Docket Management
Docket: 01D-0489 - Draft Guidance: Clinical Trial Sponsors on the Establishment & Operation of Clinical Trial DMCs
Comment Number: EC -4

Accepted - Volume 1

Comment Record
Commentor Dr. Janet Wittes Date/Time 2002-01-13 20:34:16
Organization Statistics Collaborative
Category Company

Comments for FDA General
1. General Comments I think in general the guidance is excellent. It will go a long way to improve the way things run.In fact, I have already seen a difference in the way sponsors are thinking of DMCs. Congratulations! I do have a few comments. a) Section 3.2, line 2. I have never seen a Steering Committee write the final study report. They often write the paper describing the results, but in my experience the sponsor writes the study report for the FDA. And that is what most companies refer to as the final study report or the clinical study report. b) Section 4.1, last line. I think it is important that everyone make a firm commitment to participate until the end of the trial. I wouldn't limit this to the Chair. c) Section 4.2.2. I think you should mention the executive session here. You refer to it in section, but it is sort of lost. d) Section, par 1. I would delete the parenthetical (perhaps most). e) Section, par 2. I find the section too strongly in favor of face-to-face meetings. This guidance is going to increase the number of DMCs considerably and travel is difficult. I would soften this recommendation. In many settings telephone or video meetings work very well. For example, in a small study looking at very specific safety data, a telephone conference call is fine. I think you should leave more room for committees to decide how they are going to operate. This is one area in which I have already seen a difference. In a Phase I trial that is setting up a DMC, the sponsor wanted biweekly face-to-face meetings of the committee because of this section. The committee said that was impossible. f) Section I would add and on the final analytic plan to the end of the paragraph. I have seen DMC's influence the final analysis plan. (Think of HA1A). g) Section 4.4.2, last sentence. I don't know what you are referring to here. What situations will be infrequent? Is this sentence necessary? i) Section 6, line 1. independent defines independent. I have a question about the restriction against having been involved in the design of the trial. I could imagine a situation, especially for a small company or for an early phase trial, where someone has served as a consultant designing the trial. Then, when the various roles are divided, that person sits on the DMC. Why is that necessarily a problem? (I actually don't know of any specific case, but it doesn't seem problematic to me.) Other issues-- I would like to see the guidance unambiguous about the desirability of the DMC's having access to unblinded data. The language of section pretty clearly argues for unblinded data. In the public meeting, however, some FDA staff seemed to argue for blinded data. I believe that would be a mistake. Again, many members of the FDA tell sponsors that the DMC should see blinded data unless something requires unblinding. I believe this is a mistake and the guidance should be unambiguous. The big issue that is bothering me is the one that Joe Costantino brought up at the session. He and I did a webcast for FDANews discussing the guidance. The session was very lively. The main issue that we struggled with was how to ensure that the reporting statistician understands the data well enough to present an intelligent report to the DMC. Joe's position is that only the statistician working day-to-day with the data can understand the study well enough to present the data to the committee. My view, on the other hand, is that if the charge of the committee is clearly focussed, a sensible, responsible outsider can do the job very effectively. Nonetheless, Joe is correct that many people present data to the DMC without understanding much of what is going on. I have been appalled by the kinds of reports I have seen when I have served on DMCs for industry. I no longer will sit on them because I find the general quality of the reports shoddy and incomplete. I have been in situations where the DMC does not have sufficient access to data necessary for intelligent decision-making. So, there is a trade-off. It may be that you want to stress the importance not only of protecting the integrity of the study (i.e., ensuring that knowledge of ongoing data does not influence the conduct of the study) but also of ensuring high-quality presentations to the DMC. I think the current draft emphasizes the former but gives short shrift to the latter. Also, I waffle about the difference between industry and government sponsored trials. Sometimes, I agree with the spirit of the guidance and feel that both should run under the same model, but sometimes I think that government sponsors, as custodians of the public monies, cannot be excluded from the discussions at the DMC. I have been a member of DMCs for many of the institutes (NHLBI, NIDDK, NCI, NIAID, NEI) and they all run slightly differently. In all cases except the NCI trials, the NIH project officers have sat through the executive sessions. I don't think that is wrong or that it jeopardizes the integrity of the trial. In principle, yes; in practice, generally, no. Perhaps you should allow more latitude for NIH-sponsored trials, especially the very large, multi-center trials that are asking big public-health questions. As I write this, I suddenly think I understand the problem. Industry DMCs tend to have quite limited scope. They are looking at very specific questions and are not interested in examining all the data from an ongoing trial. Therefore, an independent statistician can get to know the relevant data well enough to produce a useful report that allows a DMC to make intelligent decisions. NIH DMCs, on the other hand, tend to look at huge books of data. They will review every variable collected because they have a very broad mandate for the trial. They serve not only as safety monitors, but as general advisors to the trial. There is no way that an independent statistician, not involved in the trial, can produce the kind of monitoring report that a typical NIH DMC sees. The guidance does not appear to distinguish these two types of beasts.

EC -4