Data and Safety Monitoring Board (Dsmb) Guidelines

DATA AND SAFETY MONITORING BOARD (DSMB) GUIDELINES

CCF Clinical Research Unit-CRU

Need for a Data and Safety Monitoring Board (DSMB)

All clinical trials require safety monitoring (21 CFR 312.32(c)), but not all trials require monitoring by a data and safety monitoring board (DSMB), a formal committeeexternal to the trial organizers and investigators.Safety, practicality, and scientific validity are the primary determinants of whether or not a DSMB is necessary for a particular trial. DSMBs are generally needed for large, randomized multisite studies that evaluate interventions intended to prolong life or reduce the risk of a major adverse health outcome such as a cardiovascular event or recurrence of cancer because monitoring of accumulating results is almost always essential in such trials. They may also be helpful in situations where trial participants may be at elevated risk of such outcomes even if the study intervention addresses lesser outcomes such as relief of symptoms.

1. Risk to Trial Participants

A fundamental consideration is the safety of those who would be at potential risk due to their participation in the trial. A trial that is large, of long duration, and multi-center raises more possibilities of safety concerns because of the greater overall exposure and because prolonged exposure may cause adverse effects not readily recognized as such. Some of the other issues which need to be considered are: is the study endpoint one for which a favorable or unfavorable early result might ethically require termination of the study before its planned completion; is there reason for a particular safety concern (eg., if the method of administering the test treatment involves unusually high risk); is the treatment to be tested novel, so that there is little prior information on clinical safety; or is there specific prior information that raises concerns about the potential for serious toxicity. Safety concerns are usually heightened in studies performed in potentially fragile populations such as children or the very elderly, or in any group at relatively high risk of death or morbid events in whom a medical intervention might increase such risk or cause unanticipated adverse events.

1. Practicality of DSMB Review

If the trial is likely to be completed quickly, a DSMB might not have an adequate opportunity to contribute. In short-term trials with important safety concerns that may warrant a DSMB, sponsors need mechanisms to permit the DSMB to be informed and convened quickly in the event of unexpected results that raise concerns.

1. Assurance of Scientific Validity

An important question to ask is: “would a DSMB help assure a trial’s scientific validity?”Trials of any appreciable duration can be affected by changes over time in the understanding of a disease, the affected population, and the standard treatment used outside the trial. These external changes may prompt an interest in modifying some aspects of a trial as it progresses. When the trial organizers are the ones reviewing such data, their awareness of interim results cannot help but affect their determination as to whether changes should be made. Such changes might impair a study’s credibility. If, on the other hand,a DSMB is the only group reviewing unblinded interim data, trial organizers can more freely make changes in the ongoing trial that are motivated by newly available data outside the trial. In general, recommendations to change inclusion criteria, trial endpoints, or the size of the trial are most credibly made by those without knowledge of the accumulating data.

1. The need for DSMB for Studies of Less Serious Outcomes

DSMBs have not been commonly established for short-term studies of interventions to relieve symptoms. Because the primary endpoints of such studies are not serious irreversible events, as in a major outcome study, the ethical issues for monitoring differand the need for an outside expert groupis less compelling.Monitoring considerations for this type of study are more clinical than statistical andearly study termination for effectiveness is rarely appropriate.To monitor these types of studies sponsors frequently constitute internal groups, which may be satisfactory in many cases. Nevertheless, external advisors, who will be less committed to an existing development plan, may identify problems more readily than internal reviewers and maybe be usefulto oversee all stages of a study’sdevelopment, to monitor the developing safety database, and to make recommendations for the design of successive studies based on early results.

DSMB Responsibilities

Interim Monitoring

1. Effectiveness: In the case of diseases with serious outcomes, DSMBs may need to balance recommending early trial termination on the basis of a positive result with insuring that the data are truly compelling and the risk of a false positive conclusion is acceptably low.

1. Safety: Just as efficacy assessments may lead to false positive conclusions about benefit, so toomay safety assessments.DSMBs need to assess this when considering halting a study. A DSMB will regularly review the number of adverse events (AEs) observed in each study arm. If there is an imbalance between groups, concerns will arise that some may be due to the intervention rather than the disease itself. In such cases a DSMB may recommend a change in eligibility criteria, an alteration in product dosage and/or schedule or other measures which may reduce risk. They could also recommend consent form changes.Usually it is appropriate to demand less rigorous proof of harm to justify early termination than it would be for a finding of benefit.

1. StudyConduct: Among other issues which the DSMB may considerare rates of recruitment, ineligibility, noncompliance, protocol deviations and dropouts, and proposed trial modifications. If concerns arise that some aspects of trial conduct might threaten the participants’ safety or study integrity, the DSMB may issue recommendations regarding trial conduct.

1. External Data:A DSMB may consider the impact of external information on the study. Such recommendations may include terminating the study or a study arm, changing the target population, dose and/or duration of the intervention, use of concomitant treatments, etc. The DSMB may also recommend changes to the consent form and/or letters from the sponsor to study participants describing the new results.

Committee Composition

A DSMB may have as few as 3 members, but may need to be larger when representation of multiple scientific and other disciplines, or a wider range of perspectives is desirable. It is sensible to keep a DSMB as small as possible, while still having representation of all needed skills and experience. Some redundancy may be desirable, however, in scientifically and/or ethically complex trials, trials of long duration in which DSMB attrition might be anticipated, or in trials in which the DSMB must meet so frequently that not all members would likely be able to attend all meetings.

Most DSMBs are composed of clinicians with expertise in relevant clinical specialties and at least one biostatistician knowledgeable about statistical methods for clinical trials and sequential analysis of trial data. Some DSMBs may include a medical ethicist knowledgeable about the design, conduct, and interpretation of clinical trials. Prior DSMB experience is helpful, but not essential, although it is desirable that at least some members have prior DSMB service. Some trials may require participation of other types of scientists depending upon the nature of the trial. One or more individuals (often non-scientists) who may help bring the perspectives of the population under study to the DSMB may be a useful addition. Though that individual should not be participating in the trial, they could be someone with the disease under study or a close relative of such a person. As much as is practical, DSMBs for international trials should have representation from participating countries or regions.In some trials appropriate representation of gender and ethnic groups may be important. All appointees should be prepared to maintain confidentiality of the interim results they have reviewed.

Potential DSMB members should be free of financial interests that could substantially be affected by the trial outcome Individuals who have strong views on the relative merits of the intervention under study may have an “intellectual” conflict of interest and might not be able to review the data in a fully objective manner. Ideally, DSMB members should not have relationships with those in trial leadership positions that could be considered reasonably likely to affect their objectivity. Investigators entering subjects into the trial should not be members of the DSMB. An investigator who is aware of early trends might change his or her pattern of recruitment, or modify his or her usual way of monitoring participants’ status. Sponsors/PIs should provide disclosure to all DSMB members of any member’s minor conflicts that are thought might impede objectivity. Members of the DSMB who are affiliated with the sponsoring institution should view themselves as representing the interest of patients and not that of the institution.Voting members may be from within or outside the institution, but a majority should not be affiliated with the institution.

Meetings

The frequency of DSMB meetings depends on the expected rate of accrual and event occurrence and the perceived risk of the experimental and/or control interventions. DSMB meetings should be at least annual. The study protocol should describe the schedule of interim analyses to be considered by the DSMB, or the considerations that will determine the timing of meetings. Face-to-face meetings are generally preferable, but telephone meetings may be necessary in some situations, particularly if new information must be urgently considered. In some settings, when the DSMB has already had numerous meetings and the committee is very familiar with the trial and the analytical issues, telephone meetings may be sufficient.

Each meeting should be divided into three parts. First there should be an open session in which members of the clinical trial team,at the request of the DSMB, may be present to review the trial conduct and answer questions from DSMB members. Outcome results must not be discussed during this session. Following this session, there should be a closed session involving the DSMB members and the coordinating center/statistical office statistician(s) handling the trial. The statistician(s) should present and discuss the outcome results with the DSMB. A final executive session involving only DSMB members should be held to allow the DSMB opportunity to discuss the general conduct of the trial and all outcome results, including toxicities and adverse events, develop recommendations, and vote, as necessary.

Recommendations from the DSMB

DSMB recommendations should be based on results from the trial being monitored as well as on data available to the DSMB from other studies. It is the responsibility of the coordinating center/statistical office, trial investigator(s), and individual DSMB members to ensure that the DSMB is kept apprised of non-confidential results from related studies that become available, and of any programmatic concerns related to the trial. It is the responsibility of the DSMB to determine the extent to which this information is relevant to its decisions about thetrial.

If the DSMB recommends a study change for patient safety or efficacy reasons, or that a study be closed early due to slow accrual, the trial PI/project manager must act to implement the change as expeditiously as possible. Confidentiality must be maintained during such discussions. However, in some cases, relevant data may be shared with selected trial investigators.

If a recommendation is made to change a trial for other than patient safety or efficacy reasons or for slow accrual, the DSMB will provide an adequate rationale for its decision.

Release of Outcome Data

In general, outcome data should not be made available to individuals outside the DSMB until accrual has been completed and all patients have completed their treatment. At that time, the DSMB may approve the release of outcome data on a confidential basis to the PI/project manager for planning manuscriptpreparation and/or to a small number of other investigators for purposes of planning future trials. Any release of outcome data prior to the DSMB's recommendation for general results dissemination must be reviewed and approved by the DSMB.

Each member of a DSMB, including non-voting members, must sign a statement of confidentiality. No communication, either written or oral, of the deliberations or recommendations of the DSMB is to be made outside of the DSMB. Outcome results are strictly confidential and must not be divulged to any non-member of the DSMB.

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RSA Revised 2/29/08