Guide Data Monitoring Committees in Clinical Trials: A Practical Perspective (Statistics in Practice)

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  1. Data monitoring committees: Promoting best practices to address emerging challenges
  2. Data monitoring committees: Promoting best practices to address emerging challenges
  3. Introduction
  4. Data Monitoring Committees in Clinical Trials: A Practical Perspective
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This could have been an obtuse book, but instead it really was practical. The specific trials noted were particularly helpful in demonstrating points. She does refer to a lot of her work, BUT she has done a lot of the work.

Data monitoring committees: Promoting best practices to address emerging challenges

Easy to read, delightful! Prior to that she played a prominent role in the development of statistical methods for clinical trials at the US Food and Drug Administration. They are among the world's leading experts in group sequential methods. Fleming is famous for the O'Brien-Fleming stopping rule that bears his name and DeMets is known for the Lan-DeMets alpha spending function approach to group sequential analysis.

With such experts and excellent writers you get what you should expec t, an authoritative treatment of the practical and technical aspects of the monitoring of data by Data Monitoring Committees DMCs, previously called Data Safety and Monitoring Boards, DMSBs. These committees look at interim data from a clinical trial to judge whether the trial should be stopped early for safety concerns.

In their charter they can set-up their own rule or can debate and make subjective decisions. These authors through their experience present examples and also formal statistical methods that can be used not only to stop for safety concerns but also to stop if safety and efficacy are demonstrated earlier than anticipated in the design. Also if the trial is clearly going to be unsuccessful they can stop for futility as well. The development of group sequential methods and adaptive designs make a formal analysis for the DMC possible. For a detailed account of group sequential methods see the book by Jennison and Turnbull.

For adaptive designs the two books by Mark Chang one co-authored with Professor Chow are excellent. Another excellent book similar to this text is the text by Proschan, Lan and Wittes which covers the theory and applications more than the aspects of the DMC. These bodies provide independent oversight of the safety and operation of clinical trials. Anyone heavily involved in clinical trials should be familiar with the contents of this book. See all 4 reviews. Amazon Giveaway allows you to run promotional giveaways in order to create buzz, reward your audience, and attract new followers and customers.

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Data monitoring committees: Promoting best practices to address emerging challenges

Feedback If you need help or have a question for Customer Service, contact us. Would you like to report poor quality or formatting in this book? Click here Would you like to report this content as inappropriate? Click here Do you believe that this item violates a copyright? There's a problem loading this menu right now. Get fast, free shipping with Amazon Prime. Properly designed and conducted randomized clinical trials are integral to achieving timely and reliable evidence about the benefits and risks of medical interventions.

Oversight of these clinical trials requires coordination and ongoing review of safety, efficacy, quality, ethics, adjudication, operations, and logistics. DMCs periodically conduct unblinded reviews of accumulating safety and efficacy data and serve in an advisory role to the trial leadership and sponsor. Their primary mission is to safeguard the interests of study participants and to protect the integrity and credibility of the trial. A substantial body of literature describes the role, function, and experience of DMCs; 1 — 21 see online Appendix 1 for the evolution of their role and scope.

Organizational diagram of clinical trial stakeholders and participants. The Data Monitoring Committee occupies a central position and interacts directly with some of the groups that oversee, support, and manage the trial conduct. An expert panel of representatives from academic medical centers, academic research organizations, the pharmaceutical and biotech industry, the National Institutes of Health, and the U. Food and Drug Administration discussed these challenges and proposed best practices and operating principles for the effective functioning of DMCs.

This position paper summarizes these discussions and offers recommendations to improve the DMC process, highlighting insights from meeting participants who collectively have DMC experience in hundreds of clinical trials, and who widely represent areas of expertise in the DMC process. DMCs face complex challenges, such as balancing safety signals that arise from limited data against the value of continuing the trial to obtain more conclusive results.

Most DMC members have not received formal training concerning their roles and responsibilities, in part because of a lack of infrastructure for providing such training. Few trial sponsors require formal training for DMC members. Training options for DMC service could include a combination of didactic and experiential instruction. Training might include a formal curriculum with textbooks, 5 , 6 , 8 articles, 9 — 11 web-based lectures, 12 or interactive courses. DMC members should understand basic clinical trial design and analysis 13 as well as the fundamentals of clinical trial operations.

More advanced training might include biomedical ethics, and methodologies of interim analyses. Formal DMC courses could be offered as part of comprehensive degree programs at schools of medicine or public health, or through training programs offered by Clinical Translational Science Award-funded institutions. Such training could be supplemented by web-based modules designed to highlight past dilemmas DMCs have faced.

Some universities offer similar types of instruction in other disciplines through open-source platforms such as Coursera, Open CourseWare, and iTunes U. These increasingly popular courses offer a low-cost mechanism to disseminate DMC training widely. Efforts also could target international settings, such as those by the Harvard Multiregional Clinical Trials Center in publishing insights about DMC responsibilities 23 and in providing regional training opportunities to hundreds of clinical trialists from emerging regions by sending teams of clinical trial experts to developing countries to build expertise regarding the purpose, goals and responsibilities of DMCs.

Given the nature and complexity of DMC functions, a combination of training and experience may best prepare a new generation of qualified DMC members. An apprenticeship model for initial DMC service could complement didactic and web-based training. While many expert panelists agreed with the potential value of such apprenticeships, such programs remain to be widely implemented. These could be standing internal committees formed by sponsors to monitor early-stage trials not having independent DMCs. Such a committee at Merck Research Laboratories involves both junior and senior members from clinical, quantitative, and regulatory organizations within Merck, and enables internal personnel to gain experience on safety and efficacy monitoring practices and techniques.

In some settings, these semi-independent standing committees have been formed to be supportive to DMCs that are in place. For clinical trials conducted by HIV prevention cooperative groups sponsored by the National Institute of Allergy and Infectious Diseases, such committees monitor pooled data on quality of trial conduct measures, enhancing trial integrity while providing their members substantive insights into the monitoring process.

While training and experience is important for all DMC members, this is especially true for the DMC Chair, whose leadership has considerable influence on the efficiency and effectiveness of the DMC process.


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The Chair should be prepared to serve in the lead role in all sessions of the DMC meeting, and in the development and dissemination of DMC recommendations and meeting minutes. A well-structured certification process could provide substantive experience for potential future DMC members. Defining the financial model needed to support such endeavors will be important in ensuring that DMC training options become widely available and sustainable.

DMC members face several sources of possible liability from clinical trial stakeholders, 25 including trial participants or their advocates who might argue that participants experienced trial-related injuries that the DMC could have prevented, as well as investors and employees of companies who have a financial stake in the outcomes. Historically, few DMCs have been the subject of litigation; however, over the past decade, several DMC members have been involved as defendants or have been required to provide depositions for legal proceedings personal communications.

The possibility of litigation has many important ramifications for DMC members including significant personal financial costs, substantial lost time from normal work activities, personal stress, and damage to professional reputation. Indemnification for DMC members could influence their performance. Some participants on the expert panel suggested that comprehensive sponsor indemnification could encourage overly risky decision-making by the DMC; others observed that indemnification coverage has routinely been provided by academic institutions or industry to their employees, and automobile insurance policies typically provide coverage even in instances of negligence, presumably based on judgment that such practices do not lead to unacceptable increases in irresponsible behavior.

Most of the expert panel and all authors supported the view that a robust indemnification process could favorably influence DMC decision-making by enabling members to engage in deliberations about how best to protect patient safety and trial integrity without having excessive concerns about potential legal and financial consequences of their recommendations. Some points about indemnification deserve particular emphasis. The indemnification process also is complicated for DMC members participating in National Institutes of Health-sponsored research, since the federal Antideficiency Act, Pub.

Introduction

Potential solutions to the indemnification problem have been proposed. First, DMC members as well as trial sponsors should be educated about issues such as personal liability and indemnification to ensure that they consider these when negotiating contracts for DMC membership. Second, standardized indemnification language could be developed for use in industry-sponsored DMC contracts to provide indemnification except in cases of a judicial finding of gross negligence, willful misconduct, or fraudulent acts.

Data Monitoring Committees in Clinical Trials A Practical Perspective

Fourth, central sources of indemnification for individual DMC members could be pursued, such as creating a risk pool or other type of professional liability insurance group plan to mitigate individual risk. While the financial model needed to support such an endeavor is uncertain, key clinical trial stakeholders such as the Clinical Translational Science Award program and the National Patient-Centered Clinical Research Network could be engaged to develop viable strategies for collectively addressing this issue of such importance to DMC service.

Undermining these components of trial conduct threatens the ability of the trial to provide clear answers to the questions it was designed to address. Trial sponsors with a financial or intellectual property interest in the outcome of a trial, as in industry trials, should not attend the closed DMC sessions when unblinded efficacy and safety data are reviewed. This restriction also holds for trial leadership, who might have a vested scientific interest in a specific trial outcome. Excluding non-members of the DMC protects the independence of the DMC from interference by entities with vested interests, and protects sponsors and investigators from any perception that they might have used interim results to interfere with the scientific process.

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Government-funded trials do not pose the same type of financial conflicts for the sponsors as do industry-funded trials. However, even if one accepts that a funding agency has no financial or intellectual property stake in the outcome of the trial and no institutional interest other than in assuring the trial be conducted in a scientifically rigorous and ethical manner, whether agency staff members should attend closed sessions continues to be debated.

An important aspect of trial conduct relating to confidentiality is the need, on occasion, to make changes to a protocol during the study. Data external to the trial, for example, may indicate the desirability of modifying the eligibility criteria or even changing the primary endpoint. The trial sponsor makes final decisions regarding such issues. A trial sponsor with access to the interim data, however, cannot make objective decisions about such changes, since it will usually be clear whether the change will increase or decrease the probability that the trial has the desired outcome.

This issue is relevant to all trial sponsors, public or private. While blinding other stakeholders is important to maintaining integrity of the trial, DMCs should have full access to unblinded accumulating data on safety and efficacy throughout the clinical trial. The consensus of the expert panel was that such blinding was counterproductive, even potentially dangerous to the safety of the study participants.

By having access to unblinded data on all relevant treatment outcomes, the DMC can develop timely insights about safety in the context of a benefit-to-risk assessment, as well as about irregularities in trial conduct or in the generation of the DMC reports. DMC members are expected to maintain confidentiality of emerging trial results.

Typically, members sign confidentiality agreements that cover not only the period of trial conduct but also a substantial period of time following the conclusion of the trial. In particular, what recourse do DMC members have to comment? While rare, such situations have occurred and have led to consideration about whether some type of mediation process for DMCs is needed in such situations. The DMC charter should specify the primary responsibilities of the DMC in relation to the sponsor and the trial leadership committees.

The charter should address potential conflicts of interests DMC members may have, procedures for maintaining confidentiality, the format for DMC meeting sessions, reports and minutes, additional details regarding communication pathways, and the statistical guidelines for interim analyses.

Over the years, the length of DMC charters has grown, and their tone has become increasingly legalistic rather than focusing upon a set of principles intended to serve as an operational guide. Some DMC charters require a rigid voting process rather than recognizing the importance of formulating DMC recommendations through consensus development. The expert panel agreed that DMC recommendations are best formulated by in-depth discussion of the issues leading to consensus, rather than by voting.

Extensive experience has shown broad success in achieving consensus when the DMC chair assumes responsibility for fostering communication and collaboration among the DMC members, maximizes the contributions from all members, ensures that relevant concerns are properly addressed, and guides the DMC toward developing final consensus recommendations.

Long, complex, and ritualistic DMC charters inappropriately constrain DMCs by eroding their independence and, perhaps, sometimes placing them in a legally and scientifically compromised position. Predefining exact operational procedures and contingencies for all potential scenarios is not possible. The DMC must have the flexibility to deal with unexpected challenges.

The charter should articulate principles and processes that will provide guidance to the DMC in addressing its mission. Traditionally, the format for DMC meetings includes both closed and open sessions. In the open sessions which are attended by trial leadership and sponsors as well as the DMC members, the data reviewed are typically limited to measures of the quality of trial conduct, pooled across intervention groups. Closed sessions allow the DMC to maintain confidentiality of interim data, while the open sessions allow direct interaction between the DMC and the study team about trial conduct, evidence from external sources related to the study interventions, and relevant interactions between the sponsor and regulatory authorities.

The specific meeting format can impact the independence and integrity of the DMC process. Beginning the DMC meeting with a closed session emphasizes the autonomy of the DMC and enhances the likelihood that the DMC—not the trial leadership or sponsor—is in charge of the meeting and its agenda.

Data Monitoring Committees in Clinical Trials: A Practical Perspective

This approach also offers an opportunity for DMC members to achieve a common understanding of the principal findings from interim data, and to organize and prioritize issues for discussion with the study investigators during the open session. This also provides an opportunity to remind DMC members about the confidential nature of the proceedings before they receive updates on the trial progress from the study investigators during the open session. For these reasons, we favor this format; however, alternative formats e. To perform its functions effectively, a DMC relies on reports containing timely and accurate data on efficacy, safety, and quality of trial conduct.

The SDAC may be embedded within an academic research organization or function as an independent entity. The same entity may serve not only as the SDAC but also as the data analysis center for data management and site management; in this arrangement, which is common for federally-funded trials, there are blinded and unblinded personnel in the same organization. In such settings, it is important to ensure that the unblinded statisticians can carry out their responsibilities with the DMC confidentially and independently of others in the organization.

Vol 48, Issue 3, Adaptive designs in clinical trials: Application to Healthcare Epidemiology Research. Tips on citation download. Data Monitoring Committees in Clinical Trials: John Wiley and Sons ; Google Scholar , Crossref. Confidentiality and trial integrity issues for adaptive designs. Google Scholar , Abstract.

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A multiple testing procedure for clinical trials. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, I: Approximately optimal one-parameter boundaries for sequential trials. Optimal adaptive designs for binary response trials. A year review of sequential methodology in clinical studies. Friede, T, Kieser, M. A comparison of methods for adaptive sample size adjustment.