- Email: [email protected]
Should all trials have a Data Safety and Monitoring Committee?
Should all trials have a Data Safety and Monitoring Committee? John A. Cairns, MD, Alfred Hallstrom, PhD, and Peter Held, MD, PhD Vancouver, British Columbia, Canada
When you conduct the trial, remember, we’ll be watching you. —Thomas Ryan, MD, at an investigators’ meeting at the beginning of a clinical trial Before we embark on a detailed discussion of the functions of a Data and Safety Monitoring Committee (DSMC), it is worthwhile to reflect on the fundamental role that such a group plays in a clinical trial. What characteristics of any human experiment should prompt the construction of a DSMC, and when should it be an optional component of a study? We are early enough in the evolution of modern clinical investigation that room for disagreement on these questions still exists. Different terms have been used to describe the independent committee that monitors a clinical trial. When it has a limited function, the term Data Monitoring Committee (DMC) has often been used. When given broader responsibilities for overseeing aspects of a trial beyond the data, the group is often referred to as a Data and Safety Monitoring Committee or a Data and Safety Monitoring Board (DSMB).
What is the fundamental purpose of a DSMC? A reasonable argument can be made that some kind of safety committee is needed for clinical trials when any one of several conditions is met. • When a clinical trial is large enough to detect important effects on mortality and irreversible morbidity rates, the merits of continuing the experiment assume a specific quantitative dimension. Trials aimed at demonstrating a biologic principle might be monitored in a less formal manner, as described below. Although trialists must constantly consider whether a human experiment is worth continuing, a DSMC seems essential when a trial has the power to detect statistically significant differences in tangible human outcomes. (Most trials From the University of British Columbia, Vancouver, British Columbia, Canada. Reprint requests: John A. Cairns, MD, University of British Columbia, 317-219 Health Sciences Hall, Vancouver, British Columbia V6T 1Z3, Canada. E-mail: [email protected] Am Heart J 2001;141:156-63 Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/112501 doi:10.1067/mhj.2001.112501
that address symptoms or relief of pain do not have a DSMC; however, some experts believe that even these trials would benefit from monitoring.) • When the risk of a treatment (whether experimental or control) is unknown, monitoring is necessary because adverse outcomes may occur unpredictably, sometimes with grave results (eg, unexpected deaths in studies of prostacyclin analogs [Flolan International Randomized Survival Trial (FIRST)]1 and in gene therapy studies2,3). • When a therapy has a known risk of severe side effects, special and targeted oversight is needed. Given these three criteria, it is difficult to envision any clinical trial that would not benefit from some kind of monitoring. It may be useful to plan for external monitoring in all clinical research, although, as this series of articles makes clear, most clinical research projects (that are not trials) do not require a full DSMC. Indeed, it must be recognized that a global ethical standard calls for the independent oversight of any human experimentation. The principles governing the protection of human subjects have been delineated in the Nuremberg Code (1947),4 the Declaration of Helsinki (1964),5 and 45 CFR 46 of the US Code of Federal Regulations.6 A brief review of the circumstances that led to the creation of these documents is enough to convince most people that every human experiment should have appropriate oversight. The regulatory application of these documents is reviewed in a subsequent article. Clinical trials are complex human experiments with many components. Unlike experimentation in inanimate matter, clinical trials perform experiments in intact human beings whose care is provided in a health system. Thus a clinical trial necessarily involves the motivations, desires, and values of many people. Accordingly, each clinical trial is like a unique organism with many parts that interact to form the whole, which has an unknown, frequently unpredictable life. For this reason, all clinical trials require human oversight; neither simple, objective statistical rules nor clinical judgment are sufficient to ensure the integrity of a study. Clinical trials aimed at preventing and treating cardiovascular disease involve an interaction between a health care provider and a patient that is governed by both explicit and implicit ethical constructs. The complexity of these ethical constructs, coupled with the complexity of a trial, create a tension among the principals that shape group and individual interactions, making the
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Figure 1
From Cairns handout at DSMC meeting.
conduct and the monitoring of a clinical trial both demanding and fascinating. Legitimate differences of opinion can and often do occur regarding the interpretation of trial data, and the criteria that should be used to approve, alter, or terminate a study sometimes require considerable discussion. The oversight of clinical trials may be achieved by a variety of mechanisms, and in many situations an array of entities and individuals may share monitoring functions. When a DSMC is appointed for a study, it shares responsibility with an institutional ethical committee (or an Institutional Review Board [IRB]), with government agencies, and with individual investigators, all of whom are responsible for ensuring that the trial appropriately balances the risks and rewards for its individual subjects. The DSMC also works with a Steering Committee and the trial sponsor, whether government, industry, or foundation, which together have the operational responsibility for the trial. The functions of a DSMC in its relation to the study investigators may be viewed as seen in Figure 1. The principal investigators have designed an experiment to find the truth about a particular therapeutic question, and other investigators have agreed to take part in this investigation. In pursuing the experiment, investigators agree to preserve the randomization of subjects and the blinding of data so that biased judgments can be avoided and the probability of finding the truth about the study question can be enhanced. The DSMC is charged with protecting society in general and, specifically, the individuals participating in the experiment. In fulfilling these charges, the DSMC must weigh the fact that an advantage of a treatment compared with a standard therapy may be detected earlier than expected and that this advantage may benefit both participants and nonparticipants. Finding the correct balance between the obligation to the individuals who have vol-
unteered for the trial and the implications of trial decisions on nonsubjects, both current and future, might be thought of as a form of societal efficiency. When a clinical trial is terminated too early or its objectivity is contaminated, patients may be put at risk and the financial investment in the trial jeopardized. Continuing a trial for too long carries the opposing risks of delaying the dissemination of a treatment with societal benefit and wasting scarce resources. Even in an unblinded trial, a DSMC may perform valuable functions because blinding or not blinding has no effect on the overall cross-center need for monitoring safety and benefit. Individual patients and providers know what treatment is being given, but the aggregate results across centers are not known. For example, trials of cancer treatments are almost never blinded; yet it has been documented that cancer trials conducted with DSMCs, in contrast to those in which interim results are readily available to all investigators, are more likely to be completed and to provide a consistent message.7 A DSMC may also oversee the discipline required in reporting findings; when results are not blinded, it is much more difficult to achieve objectivity and refrain from reporting bias. Given that investigators frequently design a trial because they believe in the superiority (albeit unproved) of one form of treatment compared with another, a DSMC can provide a voice of objectivity when decisions about a trial must be made.
Should the need for a DSMC vary by the type of trial? In nearly all cases, an independent DSMC should monitor the phase III trial of a therapy for a disease with significant mortality and morbidity rates. Even psychosocial interventions, often supposed harmless, may increase mortality rates.8,9 As noted earlier, an indepen-
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dent expert committee is clearly needed in large trials in which the end points include irreversible major morbid events such as death, stroke, and myocardial infarction. It is also needed in definitive studies that evaluate new therapies with potentially severe risks and in trials that evaluate a known therapy intended for a new use and characterized by a significant risk profile. Such trials usually have statistical boundaries that must be considered in light of other data regarding the trial of interest and other ongoing trials, and these kinds of studies require that decisions important to society be made. Because drug interventions have become so prominent in the field of clinical trials, the use of independent DSMCs has become routine in pharmacologic studies that focus on questions about morbidity and mortality effects. (By contrast, behavioral and administrative studies, although they involve the same ethical issues as other studies and need independent oversight, have less of a tradition of using DSMCs.) The majority of current trials, however, are undertaken by drug companies that are trying to determine whether a particular pharmaceutical agent relieves a symptom of disease, and such trials are rarely monitored by DSMCs. The need for an independent DSMC is less clear in some clinical trial arenas than in others. For example, a phase III trial of a blood pressure–lowering medication with 300 patients, when phase II has not identified any safety problems, presents a situation that differs from other trials. Although hypertension is a chronic disease responsible for substantial numbers of deaths, myocardial infarctions, strokes, and episodes of renal failure, phase III studies for this condition typically involve few patients, a short period of follow-up, and little severe disease.10 Consequently, major issues of patient safety rarely arise and DSMCs may not be needed for such trials. Phase III studies of cholesterol-lowering agents have been handled similarly because they typically involve exposing the patient population for a relatively short time. If safety issues do become a concern during such studies, the research programs tend to be discontinued. On the other hand, these trials address medical problems that, in the broadest sense, result in substantial death and disability; thus it can certainly be argued that they require some kind of oversight. In a related question, some clinical investigators have taken the position that small trials with surrogate end points should not be used to determine which therapies should be used in practice but that clinical outcome trials should be mandatory in such cases. However, even in the absence of this approach, some external oversight of phase III trials should be considered when they will be used to recommend a therapy to a large population of patients at risk for major clinical events. Another smaller trial frequently conducted is a phase II dose-finding trial in circumstances in which there is substantial risk to patients because of the disease under
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study, such as acute coronary syndromes. Often these trials include 200 to 500 patients and require considerable flexibility in design and conduct. In addition, these small phase II studies are frequently not intended to be definitive and do not require formal interim statistical analyses. For such a study, a small committee comprising several outside experts who follow the trial in a less formal manner may be desirable; alternatively, a single trusted individual with no vested interest in the trial result could function as an independent safety officer. The risks associated with relying on a single trusted person are that such an arrangement may be insufficiently formal and rigorous and that the issues that arise may be less thoroughly considered because of the absence of group discourse. If all the usual requirements surrounding a formal DSMB can be met by appointing a qualified individual, this situation may suffice; anything less, however, would raise concern. In addition, choosing one trusted person to monitor a study may provide the required external oversight, but when difficult issues must be grappled the ability to reach a consensus forged from several different perspectives can be extremely valuable to the decisionmaking process. Furthermore, all trials should have a defined goal requiring quantitative analysis, and many trials could benefit from an interim analysis. Along with a DSMC, a local IRB plays a critical role in the oversight of clinical trials. The involvement of an IRB alone, without a DSMC, may be sufficient in a trial that involves a single institution, especially when a mechanism is established for the significant involvement of a subcommittee or a particular individual. Most local IRBs, however, lack the expertise to monitor multicenter trials or lack sufficient time for the intensive work required in such cases. Indeed, the practice in which each individual IRB monitors the conduct of its own institution in multicenter trials—although no communication occurs among the IRBs themselves—makes no sense. A recent federal report has highlighted this problem; major efforts should be made to overhaul the current IRB system so that it can provide constructive oversight.11
What is the history of DSMCs? The concept of DSMCs arose during the early clinical trials conducted by the National Institutes of Health (NIH). One of the earliest DSMCs was constructed as an ad hoc group to monitor, in the late 1960s, the University Group Diabetes Project (UGDP),12 when trouble emerged in the ongoing monitoring of the study. At the time of this trial methods for interim analysis of data were not well developed; accordingly, trial leaders reviewed outcome data on a regular basis in an unblinded fashion. After a time, patients treated with tolbutamide, an oral hypoglycemic agent, were judged
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Figure 2
Typical organizational structure of clinical trials.
to have an excess cardiovascular mortality rate, and the trial was therefore terminated early.12 The clinical community expressed considerable concern about this decision, which was questioned in many subsequent articles. Partly as a result of the UGDP experience, a report known as the “Greenberg Report”13,14 recommended to the National Heart, Lung, and Blood Institute (NHBLI) the routine inclusion of a monitoring committee for all major trials. The Coronary Drug Project (CDP) was the first large NHLBI trial to incorporate a formal DSMC. Since the UGDP, the use of DSMCs has been highly variable, depending on the research sponsor and investigator affiliated with the study. Some branches of the NIH, for example, include a DSMC as a routine component of studies; other branches have almost no history of using DSMCs, although in June 1998 the NIH published guidelines requiring the use of DSMCs.15 The medical products industry has used DSMCs in only a small minority of clinical trials, although more companies are now mandating, in their standard operating procedures, consideration of DSMC oversight. The many small human studies performed in individual academic institutions have little history of involving DSMCs and are typically overseen by an IRB. In the spring of 2000, the Food and Drug Administration (FDA) published updated guidance for the use of DSMCs in clinical trials (see Appendix).16 In May of the same year the Department of Health and Human Services published a set of guidelines for monitoring clini-
cal trials.17 These guidelines will stimulate a dramatic increase in the use of DSMCs.
What are the functions of a DSMC? The most compelling issue for a DSMC in any human experiment is patient safety, and its most obvious concern is the potential of a new therapeutic agent for adverse consequences. Protecting the safety of patients by examining data for indications for early stopping, in the presence of statistical evidence of benefit or harm, is equally important. Other questions that a DSMC should independently review include the need for continued enrollment and the likelihood that the proposed experiment will yield results that will be important enough to balance the risk of conducting it. Figure 2 shows the typical organization of clinical trials designed to provide definitive information about clinical practice or a new therapy. The sponsor of such a study may be the government, the medical products industry, a health care delivery system, or a foundation. In some cases a Steering Committee may be appointed to provide independent insight into the conduct of a trial; its members represent the clinical practice community that cares for patients with the disease for which the trial has been designed. A Data Coordinating Center (DCC) collects and analyzes the data. Often an Executive Committee is formed with representatives of the Steering Committee, the study sponsor, and the DCC. Beyond analyzing issues of patient risk, many DSMCs are called on to play an advisory role regarding the con-
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duct of the studies being performed. The advisory functions can be broad. Often a DSMC is asked to follow the evidence for protocol compliance and investigator performance. It may also be required to assist in assessing the integrity of data and the performance of the DCC. In many trials a DSMC has been asked to participate in and give final approval to protocol design; at other times, it has been asked to intervene to pass judgment on whether a trial struggling to achieve its enrollment is indeed feasible. As discussed below, these functions may be handled in a variety of ways in different trials. Before a trial begins, the DSMC may play a significant role in advising the trial organizers about the project being planned. The DSMC should review the design of the trial to assess its scientific validity. Fundamental to participation in the ethical review of a proposed trial is the conviction that the experiment to be performed is valid and will yield results of societal benefit commensurate with the risk undertaken by its subjects. An independent view of whether a proposed trial is actually feasible constitutes an important component of such an assessment. Sometimes the sponsor and investigators may be overly enthusiastic about a proposed study; in such cases, independent observers can provide useful guidance about the likelihood that the experiment can actually be completed. It is imperative that the DSMC thoroughly discuss potential safety issues before the first patient is enrolled; accordingly, the appointment of a DSMC after study enrollment has already begun should be considered poor policy. At times, a DSMC may wish to recommend changes in a study protocol even as the trial is proceeding. Although the considerations behind such changes may be complex, the actual recommendations may be relatively simple, such as speeding up or extending enrollment. More difficult recommendations, such as dropping a limb of the protocol, modifying a regimen, or terminating the trial, usually require that DSMC members exercise considerable judgment because the questions involved in such cases may be extremely complicated. A DSMC may also recommend increasing or decreasing the surveillance for adverse events or outcomes because it is concerned that a particular type of event may not be adequately detected. The procedure by which a sponsor and Steering Committee accepts or rejects these potential changes in a protocol is discussed in a subsequent article in this series; it is critically important because changes that a DSMC recommends frequently have a significant impact on resource use. In a smaller phase II trial, a DSMC or a Data Monitoring Person with oversight may have a more complex, dynamic, and flexible function than in other trials. Phase II protocols are increasingly characterized by flexible, adaptive designs that allow for changing a regimen or a patient population as a study progresses.
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What are the characteristics of a good DSMC? Ideally, a DSMC should be both constructive and independent. It should provide timely review of the quality and accuracy of trial data and recognize design problems early in the study. Patient safety is its primary charge, but a good DSMC must also be able to impart a sense of comfort to investigators; a positive ambience about the progress in a trial can make an important difference in the success of a protocol. Furthermore, particularly in highly visible intervention trials, a DSMC should be able to enhance a sense of societal security in terms of the ongoing trial that it monitors. A constructive DSMC is knowledgeable, assertive, objective, and attentive. Ideally, knowledge in the medical, statistical, and ethical realms is blended within its membership. A docile committee fails to fulfill its obligation; indeed, investigators and sponsor benefit from a committee that actively confronts issues before it becomes too late to address them. When a committee does not take the time to form a balanced view of an issue or to consider all its options, it tends to act too quickly instead of waiting for a definitive answer to the question at hand; alternatively, it may overlook obvious problems that may have arisen. As it fulfills its varied responsibilities, a DSMC must respond to the needs of investigators and the sponsor (sometimes in a manner not anticipated before study start-up) while maintaining its primary focus on its responsibility to patients in the trial. An independent DSMC is free from financial conflicts, hands-on participation in a study, involvement with the DCC, and financial involvement with the sponsor. Financial conflicts may appear in many forms but, at a minimum, DSMC members should not have stock holdings with any entity involved in the study they oversee, nor should they have ongoing consultancies or advisory positions with such entities. Because a DSMC reviews data as needed during a trial, the objectivity of a member who knows the trends in the data could easily be compromised if he or she were to advise an individual study patient; thus DSMC members should be independent of clinical sites. Just as with financial conflict, direct involvement with the affairs of a trial sponsor or its coordinating center could place a DSMC member in a position in which his or her recommendations could jeopardize future relationships.
What should be the composition of DSMC membership? Some experts argue that a DSMC should reach its decisions by consensus rather than by vote; nevertheless, having an odd number of individuals on a DSMC ensures that decisions can be made by a majority of the members if a vote is taken. A DSMC should have a chair
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who is either a clinician with expertise in the field of investigation or a statistician with experience in the type of trial to be monitored. Because dialog and group dynamics can be critical when difficult recommendations are considered, it is best to restrict the size of a DSMC: three to five members is often adequate to cover the key disciplines needed for fully informed monitoring. However, there are many situations in which more members may be necessary to ensure that expertise in all relevant aspects of a study are represented in the committee. Although some ethicists are highly experienced in clinical trial issues and may contribute significantly to trial proceedings, an ethicist is not usually required to serve on a DSMC. Still, it is highly desirable that an ethical consultant be available for a DSMC to call on when needed. The major function of an ethicist is to assist the committee in framing the issues that it should debate. In some trials a patient advocate has been added to the DSMC. In most situations this addition is unnecessary, but it should be considered when a trial has substantial public visibility and patients affected by the trial believe that their concerns need to be specially represented. How regulatory agencies should interact with DSMCs in trials falling under the jurisdiction of the FDA, the Committee for Proprietary Medicinal Products in the United Kingdom, or other regulatory bodies, is an interesting issue and one with little precedent. Most trials do not formally include members of regulatory authority groups, but discussions with regulators frequently occur as a DSMC follows a trial. In some circumstances a DSMC assumes the responsibility of reporting aggregate adverse experiences to various regulatory authorities. At least one statistician from the DCC must attend the meetings of a DSMC meetings to present the data from a trial. This function can be fulfilled in several ways. Traditionally, the primary statistician for a trial (and for large trials, an assistant) becomes unblinded to prepare reports for the DSMC. In some quarters concern has arisen that these individuals then become unable to participate in discussions with the still-blinded Steering Committee about changing study design. One approach to avoiding this problem is to have different statisticians perform different roles, such as serving as a member of the Steering Committee, a sponsor representative, a DCC leader, or a member of the DSMC. An alternative approach is to have the DCC statistician and data managers remain blinded and to leave the treatment code with an independent statistical center. In this model, data are transferred to the independent statistical center and reports are prepared and presented by statisticians from that center. With this approach, the ability of a DCC statistician to participate in discussions about changing trial design is preserved because the statistician has not become unblinded.
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Guidelines for DSMC selection and interaction The study sponsor and Steering Committee, led by the principal investigator or the executive committee, should appoint the individuals who will serve as the DSMC. Appointments should be made before the trial protocol is finalized, and the qualifications of potential DSMC members should be carefully examined. Most DSMC members should have substantial knowledge of the content area of the trial and the class of the study intervention. Several should have expertise in the method that will be used to examine study results. One or more members should be statistical experts. In addition, all members should possess a high level of integrity and significant experience with clinical trial decision making and politics. Records of his or her past experiences should show evidence that a member has both common sense and also “nerve,” as demonstrated by a willingness to make difficult decisions. The DSMC should be constructed with a view toward achieving a compatibility among its individual members, although in some circumstances, for trials of active treatment comparisons, it may be worthwhile for the committee to include experts on competing therapies. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study (GUSTO 1), for example, the DSMC included Dr Eugene Braunwald, who chaired the Steering Committee for the Thrombolysis in Myocardial Infarction (TIMI) 1 trial, which found alteplase superior to streptokinase for vessel patency. The same DSMC also included Dr Peter Sleight, a clinical leader of the International Study of Infarct Survival (ISIS 3), which found no mortality benefit for tissue plasminogen activator compared with streptokinase.
Interactions of a DSMC Because interactions within a DSMC and between a DSMC and other trial entities may become complicated as a study proceeds, it is important that rules of engagement be defined as much as possible before a trial begins. After a DSMC is appointed, it is beneficial to ensure that it be allowed to offer suggestions about the structure and function of the trial. Before the trial starts, the DSMC should meet formally to review expectations for the trial, to examine issues that may arise during its course, and to establish a sense of comfort among the various constituents. When it convenes, the DSMC should welcome both the sponsor and principal investigator to an open portion of the meeting, one in which the ground rules for the committee are established. At this time the committee may ask questions about the conduct of the trial, its goals, and new developments in the field. During the open session with the
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DSMC, only open data should be discussed; a closed session is intended to allow for analysis of data by treatment groups. However, the DSMC should also have a private session without the sponsor or principal investigator present, during which it should review outcome data as a function of treatment assignment. To perform the independent oversight function without compromise, committee members should be immune to any suggestion that the trial leadership has influenced them to alter their opinions. In addition to rules of engagement, “rules of escalation” should also be defined and implemented as early as possible. What should be done if a major disagreement occurs within the DSMC itself, or between the DSMC and the Steering Committee or sponsor? In the end, the funding agency holds ultimate control, because without financing, the trial cannot be conducted. There are, however, multiple examples of embarrassing disagreements between trial decision makers; such disagreements may lead the public or the physician community to form unnecessarily adverse perceptions about a trial. All parties stand to benefit if clearly defined, and appropriate mechanisms for addressing and reporting such disagreements can be established at the outset of a trial.
Conclusion Historically, we are still in the early stages of the science of clinical trials; thus the exact method of these trials continues to evolve. All clinical trials involve individual patients, and the ethical imperative generally accepted in the past half century is that all human experiments should have some form of a “conscience” to ensure the safety and ethical treatment of subjects. In small, straightforward studies a single individual may serve this function. For more complex studies, it is recommended that there be a diverse DSMC with an odd number of members whose expertise includes not only the medical question under investigation but also biostatistics and the practical issues of trial conduct, decision making, and the complex relationships that exist within a trial.
References 1. Califf RM, McNulty SE, Adams KF, et al. A randomized controlled trial of epoprostenol therapy for heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:4455. 2. Nelson D, Weiss R. FDA stops researcher’s human gene therapy experiments. Washington Post; 2000 March 2. p A08. 3. Hilts PJ. FDA says researchers failed to report a second death linked to gene therapy. New York Times; 2000 May 4. p A-20. 4. Permissible medical experiments: trials of war criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Nuremberg, October 1946–April 1949. Volume 2. Washington (DC): US Government Printing Office. p 181-2.
5. Declaration of Helsinki. Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, and amended in Tokyo in 1975, in Venice in 1983, in Hong Kong in 1989, and in South Africa in 1996. 6. US Code of Federal Regulations. Title 45, Public Welfare, Department of Health and Human Services; National Institutes of Health, Office for Protection from Research Risks; Section 46: Protection of human subjects. Revised 18 June 1991; effective 19 August 1991. 7. Green SJ, Fleming TR, O’Fallon JR. Policies for study monitoring and interim reporting of results. J Clin Oncol 1987;5:1477-84. 8. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993; 270:1819-25. 9. Frasure-Smith N, Lesperance F, Talajic M. Depression and survival following myocardial infarction. JAMA 1994;271:1080-2. 10. Office of Inspector General. Institutional Review Boards: a time for reform. The Office; 1998. Publication No.: OEI-01-97-00193. 11. Meinert CL, Knatterud GL, Prout TE, et al. University Group Diabetes Program: a study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970;19:789-830. 12. Anonymous. Organization, review, and administration of cooperative studies (Greenberg Report): a report from the Heart Special Project Committee to the National Advisory Heart Council, May 1967. Controlled Clin Trials 1988;9:137-48. 13. Halperin M, DeMets DL, Ware JH. Early methodological developments for clinical trials at the National Heart, Lung and Blood Institute. Stat Med 1990;9:881-92, 903-6. 14. National Institutes of Health. NIH policy for data and safety monitoring. Release date: June 10, 1998. Available at: http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 15. US Food and Drug Administration, Department of Health and Human Services: Office of Regulatory Affairs. Guidance for Institutional Review Boards, clinical investigators, and sponsors: exception from informed consent requirements for emergency research. Draft guidance (released for comment on 3-30-2000). Section VII: Data monitoring. Available at: http://www.fda.gov/ora/compliance_ref/bimo/err_guide.htm. 16. National Institutes of Health. Further guidance on data and safety monitoring for phase I and phase II trials. June 5, 2000. Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00038.html.
Appendix FDA draft guidance on Data Monitoring, cited above in reference 16; text available at the FDA web site.
VIII. DATA MONITORING COMMITTEE (DMC) Before a study may be initiated, the IRB must find and document that the sponsor has established an independent DMC to serve as an advisory body to the sponsor (21 CFR 50.24[a] [7][iv]). Definition. A DMC, sometimes called a DSMB, is a group of experts established by the sponsor to assess at intervals the progress of a clinical trial (the safety data and the critical efficacy end points) and to recommend to the sponsor whether to continue, modify, or stop a trial. DMCs for trials implemented under 21 CFR 50.24 must be “independent,” by which the agency means that the committee should be composed solely of individuals who have no financial interest in
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the outcome of the study and who have not been involved in the design or conduct of the study (21 CFR 50.24[a][7][iv]). Purpose. The DMC helps ensure subject safety by reviewing ongoing results on a periodic basis and considering whether an investigation ought to be modified to minimize any identified risks or halted. Factors to consider in this decision include whether (1) the potential benefits of the investigational intervention have been established or (2) the risks are greater than anticipated. The DMC is responsible for informing and making recommendations to the sponsor about safety or efficacy concerns related to continuing the investigation. Membership. The DMC should be composed of individuals not otherwise connected with the particular clinical investigation or the sponsor. A DMC under this rule typically would include one or more clinicians specializing in the relevant medical field(s), biostatisticians, and bioethicists. Operation. The DMC reviews study data and adverse event reports on a schedule generally defined by the sponsor, which may include review of study data on an ongoing basis (real time) if necessary for adequate safety monitoring in specific situations. It is essential that the DMC have access to all the
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information it needs to effectively evaluate the progress of the study. Thus the DMC may need access to data unblinded by treatment arms to ensure reliable and complete assessment of the safety and efficacy data. The sponsor is responsible for determining the scope of the DMC’s responsibilities. Operations of the DMC should include: (1) the manner in which, and the frequency with which, study data and information about adverse events are forwarded to and reviewed by the DMC (eg, after 10%, 25%, 50%, 75%, or 100% enrollment), (2) criteria for assessing data and pre-established “stopping” criteria, (3) qualifications of DMC members, (4) assurance that members of the DMC have no financial interest in the outcome of the study and have not been involved in the design or conduct of the study, and (5) preparation and maintenance of written records for all meetings. May an IRB serve as a DMC? Because most IRBs are not constituted to meet the special membership requirements of a DMC and the duties and scope of activities of an IRB and a DMC are quite different, entities performing each of these separate functions should be established. Any committee serving as a DMC should ensure that its membership is appropriate to the study and that it operates as a separate, independent entity.
When you conduct the trial, remember, we’ll be watching you. —Thomas Ryan, MD, at an investigators’ meeting at the beginning of a clinical trial Before we embark on a detailed discussion of the functions of a Data and Safety Monitoring Committee (DSMC), it is worthwhile to reflect on the fundamental role that such a group plays in a clinical trial. What characteristics of any human experiment should prompt the construction of a DSMC, and when should it be an optional component of a study? We are early enough in the evolution of modern clinical investigation that room for disagreement on these questions still exists. Different terms have been used to describe the independent committee that monitors a clinical trial. When it has a limited function, the term Data Monitoring Committee (DMC) has often been used. When given broader responsibilities for overseeing aspects of a trial beyond the data, the group is often referred to as a Data and Safety Monitoring Committee or a Data and Safety Monitoring Board (DSMB).
What is the fundamental purpose of a DSMC? A reasonable argument can be made that some kind of safety committee is needed for clinical trials when any one of several conditions is met. • When a clinical trial is large enough to detect important effects on mortality and irreversible morbidity rates, the merits of continuing the experiment assume a specific quantitative dimension. Trials aimed at demonstrating a biologic principle might be monitored in a less formal manner, as described below. Although trialists must constantly consider whether a human experiment is worth continuing, a DSMC seems essential when a trial has the power to detect statistically significant differences in tangible human outcomes. (Most trials From the University of British Columbia, Vancouver, British Columbia, Canada. Reprint requests: John A. Cairns, MD, University of British Columbia, 317-219 Health Sciences Hall, Vancouver, British Columbia V6T 1Z3, Canada. E-mail: [email protected] Am Heart J 2001;141:156-63 Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/112501 doi:10.1067/mhj.2001.112501
that address symptoms or relief of pain do not have a DSMC; however, some experts believe that even these trials would benefit from monitoring.) • When the risk of a treatment (whether experimental or control) is unknown, monitoring is necessary because adverse outcomes may occur unpredictably, sometimes with grave results (eg, unexpected deaths in studies of prostacyclin analogs [Flolan International Randomized Survival Trial (FIRST)]1 and in gene therapy studies2,3). • When a therapy has a known risk of severe side effects, special and targeted oversight is needed. Given these three criteria, it is difficult to envision any clinical trial that would not benefit from some kind of monitoring. It may be useful to plan for external monitoring in all clinical research, although, as this series of articles makes clear, most clinical research projects (that are not trials) do not require a full DSMC. Indeed, it must be recognized that a global ethical standard calls for the independent oversight of any human experimentation. The principles governing the protection of human subjects have been delineated in the Nuremberg Code (1947),4 the Declaration of Helsinki (1964),5 and 45 CFR 46 of the US Code of Federal Regulations.6 A brief review of the circumstances that led to the creation of these documents is enough to convince most people that every human experiment should have appropriate oversight. The regulatory application of these documents is reviewed in a subsequent article. Clinical trials are complex human experiments with many components. Unlike experimentation in inanimate matter, clinical trials perform experiments in intact human beings whose care is provided in a health system. Thus a clinical trial necessarily involves the motivations, desires, and values of many people. Accordingly, each clinical trial is like a unique organism with many parts that interact to form the whole, which has an unknown, frequently unpredictable life. For this reason, all clinical trials require human oversight; neither simple, objective statistical rules nor clinical judgment are sufficient to ensure the integrity of a study. Clinical trials aimed at preventing and treating cardiovascular disease involve an interaction between a health care provider and a patient that is governed by both explicit and implicit ethical constructs. The complexity of these ethical constructs, coupled with the complexity of a trial, create a tension among the principals that shape group and individual interactions, making the
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Figure 1
From Cairns handout at DSMC meeting.
conduct and the monitoring of a clinical trial both demanding and fascinating. Legitimate differences of opinion can and often do occur regarding the interpretation of trial data, and the criteria that should be used to approve, alter, or terminate a study sometimes require considerable discussion. The oversight of clinical trials may be achieved by a variety of mechanisms, and in many situations an array of entities and individuals may share monitoring functions. When a DSMC is appointed for a study, it shares responsibility with an institutional ethical committee (or an Institutional Review Board [IRB]), with government agencies, and with individual investigators, all of whom are responsible for ensuring that the trial appropriately balances the risks and rewards for its individual subjects. The DSMC also works with a Steering Committee and the trial sponsor, whether government, industry, or foundation, which together have the operational responsibility for the trial. The functions of a DSMC in its relation to the study investigators may be viewed as seen in Figure 1. The principal investigators have designed an experiment to find the truth about a particular therapeutic question, and other investigators have agreed to take part in this investigation. In pursuing the experiment, investigators agree to preserve the randomization of subjects and the blinding of data so that biased judgments can be avoided and the probability of finding the truth about the study question can be enhanced. The DSMC is charged with protecting society in general and, specifically, the individuals participating in the experiment. In fulfilling these charges, the DSMC must weigh the fact that an advantage of a treatment compared with a standard therapy may be detected earlier than expected and that this advantage may benefit both participants and nonparticipants. Finding the correct balance between the obligation to the individuals who have vol-
unteered for the trial and the implications of trial decisions on nonsubjects, both current and future, might be thought of as a form of societal efficiency. When a clinical trial is terminated too early or its objectivity is contaminated, patients may be put at risk and the financial investment in the trial jeopardized. Continuing a trial for too long carries the opposing risks of delaying the dissemination of a treatment with societal benefit and wasting scarce resources. Even in an unblinded trial, a DSMC may perform valuable functions because blinding or not blinding has no effect on the overall cross-center need for monitoring safety and benefit. Individual patients and providers know what treatment is being given, but the aggregate results across centers are not known. For example, trials of cancer treatments are almost never blinded; yet it has been documented that cancer trials conducted with DSMCs, in contrast to those in which interim results are readily available to all investigators, are more likely to be completed and to provide a consistent message.7 A DSMC may also oversee the discipline required in reporting findings; when results are not blinded, it is much more difficult to achieve objectivity and refrain from reporting bias. Given that investigators frequently design a trial because they believe in the superiority (albeit unproved) of one form of treatment compared with another, a DSMC can provide a voice of objectivity when decisions about a trial must be made.
Should the need for a DSMC vary by the type of trial? In nearly all cases, an independent DSMC should monitor the phase III trial of a therapy for a disease with significant mortality and morbidity rates. Even psychosocial interventions, often supposed harmless, may increase mortality rates.8,9 As noted earlier, an indepen-
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dent expert committee is clearly needed in large trials in which the end points include irreversible major morbid events such as death, stroke, and myocardial infarction. It is also needed in definitive studies that evaluate new therapies with potentially severe risks and in trials that evaluate a known therapy intended for a new use and characterized by a significant risk profile. Such trials usually have statistical boundaries that must be considered in light of other data regarding the trial of interest and other ongoing trials, and these kinds of studies require that decisions important to society be made. Because drug interventions have become so prominent in the field of clinical trials, the use of independent DSMCs has become routine in pharmacologic studies that focus on questions about morbidity and mortality effects. (By contrast, behavioral and administrative studies, although they involve the same ethical issues as other studies and need independent oversight, have less of a tradition of using DSMCs.) The majority of current trials, however, are undertaken by drug companies that are trying to determine whether a particular pharmaceutical agent relieves a symptom of disease, and such trials are rarely monitored by DSMCs. The need for an independent DSMC is less clear in some clinical trial arenas than in others. For example, a phase III trial of a blood pressure–lowering medication with 300 patients, when phase II has not identified any safety problems, presents a situation that differs from other trials. Although hypertension is a chronic disease responsible for substantial numbers of deaths, myocardial infarctions, strokes, and episodes of renal failure, phase III studies for this condition typically involve few patients, a short period of follow-up, and little severe disease.10 Consequently, major issues of patient safety rarely arise and DSMCs may not be needed for such trials. Phase III studies of cholesterol-lowering agents have been handled similarly because they typically involve exposing the patient population for a relatively short time. If safety issues do become a concern during such studies, the research programs tend to be discontinued. On the other hand, these trials address medical problems that, in the broadest sense, result in substantial death and disability; thus it can certainly be argued that they require some kind of oversight. In a related question, some clinical investigators have taken the position that small trials with surrogate end points should not be used to determine which therapies should be used in practice but that clinical outcome trials should be mandatory in such cases. However, even in the absence of this approach, some external oversight of phase III trials should be considered when they will be used to recommend a therapy to a large population of patients at risk for major clinical events. Another smaller trial frequently conducted is a phase II dose-finding trial in circumstances in which there is substantial risk to patients because of the disease under
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study, such as acute coronary syndromes. Often these trials include 200 to 500 patients and require considerable flexibility in design and conduct. In addition, these small phase II studies are frequently not intended to be definitive and do not require formal interim statistical analyses. For such a study, a small committee comprising several outside experts who follow the trial in a less formal manner may be desirable; alternatively, a single trusted individual with no vested interest in the trial result could function as an independent safety officer. The risks associated with relying on a single trusted person are that such an arrangement may be insufficiently formal and rigorous and that the issues that arise may be less thoroughly considered because of the absence of group discourse. If all the usual requirements surrounding a formal DSMB can be met by appointing a qualified individual, this situation may suffice; anything less, however, would raise concern. In addition, choosing one trusted person to monitor a study may provide the required external oversight, but when difficult issues must be grappled the ability to reach a consensus forged from several different perspectives can be extremely valuable to the decisionmaking process. Furthermore, all trials should have a defined goal requiring quantitative analysis, and many trials could benefit from an interim analysis. Along with a DSMC, a local IRB plays a critical role in the oversight of clinical trials. The involvement of an IRB alone, without a DSMC, may be sufficient in a trial that involves a single institution, especially when a mechanism is established for the significant involvement of a subcommittee or a particular individual. Most local IRBs, however, lack the expertise to monitor multicenter trials or lack sufficient time for the intensive work required in such cases. Indeed, the practice in which each individual IRB monitors the conduct of its own institution in multicenter trials—although no communication occurs among the IRBs themselves—makes no sense. A recent federal report has highlighted this problem; major efforts should be made to overhaul the current IRB system so that it can provide constructive oversight.11
What is the history of DSMCs? The concept of DSMCs arose during the early clinical trials conducted by the National Institutes of Health (NIH). One of the earliest DSMCs was constructed as an ad hoc group to monitor, in the late 1960s, the University Group Diabetes Project (UGDP),12 when trouble emerged in the ongoing monitoring of the study. At the time of this trial methods for interim analysis of data were not well developed; accordingly, trial leaders reviewed outcome data on a regular basis in an unblinded fashion. After a time, patients treated with tolbutamide, an oral hypoglycemic agent, were judged
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Figure 2
Typical organizational structure of clinical trials.
to have an excess cardiovascular mortality rate, and the trial was therefore terminated early.12 The clinical community expressed considerable concern about this decision, which was questioned in many subsequent articles. Partly as a result of the UGDP experience, a report known as the “Greenberg Report”13,14 recommended to the National Heart, Lung, and Blood Institute (NHBLI) the routine inclusion of a monitoring committee for all major trials. The Coronary Drug Project (CDP) was the first large NHLBI trial to incorporate a formal DSMC. Since the UGDP, the use of DSMCs has been highly variable, depending on the research sponsor and investigator affiliated with the study. Some branches of the NIH, for example, include a DSMC as a routine component of studies; other branches have almost no history of using DSMCs, although in June 1998 the NIH published guidelines requiring the use of DSMCs.15 The medical products industry has used DSMCs in only a small minority of clinical trials, although more companies are now mandating, in their standard operating procedures, consideration of DSMC oversight. The many small human studies performed in individual academic institutions have little history of involving DSMCs and are typically overseen by an IRB. In the spring of 2000, the Food and Drug Administration (FDA) published updated guidance for the use of DSMCs in clinical trials (see Appendix).16 In May of the same year the Department of Health and Human Services published a set of guidelines for monitoring clini-
cal trials.17 These guidelines will stimulate a dramatic increase in the use of DSMCs.
What are the functions of a DSMC? The most compelling issue for a DSMC in any human experiment is patient safety, and its most obvious concern is the potential of a new therapeutic agent for adverse consequences. Protecting the safety of patients by examining data for indications for early stopping, in the presence of statistical evidence of benefit or harm, is equally important. Other questions that a DSMC should independently review include the need for continued enrollment and the likelihood that the proposed experiment will yield results that will be important enough to balance the risk of conducting it. Figure 2 shows the typical organization of clinical trials designed to provide definitive information about clinical practice or a new therapy. The sponsor of such a study may be the government, the medical products industry, a health care delivery system, or a foundation. In some cases a Steering Committee may be appointed to provide independent insight into the conduct of a trial; its members represent the clinical practice community that cares for patients with the disease for which the trial has been designed. A Data Coordinating Center (DCC) collects and analyzes the data. Often an Executive Committee is formed with representatives of the Steering Committee, the study sponsor, and the DCC. Beyond analyzing issues of patient risk, many DSMCs are called on to play an advisory role regarding the con-
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duct of the studies being performed. The advisory functions can be broad. Often a DSMC is asked to follow the evidence for protocol compliance and investigator performance. It may also be required to assist in assessing the integrity of data and the performance of the DCC. In many trials a DSMC has been asked to participate in and give final approval to protocol design; at other times, it has been asked to intervene to pass judgment on whether a trial struggling to achieve its enrollment is indeed feasible. As discussed below, these functions may be handled in a variety of ways in different trials. Before a trial begins, the DSMC may play a significant role in advising the trial organizers about the project being planned. The DSMC should review the design of the trial to assess its scientific validity. Fundamental to participation in the ethical review of a proposed trial is the conviction that the experiment to be performed is valid and will yield results of societal benefit commensurate with the risk undertaken by its subjects. An independent view of whether a proposed trial is actually feasible constitutes an important component of such an assessment. Sometimes the sponsor and investigators may be overly enthusiastic about a proposed study; in such cases, independent observers can provide useful guidance about the likelihood that the experiment can actually be completed. It is imperative that the DSMC thoroughly discuss potential safety issues before the first patient is enrolled; accordingly, the appointment of a DSMC after study enrollment has already begun should be considered poor policy. At times, a DSMC may wish to recommend changes in a study protocol even as the trial is proceeding. Although the considerations behind such changes may be complex, the actual recommendations may be relatively simple, such as speeding up or extending enrollment. More difficult recommendations, such as dropping a limb of the protocol, modifying a regimen, or terminating the trial, usually require that DSMC members exercise considerable judgment because the questions involved in such cases may be extremely complicated. A DSMC may also recommend increasing or decreasing the surveillance for adverse events or outcomes because it is concerned that a particular type of event may not be adequately detected. The procedure by which a sponsor and Steering Committee accepts or rejects these potential changes in a protocol is discussed in a subsequent article in this series; it is critically important because changes that a DSMC recommends frequently have a significant impact on resource use. In a smaller phase II trial, a DSMC or a Data Monitoring Person with oversight may have a more complex, dynamic, and flexible function than in other trials. Phase II protocols are increasingly characterized by flexible, adaptive designs that allow for changing a regimen or a patient population as a study progresses.
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What are the characteristics of a good DSMC? Ideally, a DSMC should be both constructive and independent. It should provide timely review of the quality and accuracy of trial data and recognize design problems early in the study. Patient safety is its primary charge, but a good DSMC must also be able to impart a sense of comfort to investigators; a positive ambience about the progress in a trial can make an important difference in the success of a protocol. Furthermore, particularly in highly visible intervention trials, a DSMC should be able to enhance a sense of societal security in terms of the ongoing trial that it monitors. A constructive DSMC is knowledgeable, assertive, objective, and attentive. Ideally, knowledge in the medical, statistical, and ethical realms is blended within its membership. A docile committee fails to fulfill its obligation; indeed, investigators and sponsor benefit from a committee that actively confronts issues before it becomes too late to address them. When a committee does not take the time to form a balanced view of an issue or to consider all its options, it tends to act too quickly instead of waiting for a definitive answer to the question at hand; alternatively, it may overlook obvious problems that may have arisen. As it fulfills its varied responsibilities, a DSMC must respond to the needs of investigators and the sponsor (sometimes in a manner not anticipated before study start-up) while maintaining its primary focus on its responsibility to patients in the trial. An independent DSMC is free from financial conflicts, hands-on participation in a study, involvement with the DCC, and financial involvement with the sponsor. Financial conflicts may appear in many forms but, at a minimum, DSMC members should not have stock holdings with any entity involved in the study they oversee, nor should they have ongoing consultancies or advisory positions with such entities. Because a DSMC reviews data as needed during a trial, the objectivity of a member who knows the trends in the data could easily be compromised if he or she were to advise an individual study patient; thus DSMC members should be independent of clinical sites. Just as with financial conflict, direct involvement with the affairs of a trial sponsor or its coordinating center could place a DSMC member in a position in which his or her recommendations could jeopardize future relationships.
What should be the composition of DSMC membership? Some experts argue that a DSMC should reach its decisions by consensus rather than by vote; nevertheless, having an odd number of individuals on a DSMC ensures that decisions can be made by a majority of the members if a vote is taken. A DSMC should have a chair
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who is either a clinician with expertise in the field of investigation or a statistician with experience in the type of trial to be monitored. Because dialog and group dynamics can be critical when difficult recommendations are considered, it is best to restrict the size of a DSMC: three to five members is often adequate to cover the key disciplines needed for fully informed monitoring. However, there are many situations in which more members may be necessary to ensure that expertise in all relevant aspects of a study are represented in the committee. Although some ethicists are highly experienced in clinical trial issues and may contribute significantly to trial proceedings, an ethicist is not usually required to serve on a DSMC. Still, it is highly desirable that an ethical consultant be available for a DSMC to call on when needed. The major function of an ethicist is to assist the committee in framing the issues that it should debate. In some trials a patient advocate has been added to the DSMC. In most situations this addition is unnecessary, but it should be considered when a trial has substantial public visibility and patients affected by the trial believe that their concerns need to be specially represented. How regulatory agencies should interact with DSMCs in trials falling under the jurisdiction of the FDA, the Committee for Proprietary Medicinal Products in the United Kingdom, or other regulatory bodies, is an interesting issue and one with little precedent. Most trials do not formally include members of regulatory authority groups, but discussions with regulators frequently occur as a DSMC follows a trial. In some circumstances a DSMC assumes the responsibility of reporting aggregate adverse experiences to various regulatory authorities. At least one statistician from the DCC must attend the meetings of a DSMC meetings to present the data from a trial. This function can be fulfilled in several ways. Traditionally, the primary statistician for a trial (and for large trials, an assistant) becomes unblinded to prepare reports for the DSMC. In some quarters concern has arisen that these individuals then become unable to participate in discussions with the still-blinded Steering Committee about changing study design. One approach to avoiding this problem is to have different statisticians perform different roles, such as serving as a member of the Steering Committee, a sponsor representative, a DCC leader, or a member of the DSMC. An alternative approach is to have the DCC statistician and data managers remain blinded and to leave the treatment code with an independent statistical center. In this model, data are transferred to the independent statistical center and reports are prepared and presented by statisticians from that center. With this approach, the ability of a DCC statistician to participate in discussions about changing trial design is preserved because the statistician has not become unblinded.
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Guidelines for DSMC selection and interaction The study sponsor and Steering Committee, led by the principal investigator or the executive committee, should appoint the individuals who will serve as the DSMC. Appointments should be made before the trial protocol is finalized, and the qualifications of potential DSMC members should be carefully examined. Most DSMC members should have substantial knowledge of the content area of the trial and the class of the study intervention. Several should have expertise in the method that will be used to examine study results. One or more members should be statistical experts. In addition, all members should possess a high level of integrity and significant experience with clinical trial decision making and politics. Records of his or her past experiences should show evidence that a member has both common sense and also “nerve,” as demonstrated by a willingness to make difficult decisions. The DSMC should be constructed with a view toward achieving a compatibility among its individual members, although in some circumstances, for trials of active treatment comparisons, it may be worthwhile for the committee to include experts on competing therapies. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study (GUSTO 1), for example, the DSMC included Dr Eugene Braunwald, who chaired the Steering Committee for the Thrombolysis in Myocardial Infarction (TIMI) 1 trial, which found alteplase superior to streptokinase for vessel patency. The same DSMC also included Dr Peter Sleight, a clinical leader of the International Study of Infarct Survival (ISIS 3), which found no mortality benefit for tissue plasminogen activator compared with streptokinase.
Interactions of a DSMC Because interactions within a DSMC and between a DSMC and other trial entities may become complicated as a study proceeds, it is important that rules of engagement be defined as much as possible before a trial begins. After a DSMC is appointed, it is beneficial to ensure that it be allowed to offer suggestions about the structure and function of the trial. Before the trial starts, the DSMC should meet formally to review expectations for the trial, to examine issues that may arise during its course, and to establish a sense of comfort among the various constituents. When it convenes, the DSMC should welcome both the sponsor and principal investigator to an open portion of the meeting, one in which the ground rules for the committee are established. At this time the committee may ask questions about the conduct of the trial, its goals, and new developments in the field. During the open session with the
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DSMC, only open data should be discussed; a closed session is intended to allow for analysis of data by treatment groups. However, the DSMC should also have a private session without the sponsor or principal investigator present, during which it should review outcome data as a function of treatment assignment. To perform the independent oversight function without compromise, committee members should be immune to any suggestion that the trial leadership has influenced them to alter their opinions. In addition to rules of engagement, “rules of escalation” should also be defined and implemented as early as possible. What should be done if a major disagreement occurs within the DSMC itself, or between the DSMC and the Steering Committee or sponsor? In the end, the funding agency holds ultimate control, because without financing, the trial cannot be conducted. There are, however, multiple examples of embarrassing disagreements between trial decision makers; such disagreements may lead the public or the physician community to form unnecessarily adverse perceptions about a trial. All parties stand to benefit if clearly defined, and appropriate mechanisms for addressing and reporting such disagreements can be established at the outset of a trial.
Conclusion Historically, we are still in the early stages of the science of clinical trials; thus the exact method of these trials continues to evolve. All clinical trials involve individual patients, and the ethical imperative generally accepted in the past half century is that all human experiments should have some form of a “conscience” to ensure the safety and ethical treatment of subjects. In small, straightforward studies a single individual may serve this function. For more complex studies, it is recommended that there be a diverse DSMC with an odd number of members whose expertise includes not only the medical question under investigation but also biostatistics and the practical issues of trial conduct, decision making, and the complex relationships that exist within a trial.
References 1. Califf RM, McNulty SE, Adams KF, et al. A randomized controlled trial of epoprostenol therapy for heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:4455. 2. Nelson D, Weiss R. FDA stops researcher’s human gene therapy experiments. Washington Post; 2000 March 2. p A08. 3. Hilts PJ. FDA says researchers failed to report a second death linked to gene therapy. New York Times; 2000 May 4. p A-20. 4. Permissible medical experiments: trials of war criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Nuremberg, October 1946–April 1949. Volume 2. Washington (DC): US Government Printing Office. p 181-2.
5. Declaration of Helsinki. Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, and amended in Tokyo in 1975, in Venice in 1983, in Hong Kong in 1989, and in South Africa in 1996. 6. US Code of Federal Regulations. Title 45, Public Welfare, Department of Health and Human Services; National Institutes of Health, Office for Protection from Research Risks; Section 46: Protection of human subjects. Revised 18 June 1991; effective 19 August 1991. 7. Green SJ, Fleming TR, O’Fallon JR. Policies for study monitoring and interim reporting of results. J Clin Oncol 1987;5:1477-84. 8. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993; 270:1819-25. 9. Frasure-Smith N, Lesperance F, Talajic M. Depression and survival following myocardial infarction. JAMA 1994;271:1080-2. 10. Office of Inspector General. Institutional Review Boards: a time for reform. The Office; 1998. Publication No.: OEI-01-97-00193. 11. Meinert CL, Knatterud GL, Prout TE, et al. University Group Diabetes Program: a study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970;19:789-830. 12. Anonymous. Organization, review, and administration of cooperative studies (Greenberg Report): a report from the Heart Special Project Committee to the National Advisory Heart Council, May 1967. Controlled Clin Trials 1988;9:137-48. 13. Halperin M, DeMets DL, Ware JH. Early methodological developments for clinical trials at the National Heart, Lung and Blood Institute. Stat Med 1990;9:881-92, 903-6. 14. National Institutes of Health. NIH policy for data and safety monitoring. Release date: June 10, 1998. Available at: http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 15. US Food and Drug Administration, Department of Health and Human Services: Office of Regulatory Affairs. Guidance for Institutional Review Boards, clinical investigators, and sponsors: exception from informed consent requirements for emergency research. Draft guidance (released for comment on 3-30-2000). Section VII: Data monitoring. Available at: http://www.fda.gov/ora/compliance_ref/bimo/err_guide.htm. 16. National Institutes of Health. Further guidance on data and safety monitoring for phase I and phase II trials. June 5, 2000. Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00038.html.
Appendix FDA draft guidance on Data Monitoring, cited above in reference 16; text available at the FDA web site.
VIII. DATA MONITORING COMMITTEE (DMC) Before a study may be initiated, the IRB must find and document that the sponsor has established an independent DMC to serve as an advisory body to the sponsor (21 CFR 50.24[a] [7][iv]). Definition. A DMC, sometimes called a DSMB, is a group of experts established by the sponsor to assess at intervals the progress of a clinical trial (the safety data and the critical efficacy end points) and to recommend to the sponsor whether to continue, modify, or stop a trial. DMCs for trials implemented under 21 CFR 50.24 must be “independent,” by which the agency means that the committee should be composed solely of individuals who have no financial interest in
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the outcome of the study and who have not been involved in the design or conduct of the study (21 CFR 50.24[a][7][iv]). Purpose. The DMC helps ensure subject safety by reviewing ongoing results on a periodic basis and considering whether an investigation ought to be modified to minimize any identified risks or halted. Factors to consider in this decision include whether (1) the potential benefits of the investigational intervention have been established or (2) the risks are greater than anticipated. The DMC is responsible for informing and making recommendations to the sponsor about safety or efficacy concerns related to continuing the investigation. Membership. The DMC should be composed of individuals not otherwise connected with the particular clinical investigation or the sponsor. A DMC under this rule typically would include one or more clinicians specializing in the relevant medical field(s), biostatisticians, and bioethicists. Operation. The DMC reviews study data and adverse event reports on a schedule generally defined by the sponsor, which may include review of study data on an ongoing basis (real time) if necessary for adequate safety monitoring in specific situations. It is essential that the DMC have access to all the
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information it needs to effectively evaluate the progress of the study. Thus the DMC may need access to data unblinded by treatment arms to ensure reliable and complete assessment of the safety and efficacy data. The sponsor is responsible for determining the scope of the DMC’s responsibilities. Operations of the DMC should include: (1) the manner in which, and the frequency with which, study data and information about adverse events are forwarded to and reviewed by the DMC (eg, after 10%, 25%, 50%, 75%, or 100% enrollment), (2) criteria for assessing data and pre-established “stopping” criteria, (3) qualifications of DMC members, (4) assurance that members of the DMC have no financial interest in the outcome of the study and have not been involved in the design or conduct of the study, and (5) preparation and maintenance of written records for all meetings. May an IRB serve as a DMC? Because most IRBs are not constituted to meet the special membership requirements of a DMC and the duties and scope of activities of an IRB and a DMC are quite different, entities performing each of these separate functions should be established. Any committee serving as a DMC should ensure that its membership is appropriate to the study and that it operates as a separate, independent entity.