Letter to FDA with General Comments

Dockets Management Branch (HFA-305) May 30, 1997

Food and Drug Administration
12420 Parklawn Drive
Room 1-23
Rockville, MD 20857

Dear Madam or Sir,

On behalf of the Georgetown Center for Drug Development Science (CDDS), I submit herein comments on the draft Guidance for Industry--Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. Our comments reflect the opinion of CDDS staff, derived with the advice and counsel of Science Advisory Board members and other advisors.

We appreciate the quality effort expended by FDA in developing and presenting the draft guidance on evidence of effectiveness for public comment. The draft guidance represents a unique, very important and comprehensive public statement of Agency thinking and rationale regarding quantitative and qualitative standards for demonstrating effectiveness of drug and biologics.

CDDS's comments comprise both general ones and those relating to specific paragraphs in the draft guidance. Deriving its views independently of those of the pharmaceutical industry or government, CDDS presents comments and recommendations that aim to advance the science of drug development for the benefit of patients and the public health, through optimization of effectiveness determination using advanced scientific methods. Lest these comments seem overly critical, demanding, or suggest hesitation pending further

research, CDDS urges that a finalized guidance, modifiable in the future, be issued in a timely fashion according the Agency Staff's best judgment. Subsequent improvement of the guidance may ensue via collaborative research and dialogue by industry, academic, and regulatory scientists, such as in the Collaboration on Drug Development Improvement which has been proposed by FDA and others.

CDDS has four overarching comments to bring to your attention below that are amplified in detail later in the general and specific comments.

1. Consideration of a fundamental issue is missing from the draft guidance: the meaning of "substantial evidence". "Substantial evidence" is presented as if an absolute standard can be applied identically in all cases. The variation in required new evidence that is discussed in the draft guidance is not in terms of total weight of evidence needed, but only in terms of substitution of alternative sources of evidence for some of the traditional ones. The Agency is encouraged to base the requirements for substantial evidence upon a consideration of what the Agency really needs to know, how certain it has to be, and what assumptions it is willing to make in certifying effectiveness in the context of its public health mission (see the expanded comment in Section II.C.).

2. In rationalizing a requirement for independent empirical substantiation, the draft guidance pays insufficient attention to advances in understanding of the sciences of drug action in man (clinical pharmacology) and drug development that have occurred during the three decades since the effectiveness requirement was established 1962. Together, these advances form the foundation for a mechanistic understanding of the clinical effects of most new drugs that can now be efficiently incorporated into clinical trials that comprise the basis for providing substantial evidence of effectiveness. (see Section I).

3. Reflecting past policy, the draft guidance principally comprises a rationale for a standard for evidence of effectiveness that is oriented to justify a requirement for one or more confirmatory clinical trials, interpreted as an independent empirical substantiation. As articulated in a related FDA guideline (see 4. Below), evidence of effectiveness derived from all clinical trials in a development program, interpreted as a whole, should be incorporated in the draft guideline. This issue bears importantly on both the design of a confirmatory trial, and the total weight of evidence required for documenting effectiveness.

4. The present draft guidance incompletely incorporates related scientific and regulatory advances that are articulated in other Agency draft or issued guidances and guidelines. For example the draft ICH guideline on statistical principles for clinical trials (E9) proposes using evidence of effectiveness derived from all other clinical trials, interpreted as a whole (as in 3. above), and cites Bayesian approaches to data analysis of clinical trials. ICH guidelines on dose-response information (E4), ethnic factors (E5), special populations (E9), choice of control group in clinical trials (E10) each contain elements in common with the present guidance. The Agency is encouraged to harmonize this guidance with all related guidelines and guidances.

Sincerely yours,

Carl C. Peck, M.D.
Professor of Pharmacology and Medicine
Director, Center for Drug Development Science

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