defensive strategies are those design strategies that seek to minimize or eliminate the effect of fraud. This leads to a proposed fraud recovery plan (FRP) that would be specified before the start of a clinical trial and would indicate actions to be taken upon detecting fraud of different types. Statistical/regulatory issues related to fraud include: dropping all patients from a site that committed fraud, or just the fraudulent data (perhaps replacing the latter through imputation); the role of intent-to-treat analysis; effect on a planned interim analysis; effect on stratified analyses and model adjustment when fraud is detected in covariates; effect on trial-wide randomization, etc. The details of a typical defensive strategy are also presented. It is concluded that it is best to follow a defensive strategy and to have an FRP in place to follow if fraud is detected during the trial.
Alex D McMahon
Full Text Available Alex McMahon and colleagues critique the International Conference on Harmonisation (ICH guidance on good clinical practice (GCP, arguing that it is having a disastrous effect on noncommerical randomized clinical trials in Europe.
Alex D McMahon; Conway, David I; MacDonald, Tom M; McInnes, Gordon T
Alex McMahon and colleagues critique the International Conference on Harmonisation (ICH) guidance on good clinical practice (GCP), arguing that it is having a disastrous effect on noncommerical randomized clinical trials in Europe.
Shakuri Seyed Kazem
Full Text Available Introduction: Prevention of pulmonary complications after coronary artery bypass graft is attended as a very important issue. The aim of this study was to evaluate the role of pulmonary rehabilitation before surgery for reducing the risk of pulmonary complications after surgery. Methods: In a randomized clinical trial, 60 patients undergoing heart surgery were randomly divided into two groups A and B. Chest physiotherapy was performed before and after surgery on group A patients however it was done on group B’s, only after surgery. Effects of preoperative pulmonary rehabilitation were compared between two groups, using spirometry and arterial blood gas (ABG. Results: Thirty nine males (65% and 21 females (35% with mean age of 8.10 ± 9.56 were analyzed.The mean differences were statistically significant for predicted forced vital capacity (FVC (CI95%:1.3 to 8.7 and Predicted Peak Flow indices (PEF (CI 95%: 1.9 to 9.4 of spirometry indicator,PCO2 index (of ABG parameter (CI 95%: 1.4 to 8.9 and mean oxygen saturation (mean Spo2 (CI 95%: 0.6 to 1.7 of ABG index in two groups. Conclusion: The performance of pulmonary rehabilitation program before surgery is recommended, as it may result in the reduction of complications of heart surgery.
C. A. Caramori
Full Text Available Scientific development that has been achieved through decades finds in clinical research a great possibility of translating findings to human health application. Evidence given by clinical trials allows everyone to have access to the best health services. However, the millionaire world of pharmaceutical industries has stained clinical research with doubt and improbability. Study results (fruits of controlled clinical trials and scientific publications (selective, manipulated and with wrong conclusions led to an inappropriate clinical practice, favoring the involved economic aspect. In 2005, the International Committee of Medical Journal Editors (ICMJE, supported by the World Association of Medical Editors, started demanding as a requisite for publication that all clinical trials be registered at the database ClinicalTrials.gov. In 2006, the World Health Organization (WHO created the International Clinical Trial Registry Platform (ICTRP, which gathers several registry centers from all over the world, and required that all researchers and pharmaceutical industries register clinical trials. Such obligatory registration has progressed and will extend to all scientific journals indexed in all worldwide databases. Registration of clinical trials means another step of clinical research towards transparency, ethics and impartiality, resulting in real evidence to the forthcoming changes in clinical practice as well as in the health situation.
Klimt, C R
The subject of varied acceptance of clinical trial results is discussed in the context of review of trials with which I have been involved and my subjective evaluation of their impact on the practice of clinical medicine. My experience goes back to 1949 and a World Health Organization trial of hyperimmune gamma globulin against rabies. This was followed by a large trial of secondary prevention of poliomyelitis. I participated in the planning and initiation of the first chronic disease trial, the University Group Diabetes Program (UGDP). The latter lasted for 15 years and its ramifications continue to this day. My next trial was the Coronary Drug Project (CDP), a complex trial with more than 8,000 patients. The trials of aspirin and aspirin combined with persantine (the CDPA, AMIS, PARIS I, and PARIS II) followed. My last three trials were a trial of photocoagulation in diabetic retinopathy (DRS), a six-country trial of the antiarrhythmic drug mexiletine (IMPACT), and a study involving two diagnostic procedures for pulmonary embolism (PIOPED). When one considers, in retrospect, the plethora of trials one is struck by the uniform absence of a priori considerations of the impact on medical practice, or likely lack thereof, of possible outcomes.
Full Text Available n(s) being investigated Acute Stroke MedDRA Classification E.1.3Condition being s... General Information on the Trial E.1 Medical condition or disease under investigation E.1.1Medical conditio
Gupta, Sandeep K.
There is an urgent need to expedite the time-to-market for new drugs and to make the approval process simpler. But clinical trials are a complex process and the increased complexity leads to decreased efficiency. Hence, pharmaceutical organizations want to move toward a more technology-driven clinical trial process for recording, analyzing, reporting, archiving, etc., In recent times, the progress has certainly been made in developing paperless systems that improve data capture and management. The adaptation of paperless processes may require major changes to existing procedures. But this is in the best interests of these organizations to remain competitive because a paperless clinical trial would lead to a consistent and streamlined framework. Moreover, all major regulatory authorities also advocate adoption of paperless trial. But challenges still remain toward implementation of paperless clinical trial process. PMID:26288464
Sandeep K Gupta
Full Text Available There is an urgent need to expedite the time-to-market for new drugs and to make the approval process simpler. But clinical trials are a complex process and the increased complexity leads to decreased efficiency. Hence, pharmaceutical organizations want to move toward a more technology-driven clinical trial process for recording, analyzing, reporting, archiving, etc., In recent times, the progress has certainly been made in developing paperless systems that improve data capture and management. The adaptation of paperless processes may require major changes to existing procedures. But this is in the best interests of these organizations to remain competitive because a paperless clinical trial would lead to a consistent and streamlined framework. Moreover, all major regulatory authorities also advocate adoption of paperless trial. But challenges still remain toward implementation of paperless clinical trial process.
Gupta, Sandeep K
There is an urgent need to expedite the time-to-market for new drugs and to make the approval process simpler. But clinical trials are a complex process and the increased complexity leads to decreased efficiency. Hence, pharmaceutical organizations want to move toward a more technology-driven clinical trial process for recording, analyzing, reporting, archiving, etc., In recent times, the progress has certainly been made in developing paperless systems that improve data capture and management. The adaptation of paperless processes may require major changes to existing procedures. But this is in the best interests of these organizations to remain competitive because a paperless clinical trial would lead to a consistent and streamlined framework. Moreover, all major regulatory authorities also advocate adoption of paperless trial. But challenges still remain toward implementation of paperless clinical trial process.
Klimt, C R
Long-term clinical trials often include more than one active treatment group. These may be discontinued independently if found to be ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet another kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.
Breitkopf, Carmen Radecki; Loza, Melissa; Vincent, Kathleen; Moench, Thomas; Stanberry, Lawrence R; Rosenthal, Susan L
A greater understanding of participant views regarding reimbursement will help investigators plan studies that have better potential for reaching target enrollment, maximize efficient recruitment, maintain scientific integrity, and enhance retention over time. As part of a clinical trial in the area of sexual health, healthy women's perceptions of reimbursement for research participation were investigated. Semi-structured, audio-recorded, qualitative interviews were conducted immediately upon women's completion of the clinical trial to enable a participant-driven understanding of perceptions about monetary reimbursement. Audio-recordings were transcribed and analyzed using framework analysis. Women (N = 30) had a mean age of 29.5 ± 5.7 years (range 22-45 years). Sixty-three percent of participants (n = 19) were non-Hispanic (white n = 13, black n = 4, and Asian n = 2), while the remaining were Hispanic (n = 11). Seventy-three percent (n = 22) reported previous participation in research. In general, women viewed reimbursement as a benefit to research participation, the amount of which should reflect time, the inconvenience to the research subject, and the potential for unknown risks in the short- and long-term. They believed reimbursement should take into account the degree of risk of the study, with investigations of experimental products offering greater reimbursement. Women believed that monetary reimbursement is unlikely to coerce an individual to volunteer for a study involving procedures or requirements that they found unacceptable. The results of this study can be used to provide guidance to those planning and evaluating reimbursement for research participation.
C. A. Caramori
Scientific development that has been achieved through decades finds in clinical research a great possibility of translating findings to human health application. Evidence given by clinical trials allows everyone to have access to the best health services. However, the millionaire world of pharmaceutical industries has stained clinical research with doubt and improbability. Study results (fruits of controlled clinical trials) and scientific publications (selective, manipulated and with wrong c...
K. O. Zupanets
Full Text Available Protection of rights, health and well-being of persons who are taking the drug during the trial (trial subjects is one of the basic principles of clinical trials (CT management. Aim. In order to study key aspects of volunteer protection, determine factors that influence these indicators and estimate the importance of ensuring their proper implementation on the clinical site (CS three survey of 135 trial subjects were carried out to evaluate the importance of assessing the impact of factors such as the procedure of signing the informed consent (IC at the CS and testing procedures for HIV / AIDS, hepatitis and others. Assessment of the quality of life of trial subjects as indirect indicator of the quality of clinical trials that ensures the proper protection of their life was the subject of the third survey. Methods and results. The general model of the relationship between the key aspects of the trial subjects protection and the factors which are providing them during the clinical trials of drugs management was substantiated, which included the main aspects of the trial subjects’ protection, protective factors and basic CT management procedures, the impact of the above factors on the possibility of providing protection aspects depends on their implementation quality. It was found that trial subjects’ protection improvement can be achieved during the IC signing process. It is necessary to ensure a higher level of volunteers understanding of the terms that could be used in the IC form. Regarding the procedure of compulsory testing for HIV/AIDS in the course of screening, we can conclude that the majority of the trial subjects believe that this procedure is an additional factor in their health protection and do not consider it as an excessive psychological pressure on them. Conclusion. Assessing the quality of life during the bioequivalence study at the CS makes possible to reach a conclusion on general well-being and satisfaction with those
Full Text Available The Clinical Trials Transformation Initiative (CTTI is a public-private partnership created in 2007 between the United States Food and Drug Administration (FDA and Duke University for the purpose of identifying practices that will increase the quality and efficiency of clinical trials. The initiative was generated from the realization that the clinical trials system in the United States has been suffering as a result of increasingly longer study start-up times, slowing enrollment of patients into trials, increasing clinical trial costs, and declining investigator interest in participating in clinical trials. Although CTTI was created to address a crisis for US clinical research, it seeks to identify practice improvements that can be applied internationally, and is therefore engaging international collaborators with international efforts that have similar objectives. CTTI's approach is to involve all sectors in the selection, conduct, and interpretation of its projects; to keep the dialogue open across sectors; to provide evidence that can influence regulatory guidance, and to attempt to create a "level playing field" when recommending change. The hope is that a broad and diverse data-driven discussion of the important issues in clinical trials will lead to meaningful change for the benefit of all concerned, and importantly for patients.
Full Text Available After two decades of microbicide clinical trials it remains uncertain if vaginally- delivered products will be clearly shown to reduce the risk of HIV infection in women and girls. Furthermore, a microbicide product with demonstrated clinical efficacy must be used correctly and consistently if it is to prevent infection. Information on adherence that can be gleaned from microbicide trials is relevant for future microbicide safety and efficacy trials, pre-licensure implementation trials, Phase IV post-marketing research, and microbicide introduction and delivery. Drawing primarily from data and experience that has emerged from the large-scale microbicide efficacy trials completed to-date, the paper identifies six broad areas of adherence lessons learned: (1 Adherence measurement in clinical trials, (2 Comprehension of use instructions/Instructions for use, (3 Unknown efficacy and its effect on adherence/Messages regarding effectiveness, (4 Partner influence on use, (5 Retention and continuation and (6 Generalizability of trial participants' adherence behavior. Each is discussed, with examples provided from microbicide trials. For each of these adherence topics, recommendations are provided for using trial findings to prepare for future microbicide safety and efficacy trials, Phase IV post-marketing research, and microbicide introduction and delivery programs.
Østervig, R M; Sonne, A; Rasmussen, L S
BACKGROUND: Registration of interventional studies is necessary according to the Declaration of Helsinki but implementation has been a challenge for many journals. Acta Anaesthesiologica Scandinavica (Acta) requires registration for studies conducted after January 1(st) 2010. We aimed to assess...... registered when it could be verified that patient enrolment was started after registration in a trial registry. RESULTS: We identified 200 RCTs. Dates for patient enrolment were not specified in 51 (25.5%). The proportion of correctly registered trials increased significantly from 17.1% (19/111) for trials...
Ness, Elizabeth A; Royce, Cheryl
Clinical trials are paramount to improving human health. New trial designs and informed consent issues are emerging as a result of genomic profiling and the development of molecularly targeted agents. Many groups and individuals are responsible for ensuring the protection of research participants and the quality of the data produced. The specialty role of the clinical trials nurse (CTN) is critical to clinical trials. Oncology CTNs have competencies that can help guide their practice; however, not all oncology clinical trials are supervised by a nurse. Using the process of engagement, one organization has restructured oncology CTNs under a nurse-supervised model.
Full Text Available nter, Randomized, Double-blind, Placebo-controlled Trial of Three Fixed Doses of OPC-34712 in the Treatment of Adults With Acute...2 in the Treatment of Adults With Acute Schizophrenia A.4.1Sponsor's protocol code number331-10-231 A.5.2US ... Information on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute...ition or disease under investigation E.1.2Version 14.1 E.1.2Level LLT E.1.2Classification code 10001064 E.1.2Term Acute
Full Text Available 2, and 1 mg/day) in the Treatment of Adults With Acute Schizophrenia A.3.1Title ...of the trial for lay people, in easily understood, i.e. non-technical, language Efficacy Study of OPC-34712 in Adults With Acute...e Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute...nder investigation E.1.2Version 14.0 E.1.2Level LLT E.1.2Classification code 10001064 E.1.2Term Acute schizo
Ellis, Cara E; Korbutt, Gregory S
The development of the Edmonton Protocol encouraged a great deal of optimism that a cell-based cure for type I diabetes could be achieved. However, donor organ shortages prevent islet transplantation from being a widespread solution as the supply cannot possibly equal the demand. Porcine islet xenotransplantation has the potential to address these shortages, and recent preclinical and clinical trials show promising scientific support. Consequently, it is important to consider whether the current science meets the ethical requirements for moving toward clinical trials. Despite the potential risks and the scientific unknowns that remain to be investigated, there is optimism regarding the xenotransplantation of some types of tissue, and enough evidence has been gathered to ethically justify clinical trials for the most safe and advanced area of research, porcine islet transplantation. Researchers must make a concerted effort to maintain a positive image for xenotransplantation, as a few well-publicized failed trials could irrevocably damage public perception of xenotransplantation. Because all of society carries the burden of risk, it is important that the public be involved in the decision to proceed. As new information from preclinical and clinical trials develops, policy decisions should be frequently updated. If at any point evidence shows that islet xenotransplantation is unsafe, then clinical trials will no longer be justified and they should be halted. However, as of now, the expected benefit of an unlimited supply of islets, combined with adequate informed consent, justifies clinical trials for islet xenotransplantation.
Fitzgerald, G K; Hinman, R S; Zeni, J; Risberg, M A; Snyder-Mackler, L; Bennell, K L
A Task Force of the Osteoarthritis Research Society International (OARSI) has previously published a set of guidelines for the conduct of clinical trials in osteoarthritis (OA) of the hip and knee. Limited material available on clinical trials of rehabilitation in people with OA has prompted OARSI to establish a separate Task Force to elaborate guidelines encompassing special issues relating to rehabilitation of OA. The Task Force identified three main categories of rehabilitation clinical trials. The categories included non-operative rehabilitation trials, post-operative rehabilitation trials, and trials examining the effectiveness of devices (e.g., assistive devices, bracing, physical agents, electrical stimulation, etc.) that are used in rehabilitation of people with OA. In addition, the Task Force identified two main categories of outcomes in rehabilitation clinical trials, which include outcomes related to symptoms and function, and outcomes related to disease modification. The guidelines for rehabilitation clinical trials provided in this report encompass these main categories. The report provides guidelines for conducting and reporting on randomized clinical trials. The topics include considerations for entering patients into trials, issues related to conducting trials, considerations for selecting outcome measures, and recommendations for statistical analyses and reporting of results. The focus of the report is on rehabilitation trials for hip, knee and hand OA, however, we believe the content is broad enough that it could be applied to rehabilitation trials for other regions as well.
Francis, David; Roberts, Ian; Elbourne, Diana R; Shakur, Haleema; Knight, Rosemary C; Garcia, Jo; Snowdon, Claire; Entwistle, Vikki A; McDonald, Alison M; Grant, Adrian M; Campbell, Marion K
Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials. The case study demonstrates that trials need various categories of people to buy in - hence, to be successful, trialists must embrace marketing strategies to some extent. The performance of future clinical trials could be enhanced if trialists routinely considered these factors.
Full Text Available lot Trial of Indomethacin in Acute Pancreatitis Ensayo piloto controlado y aleatorizado con indometacina en ....1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute...n criteria Patients ages 18 or above admitted to hospital with a diagnosis of Acute pancreatitis (AP) based
Full Text Available edical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute Rhinosinu....2.3Trial contains a sub-study No E.3Principal inclusion criteria 1. Adult male and female outpatients aged ≥ 18 - 75 years 2. Acute
... Releases & Announcements Public Service Announcements Partnering with DBSA Clinical Trials: Information and Options for People with Mood Disorders What are clinical trials? Clinical trials are research studies involving people, which ...
@@ Introduction The mission of the WHO Intemational Clinical Trials Registry Platform is to ensure that a complete view of research is accessible to all those involved in health care decision making.This will improve research transparency and will ultimately strengthen tha validity and value of the scientific evidence base.The registration of all interventional trials is a scientific, ethical and moral responsibility.
Hróbjartsson, A; Boutron, I
Blinding, or "masking," is a crucial method for reducing bias in randomized clinical trials. In this paper, we review important methodological aspects of blinding, emphasizing terminology, reporting, bias mechanisms, empirical evidence, and the risk of unblinding. Theoretical considerations...
Molloy, Síle F; Henley, Patricia
This article describes the processes and procedures involved in planning, conducting and reporting monitoring activities for large Clinical Trials of Investigational Medicinal Products (CTIMPs), focusing on those conducted in resource-limited settings. © 2016 John Wiley & Sons Ltd.
... altering them as they run to take into account accumulating results. Although Bayesian designs are now widely used in everything from astrophysics to ecology, they've been slower to catch on in medical research, particularly clinical trials...
Geller, Nancy L; Kim, Dong-Yun; Tian, Xin
This article describes the use of smart technology by investigators and patients to facilitate lung disease clinical trials and make them less costly and more efficient. By "smart technology" we include various electronic media, such as computer databases, the Internet, and mobile devices. We first describe the use of electronic health records for identifying potential subjects and then discuss electronic informed consent. We give several examples of using the Internet and mobile technology in clinical trials. Interventions have been delivered via the World Wide Web or via mobile devices, and both have been used to collect outcome data. We discuss examples of new electronic devices that recently have been introduced to collect health data. While use of smart technology in clinical trials is an exciting development, comparison with similar interventions applied in a conventional manner is still in its infancy. We discuss advantages and disadvantages of using this omnipresent, powerful tool in clinical trials, as well as directions for future research.
Jan 22, 2008 ... Manufacturers Association, on the basis of a survey of its members ... from this information. The US database, on the other hand, clearly identifies 172 ... workforce involved in clinical trials outside the public sector. This figure ...
Califf, Robert M; Zarin, Deborah A; Kramer, Judith M; Sherman, Rachel E; Aberle, Laura H; Tasneem, Asba
Recent reports highlight gaps between guidelines-based treatment recommendations and evidence from clinical trials that supports those recommendations. Strengthened reporting requirements for studies registered with ClinicalTrials.gov enable a comprehensive evaluation of the national trials portfolio. To examine fundamental characteristics of interventional clinical trials registered in the ClinicalTrials.gov database. A data set comprising 96,346 clinical studies from ClinicalTrials.gov was downloaded on September 27, 2010, and entered into a relational database to analyze aggregate data. Interventional trials were identified and analyses were focused on 3 clinical specialties-cardiovascular, mental health, and oncology-that together encompass the largest number of disability-adjusted life-years lost in the United States. Characteristics of registered clinical trials as reported data elements in the trial registry; how those characteristics have changed over time; differences in characteristics as a function of clinical specialty; and factors associated with use of randomization, blinding, and data monitoring committees (DMCs). The number of registered interventional clinical trials increased from 28,881 (October 2004-September 2007) to 40,970 (October 2007-September 2010), and the number of missing data elements has generally declined. Most interventional trials registered between 2007 and 2010 were small, with 62% enrolling 100 or fewer participants. Many clinical trials were single-center (66%; 24,788/37,520) and funded by organizations other than industry or the National Institutes of Health (NIH) (47%; 17,592/37,520). Heterogeneity in the reported methods by clinical specialty; sponsor type; and the reported use of DMCs, randomization, and blinding was evident. For example, reported use of DMCs was less common in industry-sponsored vs NIH-sponsored trials (adjusted odds ratio [OR], 0.11; 95% CI, 0.09-0.14), earlier-phase vs phase 3 trials (adjusted OR, 0
Full Text Available E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute Gou...t E.1.1.1Medical condition in easily understood language Acute Gout E.1.1.2Therapeutic area Diseases [C] - M...n the trial (if it is different from the expected normal treatment of that condition) Acute gout is a self l
Kjaergard, L L; Nikolova, D; Gluud, C
. Quality was assessed by means of a validated 5-point scale and separate quality components associated with empirical evidence of bias. Only 26% of all RCTs reported sample size calculations, 52% adequate generation of the allocation sequence, 34% adequate allocation concealment and 34% double......, single-center trials, and trials with no external funding. Quality did not improve with time and was not associated with country of origin. The main conclusions are that the quality of RCTs in HEPATOLOGY needs improvement and that the probability of high quality increased with the number of centers...
Olga Lidia Cuevas Pérez
Full Text Available Today there are countless examples that illustrate the nature of technoscience, including biotechnology and pharmacology. The clinical trial is the appropriate methodology used by clinical pharmacology to test the efficacy and safety of a treatment or intervention in humans. It constitutes the cornerstone of research. Once the preclinical research is completed, one of the biggest challenges currently facing the Cuban Pharmaceutical and Biotechnological Industry is precisely the clinical evaluation. Therefore, this work aims to provide a reflection on the most significant aspects of clinical trials and their impact on society.
Liu, Fei-Fei; Okunieff, Paul; Bernhard, Eric J.; Stone, Helen B.; Yoo, Stephen; Coleman, C. Norman; Vikram, Bhadrasain; Brown, Martin; Buatti, John; Guha, Chandan
A Workshop entitled “Lessons Learned from Radiation Oncology Trials” was held on December 7–8th, 2011 in Bethesda, MD, to present and discuss some of the recently conducted Radiation Oncology clinical trials with a focus on those that failed to refute the null hypothesis. The objectives of this Workshop were to summarize and examine the questions that these trials provoked, to assess the quality and limitations of the pre-clinical data that supported the hypotheses underlying these trials, an...
Oud, Johan; Ghidey, Wendimagegn
This book describes various ways of approaching and interpreting the data produced by clinical trial studies, with a special emphasis on the essential role that biostatistics plays in clinical trials. Over the past few decades the role of statistics in the evaluation and interpretation of clinical data has become of paramount importance. As a result the standards of clinical study design, conduct and interpretation have undergone substantial improvement. The book includes 18 carefully reviewed chapters on recent developments in clinical trials and their statistical evaluation, with each chapter providing one or more examples involving typical data sets, enabling readers to apply the proposed procedures. The chapters employ a uniform style to enhance comparability between the approaches.
Witsell, David L; Schulz, Kristine A; Lee, Walter T; Chiswell, Karen
To describe the conditions studied, interventions used, study characteristics, and funding sources of otolaryngology clinical trials from the ClinicalTrials.gov database; compare this otolaryngology cohort of interventional studies to clinical visits in a health care system; and assess agreement between clinical trials and clinical activity. Database analysis. Trial registration data downloaded from ClinicalTrials.gov and administrative data from the Duke University Medical Center from October 1, 2007 to September 27, 2010. Data extraction from ClinicalTrials.gov was done using MeSH and non-MeSH disease condition terms. Studies were subcategorized to create the following groupings for descriptive analysis: ear, nose, allergy, voice, sleep, head and neck cancer, thyroid, and throat. Duke Health System visits were queried by using selected ICD-9 codes for otolaryngology and non-otolaryngology providers. Visits were grouped similarly to ClinicalTrials.gov for further analysis. Chi-square tests were used to explore differences between groups. A total of 1115 of 40,970 registered interventional trials were assigned to otolaryngology. Head and neck cancer trials predominated. Study models most frequently incorporated parallel design (54.6%), 2 study groups (46.6%), and randomization (69.1%). Phase 2 or 3 studies constituted 46.4% of the cohort. Comparison of the ClinicalTrials.gov database with administrative health system visit data by disease condition showed discordance between national research activity and clinical visit volume for patients with otolaryngology complaints. Analysis of otolaryngology-related clinical research as listed in ClinicalTrials.gov can inform patients, physicians, and policy makers about research focus areas. The relative burden of otolaryngology-associated conditions in our tertiary health system exceeds research activity within the field.
Yankeelov, Thomas E; Mankoff, David A; Schwartz, Lawrence H; Lieberman, Frank S; Buatti, John M; Mountz, James M; Erickson, Bradley J; Fennessy, Fiona M M; Huang, Wei; Kalpathy-Cramer, Jayashree; Wahl, Richard L; Linden, Hannah M; Kinahan, Paul E; Zhao, Binsheng; Hylton, Nola M; Gillies, Robert J; Clarke, Laurence; Nordstrom, Robert; Rubin, Daniel L
As anticancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. Although traditional, anatomic CT, and MRI examinations are useful in many settings, increasing evidence suggests that these methods cannot answer the fundamental biologic and physiologic questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients and to provide a more efficient path for the development of improved targeted therapies.
Plétan, Yannick; Zannad, Faïez; Jaillon, Patrice
Be it to restore the confused image of clinical research in relation to the lay public, or to develop new ways of accruing healthy volunteers or patients for clinical trials, there is a need to draft some guidance on how best to provide information on research. Although the French legal and regulatory armamentarium in this area is essentially liberal, there is currently little-justified reluctance among study sponsors to advertise publicly. A group of academic and pharmaceutical industry researchers, assembled for a workshop, together with regulators, journalists, representatives from ethics committees, social security, patient and health consumer groups and other French institutional bodies, has suggested the following series of recommendations: there is no need for additional legal or regulatory constraints; sponsors should be aware of and make use of direct public information on trials; a 'good practice charter' on public communication about clinical trials should be developed; all professionals should be involved in this communication platform; communication in the patient's immediate vicinity should be preferred (primary-care physician, local press); clinical databases and websites accessible to professionals, but also to patients and non-professionals, should be developed; genuine instruction on clinical trials for physicians and health professionals unfamiliar with such trials should be developed and disseminated; media groups should receive at least some training in the fundamentals of clinical research.
Full Text Available ion E.1.1Medical condition(s) being investigated Acute cough Akuter Husten E.1.1.1Medical condition in easily understood language Acu...igation E.1.2Version 17.1 E.1.2Level LLT E.1.2Classification code 10066522 E.1.2Term Acute cough E.1.2System...igible for inclusion in this trial must fulfill all of the following criteria:1. Acute cough with symptoms l...based on medical history and physical examination7. CS score of at least 50 mm on a 100 mm VAS at V1 8. Acute...te cough Akuter Husten E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Dis
Aboulker, J P
Comparative judgement, which is seminal to any kind of science performing measurements, has been applied to clinical reasoning for many centuries. The need for systematizing the observational methods used in medicine in order to draw more reliable inferences about the effects of therapies has been active all along the 19th century. This has resulted in controlled studies which yielded important advances in clinical and therapeutic knowledge, although their designs were not fully satisfactory. Clinical trials have gained their status of "hard science", methodology allowing causal inference, by the end of the 1940s after having adopted the statistical theories developed in the 1930s by Fisher for experimental design in agronomy. A long way has been run since the first controlled randomized trial. However, half a century later, modern clinical trial remains essentially a controlled randomized prospective study using methods to limit potential biases and to establish statistical significance.
Clinical trials are necessary for medical advancement. They must respect legal obligations. Ethical questions related to protection of the human being's rights are yielded by these trials. Joining research to medical core is problematical in consideration of patient's consent to clinical trial. Exclusion by the Tunisian law of persons under age, pregnant or breast-feeding women from medical experimentation in the aim of protecting them against clinical research adverse events or abuses is ethically questionable since it deprives them from a possible medical progress. So why not to involve them in clinical research when there is an expected benefit, after bringing them protection as vulnerable persons like we should do for instance for the elderly, handicapped persons or prisoners. Legal creation of research ethics committees is important for the respect of experimentation rules on human beings.
Hussain-Gambles, M; Leese, B; Atkin, K; Brown, J; Mason, S; Tovey, P
To investigate how South Asian patients conceptualise the notion of clinical trials and to identify key processes that impact on trial participation and the extent to which communication difficulties, perceptions of risk and attitudes to authority influence these decisions. Also to identify whether 'South Asian' patients are homogeneous in these issues, and which factors differ between different South Asian subgroups and finally how professionals regard the involvement of South Asian patients and their views on strategies to increase participation. A review of the literature on minority ethnic participation in clinical trials was followed by three qualitative interview studies. Interviews were taped and transcribed (and translated if required) and subjected to framework analysis. Face-to-face interviews were conducted with 25 health professionals; 60 South Asian lay people who had not taken part in a trial and 15 South Asian trial participants. Motivations for trial participation were identified as follows: to help society, to improve own health or that of family and friends, out of obligation to the doctor and to increase scientific knowledge. Deterrents were concerns about drug side-effects, busy lifestyles, language, previous bad experiences, mistrust and feelings of not belonging to British society. There was no evidence of antipathy amongst South Asians to the concept of clinical trials and, overall, the younger respondents were more knowledgeable than the older ones. Problems are more likely to be associated with service delivery. Lack of being approached was a common response. Lay-reported factors that might affect South Asian participation in clinical trials include age, language, social class, feeling of not belonging/mistrust, culture and religion. Awareness of clinical trials varied between each group. There are more similarities than differences in attitudes towards clinical trial participation between the South Asian and the general population
Full Text Available Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials.
Chen, Feng; Sun, Hua-long; Shen, Tong; Yu, Hao
A perfect clinical trial must nave a solid study design, strict conduction, complete quality control, non-interference of statistical result, and acceptable risk-benefit ratio. To reach the target, the quality control (QC) should be performed from the study design to conduction, from the analysis to conclusion. We discuss the relationship between data management and biostatistics from the statistical point of view, and emphasize the importance of the statistical concept and methods in the improvement of data quality in clinical data management.
Rangan, A; Jefferson, L; Baker, P; Cook, L
The aim of this study was to review the role of clinical trial networks in orthopaedic surgery. A total of two electronic databases (MEDLINE and EMBASE) were searched from inception to September 2013 with no language restrictions. Articles related to randomised controlled trials (RCTs), research networks and orthopaedic research, were identified and reviewed. The usefulness of trainee-led research collaborations is reported and our knowledge of current clinical trial infrastructure further supplements the review. Searching yielded 818 titles and abstracts, of which 12 were suitable for this review. Results are summarised and presented narratively under the following headings: 1) identifying clinically relevant research questions; 2) education and training; 3) conduct of multicentre RCTs and 4) dissemination and adoption of trial results. This review confirms growing international awareness of the important role research networks play in supporting trials in orthopaedic surgery. Multidisciplinary collaboration and adequate investment in trial infrastructure are crucial for successful delivery of RCTs. Cite this article: Bone Joint Res 2014;3:169-74. ©2014 The British Editorial Society of Bone & Joint Surgery.
Katz, Deborah G; Dutcher, Gale A; Toigo, Theresa A; Bates, Ruthann; Temple, Freda; Cadden, Cynthia G
The AIDS Clinical Trials Information Service (ACTIS) is a central resource for information about federally and privately funded HIV/AIDS clinical trials. Sponsored by four components of the U.S. Department of Health and Human Services, ACTIS has been a key part of U.S. HIV/AIDS information and education services since 1989. ACTIS offers a toll-free telephone service, through which trained information specialists can provide callers with information about AIDS clinical trials in English or Spanish, and a website that provides access to clinical trials databases and a variety of educational resources. Future priorities include the development of new resources to target diverse and underserved populations. In addition, research needs to be conducted on the use of telephone services vs. Web-based information exchange to ensure the broadest possible dissemination of up-to-date information on HIV infection and clinical trials.
El Mouelhi, Mohamed
Drug development process faces many challenges, including those encountered in clinical trials for neuromuscular diseases. Drug development is a lengthy and highly costly process. Out of 10 compounds entering first study in man (phase 1), only one compound reaches the market after an average of 14 years with a cost of $2.7 billion. Nevertheless, according to the Centers for Medicare and Medicaid services, prescription drugs constituted only 9 % of each health care dollar spent in USA in 2013. Examples of challenges encountered in neuromuscular clinical trials include lack of validated patient-reported outcome tools, blinding issues, and the use of placebo in addition to lack of health authority guidance for orphan diseases. Patient enrollment challenge is the leading cause of missed clinical trial deadlines observed in about 80 % of clinical trials, resulting in delayed availability of potentially life-saving therapies. Another specific challenge introduced by recent technology is the use of social media and risk of bias. Sharing personal experiences while in the study could easily introduce bias among patients that would interfere with accurate interpretation of collected data. To minimize this risk, recent neuromuscular studies incorporate as an inclusion criterion the patient's agreement not to share any of study experiences through social media with other patients during the study conduct. Consideration of these challenges will allow timely response to the high unmet medical needs for many neuromuscular diseases.
Schüssler-Lenz, M; Schneider, C K
For advanced therapies, the same basic principles for assessment apply as for any other biotechnological medicinal product. Nevertheless, the extent of data for quality, safety, and efficacy can be highly specific. Until recently, advanced therapies were not uniformly regulated across Europe, e.g., tissue engineered products were regulated either as medicinal products or medical devices. Thus, for some products no data from clinical studies are available, e.g., for autologous chondrocyte products. The draft guideline on Good Clinical Practice for clinical trials with advanced therapies describes specific additional requirements, e.g., ensuring traceability. Most clinical studies with advanced therapies in Germany are still in early phase I or II trials with highly divergent types of products and clinical indications. The Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMEA) has been established to meet the scientific and regulatory challenges with advanced therapies.
Schmal, Hagen; Bernstein, Anke; Feucht, Matthias J;
clinical trial and the cytokine composition of effusions (n = 76) was analyzed. Characteristics of epidemiology and disease severity were correlated with levels of cytokines with known roles in cartilage turnover and degradation. Results. Higher synovial IL-1β concentrations were associated with clinical......-2, and BMP-7. Infections with Staphylococcus species induced higher IL-1β expression but less cartilage destruction than other bacteria. Conclusion. Articular infections have bacteria-specific implications on cartilage metabolism. Collagen type II cleavage products reliably mark destruction, which...... is associated with upregulation of typical cartilage turnover cytokines. This trial is registered with DRKS00003536, MISSinG....
Sessler, Daniel I; Imrey, Peter B
Randomized assignment of treatment excludes reverse causation and selection bias and, in sufficiently large studies, effectively prevents confounding. Well-implemented blinding prevents measurement bias. Studies that include these protections are called randomized, blinded clinical trials and, when conducted with sufficient numbers of patients, provide the most valid results. Although conceptually straightforward, design of clinical trials requires thoughtful trade-offs among competing approaches-all of which influence the number of patients required, enrollment time, internal and external validity, ability to evaluate interactions among treatments, and cost.
Full Text Available Research has established the principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis. All hormonal male contraceptives use testosterone, but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Clinical trials concentrate on testosterone combined with norethisterone, desogestrel, etonogestrel or depot-medroxyprogesterone acetate. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of testosterone undecanoate and etonogestrel in suppressing spermatogenesis in volunteers.
Reekie, J; Mocroft, A; J, Neaton;
Since the introduction of combination antiretroviral therapy, there has been a decrease in both AIDS-defining illnesses and deaths. This decrease meant that performing clinical trials with clinical outcomes in HIV infection became more time consuming and hence costly. Improved understanding...
Reekie, J; Mocroft, A; J, Neaton;
Since the introduction of combination antiretroviral therapy, there has been a decrease in both AIDS-defining illnesses and deaths. This decrease meant that performing clinical trials with clinical outcomes in HIV infection became more time consuming and hence costly. Improved understanding and k...
Kaul, Sanjay; Diamond, George A
Active control noninferiority trials are being used with increasing frequency in new drug or device development when standard placebo-controlled trials are considered unethical. Nevertheless, the design and analysis of these trials are founded on a number of assumptions and arbitrary criteria that are generally not well understood or justifiable. Trials designed to show noninferiority require an appropriate reference population, a proven active control and dose, an appropriate margin of noninferiority that is clinically relevant and statistically justifiable, a high level of adherence to treatment, and adequate statistical power to reliably conclude that a treatment is truly noninferior and therefore effective. Accordingly, if noninferiority trials are to be applied to clinical and regulatory decisions regarding the marketing and use of new treatments, the assumptions must be made explicit and their influence on the resultant conclusions must be assessed rigorously. When conservative criteria were applied to each of the key assumptions underlying 2 representative noninferiority trials, they materially undermined the conclusions regarding noninferiority failing to confirm reported conclusions regarding noninferiority despite enthusiastic dissemination and acceptance of the results. Because the clinical, regulatory, and economic impact of active control noninferiority trials is substantial, robust criteria should be used routinely in their design, analysis, and interpretation to reach their intended objectives and to keep them from becoming wasted efforts.
Lifson, Alan R; Belloso, Waldo H; Davey, Richard T
PURPOSE: Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial. METHODS: SNA definitions were...... was reached. CONCLUSION: HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication....
Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.
Ban, T A; Amin, M M
1 In an uncontrolled clinical trial, carried out in 11 psychiatric patients with the clinical diagnoses of anxiety neurosis and depressive neurosis, clobazam, a new benzodiazepine preparation, in the dosage range 10-60 mg daily produced statistically significant improvement in the total and both factor scores of the Hamilton Anxiety Scale (HAM-A). The lowest mean total HAM-A scores occurred with a mean clobazam dosage of 48 mg daily. 2 Results of the uncontrolled clinical trial were further substantiated in a standard-controlled clinical study in which no statistically significant difference between the therapeutic effectiveness of clobazam and diazepam could be revealed. The lowest mean total HAM-A scores occurred with a mean clobazam dosage of 49 mg daily. There was a lower incidence of adverse effects reported in patients receiving clobazam than in those taking the control drug (diazepam).
Full Text Available June Chen1, Stephen A Runyan1, Michael R Robinson21Department of Biological Sciences, 2Ophthalmology Clinical Research, Allergan, Inc, Irvine, CA, USAIntroduction: Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Pharmacotherapy reduces IOP by suppressing aqueous inflow and/or increasing aqueous outflow.Purpose: This review focuses on novel non-FDA approved ocular antihypertensive compounds being investigated for IOP reduction in ocular hypertensive and glaucoma patients in active clinical trials within approximately the past 2 years.Methods: The mode of IOP reduction, pharmacology, efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clinical trial registries. Compounds with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered.Results: The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compounds evaluated in clinical trials include an actin polymerization inhibitor (ie, latrunculin, Rho-associated protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist.Conclusion: The clinical value of novel compounds for the treatment of glaucoma will depend
New treatments for lung cancer and aspects of joining a clinical trial are discussed in this 30-minute Facebook Live event, hosted by NCI’s Dr. Shakun Malik, head of thoracic oncology therapeutics, and Janet Freeman-Daily, lung cancer patient activist and founding member of #LCSM.
Viergever Roderik F
Full Text Available Abstract Information on blinding is part of the data that should be provided upon registration of a trial at a clinical trials registry. Reporting of blinding is often absent or of low quality in published articles of clinical trials. This study researched the presence and quality of information on blinding in registered records of clinical trials and highlights the important role of data-recording formats at clinical trial registries in ensuring high-quality registration.
Subherwal, Sumeet; Patel, Manesh R.; Chiswell, Karen; Tidemann-Miller, Beth A.; Jones, W. Schuyler; Conte, Michael S.; White, Christopher J.; Bhatt, Deepak L.; Laird, John R.; Hiatt, William R.; Tasneem, Asba; Califf, Robert M.
Background Tremendous advances have occurred in therapies for peripheral vascular disease (PVD); however, until recently it has not been possible to examine the entire clinical trial portfolio of studies for treatment of PVD (both arterial and venous disease). Methods and Results We examined interventional trials registered in ClinicalTrials.gov from October 2007 through September 2010 (n=40,970) and identified 676 (1.7%) PVD trials (n=493 arterial only, n=170 venous only, n=13 both arterial and venous). Most arterial studies investigated lower extremity peripheral artery disease and acute stroke (35% and 24%, respectively), while most venous studies examined deep vein thrombosis/pulmonary embolus prevention (42%) or venous ulceration (25%). A placebo-controlled trial design was used in 27% of the PVD trials, and 4% of the PVD trials excluded patients aged >65 years. Enrollment in at least 1 US site decreased from 51% in 2007 to 41% of trials in 2010. Compared with non-cardiology disciplines, PVD trials were more likely to be double-blinded, investigate use of devices and procedures, and have industry sponsorship and assumed funding source, and less likely to investigate drug and behavioral therapies. Geographic access to PVD clinical trials within the United States is limited to primarily large metropolitan areas. Conclusions PVD studies represent a small group of trials registered in ClinicalTrials.gov, despite the high prevalence of vascular disease in the general population. This low number, compounded by the decreasing number of PVD trials in the United States, is concerning and may limit the ability to inform current clinical practice of patients with PVD. PMID:25239436
Kloppenburg, M; Maheu, E; Kraus, V B; Cicuttini, F; Doherty, M; Dreiser, R-L; Henrotin, Y; Jiang, G-L; Mandl, L; Martel-Pelletier, J; Nelson, A E; Neogi, T; Pelletier, J-P; Punzi, L; Ramonda, R; Simon, L S; Wang, S
Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.
Gutmann, David H; Blakeley, Jaishri O; Korf, Bruce R; Packer, Roger J
The neurofibromatoses (neurofibromatosis type 1, NF1 and neurofibromatosis type 2, NF2) comprise the most common inherited conditions in which affected children and adults develop tumors of the central and peripheral nervous system. In this review, the authors discuss how the establishment of the Neurofibromatosis Clinical Trials Consortium (NFCTC) has positively impacted on the design and execution of treatment studies for individuals with NF1 and NF2. Using an extensive PUBMED search in collaboration with select NFCTC members expert in distinct NF topics, the authors discuss the clinical features of NF1 and NF2, the molecular biology of the NF1 and NF2 genes, the development and application of clinically relevant Nf1 and Nf2 genetically engineered mouse models and the formation of the NFCTC to enable efficient clinical trial design and execution. The NFCTC has resulted in a more seamless integration of mouse preclinical and human clinical trials efforts. Leveraging emerging enabling resources, current research is focused on identifying subtypes of tumors in NF1 and NF2 to deliver the most active compounds to the patients most likely to respond to the targeted therapy.
Juul, Rasmus Vestergaard; Nyberg, Joakim; Kreilgaard, Mads
Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE...... of potency was obtained with a RTTE model accounting for both morphine effects and time-varying covariates on opioid consumption. An RTTE analysis approach proved better suited for demonstrating efficacy of opioid sparing analgesics than traditional statistical tests as a lower sample size was required due...
Lammertse, D; Tuszynski, MH; Steeves, JD; Curt, A; Fawcett, JW; Rask, C; Ditunno, JF; Fehlings, MG; Guest, JD; Ellaway, PH; Kleitman, N; Blight, AR; Dobkin, BH; Grossman, R.; Katoh, H.
The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized contro...
Milošević-Georgiev Andrijana; Krajnović Dušanka; Milovanović Srđan; Ignjatović Svetlana; Đurić Dušan; Marinković Valentina
Introduction. Every clinical trial has to meet all ethical criteria in addition to the scientific ones. The basic ethical principles in the clinical trials are the following: nonmaleficence, beneficence, respect for autonomy and the principle of justice. Objective. The aim of the study was to analyze clinical cases with the outcomes leading to the changes in regulatoryethical framework related to the clinical trials, as well as the outcomes of key clinical trials that influenced the in...
Dal-Ré, Rafael; Moher, David; Gluud, Christian;
Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends.......Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends....
Woolson Robert F
Full Text Available Abstract Background A well designed randomized clinical trial rates as the highest level of evidence for a particular intervention's efficacy. Randomization, a fundamental feature of clinical trials design, is a process invoking the use of probability to assign treatment interventions to patients. In general, randomization techniques pursue the goal of providing objectivity to the assignment of treatments, while at the same time balancing for treatment assignment totals and covariate distributions. Numerous randomization techniques, each with varying properties of randomness and balance, are suggested in the statistical literature. This paper reviews common randomization techniques often used in substance abuse research and an application from a National Institute on Drug Abuse (NIDA-funded clinical trial in substance abuse is used to illustrate several choices an investigator faces when designing a clinical trial. Results Comparisons and contrasts of randomization schemes are provided with respect to deterministic and balancing properties. Specifically, Monte Carlo simulation is used to explore the balancing nature of randomization techniques for moderately sized clinical trials. Results demonstrate large treatment imbalance for complete randomization with less imbalance for the urn or adaptive scheme. The urn and adaptive randomization methods display smaller treatment imbalance as demonstrated by the low variability of treatment allocation imbalance. For all randomization schemes, covariate imbalance between treatment arms was small with little variation between adaptive schemes, stratified schemes and unstratified schemes given that sample sizes were moderate to large. Conclusion We develop this paper with the goal of reminding substance abuse researchers of the broad array of randomization options available for clinical trial designs. There may be too quick a tendency for substance abuse researchers to implement the fashionable urn
McGraw, Deven; Greene, Sarah M; Miner, Caroline S; Staman, Karen L; Welch, Mary Jane; Rubel, Alan
With pragmatic clinical trials, an opportunity exists to answer important questions about the relative risks, burdens, and benefits of therapeutic interventions. However, concerns about protecting the privacy of this information are significant and must be balanced with the imperative to learn from the data gathered in routine clinical practice. Traditional privacy protections for research uses of identifiable information rely disproportionately on informed consent or authorizations, based on a presumption that this is necessary to fulfill ethical principles of respect for persons. But frequently, the ideal of informed consent is not realized in its implementation. Moreover, the principle of respect for persons—which encompasses their interests in health information privacy—can be honored through other mechanisms. Data anonymization also plays a role in protecting privacy but is not suitable for all research, particularly pragmatic clinical trials. In this article, we explore both the ethical foundation and regulatory framework intended to protect privacy in pragmatic clinical trials. We then review examples of novel approaches to respecting persons in research that may have the added benefit of honoring patient privacy considerations.
Beach, J E
When contract research organizations (CROs) were first formed, pharmaceutical companies outsourced to them only certain aspects of the conduct of their clinical trials. At first CROs were highly specialized entities, providing, for example, either biostatistical advice, clinical research associates who monitored investigational sites for regulatory compliance, or regulatory support. Gradually, full service CROs emerged, offering a full range of services for clinical trials, including the selection of investigators and investigational sites, assistance with patient recruitment, safety surveillance and reporting, site audits, and data management and biostatistics. This evolving relationship between CROs and the pharmaceutical and medical device industries has resulted in CROs assuming more and more of the regulatory and ethical risks and responsibilities inherent in the conduct of clinical trials. In this full service role, CROs, unlike sponsors, are not interested in the outcome of study, but like sponsors, are subject to heavy regulation by the federal government, must follow applicable state laws, must respect international guidelines, and are obliged to follow their own operating procedures. Moreover, they are judged by the industry on the basis of the scope and quality of services provided, including the degree of adherence to the research protocol, regulatory requirements, and timelines; the quality of the professional working relationships with investigators and institutions, both academic and community-based; and the validity of the data. Further, CROs are subject to comprehensive audits by sponsoring companies, FDA, and other regulatory authorities. For all these reasons, CROs are being tasked with strict vigilance of all stages of the clinical trial process to ensure that the laws, regulations, and industry standards designed for the protection of human subjects and data integrity are maintained.
Stamm, J W
The history of clinical trials would include events in 1747 on board the Salisbury, a British Navy vessel at sea with 12 seamen critically ill with scurvy. Involving these 12 sailors in a study, an officer on board by the name of Lind evaluated six potential treatments for scurvy, and rapidly reached the conclusion that daily consumption of citrus fruits returned the men fit for duty in approximately six days (Bull, 1959). The concept of experimental randomization was first developed by Sir R.A. Fisher (1925, 1926), and the method was introduced to medical research via a study of tuberculosis treatment by Amberson and co-workers (1931), who randomized 24 TB patients into two groups, one to receive the experimental therapy, the other serving as the control. Amberson et al. also incorporated the concept of blinding into their study. Sir Austin Bradford Hill codified and built on the principles of scientific experimentation developed by Fisher, and introduced the use of random numbers in the allocation of patients in the British Medical Research Council (1948) study of the effect of streptomycin in the treatment of tuberculosis (Daniels and Hill, 1952; Hill, 1952). The first applications of clinical trial methodology for testing interventions on dental, oral, and maxillofacial diseases and conditions are more difficult to determine. For dental caries prevention, however, Chilton and Fertig (1958) and Slack and Martin (1964) were certainly among the early caries clinical trial pioneers. As clinical trials have come into the mainstream of clinical research in medicine and dentistry, a great deal of developmental work has focused on their methodological enhancement. The most successful of these efforts have come from fruitful, ongoing collaborations among clinician investigators, biostatisticians, data management specialists, biomedical ethicists, and others with an academic interest in clinical trial design and utilization. During the past 25 years, the emergence of
Ard, Jamy D; Carter-Edwards, Lori; Svetkey, Laura P
Past clinical trials addressing behavior modification for cardiovascular disease (CVD) prevention have not been culturally appropriate for African Americans. This supposition is borne out by the continued challenges researchers face not only in recruiting and retaining African Americans in clinical trials, but also in achieving the desired outcomes among this population. Investigators have limited resources to develop culturally appropriate CVD prevention trials. The scientific literature reveals 2 models for implementing culturally appropriate interventions applicable to CVD prevention among African Americans; however, these models are not easily applied to the clinical trial setting. We propose a new model for developing a culturally appropriate clinical trial. The clinical trial is a function of the investigator's cultural framework, meaning that an investigator will have more difficulty designing clinical trials appropriate for use with cultures other than his or her own, a definite limitation when attempting to effectively reach diverse populations. Differences between the cultural frameworks of most clinical trials and African Americans' cultural frameworks lead to intrinsic biases, limiting the ability of African Americans to achieve the desired outcomes for any particular trial. An African-American participant's degree of immersion in traditional African-American culture, or acculturation, influences the magnitude of these biases. Investigators must be aware of, and attempt to mitigate, such biases so that the trial's potential for success is equitable across ethnic groups. In addition, investigators must understand how to effectively address relevant biases of African Americans without challenging their ethnic identity. Steps to decrease biases are described.
Full Text Available Background and Aims: Withholding findings of clinical trials for publication or presentation to the regulatory authorities is a major concern. We aimed to address the importance of clinical trial registration and whether it is needed or not. Discussion: For ethical conduct of clinical trial, registration is an important but debatable issue due to proprietary interest of the pharmaceutical industry. Over the years, investigating agencies uncovered several instances of misconduct during the clinical trial. The International committee of medical journal editors requires registration of trial methodology, but does not require registration of trial results; however, the U.S. Food and Drug Administration Amendments does require researchers to register results. Conclusion: Prospective registration of clinical trial is mandatory for more transparent research and sustaining the validity of evidence based practice and availability of reliable data. Clinical trials registration has the potential to contribute substantially to improve clinical trial transparency and reducing publication bias and selective reporting.
Grankvist, Hannah; Kimmelman, Jonathan
Launch of clinical investigation represents a substantial escalation in commitment to a particular clinical translation trajectory; it also exposes human subjects to poorly understood interventions. Despite these high stakes, there is little to guide decision-makers on the scientific and ethical evaluation of early phase trials. In this article, we review policies and consensus statements on human protections, drug regulation, and research design surrounding trial launch, and conclude that decision-making is largely left to the discretion of research teams and sponsors. We then review what is currently understood about how research teams exercise this discretion, and close by laying out a research agenda for characterizing the way investigators, sponsors, and reviewers approach decision-making in early phase research.
Lorenzen, Christian; Williams, Morgan D; Turk, Paul S; Meehan, Daniel L; Kolsky, Daniel J Cicioni
Running velocity reached at maximal oxygen uptake (vVO2(max)) can be a useful measure to prescribe training intensity for aerobic conditioning. Obtaining it in the laboratory is often not practical, and average velocities from time trials are an attractive alternative. To date, the efficacies of such practices for team sport players are unknown. This study aimed to assess the relationship between vVO2(max) obtained in the laboratory against two time-trial estimates (1500 m and 3200 m). During the early preseason, elite Australian Rules football players (n = 23, 22.7 +/- 3.4 y, 187.7 +/- 8.2 cm, 75.5 +/- 9.2 kg) participated in a laboratory test on a motorized treadmill and two outdoor time trials. Based on average velocity the 1500-m time-trial performance (5.01 +/- 0.23 m x s(-1)) overestimated (0.36 m x s(-1), d = 1.75), whereas the 3200-m time trial (4.47 +/- 0.23 m x s(-1)) underestimated (0.17 m x s(-1), d = 0.83) the laboratory vVO2(max) (4.64 +/- 0.18 m x s(-1)). Despite these differences, both 1500-m and 3200-m time-trial performances correlated with the laboratory measure (r = -0.791; r = -0.793 respectively). Both subsequent linear regressions were of good fit and predicted the laboratory measure within +/- 0.12 m x s(-1). Estimates of vVO2(max) should not be used interchangeably, nor should they replace the laboratory measure. When laboratory testing is not accessible for team sports players, prescription of training intensity may be more accurately estimated from linear regression based on either 1500-m or 3200-m time-trial performance than from the corresponding average velocity.
... Consumer Updates FDA Encourages More Participation, Diversity in Clinical Trials Share Tweet Linkedin Pin it More sharing options ... while research is conducted. back to top Do clinical trials have possible risks and benefits? Yes. Sometimes patients ...
Carpenter, William T; Appelbaum, Paul S; Levine, Robert J
The authors' goal was to consider ethical approaches to placebo-controlled clinical trials in the light of the evolving Declaration of Helsinki, with special attention to applications to research on schizophrenia. They review the Helsinki position on placebos, including the 2002 Clarification, exploring the potential negative effects of banning placebos in studies involving conditions for which at least partially effective treatments exist. The Clarification is examined as an approach to this issue that, in contrast to earlier formulations, better acknowledges the complexity of clinical research and the need for protocol-specific determinations. Placebo controls in schizophrenia studies are used to illustrate issues relevant to all clinical research on therapeutic interventions. The Helsinki Clarification provides a basis for operationalizing criteria for review of placebo use in clinical trials. Six criteria are proposed for judging the ethical acceptability of placebo controls, including the likelihood that the intervention being tested will have clinically significant advantages over existing treatments, the presence of compelling reasons for placebo use, subject selection that minimizes the possibility of serious adverse consequences, and a risk-versus-benefit analysis that favors the advantages from placebo use over the risks to subjects. The Helsinki Clarification constitutes an important advance in international approaches to placebo use, requiring protocol-by-protocol judgments on complex issues of clinical research ethics. When operationalized, it provides review boards with a useful methodology for reaching determinations on the appropriateness of placebo controls in particular studies.
ZHANG Zhi-jun; LIU Wei
How to design clinical trials for medical devices is a problem plaguing the industry today. As there are many differences in clinical trials of medical devices and drugs. This paper describes the differences of the two points from the perspectivs of defi-nition of medical devices and drugs, scope, phasing, subjects and design of clinical trials in details, aiming to help the related personnel make scientific decisions while conduct-ing clinical trial design for medical devices.
Santen, Gijs Willem Eduard
To fail or not to fail – Clinical trials in depression investigates the causes of the high failure rate of clinical trials in depression research. Apart from the difficulties in the search for new antidepressants during drug discovery, faulty clinical trial designs hinder their evaluation during dru
Bartoli, E; Sorrentino, D; Trevisi, A
Randomized clinical trials represent the final, essential link between basic medical research and human health. However, their conduction presents very complex ethical problems, since the patient is the actual target of the experiment. Proper randomization, informed consent, and preliminary disclosure of results create deep ethical conflicts between the role of caretaker and that of impartial observer, both played by the same doctor. The dilemma reproduces the conflict between two different ethics. One is based on the inalienable individual rights stemming from the concept of man as an end in himself and not a means to an end. The other, derived from utilitarian philosophies, is based on the benefit for society as a whole. If we agree that randomized clinical trials represent the best method to test the validity of a new treatment, there is no easy solution. The dilemma could be solved by separating the role of the family doctor, committed to the best treatment possible for his patient, from the role of the scientist, committed to the progress of science and humanity. The former is involved in the treatment of individual patients, the latter in clinical and scientific experiments of a therapeutic nature. The patient may trade his rights to the best possible cure for the safety and the efficiency guaranteed by the scientific institution conducting the trial. Trials on relevant issues--expected to produce important results and impeccably designed scientifically--could be endowed with the ethics of science per se and this could be considered equivalent to the individual rights waived by the patient.
Otaka, Eri; Otaka, Yohei; Kasuga, Shoko; Nishimoto, Atsuko; Yamazaki, Kotaro; Kawakami, Michiyuki; Ushiba, Junichi; Liu, Meigen
Various robotic technologies have been developed recently for objective and quantitative assessment of movement. Among them, robotic measures derived from a reaching task in the KINARM Exoskeleton device are characterized by their potential to reveal underlying motor control in reaching movements. The aim of this study was to examine the clinical usefulness and validity of these robot-derived measures in hemiparetic stroke patients. Fifty-six participants with a hemiparetic arm due to chronic stroke were enrolled. The robotic assessment was performed using the Visually Guided Reaching (VGR) task in the KINARM Exoskeleton, which allows free arm movements in the horizontal plane. Twelve parameters were derived based on motor control theory. The following clinical assessments were also administered: the proximal upper limb section in the Fugl-Meyer Assessment (FMA-UE(A)), the proximal upper limb part in the Stroke Impairment Assessment Set (SIAS-KM), the Modified Ashworth Scale for the affected elbow flexor muscles (MAS elbow), and seven proximal upper limb tasks in the Wolf Motor Function Test (WMFT). To explore which robotic measures represent deficits of motor control in the affected arm, the VGR parameters in the paretic arm were compared with those in the non-paretic arm using the Wilcoxon signed rank test. Then, to explore which VGR parameters were related to overall motor control regardless of the paresis, correlations between the paretic and non-paretic arms were examined. Finally, to investigate the relationships between the robotic measures and the clinical scales, correlations between the VGR parameters and clinical scales were investigated. Spearman's rank correlation coefficients were used for all correlational analyses. Eleven VGR parameters on the paretic side were significantly different from those on the non-paretic side with large effect sizes (|effect size| = 0.76-0.87). Ten VGR parameters correlated significantly with FMA-UE(A) (|r| = 0
Full Text Available ATL is a distinct peripheral T-lymphocytic malignancy associated with human T-cell lymphotropic virus type I (HTLV-1. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into four categories, acute, lymphoma, chronic, and smoldering types, defined by organ involvement, and LDH and calcium values. In case of acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL, intensive chemotherapy like the LSG15 regimen (VCAP-AMP-VECP is usually recommended if outside of clinical trials, based on the results of a phase 3 trial. In case of favorable chronic or smoldering ATL (indolent ATL, watchful waiting until disease progression has been recommended, although the long-term prognosis was inferior to those of, for instance, chronic lymphoid leukemia. Retrospective analysis suggested that the combination of interferon alpha and zidovudine was apparently promising for the treatment of ATL, especially for types with leukemic manifestation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT is also promising for the treatment of aggressive ATL possibly reflecting graft versus ATL effect. Several new agent trials for ATL are ongoing and in preparation, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody, IL2-fused with diphtheria toxin, histone deacetylase inhibitors, a purine nucleoside phosphorylase inhibitor, a proteasome inhibitor, and lenalidomide.
Khan, Safdar N; Mermer, Matthew J; Myers, Elizabeth; Sandhu, Harvinder S
Compared with nonfunded or peer-reviewed funded projects, industry-sponsored clinical trials have traditionally been associated with more positive results. This relationship has been extensively studied in the nonsurgical literature. Although a few authors have addressed specialties, little has been reported on orthopedic clinical trials and their association with funding, study outcome, and efforts to reduce bias after randomization across journals of multiple subspecialties. For the study reported here, we selected 5 major orthopedic subspecialty journals: Journal of Bone and Joint Surgery (American Volume), Spine, Journal of Arthroplasty, Journal of Orthopaedic Trauma, and American Journal of Sports Medicine. We chose a 2-year limit for investigation (2002-2004); included all original randomized clinical trials reported in these 5 journals; and examined these trials for their study design, funding source, outcome, bias potential, and conclusion reached. Support for the 100 eligible orthopedic clinical trials was stated as coming from industry (26 trials, 26%), nonprofit sources (19 trials, 19%), and mixed sources (5 trials, 5%); no support was stated in 46 trials (46%), and support was not reported in 4 trials (4%). Of the 26 trials reporting industry support, 22 (85%) were graded as indicating an outcome favorable to the new treatment. The association between industry funding and favorable outcome was strong and significant (PJournal of Bone and Joint Surgery and Spine, measures taken to reduce bias were not documented.
Simon, Laura J; Chinchilli, Vernon M
Two design principles are used frequently in clinical trials: 1) A subject is "matched" or "paired" with a similar subject to reduce the chance that other variables obscure the primary comparison of interest. 2) A subject serves as his/her own control by "crossing over" from one treatment to another during the course of an experiment. There are situations in which it may be advantageous to use the two design principles - crossing over and matching - simultaneously. That is, it may be advantageous to conduct a "paired crossover design," in which each subject, while paired with a similar subject, crosses over and receives each experimental treatment. In this paper, we describe two clinical trials conducted by the National Heart, Lung and Blood Institute's Asthma Clinical Research Network that used a paired 2x2 crossover design. The Beta Adrenergic Response by GEnotype (BARGE) Study compared the effects of regular use of inhaled albuterol on mildly asthmatic patients with different genotypes at the 16th position of the beta-agonist receptor gene. The Smoking Modulates Outcomes of Glucocorticoid (SMOG) Therapy in Asthma Study evaluated the hypothesis that smoking reduces the response to inhaled corticosteroids. For such paired crossover designs, the primary parameter of interest is typically the treatment-by-pairing interaction term. In evaluating the relative efficiency of the paired 2x2 crossover design to two independent crossover designs with respect to this interaction term, we show that the paired 2x2 crossover design is more efficient if the correlations between the paired members on the same treatments are greater than their correlations on different treatments. This condition should hold in most circumstances, and therefore the paired crossover design deserves serious consideration for any clinical trial in which the crossing over and matching of subjects is deemed simultaneously beneficial.
Sridharan, Kannan; Sivaramakrishnan, Gowri
Ayurveda is one of the complementary and alternative systems of medicine requiring generation of high quality evidence for rational practice. Evidence can be generated from study designs and the present study is an attempt to critically assess the registered studies in the field of Ayurveda from clinical trial registry of India. We found low number of trials conducted with more focus required on the quality of these studies to contribute to high quality evidence.
Wang, Lei; Qu, Xintao; Yu, Xiuchun
PDCA cycle was applied in special rectification activities for medical instrument clinical trial, with quality criteria of implementation made. Completed medical instrument clinical trial from January 2011 to December 2012 was believed as control group, from January 2013 to December 2014 as PDCA group, the scores of clinical trial and the score rate of items were compared and analyzed. Results show quality scores of clinical trial in PDCA group are higher than that in control group (51 vs. 81, P rectification activities with PDCA applied in our department are feasible and effective. It significantly improves implement quality of medical instrument clinical trial.
Ethics has often been ignored or evaded in clinical trials, and the conditions under which global clinical trials are conducted make this problem likely to persist. Ethics can, however, have an impact at any of several stages of a trial when the individuals involved are committed. This editorial provides historical examples of ignoring, evading or, alternatively, using ethical help to improve clinical trials, and suggests that the actual role of ethics depends on the individuals involved.
... interaction with FDA representatives. The program will focus on the relationships among FDA and clinical trial... Pharmaceutical Clinical Trial; (3) Medical Device Aspects of Clinical Research; (4) Adverse Event...
Leiter, Amanda; Sablinski, Tomasz; Diefenbach, Michael; Foster, Marc; Greenberg, Alex; Holland, John; Oh, William K; Galsky, Matthew D
Patient and physician awareness and acceptance of trials and patient ineligibility are major cancer clinical trial accrual barriers. Yet, trials are typically conceived and designed by small teams of researchers with limited patient input. We hypothesized that through crowdsourcing, the intellectual and creative capacity of a large number of researchers, clinicians, and patients could be harnessed to improve the clinical trial design process. In this study, we evaluated the feasibility and utility of using an internet-based crowdsourcing platform to inform the design of a clinical trial exploring an antidiabetic drug, metformin, in prostate cancer. Over a six-week period, crowd-sourced input was collected from 60 physicians/researchers and 42 patients/advocates leading to several major (eg, eligibility) and minor modifications to the clinical trial protocol as originally designed. Crowdsourcing clinical trial design is feasible, adds value to the protocol development process, and may ultimately improve the efficiency of trial conduct.
George, Melvin; Selvarajan, Sandhiya; S, Suresh-Kumar; Dkhar, Steven A; Chandrasekaran, Adithan
The last decade has witnessed a greater transparency in clinical research with the advent of clinical trial registries. The aim of the study was to describe the trends in the globalization of clinical trials in the last five years. We performed an internet search using the WHO International clinical trials registry platform (WHO ICTRP) to identify the clinical trials conducted from January 2007 to December 31, 2011 among 25 countries. Among the 25 countries, the United States, Japan and Germany occupy the top positions in the total number of clinical trials conducted. Clinical trials in the US (36312) constituted 31.5% of the total number of trials performed during this period. However over a period of five years both US and Western Europe appear to show a decline, while the emerging countries show a rise in clinical trials registered. Among the emerging countries China, India and Republic of Korea are most active regions involved in clinical trials. Cancer, diabetes and respiratory diseases were most widely researched areas overall. Although the study confirms the transition in the clinical trials research towards emerging countries, the developed regions of the world still contribute to more than 70% of the trials registered worldwide.
Van Pham, Phuc
In recent years, both stem cell research and the clinical application of these promising cells have increased rapidly. About 1000 clinical trials using stem cells have to date been performed globally. More importantly, more than 10 stem cell-based products have been approved in some countries. With the rapid growth of stem cell applications, some countries have used clinical trials as a tool to diminish the rate of clinical stem cell applications. However, the point at which stem cell clinical trials are essential remains unclear. This commentary discusses when stem cell clinical trials are essential for stem cell transplantation therapies.
William A. Mattingly
Conclusion: We have designed and implemented a visualization dashboard for managing multi-site clinical trial enrollment in two community acquired pneumonia studies. Information dashboards are useful for clinical trial management. They can be used in a standalone trial or can be included into a larger management system.
... HUMAN SERVICES Food and Drug Administration Dialogues in Diversifying Clinical Trials: Successful Strategies for Engaging Women and Minorities in Clinical Trials AGENCY: Food and Drug Administration, HHS... Diversifying Clinical Trials: Successful Strategies for Engaging Women and Minorities in Clinical Trials....
Research in human beings is an important chapter of medical ethics. In recent years, investigation has been taken over by profit driven corporations that must guarantee the medical and commercial application of results. This new model of investigation has generated conflicts of interest in doctor-patient, researcher-subject relationship. The inevitable debate and media reaction has led. These trials of controversial design to regions of the globe where the vulnerability of the populations continues to allow their undertaking. This article includes a historical perspective on experimentation in human beings and the conditions that led to its regulation: the Nuremberg CODE, followed by the Helsinky Declaration in its different versions, and the Belmont Report, that defend the subject according to the ethic of principles used in western medicine. There is then a review of the attempts to change international regulation to reintroduce clinical trials with placebo--which since 1996 is only permitted where there are no therapeutic or diagnostic methods--on populations that would otherwise have no access to treatment. This then leads on to the issue of double standards in medical investigation defended by many investigators and some official entities. The article concludes that it may be prudent to allow local ethical commissions to approve deviation from the established norm if such is necessary to resolve urgent questions of health in the country, but it is unacceptable that any such emergency is used as a reason to reduce the ethical prerequisites, in clinical trials. It also concludes that true urgency is in making available to all who need it the effective products already in existence. Furthermore, that the acceptance of ethical relativism can result in the exploitation of vulnerable third world populations for research programmes that cannot be undertaken in their sponsoring countries due to the ethical restrictions in place.
Phase I of clinical trials is the first stage of clinical pharmacology and body safety evaluation, including body tolerance test and pharmacokinetics test. The aim is providing evidence for dosage regimen and be the cornerstone of the preliminary assessment of efficacy and safety of phase II of clinical trials. This text discussed the technique and requirement of phase I of new drugs' clinical tolerance trials.
Xu, Jun; Zhang, Yaoyun; Wu, Yonghui; Wang, Jingqi; Dong, Xiao; Xu, Hua
In scientific writing, positive credits and negative criticisms can often be seen in the text mentioning the cited papers, providing useful information about whether a study can be reproduced or not. In this study, we focus on citation sentiment analysis, which aims to determine the sentiment polarity that the citation context carries towards the cited paper. A citation sentiment corpus was annotated first on clinical trial papers. The effectiveness of n-gram and sentiment lexicon features, and problem-specified structure features for citation sentiment analysis were then examined using the annotated corpus. The combined features from the word n-grams, the sentiment lexicons and the structure information achieved the highest Micro F-score of 0.860 and Macro-F score of 0.719, indicating that it is feasible to use machine learning methods for citation sentiment analysis in biomedical publications. A comprehensive comparison between citation sentiment analysis of clinical trial papers and other general domains were conducted, which additionally highlights the unique challenges within this domain. PMID:26958274
Kelen, G D; Brown, C G; Ashton, J
Hypothesis testing is based on certain statistical and mathematical principles that allow investigators to evaluate data by making decisions based on the probability or implausibility of observing the results obtained. However, classic hypothesis testing has its limitations, and probabilities mathematically calculated are inextricably linked to sample size. Furthermore, the meaning of the p value frequently is misconstrued as indicating that the findings are also of clinical significance. Finally, hypothesis testing allows for four possible outcomes, two of which are errors that can lead to erroneous adoption of certain hypotheses: 1. The null hypothesis is rejected when, in fact, it is false. 2. The null hypothesis is rejected when, in fact, it is true (type I or alpha error). 3. The null hypothesis is conceded when, in fact, it is true. 4. The null hypothesis is conceded when, in fact, it is false (type II or beta error). The implications of these errors, their relation to sample size, the interpretation of negative trials, and strategies related to the planning of clinical trials will be explored in a future article in this journal.
Xu, Jun; Zhang, Yaoyun; Wu, Yonghui; Wang, Jingqi; Dong, Xiao; Xu, Hua
In scientific writing, positive credits and negative criticisms can often be seen in the text mentioning the cited papers, providing useful information about whether a study can be reproduced or not. In this study, we focus on citation sentiment analysis, which aims to determine the sentiment polarity that the citation context carries towards the cited paper. A citation sentiment corpus was annotated first on clinical trial papers. The effectiveness of n-gram and sentiment lexicon features, and problem-specified structure features for citation sentiment analysis were then examined using the annotated corpus. The combined features from the word n-grams, the sentiment lexicons and the structure information achieved the highest Micro F-score of 0.860 and Macro-F score of 0.719, indicating that it is feasible to use machine learning methods for citation sentiment analysis in biomedical publications. A comprehensive comparison between citation sentiment analysis of clinical trial papers and other general domains were conducted, which additionally highlights the unique challenges within this domain.
Foster, Jared C; Taylor, Jeremy M G; Ruberg, Stephen J
We consider the problem of identifying a subgroup of patients who may have an enhanced treatment effect in a randomized clinical trial, and it is desirable that the subgroup be defined by a limited number of covariates. For this problem, the development of a standard, pre-determined strategy may help to avoid the well-known dangers of subgroup analysis. We present a method developed to find subgroups of enhanced treatment effect. This method, referred to as 'Virtual Twins', involves predicting response probabilities for treatment and control 'twins' for each subject. The difference in these probabilities is then used as the outcome in a classification or regression tree, which can potentially include any set of the covariates. We define a measure Q(Â) to be the difference between the treatment effect in estimated subgroup Â and the marginal treatment effect. We present several methods developed to obtain an estimate of Q(Â), including estimation of Q(Â) using estimated probabilities in the original data, using estimated probabilities in newly simulated data, two cross-validation-based approaches, and a bootstrap-based bias-corrected approach. Results of a simulation study indicate that the Virtual Twins method noticeably outperforms logistic regression with forward selection when a true subgroup of enhanced treatment effect exists. Generally, large sample sizes or strong enhanced treatment effects are needed for subgroup estimation. As an illustration, we apply the proposed methods to data from a randomized clinical trial.
Andres E. Morales La Madrid
Full Text Available In spite of major recent advances in DIPG molecular characterization, this body of knowledge has not yet translated into better treatments.To date,more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy as well as newer biologic agents,have failed to improve the dismal outcome when compared to palliative radiation alone.The biology of DIPG remained unknown until recently when the neurosurgical expertise along with the recognition by the scientific and clinical community of the importance of tissue sampling at diagnosis;ideally in the context of a clinical trial and by trained neurosurgical teams to maximize patient safety.These pre-treatment tumor samples,and others coming from tissue obtained post-mortem,have yielded new insights into DIPG molecular biology.We now know that DIPG comprises a heterogeneous disease with variable molecular phenotypes, different from adult high grade glioma,other non-pontine pediatric high grade gliomas and even between pontine gliomas.The discovery of histone H3.3 or H3.1 mutations has been an important step forward in understanding tumor formation,maintenance and progression.Pharmacologic reversal of DIPG histone demethylation therefore offers an important potential intervention strategy for the treatment of DIPG.To date,clinical trials of newly diagnosed or progressive DIPG with epigenetic modifiers have been unsuccessful.Whether this failure represents limited activity of the agents used,their CNS penetration,redundant pathways within the tumor,or the possibility that histone mutations are necessary only to initiate DIPGs but not maintain their growth,suggest that a great deal still needs to be elucidated in both the underlying biology of these pathways,and the drugs designed to target them.In this review, we discuss the role of both epigenetic and genetic mutations within DIPG and the development of treatment strategies directed against the unique abnormalities
Mitschke, Diane B; Cassel, Kevin; Higuchi, Paula
Cancer clinical trials are essential to advancing the prevention and treatment of cancer, yet adult participation rates in clinical trials remain abysmal. Despite the essential contributions of clinical trials to science and medicine, adult participation in clinical trials remains exceedingly low, with only 2%-4% of all adult patients with cancer in the U.S. participating in clinical trials. Clinical trials accrual rates in Hawai'i follow this national trend of less than 3% of eligible patients participating in trials. Recognizing the need to increase awareness about clinical trials, the National Cancer Institute's Cancer Information Service-Pacific Region, through the Hawai'i Clinical Trials Education Coalition, has employed strategic dissemination plans to train and educate key target audiences, including registered nurses, nursing students, and community outreach workers about the availability of over 90 cancer clinical trials in Hawai'i. Previous research suggests that nurses often play a vital role in increasing a patient's understanding of clinical trials and may also act as a patient advocate in regards to participation in a clinical trial. A train-the-trainer model curriculum was developed using the Clinical Trials Education Series (CTES), a collection of multi-level resources designed by the National Cancer Institute, to educate various constituents about clinical trials. The training curriculum and workshop format is adapted based on both formal and informal needs assessments conducted with audiences prior to the planned training, yet key elements remain central to the training model. In addition, an interactive, internet-based case study was developed using local place names and cultural cues to allow training participants to engage in realistic and practical methods for locating and sharing information about clinical trials with patients and the public. This training model has been implemented in a variety of settings including three statewide nursing
Melloni, Chiara; Berger, Jeffrey S; Wang, Tracy Y; Gunes, Funda; Stebbins, Amanda; Pieper, Karen S; Dolor, Rowena J; Douglas, Pamela S; Mark, Daniel B; Newby, L Kristin
The 2007 American Heart Association guidelines for cardiovascular disease prevention in women drew heavily on results from randomized clinical trials; however, representation of women in trials of cardiovascular disease prevention has not been systematically assessed. We abstracted 156 randomized clinical trials cited by the 2007 women's prevention guidelines to determine female representation over time and by clinical indication, prevention type, location of trial conduct, and funding source. Both women and men were represented in 135 of 156 (86.5%) trials; 20 trials enrolled only men; 1 enrolled only women. Among all trials, the proportion of women increased significantly over time, from 9% in 1970 to 41% in 2006. Considering only trials that enrolled both women and men, female enrollment was 18% in 1970 and increased to 34% in 2006. Female representation was higher in international versus United States-only trials (32.7% versus 26.7%) and primary versus secondary prevention trials (42.6% versus 26.6%). Female enrollment was comparable in government/foundation-funded versus industry-funded trials (31.9% versus 31.5%). Representation of women was highest among trials in hypertension (44%), diabetes (40%), and stroke (38%) and lowest for heart failure (29%), coronary artery disease (25%), and hyperlipidemia (28%). By contrast, women accounted for 53% of all individuals with hypertension, 50% with diabetes, 51% with heart failure, 49% with hyperlipidemia, and 46% with coronary artery disease. Sex-specific results were discussed in only 31% of primary trial publications. Enrollment of women in randomized clinical trials has increased over time but remains low relative to their overall representation in disease populations. Efforts are needed to reach a level of representation that is adequate to ensure evidence-based sex-specific recommendations.
McDonald, Alison M; Treweek, Shaun; Shakur, Haleema; Free, Caroline; Knight, Rosemary; Speed, Chris; Campbell, Marion K
Randomised controlled trials (RCTs) are generally regarded as the gold standard for evaluating health care interventions. The level of uncertainty around a trial's estimate of effect is, however, frequently linked to how successful the trial has been in recruiting and retaining participants. As recruitment is often slower or more difficult than expected, with many trials failing to reach their target sample size within the timescale and funding originally envisaged, the results are often less reliable than they could have been. The high number of trials that require an extension to the recruitment period in order to reach the required sample size potentially delays the introduction of more effective therapies into routine clinical practice. Moreover, it may result in less research being undertaken as resources are redirected to extending existing trials rather than funding additional studies.Poor recruitment to publicly-funded RCTs has been much debated but there remains remarkably little clear evidence as to why many trials fail to recruit well, which recruitment methods work, in which populations and settings and for what type of intervention. One proposed solution to improving recruitment and retention is to adopt methodology from the business world to inform and structure trial management techniques.We review what is known about interventions to improve recruitment to trials. We describe a proposed business approach to trials and discuss the implementation of using a business model, using insights gained from three case studies.
Full Text Available Abstract Randomised controlled trials (RCTs are generally regarded as the gold standard for evaluating health care interventions. The level of uncertainty around a trial's estimate of effect is, however, frequently linked to how successful the trial has been in recruiting and retaining participants. As recruitment is often slower or more difficult than expected, with many trials failing to reach their target sample size within the timescale and funding originally envisaged, the results are often less reliable than they could have been. The high number of trials that require an extension to the recruitment period in order to reach the required sample size potentially delays the introduction of more effective therapies into routine clinical practice. Moreover, it may result in less research being undertaken as resources are redirected to extending existing trials rather than funding additional studies. Poor recruitment to publicly-funded RCTs has been much debated but there remains remarkably little clear evidence as to why many trials fail to recruit well, which recruitment methods work, in which populations and settings and for what type of intervention. One proposed solution to improving recruitment and retention is to adopt methodology from the business world to inform and structure trial management techniques. We review what is known about interventions to improve recruitment to trials. We describe a proposed business approach to trials and discuss the implementation of using a business model, using insights gained from three case studies.
Vandenheuvel, Dieter; Lavigne, Rob; Brüssow, Harald
Recently, a number of phage therapy phase I and II safety trials have been concluded, showing no notable safety concerns associated with the use of phage. Though hurdles for efficient treatment remain, these trials hold promise for future phase III clinical trials. Interestingly, most phage formulations used in these clinical trials are straightforward phage suspensions, and not much research has focused on the processing of phage cocktails in specific pharmaceutical dosage forms. Additional research on formulation strategies and the stability of phage-based drugs will be of key importance, especially with phage therapy advancing toward phase III clinical trials.
Roumiantseva, Dina; Carini, Simona; Sim, Ida; Wagner, Todd H
We examine the extent to which ClinicalTrials.gov is meeting its goal of providing oversight and transparency of clinical trials with human subjects. We analyzed the ClinicalTrials.gov database contents as of June 2011, comparing interventions, medical conditions, and trial characteristics by sponsor type. We also conducted a detailed analysis of incomplete data. Among trials with only government sponsorship (N=9252), 36% were observational and 64% interventional; in contrast, almost all (90%) industry-only sponsored trials were interventional. Industry-only sponsored interventional trials (N=30,036) were most likely to report a drug intervention (81%), followed by biologics (9%) and devices (8%). Government-only interventional trials (N=5886) were significantly more likely to test behavioral interventions (28%) and procedures (13%) than industry-only trials (pgov. Published by Elsevier Inc.
Conclusion: The number of clinical trials done in allied fields of medicine other than the allopathic system has lowered down, and furthermore focus is required regarding the methodological quality of these trials and more support from various organizations.
Elad Sharon; Howard Streicher; Priscila Goncalves; Helen XChen
Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called“immune checkpoints.” These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibody-based therapies targeting cytotoxic T-lymphocyte antigen4 (CTLA4), programmed cell death1 (PD-1), and programmed cell death ligand 1 (PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cellcarcinoma, non-smal celllung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.
Tandava Krishnan Panakanti
Full Text Available Branch retinal vein occlusion (BRVO is the second most common retinal vascular disorder. The management of macular edema has changed considerably over time. The laser is considered the gold standard treatment for over two decades. However, visual recovery with laser is usually slow and incomplete. The advent of intravitreal agents, specifically anti-vascular endothelial growth factors (VEGF have heralded a new era which promises rapid recovery of vision and quality of vision. Randomized clinical trials have reported optimal results with anti-VEGF agents (ranibizumab, bevacizumab, and aflibercept compared to laser therapy or steroids. However, nearly 50% of the patients require repeat intravitreal anti-VEGF therapy up to 4 years after initiating therapy to sustain the visual gains. The adverse events (systemic and ocular of these agents are minimal. Monotherapy with anti-VEGF agents have been found to provide better results than any combination with laser. This review article summarizes evidence from randomized controlled trials evaluating treatment options for the treatment of macular edema secondary to BRVO with a special focus on anti-VEGF therapy.
Panakanti, Tandava Krishnan; Chhablani, Jay
Branch retinal vein occlusion (BRVO) is the second most common retinal vascular disorder. The management of macular edema has changed considerably over time. The laser is considered the gold standard treatment for over two decades. However, visual recovery with laser is usually slow and incomplete. The advent of intravitreal agents, specifically anti-vascular endothelial growth factors (VEGF) have heralded a new era which promises rapid recovery of vision and quality of vision. Randomized clinical trials have reported optimal results with anti-VEGF agents (ranibizumab, bevacizumab, and aflibercept) compared to laser therapy or steroids. However, nearly 50% of the patients require repeat intravitreal anti-VEGF therapy up to 4 years after initiating therapy to sustain the visual gains. The adverse events (systemic and ocular) of these agents are minimal. Monotherapy with anti-VEGF agents have been found to provide better results than any combination with laser. This review article summarizes evidence from randomized controlled trials evaluating treatment options for the treatment of macular edema secondary to BRVO with a special focus on anti-VEGF therapy. PMID:26957837
Vawdrey, David K; Hripcsak, George
To measure the rate of non-publication and assess possible publication bias in clinical trials of electronic health records. We searched ClinicalTrials.gov to identify registered clinical trials of electronic health records and searched the biomedical literature and contacted trial investigators to determine whether the results of the trials were published. Publications were judged as positive, negative, or neutral according to the primary outcome. Seventy-six percent of trials had publications describing trial results; of these, 74% were positive, 21% were neutral, and 4% were negative (harmful). Of unpublished studies for which the investigator responded, 43% were positive, 57% were neutral, and none were negative; the lower rate of positive results was significant (pelectronic health record studies is similar to that in other biomedical studies. There appears to be a bias toward publication of positive trials in this domain. Copyright © 2012 Elsevier Inc. All rights reserved.
As much information as possible should be obtained in clinical trials to assess possible interactions between test drugs and concomitant medications prescribed for other medical indications. Side effect profiles were compared in patients taking buspirone, mean = 20 mg/day; diazepam, 20 mg/day; clorazepate, 23 mg/day; and placebo, with or without concomitant medications. Approximately 1,000 anxious patients were included in the analysis; 700 received buspirone. The use of a variety of common medications did not affect the side effect profile in the buspirone, clorazepate, and placebo groups, but did increase the incidence of side effects in the diazepam group. The increased incidence of sedation noted with diazepam and clorazepate, however, was not due to concomitant medication.
Cofield,Stacey; Conwit, Robin; Barsan, William; Quinn, James
The emergency medicine and pre-hospital environments are unlike any other clinical environments and require special consideration to allow the successful implementation of clinical trials. This article reviews the specific issues involved in Emergency Medicine Clinical Trials (EMCT), and provides strategies from emergency medicine and non-emergency medicine trials to maximize recruitment and retention. While the evidence supporting some of these strategies is deficient, addressing recruitment...
Lenio Souza Alvarenga; Elisabeth Nogueira Martins
OBJECTIVE: To evaluate biopharmaceutical industry-sponsored clinical trials placed in countries previously described as emerging regions for clinical research, and potential differences for those placed in Brazil. METHODS: Data regarding recruitment of subjects for clinical trials were retrieved from www.clinicaltrials.gov on February 2nd 2009. Proportions of sites in each country were compared among emerging countries. Multiple logistic regressions were performed to evaluate whether trial pl...
Joseph S Ross
Full Text Available BACKGROUND: ClinicalTrials.gov is a publicly accessible, Internet-based registry of clinical trials managed by the US National Library of Medicine that has the potential to address selective trial publication. Our objectives were to examine completeness of registration within ClinicalTrials.gov and to determine the extent and correlates of selective publication. METHODS AND FINDINGS: We examined reporting of registration information among a cross-section of trials that had been registered at ClinicalTrials.gov after December 31, 1999 and updated as having been completed by June 8, 2007, excluding phase I trials. We then determined publication status among a random 10% subsample by searching MEDLINE using a systematic protocol, after excluding trials completed after December 31, 2005 to allow at least 2 y for publication following completion. Among the full sample of completed trials (n = 7,515, nearly 100% reported all data elements mandated by ClinicalTrials.gov, such as intervention and sponsorship. Optional data element reporting varied, with 53% reporting trial end date, 66% reporting primary outcome, and 87% reporting trial start date. Among the 10% subsample, less than half (311 of 677, 46% of trials were published, among which 96 (31% provided a citation within ClinicalTrials.gov of a publication describing trial results. Trials primarily sponsored by industry (40%, 144 of 357 were less likely to be published when compared with nonindustry/nongovernment sponsored trials (56%, 110 of 198; p<0.001, but there was no significant difference when compared with government sponsored trials (47%, 57 of 122; p = 0.22. Among trials that reported an end date, 75 of 123 (61% completed prior to 2004, 50 of 96 (52% completed during 2004, and 62 of 149 (42% completed during 2005 were published (p = 0.006. CONCLUSIONS: Reporting of optional data elements varied and publication rates among completed trials registered within ClinicalTrials.gov were low
Pariera, Katrina L; Murphy, Sheila T; Meng, Jingbo; McLaughlin, Margaret L
African-Americans and Hispanic-Americans are disproportionately affected by cancer, yet underrepresented in cancer clinical trials. Because of this, it is important to understand how attitudes and beliefs about clinical trials vary by ethnicity. A national, random sample of 860 adults was given an online survey about attitudes toward clinical trials. We examined willingness to participate in clinical trials, attitudes toward clinical trials, trust in doctors, attitudes toward alternative and complementary medicine, and preferred information channels. Results indicate that African-American and Hispanic-American participants have more negative attitudes about clinical trials, more distrust toward doctors, more interest in complementary and alternative medicine, and less willingness to participate in clinical trials than white/non-Hispanics, although specific factors affecting willingness to participate vary. The channels people turn to for information on clinical trials also varied by ethnicity. These results help explain the ethnic disparities in cancer clinical trial enrollment by highlighting some potential underlying causes and drawing attention to areas of importance to these groups.
Cofield, Stacey; Conwit, Robin; Barsan, William; Quinn, James
The emergency medicine and pre-hospital environments are unlike any other clinical environments and require special consideration to allow the successful implementation of clinical trials. This article reviews the specific issues involved in Emergency Medicine Clinical Trials (EMCT), and provides strategies from emergency medicine and non-emergency medicine trials to maximize recruitment and retention. While the evidence supporting some of these strategies is deficient, addressing recruitment and retention issues with specific strategies will help researchers deal with these issues in their funding applications and in turn develop the necessary infrastructure to participate in emergency medicine clinical trials. PMID:21040112
Scardino Peter T
Full Text Available Abstract Introduction Randomized controlled trials provide the best method of determining which of two comparable treatments is preferable. Unfortunately, contemporary randomized trials have become increasingly expensive, complex and burdened by regulation, so much so that many trials are of doubtful feasibility. Discussion Here we present a proposal for a novel, streamlined approach to randomized trials: the "clinically-integrated randomized trial". The key aspect of our methodology is that the clinical experience of the patient and doctor is virtually indistinguishable whether or not the patient is randomized, primarily because outcome data are obtained from routine clinical data, or from short, web-based questionnaires. Integration of a randomized trial into routine clinical practice also implies that there should be an attempt to randomize every patient, a corollary of which is that eligibility criteria are minimized. The similar clinical experience of patients on- and off-study also entails that the marginal cost of putting an additional patient on trial is negligible. We propose examples of how the clinically-integrated randomized trial might be applied in four distinct areas of medicine: comparisons of surgical techniques, "me too" drugs, rare diseases and lifestyle interventions. Barriers to implementing clinically-integrated randomized trials are discussed. Conclusion The proposed clinically-integrated randomized trial may allow us to enlarge dramatically the number of clinical questions that can be addressed by randomization.
Hu, Min; Liu, Jian-Ping; Wu, Xiao-Ke
Acupuncture clinical trials are designed to provide reliable evidence of clinical efficacy, and SCI papers is one of the high-quality clinical efficacy of acupuncture research. To analyze these papers published in high impact factor journals on acupuncture clinical trials, we can study clinical trials from design to implementation, the efficacy of prevention and cure, combined with international standard practices to evaluate the effectiveness and safety of acupuncture. That is the core of acupuncture clinical trials, as well as a prerequisite for outstanding academic output. A scientific and complete acupuncture clinical trial should be topically novel, designed innovative, logically clear, linguistically refining, and the most important point lies in a great discovery and solving the pragmatic problem. All of these are critical points of papers to be published in high impact factor journal, and directly affect international evaluation and promotion of acupuncture.
Full Text Available Abstract Background Citizens, patients and their representatives are increasingly insisting on working with health professionals to organize and discuss research protocols. The International Committee of Medical Journal Editors recommended setting up a public clinical trial registry where anyone can find key information about a trial. Around the world, governments have, in fact, now begun to legislate mandatory disclosure of all clinical trials. The aims of the present survey were to assess the availability of clinical trial registries for Italian citizens and to examine the transparency of the data items reported. Methods The availability of open-access clinical trial registries was surveyed on a sample of 182 websites, including research institutes and centers of excellence (IRCCS-teaching hospitals, hospitals and associations. For each registry we downloaded a sample of two trials to assess the correspondence of the data items reported. Results from the Italian and international registries were compared. Results Fifteen percent of the sample had an open-access registry of clinical trials. Comparison of the data items available, in terms of completeness and transparency, from institutional and international registries indicated wide variability. Conclusions Italian citizens, patients and their associations have scant access to local registries of clinical trials, and international registries are generally more informative. On the European level, advocacy and lobby actions are needed among citizens and patients to boost the diffusion of open-access clinical trial registries without language barriers, thereby facilitating participation, access to information, and the coordination of clinical research.
Winstanley, P; Olliaro, P
Plasmodium falciparum remains one of the World's most prevalent and devastating pathogens. Mainly for economic reasons, the parasite's ability to develop resistance to drugs has not been matched by the rate at which new compounds are developed. Even so, there are new drugs (or new combinations of old drugs) currently under investigation, or in the process of development (at the moment): Pyronaridine, a well-tolerated, synthetic drug that may have utility for multi-resistant falciparum malaria in many parts of the world; however,problems remain over the formulation of this drug (which is a major determinant of its bioavailability) and its eventual cost. Chlorproguanil-dapsone (lap dap) is being studied as a possible low-cost'successor' to pyrimethamine-sulfadoxine; the utility of chlorproguanil-dapsone as 'salvage' therapy for clinical cases of pyrimethamine-sulfadoxine failure has yet to be tested in clinical trials. Atovaquone-proguanil (malarone) has utility against multi-resistant parasites; however, it is likely to be expensive (but is currently being provided free-of-charge in certain areas of Africa). Artemether-benflumetol (coartemether) combines the advantages of artemether (a rapid reduction in parasite load) with a second drug that reduces the risk of recrudescence; the cost of this combination is unclear. Rectal artesunate is being studied as an intervention to reduce the proportion of children with falciparum malaria who deteriorate to severe disease; the formulation is appropriate for use in rural health centres.
DePasse, J Mason; Park, Sara; Eltorai, Adam E M; Daniels, Alan H
Treatment options for spinal cord injuries are currently limited, but multiple clinical trials are underway for a variety of interventions, drugs, and devices. The Food and Drug Administration website www.ClinicalTrials.gov catalogues these trials and includes information on the status of the trial, date of initiation and completion, source of funding, and region. This investigation assesses the factors associated with publication and the publication rate of spinal cord injury trials. Retrospective analysis of publically available data on www.ClinicalTrials.gov. The www.ClinicalTrials.gov was queried for all trials on patients with spinal cord injury, and these trials were assessed for status, type of intervention, source of funding, and region. Multiple literature searches were performed on all completed trials to determine publication status. There were 626 studies identified concerning the treatment of patients with spinal cord injury, of which 250 (39.9%) were completed. Of these, only 119 (47.6%) were published. There was no significant difference in the rate of publication between regions (p> 0.16) or by study type (p> 0.29). However, trials that were funded by the NIH were more likely to be published than trials funded by industry (p= 0.01). The current publication rate of spinal cord injury trials is only 47.6%, though this rate is similar to the publication rate for trials in other fields. NIH-funded trials are significantly more likely to become published than industry-funded trials, which could indicate that some trials remain unpublished due to undesirable results. However, it is also likely that many trials on spinal cord injury yield negative results, as treatments are often ineffective.
Skip Navigation Bar Home Current Issue Past Issues Clinical Trials: A Crucial Key to Human Health Research Past ... the forefront of human health research today are clinical trials—studies that use human volunteers to help medical ...
The article analyses the importance of laboratory test methods, namely pathomorfological at conduct of clinical trials. The article focuses on complex laboratory diagnostics at determination of clinical condition of animals, safety and efficacy of tested medicinal product.
Scifres, Christina M; Iams, Jay D; Klebanoff, Mark; Macones, George A
Large, randomized clinical trials have long been considered the gold standard to guide clinical care. Metaanalysis is a type of analysis in which results of a number of randomized clinical trials are combined and a summary measure of effect for a given treatment is ascertained. The clinician in practice often is faced with a dilemma regarding the type of evidence that should be used to guide clinical practice; for many clinical problems, there are both randomized controlled trials and metaanalyses available. The cases of calcium and aspirin therapy for the prevention of preeclampsia afford an opportunity to explore the benefits and limitations of each type of study to guide clinical practice. We conclude that, when available, large randomized clinical trials should be used to guide clinical practice.
Anderson, Monique L; Chiswell, Karen; Peterson, Eric D; Tasneem, Asba; Topping, James; Califf, Robert M
The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results. Using an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions (highly likely applicable clinical trials, or HLACTs) from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period. From all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health (NIH) and 9% of trials that were funded by other government or academic institutions. Despite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic
Hróbjartsson, Asbjørn; Thomsen, Ann Sofia Skou; Emanuelsson, Frida;
BACKGROUND:Clinical trials are commonly done without blinded outcome assessors despite the risk of bias. We wanted to evaluate the effect of nonblinded outcome assessment on estimated effects in randomized clinical trials with outcomes that involved subjective measurement scales. METHODS......:We conducted a systematic review of randomized clinical trials with both blinded and nonblinded assessment of the same measurement scale outcome. We searched PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, HighWire Press and Google Scholar for relevant studies. Two......%). Heterogeneity was moderate (I(2) = 46%, p = 0.02) and unexplained by metaregression. INTERPRETATION:We provide empirical evidence for observer bias in randomized clinical trials with subjective measurement scale outcomes. A failure to blind assessors of outcomes in such trials results in a high risk...
Goldenholz, Daniel M; Tharayil, Joseph J; Kuzniecky, Rubin; Karoly, Philippa; Theodore, William H; Cook, Mark J
It is currently unknown if knowledge of clinically silent (electrographic) seizures improves the statistical efficiency of clinical trials. Using data obtained from 10 patients with chronically implanted subdural electrodes over an average of 1 year, a Monte Carlo bootstrapping simulation study was performed to estimate the statistical power of running a clinical trial based on A) patient reported seizures with intracranial EEG (icEEG) confirmation, B) all patient reported events, or C) all icEEG confirmed seizures. A "drug" was modeled as having 10%, 20%, 30%, 40% and 50% efficacy in 1000 simulated trials each. Outcomes were represented as percentage of trials that achieved pseizures (pseizure detection using chronically implanted icEEG improves statistical power of clinical trials. Newer invasive and noninvasive seizure detection devices may have the potential to provide greater statistical efficiency, accelerate drug discovery and lower trial costs.
Full Text Available First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field.
Smed, Marie; Getz, Kenneth A.
in the industry and site representatives are changing. The process of clinical trials has increased in complexity over the years, resulting in additional management layers. Besides an increase in internal management layers, sponsors often also outsource various tasks related to clinical trials to a CRO (Contract...... knowledge gained by physicians in the process of clinical trials. These restrictions to knowledge-transfer between site and sponsor are further challenged if CRO partners are integrated in the trial process. © 2013 Elsevier Inc. All rights reserved....
MANINDER KAUR; AMRITPAL SINGH
Objective: The main objective of this study is to know clinical trials in nutshell and phase 0 clinical trial are to establish at the very earliest opportunity-before large numbers of patients have been accrued and exposed to potential drug-associated toxicity-whether an agent is modulating its target in a tumor, and consequently whether further clinical development is warranted. We review here the fundamental requirements of clinical studies conducted under an exploratory IND and address som...
Mandel, Jacob J; Yust-Katz, Shlomit; Patel, Akash J; Cachia, David; Liu, Diane; Park, Minjeong; Yuan, Ying; A Kent, Thomas; de Groot, John F
Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials. A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative. Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care. The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.
Grønbech, Bettina Ellen
People with severe mental illness, such as schizophrenia have higher rates of mortality especially due to cardiovascular disease. We have established a clinical trial named “Coronary artery disease and schizophrenia”. However, patients with schizophrenia have cognitive disturbances, which make re...... recruitment of patients challenging. The purpose of this study is to understand which type of recruitment strategy is needed in clinical trials....
Hróbjartsson, Asbjørn; Thomsen, Ann Sofia Skou; Emanuelsson, Frida;
To evaluate the impact of non-blinded outcome assessment on estimated treatment effects in randomised clinical trials with binary outcomes.......To evaluate the impact of non-blinded outcome assessment on estimated treatment effects in randomised clinical trials with binary outcomes....
Jakobsen, Jan Nyrop; Sørensen, Jens Benn
Malignant mesothelioma (MM) is an aggressive tumor of the serosal surfaces with a poor prognosis. Advances in the understanding of tumor biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. This article is a comprehensive review of all...... clinical trials evaluating the effect of targeted treatments in MM....
Lambers Heerspink, Hiddo Jan
Large scale randomized clinical trials are needed to detect small but meaningful effects of new drugs. However, large scale randomized clinical trials are expensive undertakings and they are in imbalance with the scientific output. As a consequence there is a strong voice for more efficacious random
Thomas eFitzGerald, MD
Full Text Available The National Cancer Institute clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence based process improvements for clinical oncology patient care. The cooperative groups are undergoing a transformation process as we further integrate molecular biology into personalized patient care and move to incorporate international partners in clinical trials. To support this vision, data acquisition and data management informatics tools must become both nimble and robust to support transformational research at an enterprise level. Information, including imaging, pathology, molecular biology, radiation oncology, surgery, systemic therapy and patient outcome data needs to be integrated into the clinical trial charter using adaptive clinical trial mechanisms for design of the trial. This information needs to be made available to investigators using digital processes for real time data analysis. Future clinical trials will need to be designed and completed in a timely manner facilitated by nimble informatics processes for data management. This paper discusses both past experience and future vision for clinical trials as we move to develop data management and quality assurance processes to meet the needs of the modern trial.
NCI is launching a new clinical trials research network intended to improve treatment for the more than 1.6 million Americans diagnosed with cancer each year. The new system, NCI’s National Clinical Trials Network (NCTN), will facilitate the rapid initia
Hróbjartsson, Asbjørn; Thomsen, Ann Sofia Skou; Emanuelsson, Frida
To evaluate the impact of non-blinded outcome assessment on estimated treatment effects in randomised clinical trials with binary outcomes.......To evaluate the impact of non-blinded outcome assessment on estimated treatment effects in randomised clinical trials with binary outcomes....
Puterman, Jared; Alter, David A
The utilization of disease management (DM) as a minimum standard of care is believed to facilitate pronounced benefits in overall patient outcome and cost management. Randomized clinical trials remain the gold standard evaluative tool in clinical medicine. However, the extent to which contemporary cardiovascular clinical trials incorporate DM components into their treatment or control arms is unknown. Our study is the first to evaluate the extent to which clinical trials incorporate DM as a minimum standard of care for both the intervention and control groups. In total, 386 clinical trials published in 3 leading medical journals between 2003 and 2006 were evaluated. For each study, elements related to DM care, as defined using the American Heart Association Taxonomy, were abstracted and characterized. Our results demonstrate that while the application of DM has increased over time, only 3.4% of the clinical trials examined incorporated all 8 DM elements (and only 11% of such trials incorporated 4 DM elements). A significant association was found between study year and the inclusion of more than 3 elements of DM (chi(2) = 10.10 (3); p = 0.018). In addition, associations were found between study objective and DM criteria, as well as between cohort type and domains described. Our study serves as a baseline reference for the tracking of DM within, and its application to, randomized clinical trials. Moreover, our results underscore the need for broader implementation and evaluation of DM as a minimum care standard within clinical trial research.
Russo, Ethan B.
This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain. PMID:27683558
Full Text Available Betty Tai, Steven Sparenborg, David Liu, Michele StrausCenter for the Clinical Trials Network, National Institute on Drug Abuse, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USAAbstract: The National Drug Abuse Treatment Clinical Trials Network (CTN has faced many challenges over its first eleven years. This review explores some of these challenges and the paths the CTN took to meet these challenges, including: designing clinical trials that reflect the CTN’s mission and changing public health needs, finding the synergies in the varied expertise of clinical treatment providers and academic researchers, promoting evidence-based practices and expanding the Network into mainstream medical practices to reach a broader patient population. Included in this exploration are specific examples from CTN clinical trials.Keywords: Clinical Trials Network, drug abuse, addiction
Ginn, Samantha L; Alexander, Ian E; Edelstein, Michael L; Abedi, Mohammad R; Wixon, Jo
To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future.
Stensland, Kristian D; McBride, Russell B; Latif, Asma; Wisnivesky, Juan; Hendricks, Ryan; Roper, Nitin; Boffetta, Paolo; Hall, Simon J; Oh, William K; Galsky, Matthew D
The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.
Qi, Guan D; We, Ding A; Chung, Leung P; Fai, Cheng K
One of the important components in randomized Controlled Trial (RCT) is blinding. The gold standard of clinical trials is to achieve a double blind design. However, only a small number of randomized controlled trials in traditional Chinese medicine have been reported, most of them are of poor quality in methodology including placebo preparation and verification. The purpose of the article is to review the validity of placebo used in blinded clinical trials for Chinese herbal medicine (CHM) in recent years and related patents. We searched the Wanfang Database (total of 827 Chinese journals of medicine and/or pharmacy, from 1999 to 2005) and 598 full-length articles related to placebo clinical trials were found. 77 placebo blinded clinical trials for Chinese medicine were extracted by manual search from the 598 articles. After reviewing the 77 full-length articles, we found that nearly half of the clinical trials did not pay attention to the physical quality of the testing drug and placebo and whether they were of comparable physical quality. The rest provided very limited placebo information so that blinding assurance could not be assumed. Only 2 articles (2.6%) specifically validated the comparability between the testing drug and the placebo. Researchers in Chinese medicine commonly ignored the quality of the placebo in comparison to the test drug. This may be causing bias in the clinical trials. Quality specifications and evaluation of the placebo should deserve special attention to reduce bias in randomized controlled trials in TCM study.
As Japan becomes more integrated into the global market, pharmaceutical research and development (R&D) in Japan faces considerable challenges. While global simultaneous development including Asian countries has become a common strategy for multi-national pharmaceutical companies, Japan has been frequently set aside because of its provincial regulatory and clinical trial infrastructure. Meanwhile, many improvement programs in pharmaceutical area have been initiated in Japan. With this increased scrutiny, significant improvements in regulatory process, clinical trial costs, and site performance are anticipated over the next few years. RENAAL is the first multi-national clinical trial involving Japanese patients diabetic nephropathy associated with type II diabetes mellitus. In this article, issues which have been observed in the process of conducting multi-national clinical trial were discussed based on the experience with RENAAL. It is hoped that, as we gain more experiences in multi-national clinical trials, solutions for these issues are found in near future.
Buonansegna, Erika; Salomo, Søren; Maier, Anja
Clinical trials in the pharmaceutical industry are the most critical part of the drug development process with respect to obtaining the market approval from the authorities. Clinical trials are highly expensive, time-consuming and often unsuccessful. While new product development (NPD) literature...... clinical trials reducing failures and increasing profits. The framework directs managerial focus on the most important factors for success and helps managers in decision-making of operational tasks. The framework can also be applied as a checklist for assessing the status of a clinical trial and later...... as a benchmarking tool to compare clinical trial processes. Dependencies among the identified factors seem to exist, thus a set of propositions, can be developed from the success factors and be the basis for future empirical testing....
Buonansegna, Erika; Salomo, Søren; Maier, Anja
of success factors. This paper creates the new framework by combining success factors from NPD literature and from empirical evidence collected through 11 semi-structured interviews with experts in clinical trials. The framework of success factors provides managerial guidelines for practitioners to optimize...... clinical trials reducing failures and increasing profits. The framework directs managerial focus on the most important factors for success and helps managers in decision-making of operational tasks. The framework can also be applied as a checklist for assessing the status of a clinical trial and later......Clinical trials in the pharmaceutical industry are the most critical part of the drug development process with respect to obtaining the market approval from the authorities. Clinical trials are highly expensive, time-consuming and often unsuccessful. While new product development (NPD) literature...
Ormarsson, Orri Thor; Geirsson, Thormodur; Bjornsson, Einar Stefan; Jonsson, Tomas; Moller, Pall; Loftsson, Thorsteinn; Stefansson, Einar
Cod-liver oil and other marine products containing polyunsaturated fatty acids have anti-inflammatory, anti-bacterial and anti-viral effects and may be useful in the treatment of various inflammatory and infectious diseases. We developed suppositories and ointment with 30% free fatty acid (FFA) extract from omega-3 fish oil. Our purpose was to evaluate the safety of marine lipid suppositories and ointment in healthy volunteers and to explore the laxative effect of the suppositories. Thirty healthy volunteers were randomized either to a study group administrating 30% FFA suppositories and applying 30% FFA ointment to the perianal region twice per day for two weeks, or to a control group using placebo suppositories and ointment in a double blinded manner. Results: No serious toxic effects or irritation were observed. In the study group 93% felt the urge to defecate after administration of the suppositories as compared to 37% in the control group (P = 0.001). Subsequently 90% in the study group defecated, compared to 33% in the control group (P = 0.001). Conclusion: The marine lipid suppositories and ointment were well tolerated with no significant toxic side effects observed during the study period. The suppositories have a distinct laxative effect and we aim to explore this effect in further clinical trials. PMID:23118720
Ogawa, Hisao; Kojima, Sunao
"Evidence-based medicine (EBM)" implies effective and high quality practice for patients based on well-grounded medical science. The success of clinical trials in Japan is essential to build original evidence specific for Japanese patients. Based on this concept, we have performed several large-scale clinical trials to provide EBM, including the Japanese Antiplatelets Myocardial Infarction Study [JAMIS; clinical improvement in acute myocardial infarction (AMI) patients with antiplatelet therapy], the Japanese beta-Blockers and Calcium Antagonists Myocardial Infarction (JBCMI; comparison of the effects of beta-blockers and calcium antagonists on cardiovascular events in post-AMI patients), a multicenter study for aggressive lipid-lowering strategy by HMG-CoA reductase inhibitors in patients with AMI (MUSASHI; effects of statin therapy on cardiovascular events in patients with AMI), and the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD trial; efficacy of low-dose aspirin therapy for primary prevention of atherosclerotic events in type 2 diabetic patients). The results of these prospective studies were directly linked with clinical practice. We have acquired the know-how of large-scale clinical trials; an important point is to have passion for "buildup evidence specific for the Japanese" and to recruit subjects for enrollment after explaining the significance of "clinical trials for the Japanese".
Carlini Beatriz H
Full Text Available Abstract Background Tobacco dependence is a chronic, relapsing condition that typically requires multiple quit attempts and extended treatment. When offered the opportunity, relapsed smokers are interested in recycling back into treatment for a new, assisted quit attempt. This manuscript presents the results of a randomized controlled trial testing the efficacy of interactive voice response (IVR in recycling low income smokers who had previously used quitline (QL support back to QL support for a new quit attempt. Methods A sample of 2985 previous QL callers were randomized to either receive IVR screening for current smoking (control group or IVR screening plus an IVR intervention. The IVR intervention consists of automated questions to identify and address barriers to re-cycling in QL support, followed by an offer to be transferred to the QL and reinitiate treatment. Re-enrollment in QL services for both groups was documented. Results The IVR system successfully reached 715 (23.9% former QL participants. Of those, 27% (194/715 reported to the IVR system that they had quit smoking and were therefore excluded from the study and analysis. The trial’s final sample was composed of 521 current smokers. The re-enrollment rate was 3.3% for the control group and 28.2% for the intervention group (p Conclusion Proactive IVR outreach is a promising tool to engage low income, relapsed smokers back into a new cycle of treatment. Integration of IVR intervention for recycling smokers with previous QL treatment has the potential to decrease tobacco-related disparities. Trial registration ClinicalTrials.gov Identifier: NCT01260597
Kyte, DG; Draper, H; Ives, J.; Liles, C; Gheorghe, A.; Calvert, M
BACKGROUND: Patient reported outcomes (PROs) are increasingly assessed in clinical trials, and guidelines are available to inform the design and reporting of such trials. However, researchers involved in PRO data collection report that specific guidance on 'in-trial' activity (recruitment, data collection and data inputting) and the management of 'concerning' PRO data (i.e., data which raises concern for the well-being of the trial participant) appears to be lacking. The purpose of this revie...
Berry, Donald A
Clinical trials are the final links in the chains of knowledge and for determining the roles of therapeutic advances. Unfortunately, in an important sense they are the weakest links. This article describes two designs that are being explored today: platform trials and basket trials. Both are attempting to merge clinical research and clinical practice.
Fennell, Reginald; Escue, Christopher
Background: The mobile health unit (MHU) was a grant-funded national initiative to explore the utilization of a mobile clinic to provide health promotion and clinical services for college students in the United States. Purpose: In 2010 and 2011, a 38-foot mobile clinic tested the feasibility of utilizing the clinic to deliver health promotion and…
Weisskopf, Michael; Bucklar, Guido; Blaser, Jürg
Issues concerning inadequate source data of clinical trials rank second in the most common findings by regulatory authorities. The increasing use of electronic clinical information systems by healthcare providers offers an opportunity to facilitate and improve the conduct of clinical trials and the source documentation. We report on a number of tools implemented into the clinical information system of a university hospital to support clinical research. In 2011/2012, a set of tools was developed in the clinical information system of the University Hospital Zurich to support clinical research, including (1) a trial registry for documenting metadata on the clinical trials conducted at the hospital, (2) a patient-trial-assignment-tool to tag patients in the electronic medical charts as participants of specific trials, (3) medical record templates for the documentation of study visits and trial-related procedures, (4) online queries on trials and trial participants, (5) access to the electronic medical records for clinical monitors, (6) an alerting tool to notify of hospital admissions of trial participants, (7) queries to identify potentially eligible patients in the planning phase as trial feasibility checks and during the trial as recruitment support, and (8) order sets to facilitate the complete and accurate performance of study visit procedures. The number of approximately 100 new registrations per year in the voluntary trial registry in the clinical information system now matches the numbers of the existing mandatory trial registry of the hospital. Likewise, the yearly numbers of patients tagged as trial participants as well as the use of the standardized trial record templates increased to 2408 documented trial enrolments and 190 reports generated/month in the year 2013. Accounts for 32 clinical monitors have been established in the first 2 years monitoring a total of 49 trials in 16 clinical departments. A total of 15 months after adding the optional feature of
Dear, R F; Barratt, A L; Askie, L M; Butow, P N; McGeechan, K; Crossing, S; Currow, D C; Tattersall, M H N
Cancer patients want access to reliable information about currently recruiting clinical trials. Oncologists and their patients were randomly assigned to access a consumer-friendly cancer clinical trials web site [Australian Cancer Trials (ACT), www.australiancancertrials.gov.au] or to usual care in a cluster randomized controlled trial. The primary outcome, measured from audio recordings of oncologist-patient consultations, was the proportion of patients with whom participation in any clinical trial was discussed. Analysis was by intention-to-treat accounting for clustering and stratification. Thirty medical oncologists and 493 patients were recruited. Overall, 46% of consultations in the intervention group compared with 34% in the control group contained a discussion about clinical trials (P=0.08). The mean consultation length in both groups was 29 min (P=0.69). The proportion consenting to a trial was 10% in both groups (P=0.65). Patients' knowledge about randomized trials was lower in the intervention than the control group (mean score 3.0 versus 3.3, P=0.03) but decisional conflict scores were similar (mean score 42 versus 43, P=0.83). Good communication between patients and physicians is essential. Within this context, a web site such as Australian Cancer Trials may be an important tool to encourage discussion about clinical trial participation.
Menezes, Amber S; Barnes, Alison; Scheer, Adena S; Martel, Guillaume; Moloo, Husein; Boushey, Robin P; Sabri, Elham; Auer, Rebecca C
The objective of this study was to provide a descriptive analysis of registered clinical trials in surgical oncology at ClinicalTrials.gov. Data was extracted from ClinicalTrials.gov using the following search engine criteria: "Cancer" as Condition, "Surgery OR Operation OR Resection" as Intervention, and Non-Industry sponsored. The search was limited to Canada and the United States and included trials registered from January 1, 2001 to January 1, 2011. Of 9,961 oncology trials, 1,049 (10.5%) included any type of surgical intervention. Of these trials, 125 (11.9%, 1.3% of all oncology trials) assessed a surgical variable, 773 (73.7%) assessed adjuvant/neoadjuvant therapies, and 151 (14.4%) were observational studies. Of the trials assessing adjuvant therapies, systemic treatment (362 trials, 46.8%) and multimodal therapy (129 trials, 16.7%) comprised a large focus. Of the 125 trials where surgery was the intervention, 59 trials (47.2%) focused on surgical techniques or devices, 45 trials (36.0%) studied invasive diagnostic methods, and 21 trials (16.8%) evaluated surgery versus no surgery. The majority of the 125 trials were nonrandomized (72, 57.6%). The number of registered surgical oncology trials is small in comparison to oncology trials as a whole. Clinical trials specifically designed to assess surgical interventions are vastly outnumbered by trials focusing on adjuvant therapies. Randomized surgical oncology trials account for <1% of all registered cancer trials. Barriers to the design and implementation of randomized trials in surgical oncology need to be clarified in order to facilitate higher-level evidence in surgical decision-making.
Shergis Johannah L
Full Text Available Abstract Conducting clinical trials of Chinese medicines (CM in hospitals presents challenges for researchers. The success of hospital-based CM clinical trials may be influenced by the protocol design, including the maintenance of CM theory in compliance with scientific rigour and hospital guidelines and justified treatment approaches with results that can translate into clinical practice. Other influences include personnel and resources such as a dedicated team open to CM with an established research culture and the ability to maximise participant recruitment. This article identifies the key challenges and limitations of conducting CM clinical trials in Australian hospitals.
Alvarenga, Lenio Souza; Martins, Elisabeth Nogueira
To evaluate biopharmaceutical industry-sponsored clinical trials placed in countries previously described as emerging regions for clinical research, and potential differences for those placed in Brazil. Data regarding recruitment of subjects for clinical trials were retrieved from www.clinicaltrials.gov on February 2nd 2009. Proportions of sites in each country were compared among emerging countries. Multiple logistic regressions were performed to evaluate whether trial placement in Brazil could be predicted by trial location in other countries and/or by trial features. A total of 8,501 trials were then active and 1,170 (13.8%) included sites in emerging countries (i.e., Argentina, Brazil, China, Czech Republic, Hungary, India, Mexico, Poland, Russia, South Korea, and South Africa). South Korea and China presented a significantly higher proportion of sites when compared to other countries (plogistic regressions detected no negative correlation between placement in other countries when compared to Brazil. Trials involving subjects with less than 15 years of age, those with targeted recruitment of at least 1,000 subjects, and seven sponsors were identified as significant predictors of trial placement in Brazil. No clear direct competition between Brazil and other emerging countries was detected. South Korea showed the higher proportion of sites and ranked third in total number of trials, appearing as a major player in attractiveness for biopharmaceutical industry-sponsored clinical trials.
Recently, the complexity and costs of clinical trials have increased dramatically, especially in the area of new drug development. Risk-based monitoring (RBM) has been attracting attention as an efficient and effective trial monitoring approach, which can be applied irrespectively of the trial sponsor, i.e., academic institution or pharmaceutical company. In the RBM paradigm, it is expected that a statistical approach to central monitoring can help improve the effectiveness of on-site monitoring by prioritizing and guiding site visits according to central statistical data checks, as evidenced by examples of actual trial datasets. In this review, several statistical methods for central monitoring are presented. It is important to share knowledge about the role and performance capabilities of statistical methodology among clinical trial team members (i.e., sponsors, investigators, data managers, monitors, and biostatisticians) in order to adopt central statistical monitoring for assessing data quality in the actual clinical trial.
Dimitrios Zardavas; Martine Piccart-Gebhart
The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients' enrolment in oncology trials shifts towards the implementation of molecular profiling as pre-screening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i) longitudinal cohort studies that implement (or not) "nested" downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) "master" protocol trials, iv) "basket" trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials.
Umscheid, Craig A.; Margolis, David J.; Grossman, Craig E.
The recent focus of federal funding on comparative effectiveness research underscores the importance of clinical trials in the practice of evidence-based medicine and health care reform. The impact of clinical trials not only extends to the individual patient by establishing a broader selection of effective therapies, but also to society as a whole by enhancing the value of health care provided. However, clinical trials also have the potential to pose unknown risks to their participants, and biased knowledge extracted from flawed clinical trials may lead to the inadvertent harm of patients. Although conducting a well-designed clinical trial may appear straightforward, it is founded on rigorous methodology and oversight governed by key ethical principles. In this review, we provide an overview of the ethical foundations of trial design, trial oversight, and the process of obtaining approval of a therapeutic, from its pre-clinical phase to post-marketing surveillance. This narrative review is based on a course in clinical trials developed by one of the authors (DJM), and is supplemented by a PubMed search predating January 2011 using the keywords “randomized controlled trial,” “patient/clinical research,” “ethics,” “phase IV,” “data and safety monitoring board,” and “surrogate endpoint.” With an understanding of the key principles in designing and implementing clinical trials, health care providers can partner with the pharmaceutical industry and regulatory bodies to effectively compare medical therapies and thereby meet one of the essential goals of health care reform. PMID:21904102
Natale, Enrico; Marsocci, Alfiera
Generally in the clinical practice patients are more complex in comparison with those included in the clinical trials. In this article, we discuss three relevant items, which may implement the transferability of the clinical trial results in the real world. The observational studies have fewer restrictions on the number of patients included, due to more relaxed inclusion and exlusion criteria than in randomized clinical trials. The absence of randomization however may lead to potential for bias. The recurrent event analysis may extend the positive results of clinical trials regarding the reductions of the first primary endpoint event to total events, including those beyond the first event. This analysis is of great interest in the clinical practice, where recurrent events are common. Finally the reliability of subgroup analysis is discussed. Pre-specified subgroup analyses are more credible and valuable than post-hoc analyses.
Sozu, Takashi; Hamasaki, Toshimitsu; Evans, Scott R
This book integrates recent methodological developments for calculating the sample size and power in trials with more than one endpoint considered as multiple primary or co-primary, offering an important reference work for statisticians working in this area. The determination of sample size and the evaluation of power are fundamental and critical elements in the design of clinical trials. If the sample size is too small, important effects may go unnoticed; if the sample size is too large, it represents a waste of resources and unethically puts more participants at risk than necessary. Recently many clinical trials have been designed with more than one endpoint considered as multiple primary or co-primary, creating a need for new approaches to the design and analysis of these clinical trials. The book focuses on the evaluation of power and sample size determination when comparing the effects of two interventions in superiority clinical trials with multiple endpoints. Methods for sample size calculation in clin...
World Health Organization aims to develop safe, effective and practical traditional medicine. Traditional Chinese medicine (TCM) and other complementary and alternative medicine are being recognized in the whole world nowadays. However, the definite effect of Chinese medicine is still in need of scientific research proof. Placebo control is of equal importance to active control and blank control in clinical trial of TCM. This article briefly reviewed the importance of placebo control and commented on its present situation in clinical trial of TCM. This article also brought up the preliminary proposals of placebo application in TCM clinical trial. We should emphasize scientific placebo preparation and good design of placebo-controlled trial, which are directed by International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. A good clinical trial project will avoid unnecessary wastes and provide safe and effective treatment for people.
Klimt, C R
Some of the guiding principles as well as the pitfall of long-term randomized clinical trials are presented. Examples have been chosen from trials in the cardiovascular field. A typical long-term clinical trial is divided into five phases: planning, preparation, recruitment, clinical follow-up and termination, and finally analysis. Administrative, legal, and ethical aspects of a trial are discussed, as well as the cost of clinical trials. Organization patterns are described and some prevalent ones are criticized. Further, practical matters such as recruitment techniques, obtaining informed consent from the patients, determining drug dosage and formulation as well as the problem of interaction with nonstudy drugs are referred to. Adherence testing remains a problem, because of our inability to test for placebo adherence.
Aman, Michael G; Novotny, Sherie; Samango-Sprouse, Carole; Lecavalier, Luc; Leonard, Elizabeth; Gadow, Kenneth D.; King, Bryan H; Pearson, Deborah A.; Gernsbacher, Morton Ann; Chez, Michael
This paper identifies instruments and measures that may be appropriate for randomized clinical trials in participants with autism spectrum disorders (ASDs). The Clinical Global Impressions scale was recommended for all randomized clinical trials. At this point, however, there is no “perfect” choice of outcome measure for core features of autism, although we will discuss five measures of potential utility. Several communication instruments are recommended, based in part on suitability across t...
With the increasing amounts of clinical data required for drug regulatory approval and the fierce competition for patients in the Western countries, the cost of clinical trials continues to rise considerably. This study suggests that outsourcing clinical trials to China is an effective strategy to reduce cost and cycle time of drug development. China offers a high market potential and strong research capacity that can provide long term benefits to pharmaceutical and biotech companies. An inte...
Shergis Johannah L; Parker Shefton; Coyle Meaghan E; Zhang Anthony L; Xue Charlie C
Abstract Conducting clinical trials of Chinese medicines (CM) in hospitals presents challenges for researchers. The success of hospital-based CM clinical trials may be influenced by the protocol design, including the maintenance of CM theory in compliance with scientific rigour and hospital guidelines and justified treatment approaches with results that can translate into clinical practice. Other influences include personnel and resources such as a dedicated team open to CM with an establishe...
gene therapy program with Oxford Biomedica to bring gene therapy for juvenile macular degeneration (Stargardt’s disease). This phase I clinical trial...working with Oxford Biomedica and a separate project with academic investigators on gene therapy for Usher lb syndrome (deaf-blindness due to a gene... Biomedica collaboration will begin no later than 04 2011. 3. NNRI has held multiple clinical investigator meetings to define clinical trial outcomes for
Shimizu, Reiko; Ogata, Katsuhisa; Tamaura, Akemi; Kimura, En; Ohata, Maki; Takeshita, Eri; Nakamura, Harumasa; Takeda, Shin'ichi; Komaki, Hirofumi
Duchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely "orphan drugs", have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases. To accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation. Thirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time. Counting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to
Mentz, Robert J; Hernandez, Adrian F; Berdan, Lisa G; Rorick, Tyrus; O'Brien, Emily C; Ibarra, Jenny C; Curtis, Lesley H; Peterson, Eric D
Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. Although the application of Good Clinical Practice principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, the growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials. The central tenets of Good Clinical Practice and pragmatic clinical trials represent potential tensions in trial design (stringent quality and highly efficient operations). In the present article, we highlight potential areas of discordance between Good Clinical Practice guidelines and the principles of pragmatic clinical trials and suggest strategies to streamline study conduct in an ethical manner to optimally perform clinical trials in the electronic age.
Pediatric Clinical Trials Conducted in South Korea from 2006 to 2015: An Analysis of the South Korean Clinical Research Information Service, US ClinicalTrials.gov and European Clinical Trials Registries.
Choi, Sheung-Nyoung; Lee, Ji-Hyun; Song, In-Kyung; Kim, Eun-Hee; Kim, Jin-Tae; Kim, Hee-Soo
The status of pediatric clinical trials performed in South Korea in the last decade, including clinical trials of drugs with unapproved indications for children, has not been previously examined. The aim was to provide information regarding the current state of pediatric clinical trials and create a basis for future trials performed in South Korea by reviewing three databases of clinical trials registrations. We searched for pediatric clinical studies (participants gov, and the European Clinical Trials Registry (EuCTR). Additionally, we reviewed whether unapproved indications were involved in each trial by comparing the trials with a list of authorized trials provided by the Ministry of Food and Drug Safety (MFDS). The primary and secondary outcomes were to determine the change in number of pediatric clinical trials with unapproved indications over time and to assess the status of unauthorized pediatric clinical trials from the MFDS and the publication of articles after these clinical trials, respectively. We identified 342 clinical studies registered in the CRIS (n = 81), ClinicalTrials.gov (n = 225), and EuCTR (n = 36), of which 306 were reviewed after excluding duplicate registrations. Among them, 181 studies were interventional trials dealing with drugs and biological agents, of which 129 (71.3%) involved unapproved drugs. Of these 129 trials, 107 (82.9%) were authorized by the MFDS. Pediatric clinical trials in South Korea aiming to establish the safety and efficacy of drugs in children are increasing; however, non-MFDS-authorized studies remain an issue.
Utami, Dina; Bickmore, Timothy W; Barry, Barbara; Paasche-Orlow, Michael K
Several web-based search engines have been developed to assist individuals to find clinical trials for which they may be interested in volunteering. However, these search engines may be difficult for individuals with low health and computer literacy to navigate. The authors present findings from a usability evaluation of clinical trial search tools with 41 participants across the health and computer literacy spectrum. The study consisted of 3 parts: (a) a usability study of an existing web-based clinical trial search tool; (b) a usability study of a keyword-based clinical trial search tool; and (c) an exploratory study investigating users' information needs when deciding among 2 or more candidate clinical trials. From the first 2 studies, the authors found that users with low health literacy have difficulty forming queries using keywords and have significantly more difficulty using a standard web-based clinical trial search tool compared with users with adequate health literacy. From the third study, the authors identified the search factors most important to individuals searching for clinical trials and how these varied by health literacy level.
de Bruijn, Berry; Carini, Simona; Kiritchenko, Svetlana; Martin, Joel; Sim, Ida
Clinical trials are one of the most valuable sources of scientific evidence for improving the practice of medicine. The Trial Bank project aims to improve structured access to trial findings by including formalized trial information into a knowledge base. Manually extracting trial information from published articles is costly, but automated information extraction techniques can assist. The current study highlights a single architecture to extract a wide array of information elements from full-text publications of randomized clinical trials (RCTs). This architecture combines a text classifier with a weak regular expression matcher. We tested this two-stage architecture on 88 RCT reports from 5 leading medical journals, extracting 23 elements of key trial information such as eligibility rules, sample size, intervention, and outcome names. Results prove this to be a promising avenue to help critical appraisers, systematic reviewers, and curators quickly identify key information elements in published RCT articles.
Flight, Laura; Julious, Steven A; Goodacre, Steve
Adaptive design clinical trials use preplanned interim analyses to determine whether studies should be stopped or modified before recruitment is complete. Emergency medicine trials are well suited to these designs as many have a short time to primary outcome relative to the length of recruitment. We hypothesised that the majority of published emergency medicine trials have the potential to use a simple adaptive trial design. We reviewed clinical trials published in three emergency medicine journals between January 2003 and December 2013. We determined the proportion that used an adaptive design as well as the proportion that could have used a simple adaptive design based on the time to primary outcome and length of recruitment. Only 19 of 188 trials included in the review were considered to have used an adaptive trial design. A total of 154/165 trials that were fixed in design had the potential to use an adaptive design. Currently, there seems to be limited uptake in the use of adaptive trial designs in emergency medicine despite their potential benefits to save time and resources. Failing to take advantage of adaptive designs could be costly to patients and research. It is recommended that where practical and logistical considerations allow, adaptive designs should be used for all emergency medicine clinical trials. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Edelstein, Michael L; Abedi, Mohammad R; Wixon, Jo; Edelstein, Richard M
In 1989, Rosenberg et al. performed the first human gene therapy trial when they used a retrovirus to introduce the gene coding for resistance to neomycin into human tumor-infiltrating lymphocytes before infusing them into five patients with advanced melanoma. This study demonstrated the feasibility of using retroviral gene transduction in humans and set the stage for further studies. Since then, over 900 clinical trials have been completed, are ongoing or have been approved worldwide. These trials have been designed to establish feasibility and safety, to demonstrate the reality of expression of therapeutic protein(s) in vivo by the genes transferred and, in some cases, to show therapeutic benefit. There is no single source of information that presents an overview of all the clinical trials undertaken worldwide. In 1997 we set up a database to bring all the information on clinical trials together as comprehensively and as globally as possible. The data were compiled and are regularly updated from official agency sources, the published literature, presentations at conferences and from information kindly provided by investigators or trial sponsors themselves. As of January 31, 2004, we have identified 918 trials in 24 countries. The USA accounts for two-thirds of these trials. Cancer is by far the most common disease indication, followed by inherited monogenic diseases, and cardiovascular diseases. Viral vectors have been the most frequently used vehicles for transferring genes into human cells, with retroviruses and adenoviruses representing the vast majority. Plasmid (naked) DNA and other non-viral vectors have been used in one-quarter of the trials. Over 100 distinct genes have been transferred. This article aims to provide a descriptive overview of the clinical trials that, to the best of our knowledge, have been or are being performed worldwide. Details of the data presented, including an interactive, searchable database that currently holds information on 918
Sami F Shaban
Full Text Available Sayeeda Rahman1, Md Anwarul Azim Majumder1, Sami F Shaban2, Nuzhat Rahman3, Moslehuddin Ahmed4, Khalid Bin Abdulrahman5, Urban JA D’Souza61Department of Clinical Sciences, School of Life Sciences, University of Bradford, West Yorkshire, Bradford, UK; 2Department of Medical Education, Faculty of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates; 3Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; 4Department of Community Medicine, Uttara Adhunik Medical College, Dhaka, Bangladesh; 5Department of Family Medicine and Medical Education, College of Medicine, Al-Imam University, Riyadh, Saudi Arabia; 6Department of Post Graduate Studies, School of Medicine, University Malaysia Sabah, Kota Kinabalu, Sabah, MalaysiaAbstract: The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of clinical research studies that highlights the need for greater participation in research by physicians as well as patients. Furthermore, the potential of clinical research is unlikely to be reached without greater participation of physicians in research. Physicians face a variety of barriers with regard to participation in clinical research. These barriers are system- or organization-related as well as research- and physician-related. To encourage physician participation, appropriate organizational and operational infrastructures are needed in health care institutes to support research planning and management. All physicians should receive education and training in the fundamentals of research design and methodology, which need to be incorporated into undergraduate medical education and postgraduate training curricula and then reinforced through continuing medical education. Medical schools need to analyze current practices of teaching–learning and research, and reflect upon possible changes needed to develop a ‘student-focused teaching–learning and
Smaïl-Faugeron, V; Fron-Chabouis, H; Durieux, P
Prospective registration of randomized controlled trials (RCTs) represents the best solution to reporting bias. The extent to which oral health journals have endorsed and complied with RCT registration is unknown. We identified journals publishing RCTs in dentistry, oral surgery, and medicine in the Journal Citation Reports. We classified journals into 3 groups: journals requiring or recommending trial registration, journals referring indirectly to registration, and journals providing no reference to registration. For the 5 journals with the highest 2012 impact factors in each group, we assessed whether RCTs with results published in 2013 had been registered. Of 78 journals examined, 32 (41%) required or recommended trial registration, 19 (24%) referred indirectly to registration, and 27 (35%) provided no reference to registration. We identified 317 RCTs with results published in the 15 selected journals in 2013. Overall, 73 (23%) were registered in a trial registry. Among those, 91% were registered retrospectively and 32% did not report trial registration in the published article. The proportion of trials registered was not significantly associated with editorial policies: 29% with results in journals that required or recommended registration, 15% in those that referred indirectly to registration, and 21% in those providing no reference to registration (P = 0.05). Less than one-quarter of RCTs with results published in a sample of oral health journals were registered with a public registry. Improvements are needed with respect to how journals inform and require their authors to register their trials.
Smith Richard M
Full Text Available Abstract Background This article provides the rationale and methodology, of the first randomised controlled trial to our knowledge designed to assess the efficacy of progressive resistance training on cartilage morphology in women with knee osteoarthritis. Development and progression of osteoarthritis is multifactorial, with obesity, quadriceps weakness, joint malalignment, and abnormal mechanical joint forces particularly relevant to this study. Progressive resistance training has been reported to improve pain and disability in osteoarthritic cohorts. However, the disease-modifying potential of progressive resistance training for the articular cartilage degeneration characteristic of osteoarthritis is unknown. Our aim was to investigate the effect of high intensity progressive resistance training on articular cartilage degeneration in women with knee osteoarthritis. Methods Our cohort consisted of women over 40 years of age with primary knee osteoarthritis, according to the American College of Rheumatology clinical criteria. Primary outcome was blinded measurement of cartilage morphology via magnetic resonance imaging scan of the tibiofemoral joint. Secondary outcomes included walking endurance, balance, muscle strength, endurance, power, and velocity, body composition, pain, disability, depressive symptoms, and quality of life. Participants were randomized into a supervised progressive resistance training or sham-exercise group. The progressive resistance training group trained muscles around the hip and knee at 80% of their peak strength and progressed 3% per session, 3 days per week for 6 months. The sham-exercise group completed all exercises except hip adduction, but without added resistance or progression. Outcomes were repeated at 3 and 6 months, except for the magnetic resonance imaging scan, which was only repeated at 6 months. Discussion Our results will provide an evaluation of the disease-modifying potential of progressive
Full Text Available Economic evaluation in the form of cost-effectiveness analysis has become a popular means to inform decisions in healthcare. With multi-regional clinical trials in a global development program becoming a new venue for drug efficacy testing in recent decades, questions in methods for cost-effectiveness analysis in the multi-regional clinical trials setting also emerge. This paper addresses some challenges from variation across regions in cost effectiveness analysis in multi-regional clinical trials. Several discussion points are raised for further attention and a multi-regional clinical trial example is presented to illustrate the implications in industrial application. A general message is delivered to call for a depth discussion by all stakeholders to reach an agreement on a good practice in cost-effectiveness analysis in the multi-regional clinical trials. Meanwhile, we recommend an additional consideration of cost-effectiveness analysis results based on the clinical evidence from a certain homogeneous population as sensitivity or scenario analysis upon data availability.
Ohmann, Christian; Canham, Steve; Danielyan, Edgar; Robertshaw, Steve; Legré, Yannick; Clivio, Luca; Demotes, Jacques
Growing use of cloud computing in clinical trials prompted the European Clinical Research Infrastructures Network, a European non-profit organisation established to support multinational clinical research, to organise a one-day workshop on the topic to clarify potential benefits and risks. The issues that arose in that workshop are summarised and include the following: the nature of cloud computing and the cloud computing industry; the risks in using cloud computing services now; the lack of explicit guidance on this subject, both generally and with reference to clinical trials; and some possible ways of reducing risks. There was particular interest in developing and using a European 'community cloud' specifically for academic clinical trial data. It was recognised that the day-long workshop was only the start of an ongoing process. Future discussion needs to include clarification of trial-specific regulatory requirements for cloud computing and involve representatives from the relevant regulatory bodies.
Rashmi Ashish Kadam
Full Text Available Background: Successful recruitment of patients is known to be one of the most challenging aspects in conduct of randomized controlled trials. Inadequate patient retention during conduct of trial affects conclusive results. Objective: To assess the level of challenges faced by Indian investigators in recruitment and retention of trial subjects. Methods: We developed a survey questionnaire on challenges encountered by investigators in subject recruitment and retention which was hosted on a web portal. Results: Seventy-three investigators from India participated in the survey. The frequently encountered challenges in subject recruitment were complexity of study protocol (38%, lack of awareness about clinical trials in patients (37%, and sociocultural issues related to trial participation (37%. About 63% of participants strongly agreed that creating a positive awareness about clinical trials among people through press and media, having a dedicated clinical research coordinator for trial (50.7%, and designing a recruitment strategy prior to study initiation (46.6% would enhance recruitment. Almost 50.7% of participants agreed that interacting with medical community in vicinity of the study site and educating patients about clinical trials during routine outpatient department visits (46.6% would enhance recruitment. Experiencing a serious adverse event, subject′s fear for study procedures (47% and side effects (44% were thought to have a moderate effect on subject retention. Conclusion: Our survey has put forth factors related to negative publicity by media, lack of patient education about clinical trials; complex study designs are barriers to clinical trial recruitment in India. It is essential to devise innovative and effective strategies focusing on education of public and mass media about clinical research in India.
Kadam, Rashmi Ashish; Borde, Sanghratna Umakant; Madas, Sapna Amol; Salvi, Sundeep Santosh; Limaye, Sneha Saurabh
Successful recruitment of patients is known to be one of the most challenging aspects in conduct of randomized controlled trials. Inadequate patient retention during conduct of trial affects conclusive results. To assess the level of challenges faced by Indian investigators in recruitment and retention of trial subjects. We developed a survey questionnaire on challenges encountered by investigators in subject recruitment and retention which was hosted on a web portal. Seventy-three investigators from India participated in the survey. The frequently encountered challenges in subject recruitment were complexity of study protocol (38%), lack of awareness about clinical trials in patients (37%), and sociocultural issues related to trial participation (37%). About 63% of participants strongly agreed that creating a positive awareness about clinical trials among people through press and media, having a dedicated clinical research coordinator for trial (50.7%), and designing a recruitment strategy prior to study initiation (46.6%) would enhance recruitment. Almost 50.7% of participants agreed that interacting with medical community in vicinity of the study site and educating patients about clinical trials during routine outpatient department visits (46.6%) would enhance recruitment. Experiencing a serious adverse event, subject's fear for study procedures (47%) and side effects (44%) were thought to have a moderate effect on subject retention. Our survey has put forth factors related to negative publicity by media, lack of patient education about clinical trials; complex study designs are barriers to clinical trial recruitment in India. It is essential to devise innovative and effective strategies focusing on education of public and mass media about clinical research in India.
Geifman, Nophar; Butte, Atul J
Open clinical trial data offer many opportunities for the scientific community to independently verify published results, evaluate new hypotheses and conduct meta-analyses. These data provide a springboard for scientific advances in precision medicine but the question arises as to how representative clinical trials data are of cancer patients overall. Here we present the integrative analysis of data from several cancer clinical trials and compare these to patient-level data from The Cancer Genome Atlas (TCGA). Comparison of cancer type-specific survival rates reveals that these are overall lower in trial subjects. This effect, at least to some extent, can be explained by the more advanced stages of cancer of trial subjects. This analysis also reveals that for stage IV cancer, colorectal cancer patients have a better chance of survival than breast cancer patients. On the other hand, for all other stages, breast cancer patients have better survival than colorectal cancer patients. Comparison of survival in different stages of disease between the two datasets reveals that subjects with stage IV cancer from the trials dataset have a lower chance of survival than matching stage IV subjects from TCGA. One likely explanation for this observation is that stage IV trial subjects have lower survival rates since their cancer is less likely to respond to treatment. To conclude, we present here a newly available clinical trials dataset which allowed for the integration of patient-level data from many cancer clinical trials. Our comprehensive analysis reveals that cancer-related clinical trials are not representative of general cancer patient populations, mostly due to their focus on the more advanced stages of the disease. These and other limitations of clinical trials data should, perhaps, be taken into consideration in medical research and in the field of precision medicine.
Moustgaard, Helene; Bello, Segun; Miller, Franklin G
providing a classification of clinical trial outcomes and a descriptive study of how outcomes were classified in 200 PubMed indexed clinical trial reports published in 2012. RESULTS: We identified 90 methodological publications with some form of a classification of outcomes. Three distinct definitions were...... "subjective outcome" and "objective outcome" are defined in methodological publications and clinical trial reports. To put this examination into perspective, we also provide an overview of how outcomes are classified more broadly. STUDY DESIGN AND SETTING: A systematic review of methodological publications...
Paganoni, Sabrina; Cudkowicz, Merit; Berry, James D
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average survival of 3–5 years. While therapies for ALS remain limited, basic and translational ALS research has been host to numerous influential discoveries in recent years. These discoveries have led to a large pipeline of potential therapies that await testing in clinical trials. Until recently, ALS clinical trials have relied on a limited cadre of ‘traditional’ outcome measures, including survival and measures of function. These measures have proven useful, although imperfect, in Phase III ALS trials. However, their utility in early-phase ALS trials is limited. For these early trials, outcome measures focused on target engagement or biological pathway analysis might improve trial outcomes and better support the drug development process.
networks, namely the HIV Vaccine Trials Network (HVTN - www.hvtn.org) and the International ... These include life skills education, sanitation, potable water supply ... and data management centre, central laboratories, a community advisory ...
Meropol, Neal J; Wong, Yu-Ning; Albrecht, Terrance; Manne, Sharon; Miller, Suzanne M; Flamm, Anne Lederman; Benson, Al Bowen; Buzaglo, Joanne; Collins, Michael; Egleston, Brian; Fleisher, Linda; Katz, Michael; Kinzy, Tyler G; Liu, Tasnuva M; Margevicius, Seunghee; Miller, Dawn M; Poole, David; Roach, Nancy; Ross, Eric; Schluchter, Mark D
Lack of knowledge and negative attitudes have been identified as barriers to participation in clinical trials by patients with cancer. We developed Preparatory Education About Clinical Trials (PRE-ACT), a theory-guided, Web-based, interactive computer program, to deliver tailored video educational content to patients in an effort to overcome barriers to considering clinical trials as a treatment option. A prospective, randomized clinical trial compared PRE-ACT with a control condition that provided general clinical trials information produced by the National Cancer Institute (NCI) in text format. One thousand two hundred fifty-five patients with cancer were randomly allocated before their initial visit with an oncologist to PRE-ACT (n = 623) or control (n = 632). PRE-ACT had three main components: assessment of clinical trials knowledge and attitudinal barriers, values assessment with clarification back to patients, and provision of a video library tailored to address each patient's barriers. Outcomes included knowledge and attitudes and preparation for decision making about clinical trials. Both PRE-ACT and control interventions improved knowledge and attitudes (all P < .001) compared with baseline. Patients randomly allocated to PRE-ACT showed a significantly greater increase in knowledge (P < .001) and a significantly greater decrease in attitudinal barriers (P < .001) than did their control (text-only) counterparts. Participants in both arms significantly increased their preparedness to consider clinical trials (P < .001), and there was a trend favoring the PRE-ACT group (P < .09). PRE-ACT was also associated with greater patient satisfaction than was NCI text alone. These data show that patient education before the first oncologist visit improves knowledge, attitudes, and preparation for decision making about clinical trials. Both text and tailored video were effective. The PRE-ACT interactive video program was more effective than NCI text in improving
Hauke, C; Meisser, A; Perren, S M
Once development and mechanical and biological laboratory testing have been completed, new technologies to be used in orthopaedic and trauma surgery must be investigated in humans before they can be used routinely. Prospective clinical investigations with or without randomization to standard treatments conducted according to the current standards and guidelines for Good Clinical Practice must be performed to prove the safety and efficacy of the new device. Furthermore, these tests serve to determine the specific indications, contraindications, tips and tricks as well as the pitfalls and how to avoid them. Last, but not least, the study must result in improved teaching of the use of the device and in improved follow-up of patients. The basis of every conclusion drawn from such a study is the complete documentation of each single use of the new device. We present the modalities and methodology for conducting a prospective clinical multicentre investigation in trauma surgery, focusing on the clinical trials carried out on the Point Contact Fixator (PC-Fix), a device for the internal fixation of long bone fractures developed as part of the scientific evolution towards the Less Invasive Stabilization Systems (LISS) now being introduced into clinical practice. Four prospective multicentre clinical investigations with an overall number of 1,229 PC-Fixators implanted from October 1993 to May 1998 were performed. To our knowledge this is the largest prospective series ever reported in orthopaedic trauma surgery to test a new device before market introduction. Due to a special documentation and implant replacement procedure, every PC-Fix implantation was documented. Very few patients were lost to long-term follow-up due to the personal commitment of the study monitors. Regular personal visits of the study monitor to the investigating hospitals and close communication between the surgeons, the engineers responsible for development, the study monitor, and the study sponsor
Bucur, Anca; Van Leeuwen, Jasper; Chen, Njin-Zu; Claerhout, Brecht; De Schepper, Kristof; Perez-Rey, David; Alonso-Calvo, Raul; Pugliano, Lina; Saini, Kamal
To support the efficient execution of post-genomic multi-centric clinical trials in breast cancer we propose a solution that streamlines the assessment of the eligibility of patients for available trials. The assessment of the eligibility of a patient for a trial requires evaluating whether each eligibility criterion is satisfied and is often a time consuming and manual task. The main focus in the literature has been on proposing different methods for modelling and formalizing the eligibility criteria. However the current adoption of these approaches in clinical care is limited. Less effort has been dedicated to the automatic matching of criteria to the patient data managed in clinical care. We address both aspects and propose a scalable, efficient and pragmatic patient screening solution enabling automatic evaluation of eligibility of patients for a relevant set of trials. This covers the flexible formalization of criteria and of other relevant trial metadata and the efficient management of these representations.
Gluud, C; Sørensen, T I
The urgent need for the performance of more, better designed, and better conducted randomised clinical trials is increasingly recognised. Based on structured interviews with leading persons of 43 outstanding organisations and units involved in clinical trials in Europe and North America during 1993......, ways of organising and staffing clinical trial units were investigated. The present proposal is based on this experience from which an attempt to extract a composite set of minimal requirements has been made regarding pertinent objectives and aims, organisational aspects, staffing, and estimated costs...... to a total cost for coordination per trial of about GBP 340,000. However, with a larger staff more studies may be coordinated possibly reducing the cost per trial depending on greater effectiveness in utilisation of the basic facilities....
Mentz, Robert J; Kaski, Juan-Carlos; Dan, Gheorghe-Andrei; Goldstein, Sidney; Stockbridge, Norman; Alonso-Garcia, Angeles; Ruilope, Luis M; Martinez, Felipe A; Zannad, Faiez; Pitt, Bertram; Fiuzat, Mona; O'Connor, Christopher M
Cardiovascular clinical trials are increasingly conducted globally as a means to reduce costs, expedite timelines, provide broad applicability, and satisfy regulatory authorities. Potential problems with trial globalization include regional differences in patient characteristics, medical practice patterns, and health policies which may influence outcomes and limit generalizability. Moreover, concerns have been raised about ethical misconduct and unsatisfactory quality oversight in regions with less trial experience and infrastructure. This article reviews geographical differences in cardiovascular trials in heart failure, acute coronary syndromes, hypertension and atrial fibrillation. It also explores potential explanations for these differences and methods to standardize the presentation of trial results. This review is based on discussions between basic scientists and clinical trialists at the 8th Global Cardio Vascular Clinical Trialists Forum 2011 in Paris, France, from December 2 to 3. Copyright © 2012 Mosby, Inc. All rights reserved.
... HUMAN SERVICES Food and Drug Administration Analgesic Clinical Trials Innovation, Opportunities, and... Analgesic Clinical Trials Innovation, Opportunities, and Networks (ACTION) Initiative. The goal of the... major gaps in scientific information, which can slow down analgesic clinical trials and analgesic...
Lee Su Jin
Full Text Available Abstract Background In the past few years, the number of clinical trials has increased rapidly in East Asia, especially for gastric and hepatobiliary cancer that are prevalent in Asian populations. However, the actual degree of understanding or perceptions of clinical trials by cancer patients in East Asian countries have seldom been studied. Methods Between July 1st and November 30th of 2011, we conducted a prospective study to survey cancer patients regarding their awareness of, and willingness to participate in, a clinical trial. Patients with gastrointestinal/hepatobiliary cancer who visited the Hematology-Oncology outpatient clinic at Samsung Medical Center (SMC were enrolled. A total of 21 questions were asked including four questions which used the Visual analogue scale (VAS score. Results In this survey study, 1,000 patients were asked to participate and 675 patients consented to participate (67.5%. The awareness of clinical trials was substantially higher in patients who had a higher level of education (pp=0.004, and had a higher economic status (p=0.001. However, the willingness to participate in a clinical trial was not affected by the level of education or economic status of patients. The most influential factors for patient willingness to participate were a physician recommendation (n=181, 26.8%, limited treatment options (n=178, 26.4%, and expectations of effectiveness of new anti-cancer drugs (n=142, 21.0%. Patients with previous experience in clinical trials had a greater willingness to participate in clinical trials compared to patients without previous experience (p Conclusions This large patient cohort survey study showed that Korean cancer patients are more aware of clinical trials, but awareness did not translate into willingness to participate.
Rosenberg, Jacob; Burcharth, Jakob; Pommergaard, Hans-Christian;
Discussions about authorship often arise in multi-centre clinical trials. Such trials may involve up to hundreds of contributors of whom some will eventually co-author the final publication. It is, however, often impossible to involve all contributors in the manuscript process sufficiently for them...
The process of opening a cancer clinical trial for patient accrual often takes years, and research has shown that trials which are slow to register patients often fail to finish. Following a thorough review, NCI’s Operational Efficiency Working Group prod
Paludan-Müller, Asger Sand; Laursen, David R. T.; Hróbjartsson, Asbjørn
clinical trials. METHODS: Two systematic reviews and a theoretical analysis. We conducted one systematic review of empirical studies of motives/methods for deciphering patient allocation sequences; and another review of methods publications commenting on allocation bias. We theoretically analysed...
Mahesh J. Patel; Cris A. Slentz; William E. Kraus
Randomized clinical trials of exercise training regimens in sedentary individuals have provided a mechanistic understanding of the long-term health benefits and consequences of physical activity and inactivity...
Hanson, Sarah L; Davis, Miriam (Medical writer); Altevogt, Bruce M
"The Food and Drug Administration (FDA) now requires that all clinical trials for drugs that affect the central nervous system--including psychiatric drugs--are assessed for whether that drug might cause suicidal ideation or behavior...
Pedersen, Allan Gorm; Petersen, O B; Wara, P;
BACKGROUND: Laparoscopy in patients with a clinical suspicion of acute appendicitis has not gained wide acceptance, and its use remains controversial. METHODS: In a randomized controlled trial of laparoscopic versus open appendicectomy, 583 of 828 consecutive patients consented to participate...
Kurzrock, Razelle; Stewart, David J
The issue of compliance in a research environment in which investigators are subject to disciplinary action if they fail to ensure that patients adhere precisely to the intense monitoring mandates of a clinical trial is explored.
Mathura, Venkatarajan S; Rangareddy, Mahendiranath; Gupta, Pankaj; Mullan, Michael
Clinical trials involve multi-site heterogeneous data generation with complex data input-formats and forms. The data should be captured and queried in an integrated fashion to facilitate further analysis. Electronic case-report forms (eCRF) are gaining popularity since it allows capture of clinical information in a rapid manner. We have designed and developed an XML based flexible clinical trials data management framework in .NET environment that can be used for efficient design and deployment of eCRFs to efficiently collate data and analyze information from multi-site clinical trials. The main components of our system include an XML form designer, a Patient registration eForm, reusable eForms, multiple-visit data capture and consolidated reports. A unique id is used for tracking the trial, site of occurrence, the patient and the year of recruitment. Availability http://www.rfdn.org/bioinfo/CTMS/ctms.html. PMID:21670796
Maecker, Holden T; McCoy, J Philip; Amos, Michael; Elliott, John; Gaigalas, Adolfas; Wang, Lili; Aranda, Richard; Banchereau, Jacques; Boshoff, Chris; Braun, Jonathan; Korin, Yael; Reed, Elaine; Cho, Judy; Hafler, David; Davis, Mark; Fathman, C Garrison; Robinson, William; Denny, Thomas; Weinhold, Kent; Desai, Bela; Diamond, Betty; Gregersen, Peter; Di Meglio, Paola; DiMeglio, Paola; Nestle, Frank O; Nestle, Frank; Peakman, Mark; Villanova, Federica; Villnova, Federica; Ferbas, John; Field, Elizabeth; Kantor, Aaron; Kawabata, Thomas; Komocsar, Wendy; Lotze, Michael; Nepom, Jerry; Ochs, Hans; O'Lone, Raegan; Phippard, Deborah; Plevy, Scott; Rich, Stephen; Roederer, Mario; Rotrosen, Dan; Yeh, Jung-Hua
Complexities in sample handling, instrument setup and data analysis are barriers to the effective use of flow cytometry to monitor immunological parameters in clinical trials. The novel use of a central laboratory may help mitigate these issues.
U.S. Department of Health & Human Services — The National Database for Clinical Trials Related to Mental Illness (NDCT) is an extensible informatics platform for relevant data at all levels of biological and...
A Randomized, Controlled Clinical Trial Comparing Efficacy, Safety and Cost Effectiveness of ... Log in or Register to get access to full text downloads. ... Pharmacological control of pain is the mainstay of management of osteoarthritis.
Price, Amy; Liew, Su May; Kirkpatrick, Jo; Price, Jazmin; Lopreto, Taylor; Nelken, Yasmin
What are the strengths, gaps, expectations, and barriers to research engagement in clinical trials as communicated through social media? Clinical trials test treatments to provide reliable information for safety and effectiveness. Trials are building blocks in which what is learned in earlier research can be used to improve treatments, compare alternatives, and improve quality of life. For 20 years, the percentages of clinical trials volunteers have decreased whereas the costs of running clinical trials have multiplied. Participants enroll in trials to access latest treatments, to help others, and to advance science, but there is growing unrest. The priorities of those running the trials differ from those of the participants, and the roles for public research involvement lack clarity. Changes to bridge these gaps in the research culture are proposed through the use of participatory action research (PAR) in which stakeholders collaborate to improve research methodology, galvanize citizen participation, multiply health knowledge, problem-solve barriers to access, and explore the value of research volunteers as collaborators. PAR enabled the inclusion of citizens as full collaborators. Social media data were gathered for 120 days until saturation was reached. De-identified data were organized into a Strengths Weaknesses, Opportunities and Threats framework and coded into themes for analysis. After the analysis, the authors prioritized potential solutions for improving research engagement. Strengths and opportunities remained constant through trial phases, disease burdens, and interventions. Threats included alienation, litigation, disparity, and shaming. Poor management and barriers to inclusion were identified as weaknesses. Opportunities included improving resource management and information quality. Barriers were minimized when relationships between staff and participants were inclusive, respectful, tolerant, and open to change. Participants' communications
Ricardo Sanz-Ruiz; Enrique Gutiérrez Ibañes; Adolfo Villa Arranz; María Eugenia Fernández Santos; Pedro L. Sánchez Fernández; Francisco Fernández-Avilés
First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomize...
Multi - Agent System for Recruiting Patients for Clinical Trials Samhar Mahmoud King’s College London London, UK firstname.lastname@example.org Gareth Tyson...TYPE 3. DATES COVERED 00-00-2014 to 00-00-2014 4. TITLE AND SUBTITLE Multi - Agent System for Recruiting Patients for Clinical Trials 5a...methodology  was proposed to guide the process of de- veloping a multi - agent system from analysis to design. For brevity, we focus here on one
Full Text Available BACKGROUND: Cough is listed as an adverse drug reaction (ADR on the labels of angiotensin receptor blockers (ARB. However, a causal association with cough has also been reported for angiotensin converting enzyme inhibitors (ACEI, which have frequently been used as comparator drugs in the registration clinical trials of ARBs. This prompted us to examine the possible influence of using comparator drugs with well-known ADRs on the safety reporting of investigational drugs in blinded randomized clinical trials. METHODS AND FINDINGS: The double-blinded, randomized clinical trials with comparator drugs were identified in the Japanese dossiers for the new drug applications of ARBs. The risk ratios (RR of reporting cough and headache in ARB arms were calculated for each ARB by comparing trials using ACEIs and trials using non-ACEIs, were then combined with a meta-analysis. 23 trials with a total of 6643 patients were identified, consisting 6 trials using an ACEI comparator including 819 ARB patients and 17 trials using a non-ACEI comparator including 5824 ARB patients. The combined RR of cough reporting was significantly elevated (20.77; 95% confidence interval [CI], 7.47 to 57.76, indicating more frequent reporting of cough in clinical trials using an ACEI comparator. In contrast, the combined RR of headache, a negative control, was insignificant (1.45; 95% CI, 0.34 to 6.22. CONCLUSION: The use of comparators with well-known ADRs in blinded randomized trials produces potential bias in the reporting frequency of ADRs for investigational drugs. The selection of appropriate comparator drugs should be critical in unbiased safety assessment in double-blinded, randomized clinical trials and thus have relevance in reviewing the safety results from a regulatory point of view.
Singhal, Richa; Rana, Rakesh
Missing data is frequently encountered in clinical studies. Unfortunately, they are often neglected or not properly handled during data analysis and this may significantly bias the results of the study, reduce study power and lead to invalid conclusions. Substantial instances of missing data are a serious problem that undermines the scientific trustworthiness of causal conclusions from clinical trials. The assumption that statistical analysis methods can compensate for such missing data is not justified. Hence aspects of clinical trial design that limit the probability of missing data should be an important objective, while planning a clinical trial. In addition to specific aspects of trial design, many components of clinical trial conduct can also limit the extent of missing data. The topic of missing data is often not a major concern until it is time for data collection and data analysis. This article discusses some basic issues about missing data as well as prospective "watch outs" which could reduce the occurrence of missing data. It provides some possible design considerations that should be considered in order to alleviate patients from dropping out of a clinical trial. In addition to these the concept of the missing data mechanism has also been discussed. Three types of missing data mechanisms missing completely at random, missing at random and not missing at random have been discussed in detail.
Gonçalves, Giulliano Peixoto; Barbosa, Fabiano Timbó; Barbosa, Luciano Timbó; Duarte, José Lira
A randomized clinical trial is a prospective study that compares the effect and value of interventions in human beings, of one or more groups vs. a control group. The objective of this study was to evaluate the quality of published randomized clinical trials in Intensive care in Brazil. All randomized clinical trials in intensive care found by manual search in Revista Brasileira de Terapia Intensiva from January 2001 to March 2008 were assessed to evaluate their description by the quality scale. Descriptive statistics and a 95 % confidence interval were used for the primary outcome. Our primary outcome was the randomized clinical trial quality. Our search found 185 original articles, of which 14 were randomized clinical trials. Only one original article (7.1%) showed good quality. There was no statistical significance between the collected data and the data shown in the hypothesis of this search. It can be concluded that in the sample of assessed articles 7% of the randomized clinical trials in intensive care published in a single intensive care journal in Brazil, present good methodological quality.
Alemayehu, Demissie; Anziano, Richard J; Levenstein, Marcia
The increased demand for transparency and disclosure of data from clinical trials sponsored by pharmaceutical companies poses considerable challenges and opportunities from a statistical perspective. A central issue is the need to protect patient privacy and adhere to Good Clinical and Statistical Practices, while ensuring access to patient-level data from clinical trials to the wider research community. This paper offers options to navigate this dilemma and balance competing priorities, with emphasis on the role of good clinical and statistical practices as proven safeguards for scientific integrity, the importance of adopting best practices for reporting of data from secondary analyses, and the need for optimal collaboration among stakeholders to facilitate data sharing.
Andersen, Roger C.; Loebel, Nicolas G.; Andersen, Dane M.
Photodynamic therapy(PDT) has been demonstrated to effectively kill human periopathogens in vitro. To evaluate the efficacy of PDT in vivo a series of clinical trials was carried out in multiple centers and populations. Clinical parameters including clinical attachment level, pocket probing depth and bleeding on probing were all evaluated. All groups received the standard of care, scaling and root planing, and the treatment group additionally received a single treatment of PDT. Of the total 309 patients and over 40,000 pockets treated in these 5 trials it was determined that photodynamic therapy provided a statistically significant improvement in clinical parameters over scaling and root planing alone.
Background Qualitative research methods are increasingly used within clinical trials to address broader research questions than can be addressed by quantitative methods alone. These methods enable health professionals, service users, and other stakeholders to contribute their views and experiences to evaluation of healthcare treatments, interventions, or policies, and influence the design of trials. Qualitative data often contribute information that is better able to reform policy or influence design. Methods Health services researchers, including trialists, clinicians, and qualitative researchers, worked collaboratively to develop a comprehensive portfolio of standard operating procedures (SOPs) for the West Wales Organisation for Rigorous Trials in Health (WWORTH), a clinical trials unit (CTU) at Swansea University, which has recently achieved registration with the UK Clinical Research Collaboration (UKCRC). Although the UKCRC requires a total of 25 SOPs from registered CTUs, WWORTH chose to add an additional qualitative-methods SOP (QM-SOP). Results The qualitative methods SOP (QM-SOP) defines good practice in designing and implementing qualitative components of trials, while allowing flexibility of approach and method. Its basic principles are that: qualitative researchers should be contributors from the start of trials with qualitative potential; the qualitative component should have clear aims; and the main study publication should report on the qualitative component. Conclusions We recommend that CTUs consider developing a QM-SOP to enhance the conduct of quantitative trials by adding qualitative data and analysis. We judge that this improves the value of quantitative trials, and contributes to the future development of multi-method trials. PMID:23433341
Awerbach, Jordan D; Krasuski, Richard A; Hill, Kevin D
The investigation of pediatric pulmonary hypertension (PH) drugs has been identified as a high priority by the United States National Institutes of Health (NIH). Studying pediatric PH is challenging due to the rare and heterogeneous nature of the disease. We sought to define the pediatric PH clinical trials landscape, to evaluate areas of trial success or failure, and to identify potential obstacles to the study of pediatric PH drugs. Interventional pediatric (ages 0-17 years) PH trials registered on ClinicalTrials.gov from June 2005 through December 2014 were analyzed. There were 45 pediatric PH trials registered during the study period. Median (IQR) projected trial enrollment was 40 (24-63), with seven trials (16%) targeting > 100 participants. Industry was the most common trial sponsor (n = 23, 50%), with only two (4.4%) NIH-sponsored trials. Phosphodiesterase inhibitors were the most frequently studied drug (n = 18, 39%). Single group study designs were used in 44% (n = 20) with an active comparator (parallel, factorial, or cross-over designs) in 25 trials, including 22 with randomization and ten that were double-blinded. Study outcomes varied markedly with inconsistent use of known surrogate and composite endpoints. One-third of trials (n = 15, 33%) were terminated, predominantly due to poor participant enrollment. Of the 17 completed trials, 11 had published results and only three efficacy trials met their primary endpoint. There are unique challenges to drug development in pediatric PH, including enrolling patients, identifying appropriate study endpoints, and conducting randomized, controlled, double-blind trials where the likelihood of meeting the study endpoint is optimized.
Márquez-Ibáñez, B; Armendáriz-Anguiano, A L; Bacardí-Gascón, M; Jiménez-Cruz, A
The increased prevalence of obesity has been associated to an increment in chronic-degenerative diseases. The behavioral conduct therapies (BCT) have been used to help subjects develop a series of skills to reach a healthy weight. We conducted a review of the literature of BCT from controlled clinical trials registered at PubMed from January 2000 to november 2006. We found five long-term (> or = 12 months) studies and analyzed each study. The percent of weight loss at the end of follow up ranged from 3% to 9% of the initial weight; the percent of retention fluctuated from 92% at three months to 55% at 24 months. There were no similar reported studies conducted in Latino or Hispanic population. These results suggest that the change in loss of weight with BCT are modest at the end of the follow up period and that most of the studies report low adherence to treatment. It is recommended that public and private funds are needed to implement effective and safe multicentric long term randomized studies on different cultural populations, including most Latin-American countries.
Full Text Available The past 30 years have seen rapid growth in the number of clinical trials in liver disease; due mostly to effective drug discovery programs by the pharmaceutical industry. The advantages associated with therapeutic trials in chronic liver disease, or any other disease for that matter, go far beyond potential benefit to the individual patient, other beneficiaries include the treating physician, the sponsoring agency and their investors, the institution/university and the general public. But there is always a downside to any experiment. The disadvantages and advantages of clinical trials in liver disease are the topics for this discussion.
Muirhead, Robb J
This paper explores an approach to Bayesian sample size determination in clinical trials. The approach falls into the category of what is often called "proper Bayesian", in that it does not mix frequentist concepts with Bayesian ones. A criterion for a "successful trial" is defined in terms of a posterior probability, its probability is assessed using the marginal distribution of the data, and this probability forms the basis for choosing sample sizes. We illustrate with a standard problem in clinical trials, that of establishing superiority of a new drug over a control.
created military Vision Center of Excellence in NEER steering committee meetings and deliberations. References: 1. Cideciyan AV, Aleman TS, Boye SL, et...2008;105:15112-15117. 2. Hauswirth W, Aleman TS, Kaushal S, et al. Phase I Trial of Leber Congenital Amaurosis due to RPE65 Mutations by Ocular
A unique public-private collaboration today announced the initiation of the Lung Cancer Master Protocol (Lung-MAP) trial, a multi-drug, multi-arm, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer. Squamous cell carcinom
Jones, Rachel; Lacroix, Lorraine J; Porcher, Eloni
Advertising via Facebook to elicit involvement in clinical trials has demonstrated promise in expanding geographic reach while maintaining confidentiality. The purpose of this study is to evaluate Facebook advertising to reach at-risk, predominately African American or Black women in higher HIV prevalence communities for an HIV prevention clinical trial, and to compare baseline characteristics to those recruited on-the-ground. Maintaining confidentiality and the practical aspects of creating and posting ads on Facebook are described. The advertising strategy targeted multicultural affinities, gender, age, interest terms, and zip codes. We report on results during 205 days. A total of 516,498 Facebook users viewed the ads an average of four times, resulting in 37,133 clicks to the study website. Compared to 495 screened on-the-ground, 940 were screened via Facebook ads, of these, half (n = 477, 50.74%) were high risk, and of those at risk, 154 were randomized into the 6-month clinical trial. Black women comprised 71.60% (n = 673) of the total screened online. Roughly twice as many Black women screened via Facebook compared to on-the-ground, yet, the percentage at high risk was similar. Preliminary data suggest that the extent to which ad headlines and photos tap into authentic social experience, advertising on Facebook can extend geographic reach and provide a comparative sample to women recruited on-the-ground.
Smed, Marie; Getz, Kenneth A
Knowledge generated by site representatives through their participation in clinical trials is valuable for testing new products in use and obtaining final market approval. The leverage of this important knowledge is however challenged as the former direct relationships between in-house staff in the industry and site representatives are changing. The process of clinical trials has increased in complexity over the years, resulting in additional management layers. Besides an increase in internal management layers, sponsors often also outsource various tasks related to clinical trials to a CRO (Contract Research Organization) and thereby adding another link in the relationships between site and sponsor. These changes are intended to optimize the time-consuming and costly trial phases; however, there is a need to study whether valuable knowledge and experience is compromised in the process. Limited research exists on the full range of clinical practice insights obtained by investigators during and after clinical trials and how well these insights are transferred to study sponsors. This study explores the important knowledge-transfer processes between sites and sponsors and to what extent sites' knowledge gained in clinical trials is utilized by the industry. Responses from 451 global investigative site representatives are included in the study. The analysis of the extensive dataset reveals that the current processes of collaboration between sites and the industry restrict the leverage of valuable knowledge gained by physicians in the process of clinical trials. These restrictions to knowledge-transfer between site and sponsor are further challenged if CRO partners are integrated in the trial process.
Concannon, Thomas W; Guise, Jeanne-Marie; Dolor, Rowena J; Meissner, Paul; Tunis, Sean; Krishnan, Jerry A; Pace, Wilson D; Saltz, Joel; Hersh, William R; Michener, Lloyd; Carey, Timothy S
An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1-year learning network to identify high-priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three-stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1-day network meeting at the end of the year. The year-long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials.
Full Text Available New drug development is a time-consuming and expensive process. Recently, there has been stagnation in the development of novel compounds. Moreover, the attrition rate in clinical research is also on the rise. Fearing more stagnation, the Food and Drug Administration released the critical path initiative in 2004 and critical path opportunity list in 2006 thus highlighting the need of advancing innovative trial designs. One of the innovations suggested was the adaptive designed clinical trials, a method promoting introduction of pre-specified modifications in the design or statistical procedures of an on-going trial depending on the data generated from the concerned trial thus making a trial more flexible. The adaptive design trials are proposed to boost clinical research by cutting on the cost and time factor. Although the concept of adaptive designed clinical trials is round-the-corner for the last 40 years, there is still lack of uniformity and understanding on this issue. This review highlights important adaptive designed methodologies besides covering the regulatory positions on this issue.
Guise, Jeanne‐Marie; Dolor, Rowena J.; Meissner, Paul; Tunis, Sean; Krishnan, Jerry A.; Pace, Wilson D.; Saltz, Joel; Hersh, William R.; Michener, Lloyd; Carey, Timothy S.
Abstract An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1‐year learning network to identify high‐priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three‐stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1‐day network meeting at the end of the year. The year‐long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials. PMID:24472114
Hart, Tessa; Bagiella, Emilia
The growth of evidence-based medicine means that both researchers and clinicians must grasp the complex issues involved in implementing clinical trials, which are especially challenging for the behavioral (experience-based) treatments that predominate in rehabilitation. In this article we discuss selected issues germane to the design, implementation, and analysis of group-level clinical trials in rehabilitation. We review strengths, weaknesses, and best applications of 1-sample, between-subjects, and within-subjects study designs, including newer models such as practical clinical trials and point-of-care trials. We also discuss the selection of appropriate control conditions against which to test rehabilitation treatments, as well as issues related to trial blinding. In a section on treatment definition, we discuss the challenges of specifying the active ingredients in the complex interventions that are widely used in rehabilitation, and present an illustration of 1 approach to defining treatments via the learning mechanisms that underlie them. Issues related to treatment implementation are also discussed, including therapist allocation and training, and assessment of treatment fidelity. Finally we consider 2 statistical topics of particular importance to many rehabilitation trials: the use of multiple or composite outcomes, and factors that must be weighed in estimating sample size for clinical trials.
Full Text Available ABSTRACT: Chikungunya virus is no stranger to the Indian sub- continent. Since its first isolation in Calcutta  in 1963, there have been several reports of chikung unya virus infection in different parts of India , , . The last outbreak of chikungunya virus infection o ccurred in India in 1971. Subsequently there has been no activ e or passive surveillance carried out in the country and therefore, it ‘seemed’ that the virus h ad ‘disappeared’ from the subcontinent  However, recent reports of large scale outbreaks of fever caused by chikungunya virus infection in several parts of Southern India have confirmed th e re-emergence of this virus. It has been estimated that over 1,80,000 cases have occurred in India since December 2005  Andhra Pradesh (AP was the first state to report this dise ase in December 2005, and one of the worst affected (over 80,000 suspected cases . Over 12% of patients who contract chikungunya virus infection develop chronic joint symptoms  . OBJECTIVE: To test the efficacy of chloroquine in reducing the pain of chikungunya induced arthritis a s compared to paracetamol. METHODOLOGY: A Randomized Clinical Trial was carried out in a c ommunity attached to urban health centre of PESIMSR, Kuppam during August 2006. Among the 132 cases of arthritis, 86 persons were selected based on their availability and consent to participate. They were divided into two randomly assigned groups namely Cat egory–1(Chloroquine group and Category–2 ( Paracetamol group. Chloroquine tablet -155 mg and Paracetamol tablet - 500 mg were administered as a single dose to the two groups respectively. The groups were followed up for 8 days and the results were analyzed. STATISTICAL ANALYSIS: Analysis was carried out by using S.P.S.S. package. Asymptoic test statistic an d X 2 MH (Chi square test were used to evaluate the effect of the drugs. RESULTS OF THE STUDY: The decrease of pain in chikungunya arthritis cases was
Full Text Available Many chiropractors believe that chiropractic treatments are effective for gastrointestinal disorders. The aim of the present systematic review was to critically evaluate the evidence from controlled clinical trials supporting or not supporting this notion. Six electronic databases were searched for relevant studies. No limits were applied to language or publication date. Prospective, controlled, clinical trials of any type of chiropractic treatment for any type of gastrointestinal problem, except infant colic, were included. Only two trials were found – one was a pilot study, and the other had reached a positive conclusion; however, both had serious methodological flaws. There is no supportive evidence that chiropractic is an effective treatment for gastrointestinal disorders.
Decker, Martha; Montagu, Dominic
This paper evaluates the ability of social franchise programs, which use private providers to offer reproductive health services, to provide services to youth in western Kenya. Although franchise clinics have rarely targeted youth, they appear to offer a viable alternative for providing reproductive health services to this age group.
Nugent, Timothy; Upton, David; Cimpoesu, Mihai
The scientific credibility of findings from clinical trials can be undermined by a range of problems including missing data, endpoint switching, data dredging, and selective publication. Together, these issues have contributed to systematically distorted perceptions regarding the benefits and risks of treatments. While these issues have been well documented and widely discussed within the profession, legislative intervention has seen limited success. Recently, a method was described for using a blockchain to prove the existence of documents describing pre-specified endpoints in clinical trials. Here, we extend the idea by using smart contracts - code, and data, that resides at a specific address in a blockchain, and whose execution is cryptographically validated by the network - to demonstrate how trust in clinical trials can be enforced and data manipulation eliminated. We show that blockchain smart contracts provide a novel technological solution to the data manipulation problem, by acting as trusted administrators and providing an immutable record of trial history.
Hindryckx, Pieter; Baert, Filip; Hart, Ailsa; Armuzzi, Alessandro; Panès, Julian; Peyrin-Biroulet, Laurent
It goes back to 1932 when Dr. Burrill Bernard Crohn and co-workers published their landmark paper, describing regional ileitis as a disease entity. However, clinical trial research has been developing rather slowly in luminal Crohn's disease. It took until the early seventies before the first randomized clinical trial was set up by the National Co-operative Crohn's Disease Study (NCCDS) group. Although the efforts of this group triggered a first wave of clinical trials in Crohn's disease, the lack of guidelines for conducting a clinical trial in this research area resulted in a variety of study designs and much criticism. Besides having a rather small sample size and a short follow-up time, they were often characterized by vague and subjective assessment of disease activity and treatment response. Following the advent of a new and very potent drug class in the late nineties, the anti-TNF agents, investigators started to re-think their study protocols and the first guidelines were set up by the regulatory authorities. Over the last 15years, clinical trials in luminal Crohn's disease have been evolving significantly. Inclusion criteria have been shifting from clinical scores such as Crohn's Disease Activity Index (CDAI) to more objective disease activity parameters such as biomarkers (C-reactive protein and faecal calprotectin) and endoscopic lesions. Primary endpoints have been developing from clinical response to corticosteroid-free remission and more ambitious end-points such as mucosal healing. In this paper, we will give a historical overview on clinical trials in luminal Crohn's disease, before and within the biologic era, and provide insight into how they have shaped our current understanding of trial designs in Crohn's disease.
Clausen, J; Albrecht, H; Mathie, R T
Veterinary homeopathy has led a somewhat shadowy existence since its first introduction. Only in the last three decades has the number of clinical trials increased considerably. This literature is generally not well perceived, which may be partly a consequence of the diffuse and somewhat inaccessible nature of some of the relevant research publications. The Veterinary Clinical Research Database for Homeopathy (VetCR) was launched in 2006 to provide information on existing clinical research in veterinary homeopathy and to facilitate the preparation of systematic reviews. The aim of the present report is to provide an overview of this first database on clinical research in veterinary homeopathy, with a special focus on its content of placebo controlled clinical trials and summarising what is known about placebo effects in animals. In April 2012, the VetCR database contained 302 data records. Among these, 203 controlled trials were identified: 146 randomised and 57 non-randomised. In 97 of those 203 trials, the homeopathic medical intervention was compared to placebo. A program of formal systematic reviews of peer-reviewed randomised controlled trials in veterinary homeopathy is now underway; detailed findings from the program's data extraction and appraisal approach, including the assessment of trial quality (risk of bias), will be reported in due course. Copyright © 2012 Elsevier Ltd. All rights reserved.
Gluud, Christian; Nikolova, Dimitrinka
The number of publications on clinical trials is unknown as well as the countries publishing most trial reports. To try to examine these questions we performed an ecological study.......The number of publications on clinical trials is unknown as well as the countries publishing most trial reports. To try to examine these questions we performed an ecological study....
Wan, Mandy; Al Hashimi, Ali; Batchelor, Hannah
Availability and sourcing of investigational drugs for paediatric clinical trials is known to be a challenge for investigator-led clinical trials. The National Institute of Health Research Clinical Research Network: Children (CRN: Children) provides support for formulations and pharmacy related issues to researchers planning and setting up paediatric clinical trials within England. This paper reviews pharmacy and formulation support provided to a consecutive series of investigator-led clinical studies supported by CRN:Children. Case studies are included to describe some of the unique pharmaceutical challenges encountered. 44 trials were reviewed and a total of 103 products were required to support these clinical trials. UK authorised products were suitable for use for 62 of these 103 products. In the remaining 41 cases, 4 could be sourced as an authorised product within the European Union and the remaining 37 required bespoke manufacture. Bespoke manufacture of an investigational drug or placebo is costly. Typical costs for the initial development and testing of a bespoke investigational drug or placebo were in the range of £30,000-100,000 per product. The estimated cost for 19 out of 45 trials was available; in summary, the costs on a per patient per day of therapy basis ranged from under £1 to almost £600; short studies involving multiple agents are obviously the most expensive. This range is dependent upon the need for bespoke manufacture and also the number of participants within the trial. The arrangements for investigational drug supply can greatly affect the study design, regulatory requirements, trial logistics, as well as the total cost of research. As investigational product related activities are often costly, necessitating months of advance planning, it is imperative that specialist inputs are sought from the very start of the study design and planning process. Copyright © 2016 Elsevier B.V. All rights reserved.
Shah, Priya S; Schaffer, David V
For the first time, scientists have tested a combination of three RNA-based gene therapies, delivered via a lentiviral vector, to target HIV in patients. This study not only demonstrates the safety and long-term viability of this approach, but also highlights areas in which focused improvements in gene therapy strategies may provide the most impact in increasingly translating promise in the laboratory to efficacy in the clinic.
Schouten, Jeffrey T.; Dixon, Dennis; Varghese, Suresh; Cope, Marie T.; Marci, Joe; Kagan, Jonathan M.
Background Identifying efficacious interventions for the prevention and treatment of human diseases depends on the efficient development and implementation of controlled clinical trials. Essential to reducing the time and burden of completing the clinical trial lifecycle is determining which aspects take the longest, delay other stages, and may lead to better resource utilization without diminishing scientific quality, safety, or the protection of human subjects. Purpose In this study we modeled time-to-event data to explore relationships between clinical trial protocol development and implementation times, as well as identify potential correlates of prolonged development and implementation. Methods We obtained time interval and participant accrual data from 111 interventional clinical trials initiated between 2006 and 2011 by NIH’s HIV/AIDS Clinical Trials Networks. We determined the time (in days) required to complete defined phases of clinical trial protocol development and implementation. Kaplan-Meier estimates were used to assess the rates at which protocols reached specified terminal events, stratified by study purpose (therapeutic, prevention) and phase group (pilot/phase I, phase II, and phase III/ IV). We also examined several potential correlates to prolonged development and implementation intervals. Results Even though phase grouping did not determine development or implementation times of either therapeutic or prevention studies, overall we observed wide variation in protocol development times. Moreover, we detected a trend toward phase III/IV therapeutic protocols exhibiting longer developmental (median 2 ½ years) and implementation times (>3years). We also found that protocols exceeding the median number of days for completing the development interval had significantly longer implementation. Limitations The use of a relatively small set of protocols may have limited our ability to detect differences across phase groupings. Some timing effects
Gluud, C; Nikolova, D
Electronic searches on databases for randomised clinical trials and controlled clinical trials do not identify as many trials as handsearches, and trial reporting may be flawed. The aims were to identify all fully reported randomised clinical trials in the Journal of Hepatology and to make a qual...... a qualitative assessment of the reporting....
Lifson, A; Rahme, FS; Belloso, WH;
PURPOSE: The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials. METHOD: SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression...
Azorin, J-M; Adida, M; Blin, O; Simon, N; Fakra, E; Cermolacce, M; Bottai, T; Pringuey, D; Micoulaud-Franchi, J-A; Belzeaux, R; Kaladjian, A
To correctly interpret the results of a randomised controlled trial (RCT), practitioners have to spot bias and other potential problems present in the trial. Internal as well as external validity of the trial are linked to the presence of such bias. The internal validity is ensured by a clear definition of the objectives of the trial. The number of patients to be included in the trial is calculated on the basis of the main objective of the trial and more precisely on the basis of the primary endpoint selected to assess the efficacy of treatment. This is the best way to ensure that the statistical significance of the result may have a clinical relevance. Internal validity depends also on the process of patients selection, the methods used to ensure comparability of groups and treatments, the criteria employed to assess efficacy, and the methods for the analysis of data. External validity refers to subjects that have been excluded from the trial, limitations of RCTs, as well as the coherence and clinical relevance of the trial. Internal validity has to be fueled by external validity. © L’Encéphale, Paris, 2016.
In German and American law, clinical trials require a positive benefit-risk evaluation, free and informed consent, medical and scientific qualification of the doctor, and a written research protocol. American law requires a written consent, which is free of undue influence, the subject being instructed that he is free to withdraw from the trial. In German law, an orally given consent is sufficient for therapeutic trials. With minor or incompetent research subjects, informed consent to therapeutic clinical experimentation has to be given by their parents or guardians, the permissibility of which, in other trials, is controversial. In non-therapeutic trials, blind studies, double-bind studies, and trials involving placebos, special attention has to be paid to the risk-benefit analysis and to informed consent, which in these cases, even in Germany, must be written. The most outstanding feature of American law of clinical trial is that the experimentation is subject to previous control and approval by institutional review boards. The most interesting difference in German law is the investigator's duty to effect an insurance against the risks of the research subject's death or invalidity.
FitzGerald, Thomas J; Bishop-Jodoin, Maryann; Followill, David S; Galvin, James; Knopp, Michael V; Michalski, Jeff M; Rosen, Mark A; Bradley, Jeffrey D; Shankar, Lalitha K; Laurie, Fran; Cicchetti, M Giulia; Moni, Janaki; Coleman, C Norman; Deye, James A; Capala, Jacek; Vikram, Bhadrasain
Cancer treatment evolves through oncology clinical trials. Cancer trials are multimodal and complex. Assuring high-quality data are available to answer not only study objectives but also questions not anticipated at study initiation is the role of quality assurance. The National Cancer Institute reorganized its cancer clinical trials program in 2014. The National Clinical Trials Network (NCTN) was formed and within it was established a Diagnostic Imaging and Radiation Therapy Quality Assurance Organization. This organization is Imaging and Radiation Oncology Core, the Imaging and Radiation Oncology Core Group, consisting of 6 quality assurance centers that provide imaging and radiation therapy quality assurance for the NCTN. Sophisticated imaging is used for cancer diagnosis, treatment, and management as well as for image-driven technologies to plan and execute radiation treatment. Integration of imaging and radiation oncology data acquisition, review, management, and archive strategies are essential for trial compliance and future research. Lessons learned from previous trials are and provide evidence to support diagnostic imaging and radiation therapy data acquisition in NCTN trials.
Rutherford, Bret R; Roose, Steven P
Placebo response in clinical trials of antidepressant medications is substantial and has been increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for depression and dissuade patients from accessing mental health care. Conversely, enhancing the factors responsible for placebo response may represent a strategy for improving available treatments for major depressive disorder. A conceptual framework describing the causes of placebo response is needed in order to develop strategies for minimizing placebo response in clinical trials, maximizing placebo response in clinical practice, and talking with depressed patients about the risks and benefits of antidepressant medications. In this review, the authors examine contributors to placebo response in antidepressant clinical trials and propose an explanatory model. Research aimed at reducing placebo response should focus on limiting patient expectancy and the intensity of therapeutic contact in antidepressant clinical trials, while the optimal strategy in clinical practice may be to combine active medication with a presentation and level of therapeutic contact designed to enhance treatment response.
Mackiewicz, Jacek; Mackiewicz, Andrzej
Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.
Starren, Justin B; Payne, Philip R O; Kaufman, David R
Clinical trials increasingly rely upon web-based Clinical Trials Management Systems (CTMS). As with clinical care systems, Human Computer Interaction (HCI) issues can greatly affect the usefulness of such systems. Evaluation of the user interface of one web-based CTMS revealed a number of potential human-computer interaction problems, in particular, increased workflow complexity associated with a web application delivery model and potential usability problems resulting from the use of ambiguous icons. Because these design features are shared by a large fraction of current CTMS, the implications extend beyond this individual system.
Sinnett, Philip Marcus; Carr, Branden; Cook, Gregory; Mucklerath, Halie; Varney, Laura; Weiher, Matt; Yerokhin, Vadim; Vassar, Matt
We examined the use of clinical trials registries in published systematic reviews and meta-analyses from clinical neurology. A review of publications between January 1, 2008 and December 31, 2014 from five neuroscience journals (Annals of Neurology, Brain, Lancet Neurology, Neurology, and The Neuroscientist) was performed to identify eligible systematic reviews. The systematic reviews comprising the final sample were independently appraised to determine if clinical trials registries had been included as part of the search process. Studies acknowledging the use of a trials registry were further examined to determine whether trial data had been incorporated into the analysis. The initial search yielded 194 studies, of which 78 systematic reviews met the selection criteria. Of those, five acknowledged the use of a specific clinical trials registry: four reviewed unpublished trial data and two incorporated unpublished trial data into their results. Based on our sample of systematic reviews, there was no increase in the use of trials registries in systematic review searches over time. Few systematic reviews published in clinical neurology journals included data from relevant clinical trials registries.
Erves, Jennifer Cunningham; Mayo-Gamble, Tilicia L; Hull, Pamela C; Duke, Lauren; Miller, Stephania T
Approximately one-quarter of human papillomavirus (HPV) infections are acquired by adolescents, with a higher burden among racial/ethnic minorities. However, racial/ethnic minorities have been underrepresented in previous HPV vaccine trials. Ongoing and future HPV vaccine optimization trials would benefit from racially- and ethnically-diverse sample of adolescent trial participants. This study examined factors influencing parental willingness to consent to their adolescents' participation in HPV vaccine clinical trials and tested for possible racial differences. A convenience sample of parents of adolescents (N = 256) completed a cross-sectional survey. Chi square analyses were used to assess racial differences in parental HPV vaccine awareness and intentions and willingness to consent to their child participating in an HPV vaccine clinical trial. Ordinal logistic regression was used to identify factors associated with willingness. Approximately 47% of parents were willing to allow their adolescent to participate in HPV vaccine clinical trials (30.7% African American and 48.3% Caucasian, p = .081). African Americans had lower HPV vaccine awareness (p = .006) but not lower intentions to vaccinate (p = .086). Parental willingness was positively associated with the following variables: Child's age (p < .039), Perceived Advantages of HPV Vaccination for Adolescents (p = .002), Parental Trust in Medical Researchers (p < .001), and Level of Ease in Understanding Clinical Trial Information (p = .010). Educating parents about the advantages of HPV vaccines for younger adolescents using low-literacy educational materials and building trust between parents and researchers may increase parental willingness to consent to adolescent participation in HPV vaccine clinical trials.
Karsh, Lawrence I
The structure of modern clinical trials is designed to protect patient safety while generating safety and efficacy data. Safety is the primary concern, and United States regulations are shaped by a series of responses to incidents, including notable safety lapses and unethical trials. These regulations focus on 3 essential components, defined by the 1979 Belmont Report: respect for persons, beneficence, and justice. Further, the international community has formally outlined good clinical practice (GCP), which mandates that trials are designed to produce meaningful data, conform to international ethics regulations, and provide assurances that data are reported in a credible and reliable manner. The Food and Drug Administration (FDA) and federal government have outlined the necessary components of clinical trials in the Code of Federal Regulations (CFR). These include institutional review boards (IRBs), standard operating procedures (SOPs), sites, sponsors, investigators, and patients. The investigator is the center of the trial and is required to sign an agreement with the federal government to uphold the CFR. Investigator duties include making sure that investigator and support staff having appropriate qualifications, delegating duties, monitoring the study for compliance and record keeping, providing care, and accepting accountability for the trial, among other duties. Physicians, who already have significant time demands, need a well-trained staff, including clinical coordinators, to adequately meet these duties. Despite these requirements, trials can have significant benefits for investigators, practices, and patients, foremost of which is the ability to provide cutting edge care. However, the clinical trial process requires routine evaluation and continual performance improvement in order to ensure that patients not only receive excellent care, but also do so in the safest possible manner.
Full Text Available Abstract Background Randomised controlled clinical trials are performed to resolve uncertainty concerning comparator interventions. Appropriate acknowledgment of uncertainty enables the concurrent achievement of two goals : the acquisition of valuable scientific knowledge and an optimum treatment choice for the patient-participant. The ethical recruitment of patients requires the presence of clinical equipoise. This involves the appropriate choice of a control intervention, particularly when unapproved drugs or innovative interventions are being evaluated. Discussion We argue that the choice of a control intervention should be supported by a systematic review of the relevant literature and, where necessary, solicitation of the informed beliefs of clinical experts through formal surveys and publication of the proposed trial's protocol. Summary When clinical equipoise is present, physicians may confidently propose trial enrollment to their eligible patients as an act of therapeutic beneficence.
Keus, Frederik; van der Horst, Iwan C C; Nijsten, Maarten W
Today's clinical research faces challenges such as a lack of clinical equipoise between treatment arms, reluctance in randomizing for multiple treatments simultaneously, inability to address interactions and increasingly restricted resources. Furthermore, many trials are biased by extensive exclusion criteria, relatively small sample size and less appropriate outcome measures. We propose a 'Multiplex' trial design that preserves clinical equipoise with a continuous and factorial trial design that will also result in more efficient use of resources. This multiplex design accommodates subtrials with appropriate choice of treatment arms within each subtrial. Clinical equipoise should increase consent rates while the factorial design is the best way to identify interactions. The multiplex design may evolve naturally from today's research limitations and challenges, while principal objections seem absent. However this new design poses important infrastructural, organisational and psychological challenges that need in depth consideration.
Full Text Available .2 Objective of the trial E.2.1Main objective of the trial The purpose of this trial is to demonstrate that dextromethorphan...– IMP) before and during an OGTT- For dextromethorphan: to assess whether a dose-dependency of PD exists-To
Morrish, Alicia T; Hawley, Carmel M; Johnson, David W; Badve, Sunil V; Perkovic, Vlado; Reidlinger, Donna M; Cass, Alan
Chronic kidney disease is a major public health problem globally. Despite this, there are fewer high-quality, high-impact clinical trials in nephrology than other internal medicine specialties, which has led to large gaps in evidence. To address this deficiency, the Australasian Kidney Trials Network, a Collaborative Research Group, was formed in 2005. Since then, the Network has provided infrastructure and expertise to conduct patient-focused high-quality, investigator-initiated clinical trials in nephrology. The Network has not only been successful in engaging the nephrology community in Australia and New Zealand but also in forming collaborations with leading researchers from other countries. This article describes the establishment, development, and functions of the Network. The article also discusses the current and future funding strategies to ensure uninterrupted conduct of much needed clinical trials in nephrology to improve the outcomes of patients affected by kidney diseases with cost-effective interventions.
Hanna, Eve; Rémuzat, Cecile; Auquier, Pascal; Toumi, Mondher
Advanced therapy medicinal products (ATMPs) constitute a class of innovative products that encompasses gene therapy, somatic cell therapy, and tissue-engineered products (TEP). There is an increased investment of commercial and non-commercial sponsors in this field and a growing number of ATMPs randomized clinical trials (RCT) and patients enrolled in such trials. RCT generate data to prove the efficacy of a new therapy, but the discontinuation of RCTs wastes scarce resources. Our objective is to identify the number and characteristics of discontinued ATMPs trials in order to evaluate the rate of discontinuation. We searched for ATMPs trials conducted between 1999 to June 2015 using three databases, which are Clinicaltrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the EU Drug Regulating Authorities Clinical Trials (EudraCT). We selected the ATMPs trials after elimination of the duplicates. We identified the disease areas and the sponsors as commercial or non-commercial organizations. We classified ATMPs by type and trial status, that is, ongoing, completed, terminated, discontinued, and prematurely ended. Then, we calculated the rate of discontinuation. Between 1999 and June 2015, 143 withdrawn, terminated, or prematurely ended ATMPs clinical trials were identified. Between 1999 and June 2013, 474 ongoing and completed clinical trials were identified. Therefore, the rate of discontinuation of ATMPs trials is 23.18%, similar to that for non-ATMPs drugs in development. The probability of discontinuation is, respectively, 27.35, 16.28, and 16.34% for cell therapies, gene therapies, and TEP. The highest discontinuation rate is for oncology (43%), followed by cardiology (19.2%). It is almost the same for commercial and non-commercial sponsors; therefore, the discontinuation reason may not be financially driven. No failure risk rate per development phase is available for ATMPs. The discontinuation rate may prove helpful when assessing the
Guzman, Angelica; Irby, Megan B; Pulgar, Camila; Skelton, Joseph A
Pediatric obesity continues to be an epidemic, affecting Hispanic children disproportionately. Recent recommendations outline a step-wise approach to the treatment of overweight and obese children, culminating in tertiary-care, multidisciplinary programs. We detail here how our tertiary-care, family-based, pediatric weight management clinic addressed the problem of few Spanish-speaking families enrolling in treatment after referral by adding a Bilingual Case Manager. Utilizing a family-centered, high-contact, personal approach, our program increased the number of Hispanic families enrolling over ten-fold. Further, outcomes in Hispanic families were equal to or better than other racial/ethnic groups. Lessons learned from this experience may benefit other obesity treatment programs trying to improve care of Spanish-speaking families.
Tétreault, Pascal; Mansour, Ali; Vachon-Presseau, Etienne; Schnitzer, Thomas J.; Apkarian, A. Vania
Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active
Califf, Robert M; Sugarman, Jeremy
The need for high-quality evidence to support decision making about health and health care by patients, physicians, care providers, and policy-makers is well documented. However, serious shortcomings in evidence persist. Pragmatic clinical trials that use novel techniques including emerging information and communication technologies to explore important research questions rapidly and at a fraction of the cost incurred by more "traditional" research methods promise to help close this gap. Nevertheless, while pragmatic clinical trials can bridge clinical practice and research, they may also raise difficult ethical and regulatory challenges. In this article, the authors briefly survey the current state of evidence that is available to inform clinical care and other health-related decisions and discuss the potential for pragmatic clinical trials to improve this state of affairs. They then propose a new working definition for pragmatic research that centers upon fitness for informing decisions about health and health care. Finally, they introduce a project, jointly undertaken by the National Institutes of Health Health Care Systems Research Collaboratory and the National Patient-Centered Clinical Research Network (PCORnet), which addresses 11 key aspects of current systems for regulatory and ethical oversight of clinical research that pose challenges to conducting pragmatic clinical trials. In the series of articles commissioned on this topic published in this issue of Clinical Trials, each of these aspects is addressed in a dedicated article, with a special focus on the interplay between ethical and regulatory considerations and pragmatic clinical research aimed at informing "real-world" choices about health and health care.
Costa, Leonardo Oliveira Pena; Moseley, Anne M; Sherrington, Catherine; Maher, Christopher G; Herbert, Robert D; Elkins, Mark R
The objective of this study was to identify core journals in physical therapy by identifying those that publish the most randomized controlled trials of physical therapy interventions, provide the highest-quality reports of randomized controlled trials, and have the highest journal impact factors. This study was an audit of a bibliographic database. All trials indexed in the Physiotherapy Evidence Database (PEDro) were analyzed. Journals that had published at least 80 trials were selected. The journals were ranked in 4 ways: number of trials published; mean total PEDro score of the trials published in the journal, regardless of publication year; mean total PEDro score of the trials published in the journal from 2000 to 2009; and 2008 journal impact factor. The top 5 core journals in physical therapy, ranked by the total number of trials published, were Archives of Physical Medicine and Rehabilitation, Clinical Rehabilitation, Spine, British Medical Journal (BMJ), and Chest. When the mean total PEDro score was used as the ranking criterion, the top 5 journals were Journal of Physiotherapy, Journal of the American Medical Association (JAMA), Stroke, Spine, and Clinical Rehabilitation. When the mean total PEDro score of the trials published from 2000 to 2009 was used as the ranking criterion, the top 5 journals were Journal of Physiotherapy, JAMA, Lancet, BMJ, and Pain. The most highly ranked physical therapy-specific journals were Physical Therapy (ranked eighth on the basis of the number of trials published) and Journal of Physiotherapy (ranked first on the basis of the quality of trials). Finally, when the 2008 impact factor was used for ranking, the top 5 journals were JAMA, Lancet, BMJ, American Journal of Respiratory and Critical Care Medicine, and Thorax. There were no significant relationships among the rankings on the basis of trial quality, number of trials, or journal impact factor. Physical therapists who are trying to keep up-to-date by reading the best
For the purpose of comparing the efficacy and safety of a Similar Biotherapeutic Product (SBP) to a Reference Biotherapeutic Product (RBP), the "Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)" issued by the World Health Organisation (WHO), states that equivalence or non-inferiority studies may be acceptable. While in principle, equivalence trials are preferred, non-inferiority trials may be considered if appropriately justified, such as for a medicinal product with a wide safety margin. However, the statistical issues involved in the design, conduct, analysis and interpretation of equivalence and non-inferiority trials are complex and subtle, and require that all aspects of these trials be given careful consideration. These issues are important in order to ensure that equivalence and non-inferiority trials provide valid data that are necessary to draw reliable conclusions regarding the clinical similarity of an SBP to an RBP. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.
The relationship between the ethical standards for the governance of clinical trials and market forces can be complex and problematic. This article uses India as a case study to explore this nexus. From the mid-2000s, India became a popular destination for foreign-sponsored clinical trials. The Indian government had sought to both attract clinical trials and ensure these would be run in line with internationally accepted ethical norms. Reports of controversial medical research, however, triggered debate about the robustness and suitability of India's regulatory system. In response to civil society pressure and interventions by the Supreme Court, the Indian government proposed additional measures aimed at strengthening protections for clinical trial participants. Whilst the reforms can be seen as a victory for human rights activists, they have also been criticised as being overly burdensome for sponsors. Indeed, their announcement prompted an exodus of clinical trials from India. Fearful of losing business to 'rival' countries, the Indian government is revisiting some of its proposals. The Indian example suggests that research ethics frameworks and national policies for economic development are increasingly intertwined. Host countries are in theory free to improve the lot of research participants, but doing so may make them appear less attractive to foreign sponsors, who can simply shift their activities to more industry-friendly jurisdictions. Although these economic pressures are unlikely to lead to a regulatory 'race to the bottom', they may limit host countries' ability to enact socially desirable reforms. © 2017 John Wiley & Sons Ltd.
Charles S. Mayo
Full Text Available Emergence of big data analytics resource systems (BDARSs as a part of routine practice in Radiation Oncology is on the horizon. Gradually, individual researchers, vendors, and professional societies are leading initiatives to create and demonstrate use of automated systems. What are the implications for design of clinical trials, as these systems emerge? Gold standard, randomized controlled trials (RCTs have high internal validity for the patients and settings fitting constraints of the trial, but also have limitations including: reproducibility, generalizability to routine practice, infrequent external validation, selection bias, characterization of confounding factors, ethics, and use for rare events. BDARS present opportunities to augment and extend RCTs. Preliminary modeling using single- and muti-institutional BDARS may lead to better design and less cost. Standardizations in data elements, clinical processes, and nomenclatures used to decrease variability and increase veracity needed for automation and multi-institutional data pooling in BDARS also support ability to add clinical validation phases to clinical trial design and increase participation. However, volume and variety in BDARS present other technical, policy, and conceptual challenges including applicable statistical concepts, cloud-based technologies. In this summary, we will examine both the opportunities and the challenges for use of big data in design of clinical trials.
Dombi, Eva; Ardern-Holmes, Simone L; Babovic-Vuksanovic, Dusica; Barker, Fred G; Connor, Steve; Evans, D Gareth; Fisher, Michael J; Goutagny, Stephane; Harris, Gordon J; Jaramillo, Diego; Karajannis, Matthias A; Korf, Bruce R; Mautner, Victor; Plotkin, Scott R; Poussaint, Tina Y; Robertson, Kent; Shih, Chie-Schin; Widemann, Brigitte C
Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.
Yaman, Anil; Chakrabarti, Shreya; Sen, Anando; Weng, Chunhua
Knowledge reuse of cancer trial designs may benefit from a temporal understanding of the evolution of the target populations of cancer studies over time. Therefore, we conducted a retrospective analysis of the trends of cancer trial eligibility criteria between 1999 and 2014. The yearly distributions of eligibility concepts for chemicals and drugs, procedures, observations, and medical conditions extracted from free-text eligibility criteria of 32,000 clinical trials for 89 cancer types were analyzed. We identified the concepts that trend upwards or downwards in all or selected cancer types, and the concepts that show anomalous trends for some cancers. Later, concept trends were studied in a disease-specific manner and illustrated for breast cancer. Criteria trends observed in this study are also validated and interpreted using evidence from the existing medical literature. This study contributes a method for concept trend analysis and original knowledge of the trends in cancer clinical trial eligibility criteria.
Bernstein, Steven L; Feldman, James
Clinical trials often offer incentives to encourage individuals to enroll and to enhance follow-up. The scope and nature of incentives used in emergency department (ED)-based trials are unknown. The objective of this study is to characterize the quantity and quality of incentives and other forms of compensation used in clinical trials of human subjects recruited in US EDs. A secondary goal is to provide an historical and ethical analysis of the use of incentives in clinical trials. We reviewed English-language randomized clinical trials conducted in US EDs from 2009 to 2013. Full text of the studies was reviewed to identify whether incentives were used, their value, and timing. Funding source was noted as well. Data are presented with descriptive statistics. Of 1151 articles identified, 76 (6.6%) fit criteria for review. Of these, 7 (9.2%) provided incentive payments. A recently published eighth trial was included as well. The total cash value of incentives offered ranged from $10 to $195. Four studies offered payment at enrollment only. Incentives included cash, debit cards, and gift cards. The use of financial incentives in ED-based trials is uncommon. Studies that use incentives are generally extramurally funded, usually by a federal agency, and include waves of follow-up that continue after discharge from the ED. Payment size is modest. Incentives may improve recruitment and retention in ED-based trials, but authoritative data are lacking. Investigators need to take care to avoid incentives that may be coercive or unduly influence research participants. Copyright © 2015 Elsevier Inc. All rights reserved.
Roderik F Viergever
Full Text Available INTRODUCTION: The benefits of clinical trials registration include improved transparency on clinical trials for healthcare workers and patients, increased accountability of trialists, the potential to address publication bias and selective reporting, and possibilities for research collaboration and prioritization. However, poor quality of information in registered records of trials has been found to undermine these benefits in the past. Trialists' increasing experience with trial registration and recent developments in registration systems may have positively affected data quality. This study was conducted to investigate whether the quality of registration has improved. METHODS: We repeated a study from 2009, using the same methods and the same research team. A random sample of 400 records of clinical trials that were registered between 01/01/2012 and 01/01/2013 was taken from the International Clinical Trials Registry Platform (ICTRP and assessed for the quality of information on 1 contact details, 2 interventions and 3 primary outcomes. Results were compared to the equivalent assessments from our previous study. RESULTS: There was a small and not statistically significant increase from 81.0% to 85.5% in the percentage of records that provided a name of a contact person. There was a significant increase from 68.7% to 74.9% in the number of records that provided either an email address or a telephone number. There was a significant increase from 44.2% to 51.9% in the number of intervention arms that were complete in registering intervention specifics. There was a significant increase from 38.2% to 57.6% in the number of primary outcomes that were specific measures with a meaningful timeframe. Approximately half of all trials continued to be retrospectively registered. DISCUSSION: There have been small but significant improvements in the quality of registration since 2009. Important problems with quality remain and continue to constitute an
Myeong Soo Lee; Byung-Cheul Shin; Sun-Mi Choi; Jong Yeol Kim
The aim of this systematic review is to compile and critically evaluate the evidence from randomized clinical trials (RCTs) for the effectiveness of acupuncture using constitutional medicine compared to standard acupuncture. Ten databases were searched through to December 2008 without language restrictions. We also hand-searched nine Korean journals of oriental medicine. We included prospective RCTs of any form of acupuncture with or without electrical stimulation. The included trials had to ...
Moreno, Alberto; Joyner, Chester
Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been made in the past few years with the completion of numerous clinical trials. Each trial has utilized a unique combination of antigens, delivery platforms, and adjuvants, and the data that has been obtained provides critical information that has poises the research community for the development of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P. vivax vaccin...
Meissner, O; Modiselle, G C; Dali, P K; Joubert, P H
Randomized clinical trials are necessary for the valid assessment of treatment efficacy. To expose medical students to trial aims, techniques and terminology, we developed a scheme for active student involvement without facing the ethical problem of drug administration or application of invasive methods to a captive group of subjects. As an active drug, coffee is used and compared with an identical placebo (decaffeinated coffee). The effects on heart rate and urine volume are determined.
We conducted a single case (N-of-1) randomized trial in two patients. In the first case with bronchiolitis obliterans after lung transplantation a beneficial effect of inhaled steroids could be documented. The second patient suffered from symptoms compatible with HIV-associated M. Addison improving after cortisone, but the adrenocortical function was normal. Because the patient required the cortison treatment to be continued, we performed a n-of-1 trial which demonstrated the inefficacy of cortisone. This experience underscores the feasibility and usefulness of N-of-1 randomized clinical trials in medical practice.
Cranney, A; Welch, V; Tugwell, P; Wells, G; Adachi, J D; McGowan, J; Shea, B
As an update of our earlier paper, published as part of the Outcome Measures in Rheumatology Clinical Trials (OMERACT 3) proceedings in 1996, we surveyed the types of outcomes incorporated in recent clinical trials. A literature search was conducted on MEDLINE and Current Contents, from January 1996 to March 1998, using the search strategy recommended by the Cochrane Collaboration for the identification of randomized controlled trials (RCT). Two independent reviewers selected trials according to inclusion criteria. The same reviewers extracted data on clinical and radiographic fractures, pain, quality of life, and bone mineral density (BMD). Seventy-four RCT conducted on bone loss in postmenopausal women were identified. Most trials incorporated biochemical markers and BMD as outcome measures. Fewer trials included vertebral fractures, pain, height, and quality of life. The responsiveness is presented in terms of the sample size needed per group to show a statistically significant difference. The most responsive outcomes were pain, BMD, and biochemical markers. The number needed to treat to prevent one vertebral fracture ranged from 13 to 54, depending on the intervention and population. Investigators should examine the characteristics of the patient population and the nature of the intervention in determining the sample size required to demonstrate a significant effect. The selection of endpoints should be based on their responsiveness, feasibility, and the importance of using standardized outcomes. Standardized outcomes greatly facilitate the synthesis of available information into systematic reviews by groups such as the Cochrane Collaboration.
Devasenapathy, Niveditha; Singh, Kavita; Prabhakaran, Dorairaj
To provide a broad perspective of contextual factors involved in the conduct of clinical trials in developing countries. The quantity of research in developing countries continues to be inadequate, with clinical trials comprising a small fraction of the total research output. Most trials done in developing countries tend to be designed in developed countries and led by investigators in those nations. The main challenges in the conduct of trials in developing countries stem from the vulnerability of the populations due to illiteracy, poverty, limited research infrastructure, lack of sufficient numbers of experienced investigators and trained support personnel, and fragmented healthcare system. There is a need to formulate and conduct trials to test treatments that are context-specific and socially relevant. With careful planning in advance and shared partnership among sponsors, host-country research practitioners, government agencies and the community, many of the challenges facing clinical trial research can be overcome over the medium to long term. This would enable conformity to contemporary guidelines in both letter and spirit and hopefully develop research questions addressing the needs of developing countries.
Full Text Available Jean Davignon1, Lawrence A Leiter21Clinical Research Institute of Montreal, Montreal, QC, Canada; 2Division of Endocrinology and Metabolism, St Michael’s Hospital, Toronto, ON, CanadaBackground: The multiple effects (ie, pleiotropic effects of statins have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. Objective: To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. Method: Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000–2004, and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990–2003, abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins’ nonlipid (ie, pleiotropic effect(s. Data were extracted and trial quality was assessed by the authors. Results: Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer’s disease, multiple sclerosis, and stroke (outcomes often overlapped. Conclusion: Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients
Ahmed A. Zeeneldin
Full Text Available Registering clinical trials (CTs in public domains enhances transparency, increases trust in research, improves participation and safeguards against publication bias. This work was done to study the profile of clinical research in Egypt in three CT registries with different scopes: the WHO International CT Registry Platform (ICTRP, the continental Pan-African CT Registry (PACTR and the US clinicaltrials.gov (CTGR. In March 2014, ICTRP, PACTR and CTGR were searched for clinical studies conducted in Egypt. It was found that the number of studies conducted in Egypt (percentage was 686 (0.30% in ICTRP, 56 (11.3% in PACTR and 548 (0.34% in CTGR. Most studies were performed in universities and sponsored by university/organization, industry or individual researchers. Inclusion of adults from both genders predominated. The median number of participants per study in the three registries ranged between 63 and 155. The conditions researched differed among the three registries and study purpose was mostly treatment followed by prevention. Endpoints were mostly efficacy followed by safety. Observational:Interventional studies (i.e. clinical trials represented 15.5%:84.5% in ICTRP, 0%:100% in PACTR and 16.4%:83.6% in CTGR. Most interventions were drugs or procedures. Observational studies were mostly prospective and cohort studies. Most CTs were phase 3 and tested drugs or procedures. Parallel group assignment and random allocation predominated. Blinding was implemented in many of trials and was mostly double-blind. We conclude that CTs from Egypt in trial registries are apparently low and do not accurately reflect clinical research conducted in Egypt or its potential. Development of an Egyptian CT registry is eagerly needed. Registering all Egyptian CTs in public domains is highly recommended.
Bagg, Matthew K; Hübscher, Markus; Rabey, Martin; Wand, Benedict M; O'Hagan, Edel; Moseley, G Lorimer; Stanton, Tasha R; Maher, Chris G; Goodall, Stephen; Saing, Sopany; O'Connell, Neil E; Luomajoki, Hannu; McAuley, James H
variables) in outcome from baseline to each time point between intervention A and intervention B. This will provide effect estimates and 95% confidence intervals for any difference between the interventions. Preliminary data suggest that combining treatments that target central nervous system function with traditional interventions is a promising approach to chronic low back pain treatment. In the context of modest effects on pain intensity from most available treatments, this approach may lead to improved clinical outcomes for people with chronic low back pain. The trial will determine which, if either, of two treatment programs that combine central nervous system-directed and traditional interventions is more effective at reducing pain intensity in a chronic low back pain cohort. Central nervous system-directed interventions constitute a completely new treatment paradigm for chronic low back pain management. The results have the potential to be far reaching and change current physiotherapy management of chronic low back pain in Australia and internationally. Copyright © 2016 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.
Eskes, Anne M; Brölmann, Fleur E; Sumpio, Bauer E;
The care for chronic and acute wounds is a substantial problem around the world. This has led to a plethora of products to accelerate healing. Unfortunately, the quality of studies evaluating the efficacy of such wound care products is frequently low. Randomized clinical trials are universally...... acknowledged as the study design of choice for comparing treatment effects, as they eliminate several sources of bias. We propose a framework for the design and conduct of future randomized clinical trials that will offer strong scientific evidence for the effectiveness of wound care interventions. While...... randomization is a necessary feature of a robust comparative study, it is not sufficient to ensure a study at low risk of bias. Randomized clinical trials should also ensure adequate allocation concealment and blinding of outcome assessors, apply intention-to-treat analysis, and use patient-oriented outcomes...
Morgan, Susan E; Mouton, Ashton; Occa, Aurora; Potter, Jonell
The lack of accrual to research studies and clinical trials is a persistent problem with serious consequences: Advances in medical science depend on the participation of large numbers of people, including members of minority and underserved populations. The current study examines a critical determinant of accrual: the approach of patients by professional recruiters who request participation in research studies and clinical trials. Findings indicate that recruiters use a number of verbal strategies in the communication process, including translating study information (such as simplifying, using examples, and substituting specific difficult or problematic words), using linguistic reframing or metaphors, balancing discussions of research participation risks with benefits, and encouraging potential participants to ask questions. The identification of these verbal strategies can form the basis of new communication protocols that will help medical and nonmedical professionals communicate more clearly and effectively with patients and other potential participants about research studies and clinical trials, which should lead to increased accrual in the future.
Full Text Available Shosaku Nomura, Noboru Tanigawa, Yo Kinoshita, Koichi TomodaFirst Department of Internal Medicine, Kansai Medical University, Shinmachi, Hirakata, Osaka, JapanUndergraduate medical education has several problems.1,2 In particular, clinical training, which is the unique feature of medical education, tends to be performed less extensively. In Japan, the current clinical training method is clinical clerkship (CC. CC differs from conventional clinical training, which is study by observation. In CC, the student is a member of the medical team and participates in actual medical care. The student is allowed to practice medical actions in the definite range under the guidance and monitoring of a teaching doctor. Therefore, students can acquire practical clinical abilities. In their study of medical care, students are required to have their own sense of identity and personal responsibility. Clinical training is performed by CC following the original curriculum for diagnoses and treatments in various medical departments.
Cheng-Hakimian, A; Anderson, G D; Miller, J W
Rufinamide is a structurally novel compound with anticonvulsant activity that is undergoing evaluation through the European Medicines Agency and the American Food and Drug Administration. Its mechanism of action is thought to be inhibition of sodium-dependent action potentials in neurons, with possible membrane-stabilising effects. Absorption of the drug is significantly enhanced in the fed state. The drug is extensively metabolised by non-CYP450 systems with a half-life of 8-12 h. Most common adverse effects noted are somnolence, fatigue and tremor. Efficacy against partial seizures in adults and adolescents has been demonstrated in three randomised, placebo-controlled trials. Efficacy against seizures of Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single randomised, placebo-controlled trial. Efficacy against partial onset seizures in children has been suggested in an open-label trial. Should rufinamide become commercially available, reserving the drug as a second- or third-line agent should be considered.
Aman, Michael G.; Novotny, Sherie; Samango-Sprouse, Carole; Lecavalier, Luc; Leonard, Elizabeth; Gadow, Kenneth D.; King, Bryan H.; Pearson, Deborah A.; Gernsbacher, Morton Ann; Chez, Michael
This paper identifies instruments and measures that may be appropriate for randomized clinical trials in participants with autism spectrum disorders (ASDs). The Clinical Global Impressions scale was recommended for all randomized clinical trials. At this point, however, there is no “perfect” choice of outcome measure for core features of autism, although we will discuss five measures of potential utility. Several communication instruments are recommended, based in part on suitability across the age range. In trials where the intention is to alter core features of ASDs, adaptive behavior scales are also worthy of consideration. Several “behavior complexes” common to ASDs are identified, and instruments are recommended for assessment of these. Given the prevalence of cognitive impairment in ASDs, it is important to assess any cognitive effects, although cognitive data from ASD randomized clinical trials, thus far, are minimal. Guidance from trials in related pharmacologic areas and behavioral pharmacology may be helpful. We recommend routine elicitation of side effects, height and weight, vital signs, and (in the case of antipsychotics) extrapyramidal side-effects assessment. It is often appropriate to include laboratory tests and assessments for continence and sleep pattern. PMID:14999174
Purdom, Michelle A; Petersen, Sandra; Haas, Barbara K
To evaluate the relevance of a five-dimensional model of clinical trial nursing practice in an oncology clinical trial nurse population. . Web-based cross-sectional survey. . Online via Qualtrics. . 167 oncology nurses throughout the United States, including 41 study coordinators, 35 direct care providers, and 91 dual-role nurses who provide direct patient care and trial coordination. . Principal components analysis was used to determine the dimensions of oncology clinical trial nursing practice. . Self-reported frequency of 59 activities. . The results did not support the original five-dimensional model of nursing care but revealed a more multidimensional model. . An analysis of frequency data revealed an eight-dimensional model of oncology research nursing, including care, manage study, expert, lead, prepare, data, advance science, and ethics. . This evidence-based model expands understanding of the multidimensional roles of oncology nurses caring for patients with cancer enrolled in clinical trials.
Koenig, Franz; Slattery, Jim; Groves, Trish; Lang, Thomas; Benjamini, Yoav; Day, Simon; Bauer, Peter; Posch, Martin
In recent months one of the most controversially discussed topics among regulatory agencies, the pharmaceutical industry, journal editors, and academia has been the sharing of patient-level clinical trial data. Several projects have been started such as the European Medicines Agency´s (EMA) "proactive publication of clinical trial data", the BMJ open data campaign, or the AllTrials initiative. The executive director of the EMA, Dr. Guido Rasi, has recently announced that clinical trial data on patient level will be published from 2014 onwards (although it has since been delayed). The EMA draft policy on proactive access to clinical trial data was published at the end of June 2013 and open for public consultation until the end of September 2013. These initiatives will change the landscape of drug development and publication of medical research. They provide unprecedented opportunities for research and research synthesis, but pose new challenges for regulatory authorities, sponsors, scientific journals, and the public. Besides these general aspects, data sharing also entails intricate biostatistical questions such as problems of multiplicity. An important issue in this respect is the interpretation of multiple statistical analyses, both prospective and retrospective. Expertise in biostatistics is needed to assess the interpretation of such multiple analyses, for example, in the context of regulatory decision-making by optimizing procedural guidance and sophisticated analysis methods. © 2014 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Minisman, Greg; Bhanushali, Minal; Conwit, Robin; Wolfe, Gil I; Aban, Inmaculada; Kaminski, Henry J; Cutter, Gary
The importance of conducting medical research on a global or international platform cannot be overemphasized in current times. Sponsors are encouraging international clinical trials for a number of reasons. Globally, clinical trials are under increasing pressure to meet patient recruitment goals quickly and efficiently, at times with very limited resources. Conducting clinical trials in multiple countries increases access to potentially eligible study subjects. It is reasonable to believe that international trials will be completed more quickly and efficiently, leading to more rapid advancement in science and conservation of research-specific resources. Rapid advancement in science can reduce the burden of disease, promote health, and extend longevity for all people. In addition, generalizability, one of the major goals of translational medicine, will increase when recruiting patients from multiple countries and multiple ethnicities. Further, improvement of global health may be possible when certain types of clinical trials are conducted in countries that would not otherwise have access to an innovative drug or intervention. Published by Elsevier B.V.
health care system, as a way of supplementing the incomes and thus retaining ... Iproniazide is an analogue of isoniazide, an early anti-tuberculosis drug. The first .... reward (i.e. clinical benefit) seems to be particularly relevant. The brain has ...
GUZhi-Ping; ZHANGRcn-An; WANGYi-Xin; DANGYong-Zhi; CHENGZhen-Xing; S.J.Scgal
Hypokalemia and irreversible infertility induced by the gossypol treatment have prcvented its clinical use on a large scale as a male contraceptive. In order to avoid these serious side effects, doses of gossypol, both in the loading phase and in the maintenance phase were
Weng, Chunhua; Bigger, J Thomas; Busacca, Linda; Wilcox, Adam; Getaneh, Asqual
This paper reports a case study comparing the relative efficiency of using a Diabetes Registry or a Clinical Data Warehouse to recruit participants for a diabetes clinical trial, TECOS. The Clinical Data Warehouse generated higher positive predictive accuracy (31% vs. 6.6%) and higher participant recruitment than the Registry (30 vs. 14 participants) in a shorter time period (59 vs. 74 working days). We identify important factors that increase clinical trial recruitment efficiency and lower cost. PMID:21347102
Weng, Chunhua; Bigger, J Thomas; Busacca, Linda; Wilcox, Adam; Getaneh, Asqual
This paper reports a case study comparing the relative efficiency of using a Diabetes Registry or a Clinical Data Warehouse to recruit participants for a diabetes clinical trial, TECOS. The Clinical Data Warehouse generated higher positive predictive accuracy (31% vs. 6.6%) and higher participant recruitment than the Registry (30 vs. 14 participants) in a shorter time period (59 vs. 74 working days). We identify important factors that increase clinical trial recruitment efficiency and lower cost.
Béhier, Jehan-Michel; Reynier, Jean-Charles; Bertoye, Pierre-Henri; Vray, Muriel
Within the last few years, new technology has come to play an important part in our professional and private daily environment. Healthcare has not escaped this progressive mutation with computers reaching the bedside. Clinical research has also shown growing interest in these new tools available to the clinical investigator, the patient, as well as to specialist departments for diagnosis and follow-up of patients, and to the different professions in clinical research. If the use of new technology seems to make life easier, by centralizing data or by simplifying data-sharing between different teams, it is still a matter of private data which must remain reliable, confidential and secure, whether it is being used in ordinary healthcare or in academic or industrial research. The aim of the round table was to estimate the impact of new information technology applied to clinical trials (including source data-medical records) and to human and drug research. First, an inventory was made of the development of these new technologies in the healthcare system. The second point developed was identification of expected benefits in order to issue guidelines for their good use and hazard warnings in clinical trials. Finally, the impact of these new technologies on the investigator as well as the project manager was analysed.
Rhoades, Galena K
This study examined the effectiveness of a couple-based relationship education program, Within Our Reach. Secondary data (n = 3,609) were analyzed from the federal Supporting Healthy Marriage project. Couples were randomly assigned to receive Within Our Reach and associated services or to a no-treatment (treatment-as-usual) control group. Those assigned to Within Our Reach reported better couple and individual outcomes on 8 of 12 outcomes measured (M ES = .15) at the 12-month follow-up and 6 of 10 outcomes measured at the 30-month follow-up (M ES = .14), including higher relationship happiness, more warmth and support, more positive communication, less negative behavior and emotion, less psychological abuse, less physical assault (for men), lower psychological distress (for women), and less infidelity. They were also less likely to report that their marriage was in trouble. These effects were generally small in size and many were replicated across the two follow-ups. There were no significant differences between those assigned to Within Our Reach versus control on cooperative parenting, severe psychological assault, or percent married. Implications for future research, programming, and policy are discussed.
Palevsky, Paul M; Molitoris, Bruce A; Okusa, Mark D; Levin, Adeera; Waikar, Sushrut S; Wald, Ron; Chertow, Glenn M; Murray, Patrick T; Parikh, Chirag R; Shaw, Andrew D; Go, Alan S; Faubel, Sarah G; Kellum, John A; Chinchilli, Vernon M; Liu, Kathleen D; Cheung, Alfred K; Weisbord, Steven D; Chawla, Lakhmir S; Kaufman, James S; Devarajan, Prasad; Toto, Robert M; Hsu, Chi-yuan; Greene, Tom; Mehta, Ravindra L; Stokes, John B; Thompson, Aliza M; Thompson, B Taylor; Westenfelder, Christof S; Tumlin, James A; Warnock, David G; Shah, Sudhir V; Xie, Yining; Duggan, Emily G; Kimmel, Paul L; Star, Robert A
Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.
Stockmann, Chris; Spigarelli, Michael G.; Ampofo, Krow; Sherwin, Catherine MT
Drug development is an expensive process that is marked by a high-failure rate. For this reason early stage bioequivalence and pharmacokinetic studies are essential in determining the fate of new drug products. In this study, we sought to systematically assess the current trends of ongoing and recently completed bioequivalence and bioavailability trials that have been registered within a national clinical trials registry. All bioequivalence and bioavailability studies registered in the United...
Goodwin, Andrew J
Optimizing care in the ICU is an important goal. The heightened severity of illness in patients who are critically ill combined with the tremendous costs of critical care make the ICU an ideal target for improvement in outcomes and efficiency. Incorporation of evidence-based medicine into everyday practice is one method to optimize care; however, intensivists have struggled to define optimal practices because clinical trials in the ICU have yielded conflicting results. This article reviews examples where such conflicts have occurred and explores possible causes of these discrepant data as well as strategies to better use critical care clinical trials in the future.
Proschan, Michael A; Dodd, Lori E
This paper presents a simple procedure for clinical trials comparing several arms with control. Demand for streamlining the evaluation of new treatments has led to phase III clinical trials with more arms than would have been used in the past. In such a setting, it is reasonable that some arms may not perform as well as an active control. We introduce a simple procedure that takes advantage of negative results in some comparisons to lessen the required strength of evidence for other comparisons. We evaluate properties analytically and use them to support claims made about multi-arm multi-stage designs.
Derek G Kyte
Full Text Available BACKGROUND: Patient reported outcomes (PROs are increasingly assessed in clinical trials, and guidelines are available to inform the design and reporting of such trials. However, researchers involved in PRO data collection report that specific guidance on 'in-trial' activity (recruitment, data collection and data inputting and the management of 'concerning' PRO data (i.e., data which raises concern for the well-being of the trial participant appears to be lacking. The purpose of this review was to determine the extent and nature of published guidelines addressing these areas. METHODS AND FINDINGS: Systematic review of 1,362 articles identified 18 eligible papers containing 'in-trial' guidelines. Two independent authors undertook a qualitative content analysis of the selected papers. Guidelines presented in each of the articles were coded according to an a priori defined coding frame, which demonstrated reliability (pooled Kappa 0.86-0.97, and validity (<2% residual category coding. The majority of guidelines present were concerned with 'pre-trial' activities (72%, for example, outcome measure selection and study design issues, or 'post-trial' activities (16% such as data analysis, reporting and interpretation. 'In-trial' guidelines represented 9.2% of all guidance across the papers reviewed, with content primarily focused on compliance, quality control, proxy assessment and reporting of data collection. There were no guidelines surrounding the management of concerning PRO data. CONCLUSIONS: The findings highlight there are minimal in-trial guidelines in publication regarding PRO data collection and management in clinical trials. No guidance appears to exist for researchers involved with the handling of concerning PRO data. Guidelines are needed, which support researchers to manage all PRO data appropriately and which facilitate unbiased data collection.
Full Text Available Shourav Yathindranath,1 Amar Kureishi,2 Simranjit Singh,3 Spencer Yeow,3 Grace Geng,4 Karen Wai,1 Audrey Ho,1 Elvira Zenaida Lansang,1 Ken J Lee5 1Feasibility and Site Identification Asia, 2Drug Development Asia, 3Strategic Planning Asia, Quintiles East Asia Private Limited, Singapore; 4People’s Republic of China Site Services, Quintiles, Beijing, People’s Republic of China; 5Asia Site Services, Quintiles East Asia Private Limited, Singapore Introduction: Asia Pacific has and continues to be one of the fastest-growing pharmaceutical markets in the world. This growth has a carry-over effect of driving pharmaceutical research and development investment in the region. Coupled with this, there have been multiple initiatives conducted by governments and other research focused organizations and societies in the region to help support this growth in research. In this report, we discuss the latest developments in pharmaceutical research and development in Asia Pacific and how these various initiatives have made an impact. Methods: An extensive search of the major clinical trial registries, along with the literature and Internet review of the recent developments in clinical trials, was performed comparing two time periods – 2009–2010 and 2011–2012. Results: In overall numbers, the clinical trial industry in Asia Pacific has remained stable when comparing the two time periods, with stable volumes of clinical trial numbers and site numbers. However, on closer inspection, a dynamic change in geography, nature, and therapeutic areas of the trials being conducted is observed. Japan, South Korea, People’s Republic of China, and Taiwan continue to be major clinical trial destinations. Developing countries, such as Indonesia, Vietnam, and Philippines, have seen rising standards of living and medical care; this is starting to impact their contribution to trials. Also, there are an increasing number of local trials in Asia Pacific with a bigger role
Full Text Available Abstract Background and purpose Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. Methods We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. Results We found a high and significant correlation between placebo and treatment response rate across diseases (r = .78; p Conclusion Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated.
Berger, Vance W; Matthews, J Rosser; Grosch, Eric N
Research plays a vital role within biomedicine. Scientifically appropriate research provides a basis for appropriate medical decisions; conversely, inappropriate research may lead to flawed ;best medical practices' which, when followed, contribute to avoidable morbidity and mortality. Although an all-encompassing definition of ;appropriate medical research' is beyond the scope of this article, the concept clearly entails (among other things) that research methods be continually revised and updated as better methods become available. Despite the advent of evidence-based medicine, many research methods have become ;standard' even though there are legitimate scientific reasons to question the conclusions reached by such methods. We first illustrate prominent examples of inappropriate (yet regimented) research methods that are in widespread use. Second, as a way to improve the situation, we suggest a model of research that relies on standardized statistical analyses that individual researchers must consider as a default, but are free to challenge when they can marshal sufficient scientific evidence to demonstrate that the challenge is warranted. Third, we characterize the current system as analogous to ;unnatural selection' in the biological world and argue that our proposed model of research will enable ;natural' to replace ;unnatural' selection in the choice of research methodologies. Given the pervasiveness of inappropriate research methods, we believe that there are strong scientific and ethical reasons to create such a system, that, if properly designed, will both facilitate creativity and ensure methodological rigor while protecting the public at large from the threats posed by poor medical treatment decisions resulting from flawed research methodology.
Godskesen, T M; Kihlbom, U; Nordin, K; Silén, M; Nygren, P
While participants in clinical oncology trials are essential for the advancement of cancer therapies, factors decisive for patient participation have been described but need further investigation, particularly in the case of phase 3 studies. The aim of this study was to investigate differences in trial knowledge and motives for participation in phase 3 clinical cancer trials in relation to gender, age, education levels and former trial experience. The results of a questionnaire returned from 88 of 96 patients (92%) were analysed using the Mann-Whitney U-test. There were small, barely relevant differences in trial knowledge among patients when stratified by gender, age or education. Participants with former trial experience were less aware about the right to withdraw. Male participants and those aged ≥65 years were significantly more motivated by a feeling of duty, or by the opinions of close ones. Men seem more motivated than women by external factors. With the awareness that elderly and single male participants might be a vulnerable group and participants with former trial experience are less likely to be sufficiently informed, the information consent process should focus more on these patients. We conclude that the informed consent process seems to work well, with good results within most subgroups.
Vijayananthan, A; Nawawi, O
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. It also serves to protect the rights, integrity and confidentiality of trial subjects. It is very important to understand the background of the formation of the ICH-GCP guidelines as this, in itself, explains the reasons and the need for doing so. In this paper, we address the historical background and the events that led up to the formation of these guidelines. Today, the ICH-GCP guidelines are used in clinical trials throughout the globe with the main aim of protecting and preserving human rights.
Wildt, Signe; Krag, Aleksander; Gluud, Liselotte
Objectives To evaluate the adequacy of reporting of protocols for randomised trials on diseases of the digestive system registered in http://ClinicalTrials.gov and the consistency between primary outcomes, secondary outcomes and sample size specified in http://ClinicalTrials.gov and published...... trials. Methods Randomised phase III trials on adult patients with gastrointestinal diseases registered before January 2009 in http://ClinicalTrials.gov were eligible for inclusion. From http://ClinicalTrials.gov all data elements in the database required by the International Committee of Medical Journal...... Editors (ICMJE) member journals were extracted. The subsequent publications for registered trials were identified. For published trials, data concerning publication date, primary and secondary endpoint, sample size, and whether the journal adhered to ICMJE principles were extracted. Differences between...
Silverberg, Noah D; Crane, Paul K; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J; Lange, Rael T; Manley, Geoffrey T; McCrea, Michael; Iverson, Grant L
Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint.
Díaz Gómez, L; García Villar, C; Seguro Fernández, Á
A clinical trial is an experimental study to evaluate the efficacy and safety of a treatment or diagnostic technique in human beings. To ensure the methodological quality of a clinical trial and the validity of its results, various checklists have been elaborated to identify biases that could invalidate its conclusions. This article focuses on the points we need to consider in the critical evaluation of a clinical trial. We can usually find this information in the "materials and methods" and "results" sections of articles. Randomization, follow-up (or analysis of losses), blinding, and equivalence between groups (apart from the intervention itself) are some key aspects related to design. In the "results" section, we need to consider what measures of clinical efficacy were used (relative risk, odds ratio, or number needed to treat, among others) and the precision of the results (confidence intervals). Once we have confirmed that the clinical trial fulfills these criteria, we need to determine whether the results can be applied in our environment and whether the benefits obtained justify the risks and costs involved.
Chen, Zhao-hua; Huang, Qin; Deng, Ya-zhong; Zhang, Yue; Xu, Yu; Yu, Hao; Liu, Zong-fan
Data quality management system is essential to ensure accurate, complete, consistent, and reliable data collection in clinical research. This paper is devoted to various choices of data quality metrics. They are categorized by study status, e.g. study start up, conduct, and close-out. In each category, metrics for different purposes are listed according to ALCOA+ principles such us completeness, accuracy, timeliness, traceability, etc. Some general quality metrics frequently used are also introduced. This paper contains detail information as much as possible to each metric by providing definition, purpose, evaluation, referenced benchmark, and recommended targets in favor of real practice. It is important that sponsors and data management service providers establish a robust integrated clinical trial data quality management system to ensure sustainable high quality of clinical trial deliverables. It will also support enterprise level of data evaluation and bench marking the quality of data across projects, sponsors, data management service providers by using objective metrics from the real clinical trials. We hope this will be a significant input to accelerate the improvement of clinical trial data quality in the industry.
Demirel, Sibel; Argo, Colby; Agarwal, Aniruddha; Parriott, Jacob; Sepah, Yasir Jamal; Do, Diana V; Nguyen, Quan Dong
In this era of evidence-based medicine, significant progress has been made in the field of pharmacotherapeutics for the management of diabetic macular edema (DME). A. number of landmark clinical trials have provided strong evidence of the safety and efficacy of agents such as anti-vascular endothelial growth factors for the treatment of DME. Decades of clinical research, ranging from the early treatment of diabetic retinopathy study to the present-day randomized clinical trials (RCTs) testing novel agents, have shifted the goal of therapy from preventing vision loss to ensuring a maximum visual gain. Systematic study designs have provided robust data with an attempt to optimize the treatment regimens including the choice of the agent and timing of therapy. However, due to a number of challenges in the management of DME with approved agents, further studies are needed. For the purpose of this review, an extensive database search in English language was performed to identify prospective, RCTs testing pharmacological agents for DME. In order to acquaint the reader with the most relevant data from these clinical trials, this review focuses on pharmacological agents that are currently approved or have widespread applications in the management of DME. An update on clinical trials presently underway for DME has also been provided.
Full Text Available rnedUK - MHRA A.2EudraCT number2010-021186-70 A.3Full title of the trial Keratinocyte growth factor in Acute...reviated title of the trial where available Keratinocyte Growth Factor in Acute L...nder investigation E.1.1Medical condition(s) being investigated Acute Lung Injury
Full Text Available Abstract Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present. Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.
Cooper, Cindy; O'Cathain, Alicia; Hind, Danny; Adamson, Joy; Lawton, Julia; Baird, Wendy
The value of using qualitative research within or alongside randomised controlled trials (RCTs) is becoming more widely accepted. Qualitative research may be conducted concurrently with pilot or full RCTs to understand the feasibility and acceptability of the interventions being tested, or to improve trial conduct. Clinical Trials Units (CTUs) in the United Kingdom (UK) manage large numbers of RCTs and, increasingly, manage the qualitative research or collaborate with qualitative researchers external to the CTU. CTUs are beginning to explicitly manage the process, for example, through the use of standard operating procedures for designing and implementing qualitative research with trials. We reviewed the experiences of two UK Clinical Research Collaboration (UKCRC) registered CTUs of conducting qualitative research concurrently with RCTs. Drawing on experiences gained from 15 studies, we identify the potential for the qualitative research to undermine the successful completion or scientific integrity of RCTs. We show that potential problems can arise from feedback of interim or final qualitative findings to members of the trial team or beyond, in particular reporting qualitative findings whilst the trial is on-going. The problems include: We make recommendations for improving the management of qualitative research within CTUs.
Jiang, Silis Y.; Weng, Chunhua
Clinical trials are fundamental to the advancement of medicine but constantly face recruitment difficulties. Various clinical trial search engines have been designed to help health consumers identify trials for which they may be eligible. Unfortunately, knowledge of the usefulness and usability of their designs remains scarce. In this study, we used mixed methods, including time-motion analysis, think-aloud protocol, and survey, to evaluate five popular clinical trial search engines with 11 users. Differences in user preferences and time spent on each system were observed and correlated with user characteristics. In general, searching for applicable trials using these systems is a cognitively demanding task. Our results show that user perceptions of these systems are multifactorial. The survey indicated eTACTS being the generally preferred system, but this finding did not persist among all mixed methods. This study confirms the value of mixed-methods for a comprehensive system evaluation. Future system designers must be aware that different users groups expect different functionalities. PMID:25954590
Jiang, Silis Y; Weng, Chunhua
Clinical trials are fundamental to the advancement of medicine but constantly face recruitment difficulties. Various clinical trial search engines have been designed to help health consumers identify trials for which they may be eligible. Unfortunately, knowledge of the usefulness and usability of their designs remains scarce. In this study, we used mixed methods, including time-motion analysis, think-aloud protocol, and survey, to evaluate five popular clinical trial search engines with 11 users. Differences in user preferences and time spent on each system were observed and correlated with user characteristics. In general, searching for applicable trials using these systems is a cognitively demanding task. Our results show that user perceptions of these systems are multifactorial. The survey indicated eTACTS being the generally preferred system, but this finding did not persist among all mixed methods. This study confirms the value of mixed-methods for a comprehensive system evaluation. Future system designers must be aware that different users groups expect different functionalities.
The history of placebos in psychiatry can be understood only in the context of randomized controlled trials (RCTs). Placebo treatments are as old as medicine itself, and are particularly effective in dealing with psychosomatic symptoms. In psychiatry, placebos have mainly been featured in clinical drug trials. The earliest controlled trial in psychiatry (not involving drugs) occurred in 1922, followed by the first crossover studies during the 1930s. Meanwhile the concept of randomization was developed during the interwar years by British statistician Ronald A Fisher, and introduced in 3 trials of tuberculosis drugs between 1947 and 1951. These classic studies established the RCT as the gold standard in pharmaceutical trials, and its status was cemented during the mid-1950s. Nevertheless, while the placebo became established as a standard measure of drug action, placebo treatments became stigmatized as unethical. This is unfortunate, as they constitute one of the most powerful therapies in psychiatry. In recent years, moreover, the dogma of the placebo-controlled trial as the only acceptable data for drug licensing is also being increasingly discredited. This backlash has had 2 sources: one is the recognition that the US Food and Drug Administration has been too lax in permitting trials controlled with placebos alone, rather than also using an active agent as a test of comparative efficacy. In addition, there is evidence that in the hands of the pharmaceutical industry, the scientific integrity of RCTs themselves has been degraded into a marketing device. The once-powerful placebo is thus threatened with extinction.
Dellson, Pia; Nilbert, Mef; Carlsson, Christina
of future simplified and more attractive informed consent forms. CONCLUSIONS: The emotional and cognitive responses to written patient information reported by patient representatives provides a basis for revised formats in future trials and add to the body of information that support use of plain language......BACKGROUND: Patient enrolment into clinical trials is based on oral information and informed consent, which includes an information sheet and a consent certificate. The written information should be complete, but at the same time risks being so complex that it may be questioned if a fully informed......-III trials, randomized and non-randomized trials that evaluated chemotherapy/targeted therapy in the neoadjuvant, adjuvant and palliative settings. Data were collected through focus groups and were analysed using inductive content analysis. RESULTS: Two major themes emerged: emotional responses and cognitive...
Kjaergard, Lise L; Gluud, Christian
-1996. From each trial, we extracted the statistical significance of the primary study outcome (positive or negative), the disease area, and methodological quality (randomization and double blinding). The number of citations during two calendar years after publication was obtained from Science Citation Index......The objective of this study was to assess whether trials with a positive (i.e., statistically significant) outcome are cited more often than negative trials. We reviewed 530 randomized clinical trials on hepato-biliary diseases published in 11 English-language journals indexed in MEDLINE from 1985....... There was a significant positive association between a statistically significant study outcome and the citation frequency (beta, 0.55, 95% confidence interval, 0.39-0.72). The disease area and adequate generation of the allocation sequence were also significant predictors of the citation frequency. We concluded...
Yan, Xu; Lee, Shiowjen; Li, Ning
One of the major problems in the analysis of clinical trials is missing data caused by patients dropping out before study completion. The issue of missing data can result in biased treatment comparisons and can impact the interpretation of study results. Since the missing data mechanism is unknown and unverifiable in most situations, regulatory agencies often request various sensitivity analyses for handling missing data to evaluate the robustness of study results. This article discusses methods used to handle missing data in medical device clinical trials, focusing on tipping-point analysis as a general approach for the assessment of missing data impact. Tipping points are outcomes that result in a change of study conclusion. Such outcomes can be conveyed to clinical reviewers to determine if they are implausibly unfavorable. The analysis aids clinical reviewers in making judgment regarding treatment effect in the study. Three examples with a reasonably representative range of missing data rate are included to illustrate the methods referred.
Norenberg, Jeffrey P; Petry, Neil A; Schwarz, Sally
Clinical investigations of radiopharmaceuticals are undertaken to advance promising compounds toward approval by the Food and Drug Administration (FDA) as "legend drugs." This FDA approval requires that the safety and efficacy of the investigational drug (ID) be demonstrated through clinical trials. The investigational radiopharmaceutical drug service (IRDS) is a pharmacy service that plays a critical role in the acquisition, preparation, accountability, and distribution of radiopharmaceuticals used in clinical research. Due to their radioactive and other unique properties, and their potential role as biomarkers or tools in clinical trials of other therapeutic drugs, radiopharmaceutical drugs must be managed by a qualified IRDS rather than by a typical pharmacy-based investigational drug service (IDS). The IRDS is responsible for establishing study-specific procedures for appropriate radiopharmaceutical drug accountability, billing, procurement, storage, preparation, dispensing and destruction of investigational drugs within the hospital. All drugs, and particularly parenteral drug products, must be safe for administration to human subjects enrolled in clinical trials regardless of their FDA regulatory status as approved or investigational new drug products. The United States Pharmacopeia (USP) sterile compounding requirements provides enforceable minimum practice and quality standards for compounded sterile preparations of drug products based on current scientific information and best sterile compounding practices. Consequently, they apply equally to facilities dedicated to IDS and IRDS operations. The FDA also regulates drug manufacturing through current Good Manufacturing Practices (cGMP). This rule (21CFR Part 212) establishes cGMP regulations specific to positron emission tomography radiopharmaceuticals, separate from the regular drug cGMP rule (Parts 210 and 211). Compliance with regulatory, statutory, and sponsor requirements is a major consideration in the
Hamasaki, Toshimitsu; Evans, Scott R; Ochiai, Toshimitsu
This book focuses on group sequential methods for clinical trials with co-primary endpoints based on the decision-making frameworks for: (1) rejecting the null hypothesis (stopping for efficacy), (2) rejecting the alternative hypothesis (stopping for futility), and (3) rejecting the null or alternative hypothesis (stopping for either futility or efficacy), where the trial is designed to evaluate whether the intervention is superior to the control on all endpoints. For assessing futility, there are two fundamental approaches, i.e., the decision to stop for futility based on the conditional probability of rejecting the null hypothesis, and the other based on stopping boundaries using group sequential methods. In this book, the latter approach is discussed. The book also briefly deals with the group sequential methods for clinical trials designed to evaluate whether the intervention is superior to the control on at least one endpoint. In addition, the book describes sample size recalculation and the resulting ef...
Esbensen, Anna J; Hooper, Stephen R; Fidler, Deborah; Hartley, Sigan L; Edgin, Jamie; d'Ardhuy, Xavier Liogier; Capone, George; Conners, Frances A; Mervis, Carolyn B; Abbeduto, Leonard; Rafii, Michael; Krinsky-McHale, Sharon J; Urv, Tiina; Group, Outcome Measures Working
Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the National Institutes of Health (NIH) assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This article focuses on measures in the areas of cognition and behavior.
... HUMAN SERVICES Food and Drug Administration Clinical Trial Design for Intravenous Fat Emulsion Products... ``Clinical Trial Design for Intravenous Fat Emulsion Products.'' This workshop will provide a forum to discuss trial design of clinical trials intended to support registration of intravenous fat...
Desselas, Emilie; Pansieri, Claudia; Leroux, Stephanie; Bonati, Maurizio; Jacqz-Aigrain, Evelyne
Despite specific initiatives and identified needs, most neonatal drugs are still used off-label, with variable dosage administrations and schedules. In high risk preterm and term neonates, drug evaluation is challenging and randomized controlled trials (RCT) are difficult to conduct and even more is the use of a placebo, required in the absence of a reference validated drug to be used as comparator. We analyzed the complete ClinicalTrials.gov registry 1) to describe neonatal RCT involving a placebo, 2) to report on the medical context and ethical aspects of placebo use. Placebo versus drug RCT (n = 146), either prevention trials (n = 57, 39%) or therapeutic interventions (n = 89, 61%), represent more than a third of neonatal trials registered in the National Institute of Health clinical trial database (USA) since 1999. They mainly concerned preterm infants, evaluating complications of prematurity. Most trials were conducted in the USA, were single centered, and funded by non-profit organizations. For the three top drug trials evaluating steroids (n = 13, 9.6%), erythropoietin (EPO, n = 10, 6.8%) and nitric oxide (NO, n = 9, 6.2%), the objectives of the trial and follow-up were analyzed in more details. Although a matter of debate, the use of placebo should be promoted in neonates to evaluate a potential new treatment, in the absence of reference drug. Analysis of the trials evaluating steroids showed that long-term follow-up of exposed patients, although required by international guidelines, is frequently missing and should be planned to collect additional information and optimize drug evaluation in these high-risk patients.
Desselas, Emilie; Pansieri, Claudia; Leroux, Stephanie; Bonati, Maurizio; Jacqz-Aigrain, Evelyne
Background Despite specific initiatives and identified needs, most neonatal drugs are still used off-label, with variable dosage administrations and schedules. In high risk preterm and term neonates, drug evaluation is challenging and randomized controlled trials (RCT) are difficult to conduct and even more is the use of a placebo, required in the absence of a reference validated drug to be used as comparator. Methods We analyzed the complete ClinicalTrials.gov registry 1) to describe neonatal RCT involving a placebo, 2) to report on the medical context and ethical aspects of placebo use. Results Placebo versus drug RCT (n = 146), either prevention trials (n = 57, 39%) or therapeutic interventions (n = 89, 61%), represent more than a third of neonatal trials registered in the National Institute of Health clinical trial database (USA) since 1999. They mainly concerned preterm infants, evaluating complications of prematurity. Most trials were conducted in the USA, were single centered, and funded by non-profit organizations. For the three top drug trials evaluating steroids (n = 13, 9.6%), erythropoietin (EPO, n = 10, 6.8%) and nitric oxide (NO, n = 9, 6.2%), the objectives of the trial and follow-up were analyzed in more details. Conclusion Although a matter of debate, the use of placebo should be promoted in neonates to evaluate a potential new treatment, in the absence of reference drug. Analysis of the trials evaluating steroids showed that long-term follow-up of exposed patients, although required by international guidelines, is frequently missing and should be planned to collect additional information and optimize drug evaluation in these high-risk patients. PMID:28192509
Labrador-Velandia, Sonia; Alonso-Alonso, María Luz; Alvarez-Sanchez, Sara; González-Zamora, Jorge; Carretero-Barrio, Irene; Pastor, José Carlos; Fernandez-Bueno, Iván; Srivastava, Girish Kumar
Retinal and optic nerve diseases are degenerative ocular pathologies which lead to irreversible visual loss. Since the advanced therapies availability, cell-based therapies offer a new all-encompassing approach. Advances in the knowledge of neuroprotection, immunomodulation and regenerative properties of mesenchymal stem cells (MSCs) have been obtained by several preclinical studies of various neurodegenerative diseases. It has provided the opportunity to perform the translation of this knowledge to prospective treatment approaches for clinical practice. Since 2008, several first steps projecting new treatment approaches, have been taken regarding the use of cell therapy in patients with neurodegenerative pathologies of optic nerve and retina. Most of the clinical trials using MSCs are in I/II phase, recruiting patients or ongoing, and they have as main objective the safety assessment of MSCs using various routes of administration. However, it is important to recognize that, there is still a long way to go to reach clinical trials phase III-IV. Hence, it is necessary to continue preclinical and clinical studies to improve this new therapeutic tool. This paper reviews the latest progress of MSCs in human clinical trials for retinal and optic nerve diseases. PMID:27928464
Sampaio, Cristina; Borowsky, Beth; Reilmann, Ralf
Since the identification of the Huntington's disease (HD) gene, knowledge has accumulated about mechanisms directly or indirectly affected by the mutated Huntingtin protein. Transgenic and knock-in animal models of HD facilitate the preclinical evaluation of these targets. Several treatment approaches with varying, but growing, preclinical evidence have been translated into clinical trials. We review major landmarks in clinical development and report on the main clinical trials that are ongoing or have been recently completed. We also review clinical trial settings and designs that influence drug-development decisions, particularly given that HD is an orphan disease. In addition, we provide a critical analysis of the evolution of the methodology of HD clinical trials to identify trends toward new processes and endpoints. Biomarker studies, such as TRACK-HD and PREDICT-HD, have generated evidence for the potential usefulness of novel outcome measures for HD clinical trials, such as volumetric imaging, quantitative motor (Q-Motor) measures, and novel cognitive endpoints. All of these endpoints are currently applied in ongoing clinical trials, which will provide insight into their reliability, sensitivity, and validity, and their use may expedite proof-of-concept studies. We also outline the specific opportunities that could provide a framework for a successful avenue toward identifying and efficiently testing and translating novel mechanisms of action in the HD field.
Full Text Available Dengue is one of the most important vector-borne disease and an increasing problem worldwide because of current globalization trends. Roughly, half the world′s population lives in dengue endemic countries, and nearly 100 million people are infected annually with dengue. India has the highest burden of the disease with 34% of the global cases. In the context of an expanding and potentially fatal infectious disease without effective prevention or specific treatment, the public health value of a protective vaccine is clear. There is no licensed dengue vaccine is available still, but several vaccines are under development. Keeping in view the rise in dengue prevalence globally, there is a need to increase clinical drug and vaccine research on dengue. This paper briefly reviews on the development and current status of dengue vaccine to provide information to policymakers, researchers, and public health experts to design and implement appropriate vaccine for prophylactic intervention.
Surgical techniques are not introduced into clinical practice as the result of randomised clinical trials (RCT), but usually through the gradual evolution of existing techniques or, more rarely, through audacious departures from the norm that are decided by a surgical team on the basis of experience. Sham surgery is held by some to be not only an ethically acceptable procedure but also a perfectly fit and proper one, as it could endow surgical experiments with the strict methodological and st...
The origins of new techniques in transplant surgery vary widely. Frequently, new procedures are the result of small step-by-step departures from protocols already established in clinical practice; or they may be the result of radical innovation. Whatever their origin, experimental techniques in transplant surgery do not follow the route of randomised clinical trials; nor are they subject to the same procedures of review by an ethics committee. The present paper discusses some of the ethical implications of this situation.
Singhal, Richa; Rana, Rakesh
Missing data is frequently encountered in clinical studies. Unfortunately, they are often neglected or not properly handled during data analysis and this may significantly bias the results of the study, reduce study power and lead to invalid conclusions. Substantial instances of missing data are a serious problem that undermines the scientific trustworthiness of causal conclusions from clinical trials. The assumption that statistical analysis methods can compensate for such missing data is no...
Full Text Available r investigation E.1.1Medical condition(s) being investigated Acute Heart Failure MedDRA Classification E.1.3...in one hour of admission to ICU.3. Signed informed consent E.4Principal exclusion criteria 1. Age less than 18 years.2. Acute...y with Trimetazidine in Acute heart failure: an open pilot randomized trial (The METTA – PRAGUE 10 Trial) A....e ConcernedCzech Republic - SUKL A.2EudraCT number2007-002893-76 A.3Full title of the trial MEtabolic Therap
van Munster, Caspar E P; Uitdehaag, Bernard M J
Due to the heterogeneous nature of the disease, it is a challenge to capture disease activity of multiple sclerosis (MS) in a reliable and valid way. Therefore, it can be difficult to assess the true efficacy of interventions in clinical trials. In phase III trials in MS, the traditionally used primary clinical outcome measures are the Expanded Disability Status Scale and the relapse rate. Secondary outcome measures in these trials are the number or volume of T2 hyperintense lesions and gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) of the brain. These secondary outcome measures are often primary outcome measures in phase II trials in MS. Despite several limitations, the traditional clinical measures are still the mainstay for assessing treatment efficacy. Newer and potentially valuable outcome measures increasingly used or explored in MS trials are, clinically, the MS Functional Composite and patient-reported outcome measures, and on MRI, brain atrophy and the formation of persisting black holes. Several limitations of these measures have been addressed and further improvements will probably be proposed. Major improvements are the coverage of additional functional domains such as cognitive functioning and assessment of the ability to carry out activities of daily living. The development of multidimensional measures is promising because these measures have the potential to cover the full extent of MS activity and progression. In this review, we provide an overview of the historical background and recent developments of outcome measures in MS trials. We discuss the advantages and limitations of various measures, including newer assessments such as optical coherence tomography, biomarkers in body fluids and the concept of 'no evidence of disease activity'.
Vitiello, Benedetto; Kratochvil, Christopher J.
Optimal treatment of adolescent depression requires the use of antidepressants such as fluoxetine, and the addition of cognitive-behavioral therapy (CBT) offers better potential. Second-step pharmacological treatment of the disorder offers a success rate of around 50%. Clinical trial for the use of sertraline and CBT in treating…
Schroll, Jeppe Bennekou; Maund, Emma; Gøtzsche, Peter C
Misclassification of adverse events in clinical trials can sometimes have serious consequences. Therefore, each of the many steps involved, from a patient's adverse experience to presentation in tables in publications, should be as standardised as possible, minimising the scope for interpretation...
Herr, Harry W
In 1784, a Royal Commission headed by Benjamin Franklin and Antoine Lavoisier designed a series of ingenious experiments to debunk France's greatest medical rogue, Anton Mesmer, and his bizarre healing of illnesses based on his bogus theory of animal magnetism. Using intentional subject ignorance and sham interventions to investigate mesmerism, Franklin's commission provided a model for the controlled clinical trial.
The research community has alternatively embraced then repudiated exploratory analyses since the inception of clinical trials in the middle of the twentieth century. After a series of important but ultimately unreproducible findings, these non-prospectively declared evaluations were relegated to hypothesis generating. Since the majority of evaluations conducted in clinical trials with their rich data sets are exploratory, the absence of their persuasive power adds to the inefficiency of clinical trial analyses in an atmosphere of fiscal frugality. However, the principle argument against exploratory analyses is not based in statistical theory, but pragmatism and observation. The absence of any theoretical treatment of exploratory analyses postpones the day when their statistical weaknesses might be repaired. Here, we introduce examination of the characteristics of exploratory analyses from a probabilistic and statistical framework. Setting the obvious logistical concerns aside (i.e., the absence of planning produces poor precision), exploratory analyses do not appear to suffer from estimation theory weaknesses. The problem appears to be a difficulty in what is actually reported as the p-value. The use of Bayes Theorem provides p-values that are more in line with confirmatory analyses. This development may inaugurate a body of work that would lead to the readmission of exploratory analyses to a position of persuasive power in clinical trials.
Jun 14, 2013 ... requires clinical trial researchers to obtain an export permit from ... governs all national ethics regulations; legal aspects of using human ... cells, embryos, fetal tissue, zygotes and gametes – are important. ... is affiliated to the Cardiology Unit of Department of Internal Medicine at Tygerberg Hospital, and.
Riera, Joan; Hyttel-Sorensen, Simon; Bravo, María Carmen
BACKGROUND: The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. AIMS...
Pellicer, Adelina; Greisen, Gorm; Benders, Manon
Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the bur...
Oude Rengerink, K.
This thesis presents a number of research projects centred on ‘evidence-based medicine’. It consists of two parts. Part 1 focuses on improving recruitment of the necessary number of patients in clinical trials, as this is the major problem while evaluating the effectiveness of interventions in healt
Oude Rengerink, K.
This thesis presents a number of research projects centred on ‘evidence-based medicine’. It consists of two parts. Part 1 focuses on improving recruitment of the necessary number of patients in clinical trials, as this is the major problem while evaluating the effectiveness of interventions in healt
The development of new drugs is increasingly costly and ineffective. Most time and money is accounted for by late-stage clinical trials that aim to confirm the safety and efficacy of the investigated drug. To assure the continued arrival of new and affordable therapies, it is therefore essential to
Crittenden, Marka; Kohrt, Holbrook; Levy, Ronald; Jones, Jennifer; Camphausen, Kevin; Dicker, Adam; Demaria, Sandra; Formenti, Silvia
Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology.
Amorim, R.G. de; Leal, S.C.; Mulder, J.; Creugers, N.H.J.; Frencken, J.E.F.M.
OBJECTIVES: The aims of this study were to compare 2-year cumulative survival rates of amalgam and atraumatic restorative treatment (ART) restorations in primary molars and to investigate the determinants of the survival rate of restorations. MATERIALS AND METHODS: A controlled clinical trial using
trial research in Malawi: engendering ethical conduct in research. Abstract ... participants; minimise risk and balance benefit; and fairly ... on the Harmonisation of Good Clinical Practice (ICHGCP) to faculty ... of, and acceptable to the community'10. They can ..... any study-related questions and concerns community members ...
Vitiello, Benedetto; Kratochvil, Christopher J.
Optimal treatment of adolescent depression requires the use of antidepressants such as fluoxetine, and the addition of cognitive-behavioral therapy (CBT) offers better potential. Second-step pharmacological treatment of the disorder offers a success rate of around 50%. Clinical trial for the use of sertraline and CBT in treating…
One of the more worrying trends in globalization today is the growing practice of western companies relocating clinical trials to impoverished countries. This paper starts by providing a comprehensive description of the practice and its current regulatory oversight. It argues that this regulatory
Riera, Joan; Hyttel-Sorensen, Simon; Bravo, María Carmen
BACKGROUND: The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. AIMS: ...
Bachour, Candi C; Bachmann, Gloria A; Foster, David C; Wan, Jim Y; Rawlinson, Leslie A; Brown, Candace S
Successful recruitment in clinical trials for chronic pain conditions is challenging, especially in women with provoked vulvodynia due to reluctance in discussing pain associated with sexual intercourse. The most successful recruitment methods and the characteristics of women reached with these methods are unknown. To compare the effectiveness and efficiency of four recruitment methods and to determine socioeconomic predictors for successful enrollment in a National Institutes of Health-sponsored multicenter clinical trial evaluating a gabapentin intervention in women with provoked vulvodynia. Recruitment methods utilized mass mailing, media, clinician referrals and community outreach. Effectiveness (number of participants enrolled) and efficiency (proportion screened who enrolled) were determined. Socioeconomic variables including race, educational level, annual household income, relationship status, age, menopausal status and employment status were also evaluated regarding which recruitment strategies were best at targeting specific cohorts. Of 868 potential study participants, 219 were enrolled. The most effective recruitment method in enrolling participants was mass mailing ( p recruitment methods ( p = 0.11). Relative to clinician referral, black women were 13 times as likely to be enrolled through mass mailing (adjusted odds ratio 12.5, 95% confidence interval, 3.6-43.1) as white women. There were no differences in enrollment according to educational level, annual income, relationship status, age, menopausal status, or employment status and recruitment method. In this clinical trial, mass mailing was the most effective recruitment method. Race of participants enrolled in a provoked vulvodynia trial was related to the recruitment method.
... to facilitate interaction with FDA representatives. The program will focus on the relationships among.... Topics for discussion include the following: (1) What FDA Expects in a Pharmaceutical Clinical Trial;...
Full Text Available Abstract In recent years, the use of adaptive design methods in pharmaceutical/clinical research and development has become popular due to its flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation. The flexibility and efficiency, however, increase the risk of operational biases with resulting decrease in the accuracy and reliability for assessing the treatment effect of the test treatment under investigation. In its recent draft guidance, the United States Food and Drug Administration (FDA expresses regulatory concern of controlling the overall type I error rate at a pre-specified level of significance for a clinical trial utilizing adaptive design. The FDA classifies adaptive designs into categories of well-understood and less well-understood designs. For those less well-understood adaptive designs such as adaptive dose finding designs and two-stage phase I/II (or phase II/III seamless adaptive designs, statistical methods are not well established and hence should be used with caution. In practice, misuse of adaptive design methods in clinical trials is a concern to both clinical scientists and regulatory agencies. It is suggested that the escalating momentum for the use of adaptive design methods in clinical trials be slowed in order to allow time for development of appropriate statistical methodologies.
Full Text Available the trial The protein tyrosine kinase inhibitor nilotinib as first-line treatment of Ph+ chronic myeloid leucemia... protein tyrosine kinase inhibitor nilotinib as first-line treatment of Ph+ chronic myeloid leucemia (CML) i
Full Text Available Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute... sore throat E.1.1.1Medical condition in easily understood language Acute sore
Full Text Available on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute... lymphoblastic leukemia E.1.1.1Medical condition in easily understood language Acute lymphoblastic
Full Text Available State ConcernedFinland - Fimea A.2EudraCT number2011-003474-86 A.3Full title of the trial Albumin in Acute ...erapy for Neuroprotection in Acute Ischemic Stroke A.3.1Title of the trial for la...y people, in easily understood, i.e. non-technical, language Albumin in Acute Stroke (ALIAS) Trial-Part 2 A....se under investigation E.1.1Medical condition(s) being investigated Acute Ischemic Stroke E.1.1.2Therapeutic...n, - cognition measured at 3 months by Trailmaking A and B. E.2.3Trial contains a sub-study No E.3Principal inclusion criteria - Acut
Full Text Available 77-40 A.3Full title of the trial Evaluation of MST-188 in Acute Lower Limb Ischemia: A Phase 2 Randomized Do... and Efficacy Of MST-188 in Subjects with Acute Lower Limb Ischemia Receiving Catheter-Directed Recombinant ...3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language Evaluation of MST-188 in Acute...an A.3.2Name or abbreviated title of the trial where available Evaluation of MST-188 in Acute Lower Limb Isc...neral Information on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acut
Full Text Available pulsions to assess OCD severity) both within and between the three treatment arms w... of the trial Outcome measures will be evaluated. The variation in the Y-BOCS (a specific questionnaire looking at obsessions and com
Nagase, Hiroshi; Fujii, Hideaki
Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug . Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs . One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues  established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine . This led to the finding that the μ type opioid receptor was correlated to drug dependence . Consequently, δ, and particularly κ, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851  and TRK-820 (nalfurafine hydrochloride) .
Delrieu, Julien; Ousset, Pierre Jean; Caillaud, Céline; Vellas, Bruno
Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β (Aβ) peptide represents an important molecular target for intervention in Alzheimer's disease. Several types of Aβ peptide immunotherapy for Alzheimer's disease are under investigation, direct immunization with synthetic intact Aβ(42) , active immunization involving the administration of synthetic fragments of Aβ peptide conjugated to a carrier protein and passive administration with monoclonal antibodies directed against Aβ peptide. Pre-clinical studies showed that immunization against Aβ peptide can provide protection and reversal of the pathology of Alzheimer's disease in animal models. Indeed, several adverse events have been described like meningoencephalitis with AN1792, vasogenic edema and microhemorrhages with bapineuzumab. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several Aβ peptide immunotherapy approaches are under investigation but also against tau pathology. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Full Text Available of the trial Inhibition of δ-PROTEin kinase C for the reducTION of infarct size in Acute Myocardial Infarcti... the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute...ease under investigation E.1.2Version 9.1 E.1.2Level LLT E.1.2Classification code 10000891 E.1.2Term Acute m
Full Text Available UK - MHRA A.2EudraCT number2006-004419-24 A.3Full title of the trial The Use of Sulfasalazine as an Anti-fibrotic in Acute...General Information on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition...(s) being investigated Acute Alcoholic Hepatitis MedDRA Classification E.1.2 Medical condition or disease un
Wheate, Nial J; Walker, Shonagh; Craig, Gemma E; Oun, Rabbab
Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin and ProLindac). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.
In 2002 Helena Kraemer and colleagues published an important article on the analysis of clinical trials in mental health, which advocated a planned focus on mechanisms to investigate the processes behind treatment effects. Kraemer et al. considered not only new approaches to mediation analysis, but also a theoretical approach to factors, both pre-treatment and during treatment, that might moderate this mediation. Trials should not just be about whether a treatment 'worked', but how it worked; with the results informing modification of the intervention for the next trial by discarding aspects that were not effective and reinforcing aspects that were - an iterative procedure towards greater effectiveness. Can we enjoy similar ambitions for complex interventions within mental health? It is not so long ago when the received wisdom within the clinical and much of the research community was that it was simply impossible in practice to mount randomised controlled trials relevant to the kind of psychosocial interventions we use in child and adolescent mental health (CAMHS). How different the situation is now, with burgeoning interest in a systematic evidence base for psychological treatment and the possibilities for unexpected advances (as well as unexpected harms). Nevertheless it is probably still fair to say that the systematic use of process and mechanism study within trials in our field is the exception rather than the rule. What are the possibilities and implications for our field?
Travison Thomas G
Full Text Available Abstract Background Most clinical trial publications include figures, but there is little guidance on what results should be displayed as figures and how. Purpose To evaluate the current use of figures in Trial reports, and to make constructive suggestions for future practice. Methods We surveyed all 77 reports of randomised controlled trials in five general medical journals during November 2006 to January 2007. The numbers and types of figures were determined, and then each Figure was assessed for its style, content, clarity and suitability. As a consequence, guidelines are developed for presenting figures, both in general and for each specific common type of Figure. Results Most trial reports contained one to three figures, mean 2.3 per article. The four main types were flow diagram, Kaplan Meier plot, Forest plot (for subgroup analyses and repeated measures over time: these accounted for 92% of all figures published. For each type of figure there is a considerable diversity of practice in both style and content which we illustrate with selected examples of both good and bad practice. Some pointers on what to do, and what to avoid, are derived from our critical evaluation of these articles' use of figures. Conclusion There is considerable scope for authors to improve their use of figures in clinical trial reports, as regards which figures to choose, their style of presentation and labelling, and their specific content. Particular improvements are needed for the four main types of figures commonly used.
Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group.
Lichtman, Stuart M; Harvey, R Donald; Damiette Smit, Marie-Anne; Rahman, Atiqur; Thompson, Michael A; Roach, Nancy; Schenkel, Caroline; Bruinooge, Suanna S; Cortazar, Patricia; Walker, Dana; Fehrenbacher, Louis
Purpose Patients with organ dysfunction, prior or concurrent malignancies, and comorbidities are often excluded from clinical trials. Excluding patients on the basis of these factors results in clinical trial participants who are healthier and younger than the overall population of patients with cancer. Methods ASCO and Friends of Cancer Research established a multidisciplinary working group that included experts in trial design and conduct to examine how eligibility criteria could be more inclusive. The group analyzed current eligibility criteria; conducted original data analysis; considered safety concerns, potential benefits, research, and potential hurdles of this approach through discussion; and reached consensus on recommendations regarding updated eligibility criteria that prioritize inclusiveness without compromising patient safety. Results If renal toxicity and clearance are not of direct treatment-related concern, then patients with lower creatinine clearance values of > 30 mL/min should be included in trials. Inclusion of patients with mild to moderate hepatic dysfunction may be possible when the totality of the available nonclinical and clinical data indicates that inclusion is safe. Ejection fraction values should be used with investigator assessment of a patient's risk for heart failure to determine eligibility. Patients with laboratory parameters out of normal range as a result of hematologic disease should be included in trials. Measures of patient functional status should be included in trials to better assess fit versus frail patients. Conclusion Expanding inclusion of these patients will increase the number and diversity of patients in clinical trials and result in a more appropriate population of patients.
Full Text Available World Health Organization (WHO has defined herbal medicines as finished labeled medicinal product that contain an active ingredient, aerial, or underground parts of the plant or other plant material or combinations. According to a report of WHO, about 80% of the world population is reported to rely on traditional medicine for their primary health care needs. Even in the developed countries, complementary or alternative medicine is gaining popularity. A report of a global survey on national policy on traditional medicine and regulation of herbal medicines indicated that about 50 countries including China, Japan, and Germany already have their national policy and laws on regulations of traditional medicines. Herbal drugs possess a long history of its use and better patient tolerance. These are cheaper and easily available in countries like India due to rich agro culture conditions. However, reckless utilization of resources threatens the sustainability of several plant species. Traditional medicines are governed by the Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945. In 1959, the Government of India amended the Drugs and Cosmetics Act to include drugs that are derived from traditional Indian medicine. In 1993, the guidelines for the safety and efficacy of herbal medicines developed by an expert committee directed that the procedures laid down by the office of the Drug Controller General of India for allopathic drugs should be followed for all traditional and herbal products to enter into clinical trials for any therapeutic condition. However, there are certain loop holes in the clinical trials of herbal drugs as the lack of stringent bylaws and regulations. Hence, a deep insight of important challenges and major regulatory guidelines for clinical trial of herbal drugs and botanicals is discussed in the present communication. There is lack of scientific evidence to evaluate safety and efficacy of herbal drugs. The quality
Gupta, Umesh Chandra; Bhatia, Sandeep; Garg, Amit; Sharma, Amit; Choudhary, Vaibhav
Research focus of pharmaceutical industry has expanded to a larger extent in last few decades putting many more new molecules, particularly targeted agents, for the clinical development. On the other hand, researchers are facing serious challenges due to high failure rates of new molecules in clinical studies. The United States Food and Drug Administration (FDA) in combination with academia and industry experts identified many factors responsible for failures of new molecules, and with a vision of taking traditional drug development model toward an innovative paradigm shift, issued regulatory guidance on conduct of exploratory investigational new drug (exploratory IND) studies, often called as phase 0 clinical trials, requiring reduced preclinical testing, which has special relevance to life-threatening diseases such as cancer. Phase 0 trials, utilizing much lower drug doses, provide an opportunity to explore the clinical behavior of new molecules very early in the drug development pathway, helping to identify the promising candidates and eliminating non-promising molecules, thus improving the efficiency of overall drug development with significant savings of resources. Being non-therapeutic in nature, these studies, however, pose certain ethical challenges requiring careful study designing and informed consent process. This article reviews the insights and perspectives for the feasibility, utility, planning, designing and conduct of phase 0 clinical trials, in addition to ethical issues and industrial perspective focused at oncology new drug development.
Umesh Chandra Gupta
Full Text Available Research focus of pharmaceutical industry has expanded to a larger extent in last few decades putting many more new molecules, particularly targeted agents, for the clinical development. On the other hand, researchers are facing serious challenges due to high failure rates of new molecules in clinical studies. The United States Food and Drug Administration (FDA in combination with academia and industry experts identified many factors responsible for failures of new molecules, and with a vision of taking traditional drug development model toward an innovative paradigm shift, issued regulatory guidance on conduct of exploratory investigational new drug (exploratory IND studies, often called as phase 0 clinical trials, requiring reduced preclinical testing, which has special relevance to life-threatening diseases such as cancer. Phase 0 trials, utilizing much lower drug doses, provide an opportunity to explore the clinical behavior of new molecules very early in the drug development pathway, helping to identify the promising candidates and eliminating non-promising molecules, thus improving the efficiency of overall drug development with significant savings of resources. Being non-therapeutic in nature, these studies, however, pose certain ethical challenges requiring careful study designing and informed consent process. This article reviews the insights and perspectives for the feasibility, utility, planning, designing and conduct of phase 0 clinical trials, in addition to ethical issues and industrial perspective focused at oncology new drug development.
Full Text Available Drug development has been globalized, and multi-regional clinical trial (MRCT for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and improve patient access to new and innovative treatments. Sponsors are facing several challenges while conducting multiregional clinical trials. Challenges under the heads statistics, clinical, regulatory operational, and ethics have been discussed. Regulators in different countries such as USA, EU-Japan, and China have issued guidance documents in respect of MRCT's. Lack of harmonization in the design and planning of MRCT is perceived to create a difficult situation to sponsors adversely affecting progressing MRCT in more and more discoveries. International conference on hormonisation (ICH has initiated the process for having a harmonized guidance document on MRCT. This document is likely to be issued in early 2017.
Full Text Available Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.
Interventions aiming to slow, stop, or reverse the aging process are starting to enter clinical trials. Though this line of research is nascent, it has the potential to not only prevent prolonged human suffering, but also to extend human well-being. As this line of research develops, it is important to understand the ethical constraints of conducting such research. This paper discusses some of these constraints. In particular, it discusses the ethical difficulties of conducting this research in a way that would produce reliable data regarding the effectiveness of an anti-aging intervention. Clinical trials of such interventions, I argue, will be faced with a dilemma between two confounding variables. Eliminating the variables requires introducing ethically problematic research practices. Thus, researchers must either perform research in ethically problematic ways, or forego the conduct of high-impact clinical research on anti-aging interventions.
Doods, Justin; Dugas, Martin; Fritz, Fleur
Electronic health care records are being used more and more for patient documentation. This electronic data can be used for secondary purposes, for example through systems that support clinical research. Eligibility criteria have to be processable for such systems to work, but criteria published on ClinicalTrials.gov have been shown to be complex, making them challenging to re-use. We analysed the eligibility criteria on ClinicalTrials.gov using automatic methods to determine whether the criteria definition and number changed over time. From 1998 to 2012 the average number of words used to describe eligibility criteria per year increased by 46%, while the average number of lines used per year only slightly increases until 2000 and stabilizes afterwards. Whether the increase of words resulted in increased criteria complexity or whether more data elements are used to describe eligibility needs further investigation.
To prevent problematic outcomes of bowel-based bladder reconstructive surgery, such as prosthetic tumors and systemic metabolic complications, research works, to either regenerate and strengthen failing organ or build organ replacement biosubstitute, have been turned, from 90s of the last century, to both regenerative medicine and tissue engineering.Various types of acellular matrices, naturally-derived materials, synthetic polymers have been used for either "unseeded" (cell free) or autologous "cell seeded" tissue engineering scaffolds. Different categories of cell sources - from autologous differentiated urothelial and smooth muscle cells to natural or laboratory procedure-derived stem cells - have been taken into consideration to reach the construction of suitable "cell seeded" templates. Current clinically validated bladder tissue engineering approaches essentially consist of augmentation cystoplasty in patients suffering from poorly compliant neuropathic bladder. No clinical applications of wholly tissue engineered neobladder have been carried out to radical-reconstructive surgical treatment of bladder malignancies or chronic inflammation-due vesical coarctation. Reliable reasons why bladder tissue engineering clinical applications so far remain unusual, particularly imply the risk of graft ischemia, hence its both fibrous contraction and even worse perforation. Therefore, the achievement of graft vascular network (vasculogenesis) could allow, together with the promotion of host surrounding vessel sprouting (angiogenesis), an effective graft blood supply, so avoiding the ischemia-related serious complications.
Saenz, Carla; Reveiz, Ludovic; Tisdale, John F
A key aspect to guarantee that research with human subjects is ethical is being overlooked. Ethics review committees invest great effort examining the informed consent documents of research protocols to ensure that potential participants can provide consent validly and are not deluded into thinking that the experimental intervention they may sign up for is already known to be therapeutic. However, these efforts to avoid what is called the "therapeutic misconception" might be in vain if the title with which the studies are being introduced to the potential participants escapes ethics review. Research participants might be deceived by clinical trials entitled "novel therapy" when the point of the trial is precisely to find out whether the intervention at stake is therapeutic or not. Providing potential research participants with such misleading information hampers their ability to make informed decisions. The well-established scrutiny that ethics review committees exercise with regard to consent forms is limited if the registration of clinical trials, for which a public title is chosen, constitutes a process that is independent from the ethics review. In this article, we examine this problem, assess recent measures to integrate clinical trial registration with ethics review processes, and provide specific recommendations to solve the problem and ultimately enhance the accountability, transparency, and ethics of research with human subjects.
Full Text Available Abstract Acupuncture treatment has been widely used for many conditions, while results of the increasing numbers of randomized trials and systematic reviews remain controversial. Acupuncture is a complex intervention of both specific and non-specific factors associated with therapeutic benefit. Apart from needle insertion, issues such as needling sensation, psychological factors, acupoint specificity, acupuncture manipulation, and needle duration also have relevant influences on the therapeutic effects of acupuncture. Taking these factors into consideration would have considerable implications for the design and interpretation of clinical trials.
Malavolta, Eduardo Angeli; Demange, Marco Kawamura; Gobbi, Riccardo Gomes; Imamura, Marta; Fregni, Felipe
Randomized controlled clinical trials (RCTs) are considered to be the gold standard for evidence-based medicine nowadays, and are important for directing medical practice through consistent scientific observations. Steps such as patient selection, randomization and blinding are fundamental for conducting a RCT, but some additional difficulties are presented in trials that involve surgical procedures, as is common in orthopedics. The aim of this article was to highlight and discuss some difficulties and possible limitations on RCTs within the field of surgery. PMID:27027037
Van Der Baan, Frederieke H.; Knol, Mirjam J.; Klungel, Olaf H.; Egberts, Toine C.G.; Grobbee, Diederick E.; Roes, Kit C.B.
Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary
The financial supports for investigator-initiated post-marketing clinical trial in clinical oncology are reduced after scandals related to the other fields of clinical trials in Japan. These clinical trials are the essential final steps of clinical development in newer cancer therapy, which should be conducted in the investigator-initiated clinical trial groups with well-organized infrastructure and continuous financial supports. The present problems are discussed and summarized. Future perspectives with the national viewpoints needed to be included the idea of "health technology assessment".
Full Text Available Clinical trials that allow significant heterogeneity of population or interventions often result in uncertain outcomes. In this paper, we review the outcomes of five recent trials of endovascular interventions in acute ischemic stroke in the context of the neutral results of previous large clinical trials on the subject.
Full Text Available BACKGROUND: Retrospective single center natural history studies have shown that times to reach disability milestones and ages at which they are reached are similar in primary (PPMS and secondary (SPMS progressive multiple sclerosis suggesting that they may be phenotypic variations of the same disease. OBJECTIVE: Here we compared longitudinal disease activity in SPMS and PPMS in the context of international multicenter clinical trials. METHODS: We analyzed all objective outcome measures that were systematically collected over 2 years for all subjects randomized to placebo arms in one SPMS and one PPMS clinical trial over the last decade. Conventional and exploratory definitions of clinical disease activity were used. Disease activity was analyzed in 3 different categories intermittent activity, progression, and improvement. Conventional MRI measures and one patient reported outcome measure of quality of life were included when available for comparison. Heat maps were drawn for all results followed by hierarchical clustering. RESULTS: There were 101 outcome variables from 206 SPMS subjects and 79 outcome variables from 135 PPMS subjects. The comparison revealed that SPMS and PPMS subjects exhibited similar disease activity over 2 years in all but two of the variables in common worsening in the EDSS sensory system was more common in PPMS while worsening on the 9 hole PEG was more common in SPMS. Intermittent activity was the most common pattern of disease activity in SPMS and PPMS. Clinical worsening and improvement occurred at similar frequency in both. CONCLUSION: Longitudinal disease activity was nearly identical in SPMS and PPMS subjects in the context of the two multicenter international clinical trials we examined.
Full Text Available HRA A.2EudraCT number2011-001982-42 A.3Full title of the trial Investigation of a novel intervention in Acute..., i.e. non-technical, language A study of the effect of antiretroviral therapy and immunoglobulin on the HIV reservoir in Acute... of a novel intervention in Acute HIV Infection (AHI) A.4.1Sponsor's protocol code numberJ004 A.7Trial is pa...nformation on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute... HIV Infection E.1.1.1Medical condition in easily understood language Acute
Full Text Available te ConcernedSpain - AEMPS A.2EudraCT number2012-000233-39 A.3Full title of the trial Tratamiento de la leucemia...a A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language Tratamiento de la leucemia...on quimioterapia distinta de hidroxiurea.Leucemia promielocítica aguda con t(15;17).Crisis blástica de la leucemia...l valor límite normal, excepto cuando la alteraciones sean atribuibles a la leucemia. Pacientes con fracción
Full Text Available Barbara P Yawn,1 Suzanne Madison,1 Susan Bertram,1 Wilson D Pace,2 Anne Fuhlbrigge,3 Elliot Israel,3 Dawn Littlefield,1 Margary Kurland,1 Michael E Wechsler41Olmsted Medical Center, Department of Research, Rochester, MN, 2UCDHSC, Department of Family Medicine, University of Colorado Health Science Centre, Aurora, CO, 3Brigham and Women's Hospital, Pulmonary and Critical Care Division, Boston, MA, 4National Jewish Medical Center, Division of Pulmonology, Denver, CO, USABackground: Published reports and studies related to patient compensation for clinical trials focus primarily on the ethical issues related to appropriate amounts to reimburse for patient's time and risk burden. Little has been published regarding the method of payment for patient participation. As clinical trials move into widely dispersed community practices and more complex designs, the method of payment also becomes more complex. Here we review the decision process and payment method selected for a primary care-based randomized clinical trial of asthma management in Black Americans.Methods: The method selected is a credit card system designed specifically for clinical trials that allows both fixed and variable real-time payments. We operationalized the study design by providing each patient with two cards, one for reimbursement for study visits and one for payment of medication costs directly to the pharmacies.Results: Of the 1015 patients enrolled, only two refused use of the ClinCard, requesting cash payments for visits and only rarely a weekend or fill-in pharmacist refused to use the card system for payment directly to the pharmacy. Overall, the system has been well accepted by patients and local study teams. The ClinCard administrative system facilitates the fiscal accounting and medication adherence record-keeping by the central teams. Monthly fees are modest, and all 12 study institutional review boards approved use of the system without concern for patient
Gewandter, Jennifer S; Dworkin, Robert H; Turk, Dennis C
Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations...... for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment...... element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have...
Squillaro, Tiziana; Peluso, Gianfranco; Galderisi, Umberto
In the last year, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. Currently the most commonly used adult stem cells in regenerative medicine, MSCs, can be isolated from several tissues, exhibit a strong capacity for replication in vitro, and can differentiate into osteoblasts, chondrocytes, and adipocytes. However, heterogeneous procedures for isolating and cultivating MSCs among laboratories have prompted the International Society for Cellular Therapy (ISCT) to issue criteria for identifying unique populations of these cells. Consequently, the isolation of MSCs according to ISCT criteria has produced heterogeneous, nonclonal cultures of stromal cells containing stem cells with different multipotent properties, committed progenitors, and differentiated cells. Though the nature and functions of MSCs remain unclear, nonclonal stromal cultures obtained from bone marrow and other tissues currently serve as sources of putative MSCs for therapeutic purposes, and several findings underscore their effectiveness in treating different diseases. To date, 493 MSC-based clinical trials, either complete or ongoing, appear in the database of the US National Institutes of Health. In the present article, we provide a comprehensive review of MSC-based clinical trials conducted worldwide that scrutinizes biological properties of MSCs, elucidates recent clinical findings and clinical trial phases of investigation, highlights therapeutic effects of MSCs, and identifies principal criticisms of the use of these cells. In particular, we analyze clinical trials using MSCs for representative diseases, including hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, and diseases in the liver, kidney
Goldacre, Ben; Gray, Jonathan
OpenTrials is a collaborative and open database for all available structured data and documents on all clinical trials, threaded together by individual trial. With a versatile and expandable data schema, it is initially designed to host and match the following documents and data for each trial: registry entries; links, abstracts, or texts of academic journal papers; portions of regulatory documents describing individual trials; structured data on methods and results extracted by systematic reviewers or other researchers; clinical study reports; and additional documents such as blank consent forms, blank case report forms, and protocols. The intention is to create an open, freely re-usable index of all such information and to increase discoverability, facilitate research, identify inconsistent data, enable audits on the availability and completeness of this information, support advocacy for better data and drive up standards around open data in evidence-based medicine. The project has phase I funding. This will allow us to create a practical data schema and populate the database initially through web-scraping, basic record linkage techniques, crowd-sourced curation around selected drug areas, and import of existing sources of structured and documents. It will also allow us to create user-friendly web interfaces onto the data and conduct user engagement workshops to optimise the database and interface designs. Where other projects have set out to manually and perfectly curate a narrow range of information on a smaller number of trials, we aim to use a broader range of techniques and attempt to match a very large quantity of information on all trials. We are currently seeking feedback and additional sources of structured data.
Mijoule, Guillaume; Savy, Stéphanie; Savy, Nicolas
Taking a decision on the feasibility and estimating the duration of patients' recruitment in a clinical trial are very important but very hard questions to answer, mainly because of the huge variability of the system. The more elaborated works on this topic are those of Anisimov and co-authors, where they investigate modelling of the enrolment period by using Gamma-Poisson processes, which allows to develop statistical tools that can help the manager of the clinical trial to answer these questions and thus help him to plan the trial. The main idea is to consider an ongoing study at an intermediate time, denoted t(1). Data collected on [0,t(1)] allow to calibrate the parameters of the model, which are then used to make predictions on what will happen after t(1). This method allows us to estimate the probability of ending the trial on time and give possible corrective actions to the trial manager especially regarding how many centres have to be open to finish on time. In this paper, we investigate a Pareto-Poisson model, which we compare with the Gamma-Poisson one. We will discuss the accuracy of the estimation of the parameters and compare the models on a set of real case data. We make the comparison on various criteria : the expected recruitment duration, the quality of fitting to the data and its sensitivity to parameter errors. We discuss the influence of the centres opening dates on the estimation of the duration. This is a very important question to deal with in the setting of our data set. In fact, these dates are not known. For this discussion, we consider a uniformly distributed approach. Finally, we study the sensitivity of the expected duration of the trial with respect to the parameters of the model : we calculate to what extent an error on the estimation of the parameters generates an error in the prediction of the duration.
De Moraes, C Gustavo; Liebmann, Jeffrey M; Levin, Leonard A
Glaucomatous visual field progression has both personal and societal costs and therefore has a serious impact on quality of life. At the present time, intraocular pressure (IOP) is considered to be the most important modifiable risk factor for glaucoma onset and progression. Reduction of IOP has been repeatedly demonstrated to be an effective intervention across the spectrum of glaucoma, regardless of subtype or disease stage. In the setting of approval of IOP-lowering therapies, it is expected that effects on IOP will translate into benefits in long-term patient-reported outcomes. Nonetheless, the effect of these medications on IOP and their associated risks can be consistently and objectively measured. This helps to explain why regulatory approval of new therapies in glaucoma has historically used IOP as the outcome variable. Although all approved treatments for glaucoma involve IOP reduction, patients frequently continue to progress despite treatment. It would therefore be beneficial to develop treatments that preserve visual function through mechanisms other than lowering IOP. The United States Food and Drug Administration (FDA) has stated that they will accept a clinically meaningful definition of visual field progression using Glaucoma Change Probability criteria. Nonetheless, these criteria do not take into account the time (and hence, the speed) needed to reach significant change. In this paper we provide an analysis based on the existing literature to support the hypothesis that decreasing the rate of visual field progression by 30% in a trial lasting 12-18 months is clinically meaningful. We demonstrate that a 30% decrease in rate of visual field progression can be reliably projected to have a significant effect on health-related quality of life, as defined by validated instruments designed to measure that endpoint.
Full Text Available the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute... pulmonary embolism Embolismo pulmonar agudo E.1.1.1Medical condition in easily understood language Acute...rial contains a sub-study No E.3Principal inclusion criteria 1) Acute symptomatic PE confirmed by multidetec
Full Text Available on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute... Optic Neuritis E.1.1.1Medical condition in easily understood language Acute Optic Neuritis E.1.1.2T
Full Text Available nguage Imatinib Treatment in Acute Ischemic Stroke A.4.1Sponsor's protocol code numberIstrokepilot A.7Trial ...Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute....g. in diabetes (vision disturbances may indicate haemorrhagic retinopathy) or other haemorrhagic ophthalmic conditions - Acute
Full Text Available Information on the Trial E.1 Medical condition or disease under investigation E.1.1Medical condition(s) being investigated Acute...vestigation E.1.2Version 9.1 E.1.2Level LLT E.1.2Classification code 10000891 E.1.2Term Acute
Full Text Available n el postoperatorio de cirugia cardiaca en niños. A.3.2Name or abbreviated title of the trial where availabl...non-technical, language sildenafil in the postoperative period of cardiac surgery in children. sildenafilo e
Leach, Matthew J; Ziaian, Tahereh; Francis, Andrew; Agnew, Tamara
The burden on those caring for a person with dementia is substantial. Although quality research assists in addressing the needs of these caregivers, recruiting caregivers into clinical studies is often problematic. This investigation explores the difficulties and successes in recruiting dementia caregivers into community-based clinical research by reporting the findings of a mixed-method substudy of a multicenter randomized controlled trial involving 40 community-dwelling dementia caregivers living in Adelaide, South Australia. Data for the substudy were derived from standardized trial monitoring documentation and structured telephone interviews. From a total of 16 distinct methods used across a 12-month recruitment campaign, the most cost-effective strategy was the distribution of flyers through a single study site. This approach generated the greatest number of enrollments of all methods used, achieving a 67% recruitment yield. The least cost-effective strategy, with a 0% recruitment yield, was the publication of a newspaper advertisement. Themes that emerged from the interviews pointed toward 5 key facilitators and 3 barriers to future trial recruitment. This study has generated new insights into the effective recruitment of dementia caregivers into clinical trials. We anticipate that these lessons learnt will assist in shaping the recruitment strategies of future studies of dementia caregivers.
Giannoulis, G.; Moraitis, N.; Argyris, N.; Dris, S.; Lessi, C.; Perdikouris, S.; Kostikidou, L.; Apostolopoulos, D.; Spatharakis, C.; Papafili, I.; Agapiou, G.; Panagopoulos, A. D.; Avramopoulos, H.
The 5G era is nearly upon us, and poses several challenges for system designers; one important question is how the (soon to be standardized) mmWave bands of wireless mobile access can coexist harmoniously with optical links in fixed telecom networks. To this end, we present a Radio-over-Fiber (RoF) backhauling concept, interfaced to a 60-GHz indoor femto-cell via a field-installed optical fiber link. We successfully demonstrate generation of a RoF signal up to 1 Gb/s and transmit it optically over 43 km of deployed Single Mode Fiber (SMF), as well as investigate the performance of the 60-GHz access link as a function of distance. The optical link introduces negligible degradation, contrasting the effect of multipath fading in the 60-GHz wireless channel; the latter requires adaptive equalization using offline DSP. The proposed scheme is further validated by demonstration of a 60-GHz Remote Antenna Unit (RAU) concept, handling real traffic from commercial Gigabit Passive Optical Network (GPON) equipment. Proper RAU operation at 1.25 Gb/s is achieved, accommodating true data packets from a Media Converter emitting at 1310 nm through an in-building fiber link. System performance is confirmed through Bit Error Rate (BER) and Error Vector Magnitude (EVM) measurements. EVMs of 11 and 19% are achieved with BPSK signals, for distances of 1 and 2 m respectively. As standardization of mmWave technologies moves from 5G testbeds to field-trial prototypes, successful demonstration of such 60-GHz wireless access scenarios over a telecom operator's commercial fiber infrastructure is even more relevant.
Østgård, Lene Sofie Granfeldt; Nørgaard, Mette; Sengeløv, Henrik
Clinical trials are critical to improve AML treatment. It remains, however, unclear if clinical trial participation per se affects prognosis and to what extent the patients selected for trials differ from those of patients receiving intensive therapy off-trial.We conducted a population-based coho...
Ibrahim, Joseph G; Chen, Ming-Hui; Lakshminarayanan, Mani; Liu, Guanghan F; Heyse, Joseph F
Developing sophisticated statistical methods for go/no-go decisions is crucial for clinical trials, as planning phase III or phase IV trials is costly and time consuming. In this paper, we develop a novel Bayesian methodology for determining the probability of success of a treatment regimen on the basis of the current data of a given trial. We introduce a new criterion for calculating the probability of success that allows for inclusion of covariates as well as allowing for historical data based on the treatment regimen, and patient characteristics. A new class of prior distributions and covariate distributions is developed to achieve this goal. The methodology is quite general and can be used with univariate or multivariate continuous or discrete data, and it generalizes Chuang-Stein's work. This methodology will be invaluable for informing the scientist on the likelihood of success of the compound, while including the information of covariates for patient characteristics in the trial population for planning future pre-market or post-market trials.