Dockets Management Branch (HFA-305) July 3, 1997
Food and Drug Administration
12420 Parklawn Drive
Room 1-23
Rockville, MD 20857
RE: Docket 97D-0174
Dear Madam or Sir,
On behalf of the Georgetown Center for Drug Development Science (CDDS), I submit herein our comments on the Draft Guideline on Statistical Principles for Clinical Trials. Our comments reflect the opinion of CDDS staff, derived with the advice and counsel of the Center for Drug Development Science Advisory Board members and other advisors (Especially, Drs. Donald Rubin, Harvard University, Lewis Sheiner, UCSF, and Robert Desjardins, CDDS).
We appreciate and commend the quality effort expended by the Efficacy Expert Working Group of the ICH in developing and presenting the draft guideline on statistical principles for public comment.
CDDS's comments comprise both general ones and those relating to specific paragraphs in the draft guidance.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 and safety determinations using advanced scientific methods.
The draft guideline is an excellent presentation of traditional frequentist statistical principles applied during recent decades to human therapeutic clinical trials, which largely reflect a view that drug development persists as an essentially empirical endeavor. However, the guideline fails to adequately consider advances in clinical pharmacology and drug development science that together form the foundation for a mechanistic understanding of the clinical effects of new drugs that can now be efficiently incorporated into clinical trials that comprise the basis for confirming effectiveness of new drugs. Our comments in the text of the guideline reflect advances in statistics and drug development science that should be considered in a revised guideline.
Finally, we wish to draw your attention to our Comments on a closely related FDA draft document: "Guidance for Industry--Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products", which we submitted to the Agency on May 30, 1997.
Sincerely yours,
Carl C. Peck, M.D.
Professor of Pharmacology and Medicine
Director, Center for Drug Development Science
Comments on Docket No. 97D-0174
ICH: Draft Guideline on Statistical Principles for Clinical Trials
Center for Drug Development Science
Georgetown University Medical Center
Washington, DC
1. The draft guidance overemphasizes hypothesis testing approaches to confirmation of effectiveness and provides inadequate attention to principles of estimation for the purpose of affirming effectiveness (e.g. via dose-response trial designs).
2. Section 3.1. provides inadequate consideration of dose-response designs and is silent on concentration- and effect-controlled trial designs.
3. The draft guidance overemphasizes fixed dosage clinical trial designs. Consideration should be made of adaptive or individualized dosage designs such as individualized dose titration based on concentration or intermediate effect measurements.
4. Whereas intention-to-treat and per protocol analysis sets are discussed in the draft guidance, "as treated" analysis sets also should be considered.
5. More focused and detailed advice on common problems like subject dropouts & missing data should be provided.
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