Docket Management
Docket: 01D-0489 - Draft Guidance: Clinical Trial Sponsors on the Establishment & Operation of Clinical Trial DMCs
Comment Number: EC -2

Accepted - Volume 1

Comment Record
Commentor Dr. Donald Cutlip Date/Time 2001-12-01 09:27:38
Organization Harvard Clinical Research Institute
Category Academic

Comments for FDA General
Questions
1. General Comments I attended the public meeting and have reviewed the draft guidelines document for DMCs in detail. I congratulate FDA for a well-written and timely document that stands to make significant improvements in the protection of our human subjects (patients) and the conduct of clinical research. In my role as Medical Director and Chief Medical Officer I oversee all of my organization’s clinical safety activities. As an academic CRO we have designed, managed, and coordinated over 120 multicenter clinical trials for several industry sponsors. We have incorporated DMCs into our trial designs since our inception in 1993 and with rare exception have assembled the DMC and prepared the DMC reports for all of our studies. The role and function of the DMC has been one of our major interests in clinical trial methodology. We have also utilized an independent Clinical Events (Endpoints) committee for real-time adjudication of events in all of our trials. This coordinated activity has resulted in the first recognition (and solution by trial design modification) of late stent thrombosis in intracoronary brachytherapy trials and early stopping for proven efficacy of the pivotal trials of the Angiojet thrombectomy catheter and the Percusurge distal protection device. Last year we assembled over 20 DMCs, drawing on a limited base of experienced clinicians and biostatisticians. As we review the guidance document and prepare its final form, I think it is critical that we not force the DMC to be more than its function requires and thereby lose its effectiveness. At the same time it is equally critical that we maximize the opportunity for this guideline to make real changes in the conduct of clinical trials. To these ends, I would like to make 3 comments about the document and/or comments made by the panels at the public meeting. 1. DMC Responsibilities The primary responsibilities of the DMC historically and as included in the guidance document are for interim monitoring of the trial for data integrity, patient safety and effectiveness of the study treatment. These are critical and demanding roles and it would be unfortunate to give the appearance that the DMC should be even more than that. Other roles suggested during the meeting would be either difficult for the DMC and the study sponsor to incorporate into the DMC charter or potentially weaken the function of the DMC as it serves its primary purpose. These included a request that the DMC review and approve the study protocol and informed consent documents. I believe these functions are not appropriate or reasonable for the DMC to undertake. The DMC (and the sponsor) should be able to assume that by the time a study as gone through the development process the input from all appropriate authorities, including FDA, has resulted in the most reasonable approach to the study at that time. Changes suggested or perhaps insisted upon by the DMC just before the trial is to begin and without access to the history of the protocol development could be deleterious to the study and prevent the DMC from focusing on its more important responsibilities. Likewise, as you know, in a multi-center study the informed consent document is no longer a single document at the time a study is ready to initiate. By this time, it is likely that modifications equal to the number of clinical investigative sites have been approved. For the DMC to become involved in making suggestions at this point is impractical. This task is best left entrusted to the individual site IRBS. That is not to say the DMC should not ask for modifications to the protocol or informed consent if such modifications are felt necessary based on outcomes of study monitoring for safety. 2. DMC Composition The current wording of the guidance document allows that most DMCs should include clinicians with expertise in relevant clinical specialties and at least one biostatistican knowledgeable about statistical methods for clinical trials. This would seem to allow the DMC to perform the outlined responsibilities in most trials. I was concerned, however, that Dr. Foulkes and members of the panel elevated the role of a bioethicist from “some DMCs may include” to a required member. While the importance of medical ethics in the conduct of our studies can not be over stressed, it would seem that the requirement of an ethicist for every trial is not necessary. For those of us charged with assembling these committees from a limited pool of available experts, this requirement would add significantly to that task. I believe the current wording allows for the inclusion of this member in those trials where needed. 3. Independence of the DMC In many ways this is the most important part of the document. In our role as an academic CRO, we struggle constantly in our self-appointed role as protector of the integrity of the clinical trial. As Dr. Califf noted in his statement, the biggest threats in this battle are the industry sponsor executives. I might add to that the more junior study managers whose careers are even more predicated on the study results and are closer to the trial data. The pressures and demands on us to release data prematurely are immense and I can not imagine how a statistician in the employ of the sponsoring company could be expected to resist these demands. However, the guidance document only serves to note the problem and as with many other regulatory documents is merely window dressing. In point of fact, there is no policing of how data is released and to whom. There is not a guidance document or regulatory requirement that prohibits a sponsor from complete data management. The fact that an independent statistician is requested to prepare an official DMC report from the same data to which others have complete access is not a solution. For that matter, as Dr. Califf also noted, even if an outside independent group prepares the report, the sponsor has access to the AE reports and all they need to do is count them. The document needs to include as strong language as possible to insure independent review of the data, but we also need to consider the general conduct of clinical research as it relates to premature inspection of data and overall integrity. Perhaps, the DMC can be an instrument to validate this integrity.




EC -2