8. the original Greenberg diagram a recent representation of the NIH model The Executive Committee has “the responsibility … to review the data analysis coming from the Coordinating Center and to prepare frequent reports to the participants, as well as annual reports to the National Heart Institute”
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13. Sequential (2X2) medical trial: Hodgkin’s Disease, Stanford Medical Center, 1967 The group methods replaced the 2X2 sequential methods first developped and used in the 1960s
23. CALGB 2006 The protocol lies at the core of the new style of practice
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27. II. What kind of institution is a DMC? DMCs are reflexive institutions.
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29. A typical DMC charter Informal reflexion and formal coding
30. The Guidance process i) 2001 Draft Guidance document issued ii) 2001 Public Meeting iii) 2006 Guidance document issued Forums for Reflexion
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32. should a DMC be allowed to change sample size? ‘ A clinical trial ... is not a fixed quantity. It’s almost like a living thing. It evolves; it changes; it can change. One of the obvious ways in which a clinical trial might need to be modified has to do with the sample size. When the sample size is calculated, different things are assumed about the rate in the control arm, the rate in the treatment arm. Those assumptions may or may not be valid. And it may turn out that the trial is underpowered and the sample size needs to be adjusted. A data monitoring committee, although it’s not easy, can grapple with this’. [Gregory Campbell, FDA meeting]
33. should a DMC be allowed to change sample size? ‘ [a DMC] is seeing data on efficacy and for it to have the ability and the right to change end points and to change crucial aspects of design I think can sacrifice the integrity of the design’. [Janet Wittes, FDA meeting] ‘ the unblinded data monitoring committee really can’t credibly change end point, sample size, subset plans or anything, any more than an unblinded sponsor could without at a minimum affecting alpha or introducing bias that we don’t know how to correct’. [Robert Temple, FDA meeting]
34. should a DMC be allowed to change sample size? ‘ Not all studies are confirmatory but those studies that are confirmatory, I’d like to be able to interpret them in that manner. It means ... I’d like to have a pre-specified hypothesis that I then confirm. At the same time, there can well be during the course of a long trial external information that could enlighten us as to what the hypothesis really ought to be. I actually don’t have a problem if I’m certain that it’s external data that leads to refinement and this is the essence of where this independence and separation enables or empowers the sponsor to have that flexibility’. [Thomas Fleming, FDA meeting]
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39. Does the independent staistician have the expertise? ‘ In the multicenter, cancer cooperative group setting … the trial data manager prepares the data for the interim analysis which is carried out by the trial statistician. Within this setting we feel that it is difficult for a completely independent third party to carry out the analysis for the following reasons: 1. They will not be as familiar with the trial or the data as the trial data manager and trial statistician and are thus more likely to make mistakes in the analysis. 2. With a large number of trials it becomes much more difficult both practically and financially to have the trial analyzed by a third party’. [Richard Sylvester, FDA Dockets]
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