Docket Management
Docket: 01D-0489 - Draft Guidance: Clinical Trial Sponsors on the Establishment & Operation of Clinical Trial DMCs
Comment Number: EC -1

Accepted - Volume 1

Comment Record
Commentor Dr. Thomas Louis Date/Time 2001-11-25 12:09:11
Organization Rand
Category Academic

Comments for FDA General
Questions
1. General Comments DOCKET 01D-0489 + heightened awareness within the scientific community of problems in clinical trial conduct and analysis that might lead to inaccurate and/or biased results, especially when early termination for efficacy is a possibility, and demand for approaches to protect against such problems. COMMENT: The intended point is important, but the wording is a bit confusing. One needs a multidisciplinary group to discuss the formal and informal aspects of deciding to stop or modify a trial. The DMC serves as that multidisciplinary group, taking fiduciary responsibility for trial participants. All clinical trials require safety monitoring (21 CFR 312.32(c)), but not all trials require monitoring by a formal committee external to the trial organizers and investigators. As noted earlier, DMCs have generally been established for large, randomized multisite studies that evaluate interventions intended to prolong life or reduce 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, DMCs should be established for controlled trials with mortality or major morbidity as a primary or secondary endpoint. They may also be helpful in settings where trial participants may be at elevated risk of such outcomes even if the study intervention addresses lesser outcomes such as relief of symptoms. Although DMCs may prove valuable in other settings as well, a DMC is not needed or advised for every clinical study. Several factors are relevant to determining whether or not to establish a DMC for a particular trial. These relate primarily to safety, practicality, and scientific validity. COMMENT: State that the default option should be that a DMC is constituted, that the burden of proof should be on not having one. The oversight of a DMC in addition to typical sponsor-conducted safety monitoring can provide further protection of study participants. 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. DMCs may be more important in these trials. COMMENT: DMCs help with more than safety. Frequently, they help identify important trial modifications, review management issues and increase the credibility of a study. Most DMCs 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 DMCs may include a medical ethicist knowledgeable about the design, conduct, and interpretation of clinical trials. Prior DMC experience is helpful, but not essential, although it is DELETE(desirable) ADD(essential) that at least some members have prior DMC service. Some trials may require participation of other types of scientists; for example, a study in which the investigational drug has variable absorption or excretion might include a clinical pharmacologist on the DMC; toxicologists, epidemiologists, and laboratory scientists could be included in particular cases. One or more individuals (often non-scientists) who may help bring to the DMC the perspectives of the population under study may be a useful addition in some settings. That individual should not be participating in the trial, but could be someone with the disease under study or a close relative of such an individual, for example. DMCs for international trials should have representation from participating countries or regions to the extent practical ADD(relevant written and oral language skills are essential). Appropriate representation of gender and ethnic groups may be of particular importance for some trials. All appointees should be prepared to maintain confidentiality of the interim results they have reviewed (see Section 4.2). The study sponsor usually appoints the DMC chair. Prior DMC experience is more important for the chair than for other DMC members, as members will look to the chair for leadership on administrative as well as scientific issues. DELETE(If the DMC includes only one statistician, however, it is desirable for the statis-tician to have had prior DMC experience as well) ADD(It is very important that at least one statistician has had prior DMC experience.) The chair should be DELETE(capable of) ADD(effective in developing a proper process, in) facilitating discussion, integrating differing points of view and moving toward consensus on recommendations to be provided to the trial sponsors. It is particularly important for the chair to make a firm commitment to participate for the duration of the trial. Sponsors should establish procedures to ensure the confidentiality of the interim data (see Section 4.3.1.4.). ADD(DMC members should commit to keeping results confidential.) 4.2.1. Interim Data The interim unblinded data will be most securely protected from inadvertent or inappropriate access by the sponsor if it is prepared for analysis by an entity group independent of the sponsor and investigators (see Section 6.4). The lead investigators, the study Steering Committee, or the sponsor generally develops the analytical plan, but these individuals should generally not be involved in the actual preparation of the interim results, for reasons discussed in Section 6.4. They should, however, work with the statistician who will be preparing and presenting the interim analyses prior to the first analysis of unblinded data to develop a template for the interim reports. COMMENT: This is a bit off the mark. In multi-center trials, the statistical center is not independent of the investigators. Rather, the. center ensures that it acts independently in this aspect of the clinical trial. 4.2.2. Interim Reports to the DMC Any part of the interim report to the DMC that includes comparative effectiveness and safety data presented by study group, whether coded or uncoded, COMMENT: Some readers won't know what this means. should generally be available only to DMC members during the course of the trial, including any follow-up period-that is, until the blind is broken. If such reports are shared with the sponsor, it may become impossible for the sponsor to make potentially warranted changes in the trial design or analysis plan in an unbiased manner (see Section 6.3). COMMENT: Make the foregoing more definitive: results should not be shared unless an agreed process has been followed (in extreme circumstances). 4.3.1. Considerations for Standard Operating Procedures 4.3.1.1 Meeting Schedule and Format COMMENT: Meeting frequency should err on the side of more frequent until the study is well underway. If necessary, frequency can then be modified. Face-to-face meetings are generally preferable, but telephone meetings may be necessary in some situations, particularly when new information must be urgently considered. In some settings, when the DMC has already had numerous meetings and the committee is very familiar with the trial and the analytical issues, telephone meetings may be sufficient. COMMENT: Telephone meetings require special considerations to ensure that only those permitted to be on the call are on the call. 4.3.1.2 Meeting Structure Attendance at meetings raises the same confidentiality issues as access to interim reports to the DMC. Although confidentiality of the interim data should be maintained, the DMC may interact with the study sponsor and/or trial lead investigators to clarify issues relating to the conduct of the trial, potential impact on the trial of external data, or other topics. In order to permit such interaction without compromising confidentiality, many DMC meetings include an open session in which information in the open report is discussed. These non-confidential data may include, for example, status of recruitment, baseline characteristics, ineligibility rate, accuracy and timeliness of data submissions, and aggregated safety and outcome data. COMMENT: Some will argue that even aggregate outcome data should not be pre-sented in the open meeting. This issue will be an important discussion item in the Nov. 27th meeting. Section 6 describes the risks to study integrity when sponsor representatives have access to unblinded interim data and attend closed sessions of DMC meetings. In settings in which sponsors choose to permit its representatives or other non-DMC members to attend the closed session despite the risks of such arrangements, the DMC should have the option of conducting an executive closed session with no participants other than DMC members. COMMENT: It should be in only extraordinary circumstances that such attendance is allowed. 4.3.2. Statistical Methods Nevertheless, protection of Type I error is important even when there is a stated intention to stop early only for futility reasons since interim review of outcome data always raises the possibility that the DMC may find early results so persuasive that it would recommend early termination of the trial. COMMENT: Consider recommending that a fully sequential monitoring plan be used, one that has boundaries as though monitoring were to occur after every endpoint is re-ceived. These boundaries are very little wider than the six-look boundaries and allow assessment of the trial as necessary. COMMENT: How should the type I error be allocated? Should there be 0.05 for the main endpoint and a separate 005 for AEs, etc.? 4.4.1.4 Consideration of External Data COMMENT: A policy is needed for sharing of information between two DMCs monitoring related, active trials. 6.1. Desirability of an Independent DMC ADD( 4. Enhances the credibility of the trial.) 6.2. Value of Sponsor Interaction with the DMC COMMENT: The sponsor may be the federal government and all considerations in this section apply with equal force in that situation.




EC -1