Multiple Endpoints in Clinical Trials Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact (CDER) Scott Goldie at 301-796-2055 or (CBER) Office of Communication, Outreach, and Development, 800-835-4709 or 240-402- 8010. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) [January 2017] Clinical/Medical Multiple Endpoints in Clinical Trials Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010 Email: [email protected] http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) [January 2017] Clinical/Medical Contains Nonbinding Recommendations Draft — Not for Implementation TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND AND SCOPE ....................................................................................... 2 A. Introduction to Study Endpoints .................................................................................................. 2 B. Demonstrating the Study Objective of Effectiveness .................................................................. 3 C. Type I Error ................................................................................................................................... 4 D. Relationship Between the Observed and True Treatment Effects ............................................ 6 E. Multiplicity ..................................................................................................................................... 6 III. MULTIPLE ENDPOINTS: GENERAL PRINCIPLES .............................................. 9 A. The Hierarchy of Families of Endpoints ...................................................................................... 9 1. Primary Endpoint Family ................................................................................................................. 9 2. Secondary Endpoint Family ........................................................................................................... 10 B. Type II Error Rate and Multiple Endpoints ............................................................................. 11 C. Types of Multiple Endpoints ....................................................................................................... 12 1. When Demonstration of Treatment Effects on All of Two or More Distinct Endpoints Is Necessary to Establish Clinical Benefit (Co-Primary Endpoints) ....................................................................... 12 2. When Demonstration of a Treatment Effect on at Least One of Several Primary Endpoints Is Sufficient ............................................................................................................................................. 14 3. Composite Endpoints ..................................................................................................................... 14 4. Other Multi-Component Endpoints ................................................................................................ 15 5. Clinically Critical Endpoints Too Infrequent for Use as a Primary Endpoint .............................. 16 D. The Individual Components of Composite and Other Multi-Component Endpoints ........... 17 1. Evaluating the Components of Composite Endpoints .................................................................... 17 2. Reporting and Interpreting the Individual Component Results of a Composite Endpoint ............ 19 3. Evaluating and Reporting the Results on Other Multi-Component Endpoints .............................. 20 IV. STATISTICAL METHODS .......................................................................................... 21 A. Type I Error Rate for a Family of Endpoints and Conclusions on Individual Endpoints .... 21 B. When the Type I Error Rate Is Not Inflated or When the Multiplicity Problem Is Addressed Without Statistical Adjustment or by Other Methods ...................................................................... 22 1. Clinically Relevant Benefits Required for All Specified Primary Endpoints — the Case of “Co- Primary” Endpoints ........................................................................................................................... 22 2. Use of Multiple Analysis Methods for a Single Endpoint after Success on the Prespecified Primary Analysis Method ................................................................................................................... 22 C. Common Statistical Methods for Addressing Multiple Endpoint-Related Multiplicity Problems ................................................................................................................................................ 23 1. The Bonferroni Method .................................................................................................................. 24 2. The Holm Procedure ...................................................................................................................... 25 i Contains Nonbinding Recommendations Draft — Not for Implementation 3. The Hochberg Procedure ............................................................................................................... 26 4. Prospective Alpha Allocation Scheme ........................................................................................... 28 5. The Fixed-Sequence Method .......................................................................................................... 29 6. The Fallback Method ..................................................................................................................... 30 7. Gatekeeping Testing Strategies ...................................................................................................... 31 8. The Truncated Holm and Hochberg Procedures for Parallel Gatekeeping .................................. 32 9. Multi-Branched Gatekeeping Procedures ..................................................................................... 34 10. Resampling-Based, Multiple-Testing Procedures ..................................................................... 37 V. CONCLUSION ............................................................................................................... 37 GENERAL REFERENCES ....................................................................................................... 39 APPENDIX: THE GRAPHICAL APPROACH ..................................................................... 42 ii Contains Nonbinding Recommendations Draft — Not for Implementation 1 2 Multiple Endpoints in Clinical Trials 1 3 Guidance for Industry 4 5 6 7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 11 for this guidance as listed on the title page. 12 13 14 15 I. INTRODUCTION 16 17 This guidance provides sponsors and review staff with the Agency’s thinking about the problems 18 posed by multiple endpoints in the analysis and interpretation of study results and how these 19 problems can be managed in clinical trials for human drugs, including drugs subject to licensing 20 as biological products. Most clinical trials performed in drug development contain multiple 21 endpoints to assess the effects of the drug and to document the ability of the drug to favorably 22 affect one or more disease characteristics. As the number of endpoints analyzed in a single trial 23 increases, the likelihood of making false conclusions about a drug’s effects with respect to one or 24 more of those endpoints becomes a concern if there is not appropriate adjustment for 25 multiplicity. The purpose of this guidance is to describe various