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Protecting the confidentiality of interim data: Addressing current challenges

CLINICAL TRIALS 2015年第1期12卷 5-11页

作者： Fleming, Thomas R. Univ Washington Dept Biostat Seattle WA 98195 USA

There is compelling evidence supporting the importance of maintaining confidentiality of interim data in clinical trials designed to reliably address the benefit-to-risk profile of interventions. While this is widely recognized, creative approaches are needed to achieve this in challenging settings where interim data are released for regulatory review and action, even though the trial would be continued to address its primary hypothesis. An illustration is the recently emerging setting of cardiovascular safety trials in type 2 diabetes mellitus. At the first stage of such trials, if large relative increases in cardiovascular major morbidity/mortality can be ruled out, data can be released solely for the purpose of allowing regulatory decision making about marketing approval. The trial is then continued in the post-marketing setting to address the primary hypothesis regarding whether smaller relative increases can be ruled out. Active rather than passive approaches are needed to protect the integrity of cardiovascular safety trials. Given the importance to trial integrity of maintaining confidentiality of interim data such as the estimated relative effect on cardiovascular risk, a data Access Plan should be in place in these trials to ensure such data are not revealed to study participants and their caregivers, investigators involved in trial conduct, the sponsor's management team, and the public, until trial completion. A Performance Standards Document also should be developed to pre-specify targeted and minimally acceptable levels for recruitment rate, best real-world achievable adherence, avoidance of cross-ins, and retention rate. This document should specify creative approaches for achieving these targets, oversight procedures during trial conduct to monitor performance levels, and actions to be taken if emerging data indicate minimally acceptable levels are not being reached. In settings where meaningful breaches in confidentiality have occurred, such oversight

关键词： data monitoring committee data Access Plan Performance Standards Document cardiovascular safety trials

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Reporting remit and function of trial steering committees in randomised controlled trials: review of published literature

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TRIALS 2015年第SUPPL 2期16卷 P177-P177页

作者： Conroy, E. J. Arch, B. Lewis, S. Lane, A. Sydes, M. R. Norrie, J. Murray, G. Harman, N. I. Gamble, C. Univ Liverpool Med Children Clin Trials Unit Liverpool Merseyside England Univ Edinburgh Ctr Populat Hlth Sci Edinburgh Midlothian Scotland Bristol Randomised Trials Collaborat Trials Unit Bristol Avon England UCL MRC Clin Trials Unit London England London Hub Trials Methodol Res London England Ctr Healthcare Randomised Trials CHaRT Aberdeen Scotland Univ Liverpool MRC North West Hub Trials Methodol Res Dept Biostat Liverpool Merseyside England

P177

关键词： Monograph Series Consort Statement Trial Management data monitoring committee Reporting Practice

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Investigating possible fraudulent activity at a research site

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TRIALS 2015年第SUPPL 2期16卷 P193-P193页

作者： Knott, Carol Henderson, Joanne Bowman, Louise Landray, Martin Univ Oxford Nuffield Dept Populat Hlth Clin Trial Serv Unit Oxford England

P193

关键词： Corrective Action monitoring committee Professional Body Systemic Trial data monitoring committee

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Adaptive Clinical Trials: Overview of Early-Phase Designs and Challenges

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THERAPEUTIC INNOVATION & REGULATORY SCIENCE 2014年第1期48卷 20-30页

作者： Marchenko, Olga Fedorov, Valerii Lee, J. Jack Nolan, Christy Pinheiro, Jose Quintiles Inc Ctr Stat Drug Dev Innovat Durham NC 27703 USA Quintiles Inc Predict Analyt Innovat Durham NC 27703 USA Univ Texas MD Anderson Canc Ctr Dept Biostat Div Quantitat Sci Houston TX 77030 USA Quintiles Inc Innovat Durham NC 27703 USA Janssen Res & Dev LLC Quantitat Decis Strategies Raritan NJ USA

In this paper, the authors describe developments in adaptive design methodology and discuss implementation strategies and operational challenges in early-phase adaptive clinical trials. The BATTLE trialthe first completed biomarker-based Bayesian adaptive randomized study in lung canceris presented as a case study to illustrate main ideas and share learnings.

关键词： adaptive design early-phase designs clinical trial management data monitoring committee modeling and simulation

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Experiences with an adaptive design for a dose-finding study in patients with osteoarthritis

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CONTEMPORARY CLINICAL TRIALS 2014年第2期37卷 189-199页

作者： Miller, Frank Bjornsson, Marcus Svensson, Ola Karlsten, Rolf AstraZeneca Sodertalje Sweden

Dose-finding studies in non-oncology areas are usually conducted in Phase II of the development process of a new potential medicine and it is key to choose a good design for such a study, as the results will decide if and how to proceed to Phase III. The present article has focus on the design of a dose-finding study for pain in osteoarthritis patients treated with the TRPV1 antagonist AZD1386. We describe different design alternatives in the planning of this study, the reasoning for choosing the adaptive design and experiences with conduct and interim analysis. Three alternatives were proposed: one single dose-finding study with parallel design, a programme with a smaller Phase Ila study followed by a Phase Ilb dose-finding study, and an adaptive dose-finding study. We describe these alternatives in detail and explain why the adaptive design was chosen for the study. We give insights in design aspects of the adaptive study, which need to be pre-planned, like interim decision criteria, statistical analysis method and setup of a data monitoring committee. Based on the interim analysis it was recommended to stop the study for futility since AZD1386 showed no significant pain decrease based on the primary variable. We discuss results and experiences from the conduct of the study with the novel design approach. Huge cost savings have been done compared to if the option with one dose-finding design for Phase II had been chosen. However, we point out several challenges with this approach. (C) 2014 Elsevier Inc. All rights reserved.

关键词： Adaptive design AZD1386 data monitoring committee Dose-finding Interim analysis Osteoarthritis

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Bayesian stopping guidelines for heart valve premarket approval studies

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JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2014年第6期148卷 2813-U1470页

作者： Grunkemeier, Gary L. Wu, YingXing Wang, Lian Hamilton, Cody Providence Hlth & Serv Med Data Res Ctr Portland OR USA Edwards Lifesci Dept Global Clin Operat Irvine CA USA

Objectives: The data monitoring committee (DMC) for the premarket approval (PMA) study of a new heart valve prosthesis convenes periodically to review the accumulating results of the study, and determines, among other things, whether there is enough concern with safety to stop the study. Their deliberations are largely subjective, based on their combined experience and expertise, but an objective aid to evaluating complication rates, usually called a stopping rule, is desirable. Methods: The US Food and Drug Administration has designated objective performance criteria (OPC) for 7 heart valve complications. At the end of the PMA study, when approximately 800 patient-years have been accumulated, the complication rates must compare favorably with the OPC. Given the results to date at an interim review of the data, we use a Bayesian approach to compute the probability of passing the OPC test by the end of study. Results: We provide a method that the DMC can use to predict the probability of passing the OPC test for each complication, and a graphical aid for each number of events, observed at 100 patient-year intervals. Conclusions: Although the DMC ultimately uses combined experience and expertise to make the decision to stop a PMA valve study, we have provided an objective assessment of the probability of the valve ultimately passing the OPC test to aid in making that decision.

关键词： 35 DMC data monitoring committee DSMB data safety and monitoring board FDA US Food and Drug Administration NB negative binomial OPC objective performance criteria PMA premarket approval TE thromboembolism

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An In-Process Scaling Model: A Potential Framework for data monitoring committees and Clinical Trial Quality Improvement

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DRUG INFORMATION JOURNAL 2012年第1期46卷 8-12页

作者： Smith, Alan Seltzer, Jonathan Appl Clin Intelligence LLC Bala Cynwyd PA 19004 USA Main Line Hlth Heart Ctr Bala Cynwyd PA 19004 USA

This article discusses the application of a statistical process control methodology to improve the quality of real-time clinical trial monitoring, an especially valuable tool for data monitoring committees. This article outlines a method that may have value in bringing a data-based approach using the measures of site performance to define patterns of similarity or dissimilarity between the sites. These can then be used to provide an efficient and objective mechanism to identify those sites for closer scrutiny, monitoring, or further training, either at the end of the study or on an ongoing basis.

关键词： clinical monitoring adverse event statistical process controls metric data monitoring committee data safety monitoring board multidimensional scaling unblinding

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The use of interim data and data monitoring committee recommendations in randomized controlled trial reports: frequency, implications and potential sources of bias

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BMC MEDICAL RESEARCH METHODOLOGY 2008年第1期8卷 12-12页

作者： Tharmanathan, Puvan Calvert, Melanie Hampton, John Freemantle, Nick Univ Birmingham Dept Primary Care & Gen Practice Birmingham W Midlands England Queens Med Ctr Div Cardiovasc Med Nottingham NG7 2UH England

Background: Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs). data monitoring committees (DMCs) often undertake such analyses, but their widening role may lead to extended use of interim analysis or recommendations that could potentially bias trial results. Methods: Systematic search of eight major publications: Annals of Internal Medicine, BMJ, Circulation, CID, JAMA, JCO, Lancet and NEJM, including all randomised controlled trials ( RCTs) between June 2000 and May 2005 to identify RCTs that reported use of interim analysis, with or without DMC involvement. Recommendations made by the DMC or based on interim analysis were identified and potential sources of bias assessed. Independent double data extraction was performed on all included trials. Results: We identified 1772 RCTs, of which 470 (27%;470/1772) reported the use of a DMC and a further 116 (7%;116/1772) trials reported some form of interim analysis without explicit mention of a DMC. There were 28 trials ( 24 with a formal DMC), randomizing a total of 79396 participants, identified as recommending changes to the trial that may have lead to biased results. In most of these, some form of sample size re-estimation was recommended with four trials also reporting changes to trial endpoints. The review relied on information reported in the primary publications and methods papers relating to the trials, higher rates of use may have occurred but not been reported. Conclusion: The reported use of interim analysis and DMCs in clinical trials has been increasing in recent years. It is reassuring that in most cases recommendations were made in the interest of participant safety. However, in practice, recommendations that may lead to potentially biased trial results are being made.

关键词： CArvedilol Interim Analysis data monitoring committee Automate External Defibrillator Trial Steering committee

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Practical Considerations and Strategies for Executing Adaptive Clinical Trials

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DRUG INFORMATION JOURNAL 2012年第2期46卷 160-174页

作者： He, Weili Kuznetsova, Olga M. Harmer, Mark Leahy, Cathy Anderson, Keaven Dossin, Nicole Li, Lina Bolognese, James Tymofyeyev, Yevgen Schindler, Jerald Merck & Co Inc Clin Biostat Rahway NJ 07065 USA MSD Hoddesdon England Merck & Co Inc Global Clin Trial Operat Rahway NJ 07065 USA Merck & Co Inc MRL Sigma Rahway NJ 07065 USA Cytel Inc Boston MA USA Janssen Res & Dev J&J Quantitat Decis Strategies Dept Titusville NJ USA

There is great potential for clinical trials designed with adaptive features to result in more efficient decision making within a drug development program. However, clinical trials with adaptive features are more complex to implement than traditional designs such as fixed-sample or group sequential. Workarounds and/or inefficiencies in adaptive design (AD) trial execution may result in human and material wastes. Further, they may result in the introduction of operational biases that may potentially negate any gains in designing an AD trial and may even render trial results not interpretable. In this article, we present and share our experience and best practices in AD trial implementation in the areas of resource planning, randomization considerations including the importance of randomization schemes on clinical supply, Interactive Voice Randomization System vendor capability assessment and quality control, clinical supply strategy considerations, enrollment management and patient enrollment modeling and simulation, data quality and interim analysis planning, managing blinding and unblinding, and the use of a data monitoring committee.

关键词： adaptive designs IVRS data monitoring committee modeling and simulation clinical supply

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Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174

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BMC INFECTIOUS DISEASES 2012年第1期12卷 1-11页

作者： Nagot, Nicolas Kankasa, Chipepo Meda, Nicolas Hofmeyr, Justus Nikodem, Cheryl Tumwine, James K. Karamagi, Charles Sommerfelt, Halvor Neveu, Dorine Tylleskar, Thorkild Van de Perre, Philippe INSERM U1058 Montpellier France CHU Montpellier Dept Bacteriol Virol Montpellier France Univ Montpellier I Montpellier France CHU Montpellier Dept Med Informat Montpellier France Univ Zambia Sch Med Dept Pediat & Child Hlth Lusaka Zambia Univ Ouagadougou Fac Hlth Sci Ctr Int Res Hlth Bobo Dioulasso Burkina Faso Ctr MURAZ Bobo Dioulasso Burkina Faso Univ Western Cape Cape Town South Africa Makerere Univ Sch Med Coll Hlth Sci Dept Pediat & Child Hlth Kampala Uganda Univ Bergen Ctr Int Hlth Bergen Norway Norwegian Inst Publ Hlth Div Infect Dis Control Oslo Norway

Background: Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age. Methods: The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms. HIV-uninfected infants at day 7 (+/- 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants. The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events an

关键词： Lamivudine Nevirapine Infant Feeding data monitoring committee Resistant Viral Strain

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