Statistical/Practical Issues in Clinical Trials
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0092-8615/97 Copyright Q 1997 Drug Informarion Association Inc.
STATISTICAL/PRACTICAL ISSUES IN CLINICAL TRIALS A”PEY PONG,MS Research Statistician, Biostatistics Berlex Laboratories, Inc., Montville, New Jersey
SHEIN-CHUNG CHOW,PHD Executive Director, Biostatistics and Data Management, Covance, Inc., Princeton, New Jersey
For approval of a drug product, the United States Food and Drug Administration (FDA) requires that substantial evidence of the effectiveness and safety of the drug product be provided through the conduct of two adequate, well-controlled clinical trials. To assist the sponsors in preparation offinal clinical reports f o r regulatory submission and review, the FDA and other regulatory agencies and conferences such as the International Conference on Harmonization (ICH) have developed guidelines for the format and content of a clinical report. The FDA and ICH guidelines require that the following statistical issues be addressed in the final clinical report: 1. Baseline comparability, 2. Adjustments for covanates, 3. Dropouts or missing values, 4. Interim analyses and data monitoring, 5. Multicenter studies, 6. Multiplicity, 7. Intention-to-treat subset versus efficacy subset, 8. Active control trials, and 9. Subgroup analyses. This paper provides an overview of these statistical issues. In addition, statistical justification for these issues is also addressed. Key Words: Statistical issues: Clinical trials; ICH guidelines
INTRODUCTION FOR APPROVAL OF A drug product, the United States Food and Drug Administration requires that substantial evidence of the effectiveness and safety of the drug product be provided through the conduct of two adequate, well-controlled clinical trials. The characteristics of an adequate, well-controlled clinical trial include a study protocol with a valid statistical design, adequate controls, appropriate randomization and blinding procedures, the choice of clinical endpoints for efficacy and safety, a strict adherence to the study protocol during the conduct of the trial, and a sound statistical analysis. These components are crucial for providing a scien-
Reprint address: Annpey Pong, Berlex Laboratories, Inc., 340 Change Bridge Road, P.O. Box 1O00, Montville. NJ 07045-1000.
tific and unbiased assessment of the effectiveness and safety of the drug product. After the completion of the study, it is extremely important to summarizehnterpret the clinical results for regulatory submission. To assist the sponsors in preparation of final clinical reports for regulatory submission and review, the FDA developed guidelines for the format and content of a clinical report in 1988 (1). In addition, in 1994, the Committee for Proprietary Medicinal Products (CPMP) Working Party on Efficacy on Medicinal Products of the European Community issued a similar guideline entitled “A Note for Guidance on Biostatistical Methodology in Clinical Trials in Applications for Marketing Authorizations for Medicinal Products” (2). At the same time, the International Conference On Harmonization (ICH)
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