Guidance for Industry E 10 Choice of Control Group and Related Issues in Clinical Trials 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) May 2001 ICH Guidance for Industry E 10 Choice of Control Group and Related Issues in Clinical Trials Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http://www.fda.gov/cber/guidelines.htm Fax: 1-888-CBERFAX or 301-827-3844 Phone: the Voice Information System at 800-835-4709 or 301-827-1800 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) May 2001 ICH TABLE OF CONTENTS I. INTRODUCTION (1.0)............................................................................................................................................1 A. GENERAL SCHEME AND PURPOSE OF GUIDANCE (1.1).........................................................................................2 B. PURPOSE OF CONTROL GROUP (1.2)......................................................................................................................3 1. Randomization (1.2.1).......................................................................................................................................3 2. Blinding (1.2.2)..................................................................................................................................................4 C. TYPES OF CONTROLS (1.3) .....................................................................................................................................4 1. Placebo Concurrent Control (1.3.1)................................................................................................................5 2. No-treatment Concurrent Control (1.3.2).......................................................................................................5 3. Dose-response Concurrent Control (1.3.3).....................................................................................................5 4. Active (Positive) Concurrent Control (1.3.4)..................................................................................................6 5. External Control (Including Historical Control) (1.3.5)................................................................................6 6. Multiple Control Groups (1.3.6)......................................................................................................................6 D. PURPOSES OF CLINICAL TRIALS AND RELATED ISSUES (1.4)...............................................................................6 1. Evidence of Efficacy (1.4.1)..............................................................................................................................7 2. Comparative Efficacy and Safety (1.4.2).........................................................................................................7 3. Fairness of Comparisons (1.4.3)......................................................................................................................7 a. Dose (1.4.3.1) ....................................................................................................................................................... 8 b. Patient Population (1.4.3.2) ................................................................................................................................... 8 c. Selection and Timing of Endpoints (1.4.3.3) .......................................................................................................... 8 E. ASSAY SENSITIVITY (1.5).......................................................................................................................................9 1. Assay Sensitivity in Non-inferiority or Equivalence Trials (1.5.1)...............................................................9 a. Historical Evidence of Sensitivity to Drugs Effects and Choosing the Non-inferiority Margin (1.5.1.1) ................. 10 b. Appropriate Trial Conduct (1.5.1.2)..................................................................................................................... 12 2. Assay Sensitivity in Trials Intended to Demonstrate Superiority (1.5.2)................................................... 13 II. DETAILED CONSIDERATION OF TYPES OF CONTROL (2.0)............................................................. 14 A. PLACEBO CONTROL (2.1) .................................................................................................................................... 14 1. Description (See Section 1.3.1) (2.1.1)......................................................................................................... 14 2. Ability to Minimize Bias (2.1.2).................................................................................................................... 14 3. Ethical Issues (2.1.3)...................................................................................................................................... 14 4. Usefulness of Placebo-controlled Trials and Validity of Inference in Particular Situations (2.1.4)....... 15 5. Modifications of Design and Combinations with Other Controls That Can Resolve Ethical, Practical, or Inferential Issues (2.1.5).......................................................................................................................................... 16 a. Additional Control Groups (2.1.5.1) .................................................................................................................... 16 b. Other Modifications of Study Design (2.1.5.2) ..................................................................................................... 17 6. Advantages of Placebo-controlled Trials (2.1.6)......................................................................................... 19 a. Ability to Demonstrate Efficacy (2.1.6.1) ........................................................................................................... 19 b. Measures Absolute Efficacy and Safety (2.1.6.2).................................................................................................. 19 c. Efficiency (2.1.6.3) ............................................................................................................................................. 19 d. Minimizing the Effect of Subject and Investigator Expectations (2.1.6.4).............................................................. 20 7. Disadvantages of Placebo-controlled Trials (2.1.7).................................................................................... 20 a. Ethic al Concerns (See Sections 2.1.3 and 2.1.4) (2.1.7.1) ..................................................................................... 20 b. Patient and Physician Practical Concerns (2.1.7.2) ............................................................................................... 20 c. Generalizability (2.1.7.3) .................................................................................................................................... 20 d. No Comparative Information (2.1.7.4) ................................................................................................................. 21 B. NO-TREATMENT CONCURRENT CONTROL (SEE SECTION 1.3.2) (2.2)............................................................ 21 C. DOSE-RESPONSE CONCURRENT CONTROL (SEE SECTION 1.3.3) (2.3)............................................................ 21 1. Description (2.3.1)......................................................................................................................................... 21 2. Ability to Minimize Bias (2.3.2).................................................................................................................... 22 3. Ethical Issues (2.3.3)...................................................................................................................................... 22 4. Usefulness of Dose-response Studies and Validity of Inference in Particular Situations (2.3.4)............. 22 5. Modifications of Design and Combinations with Other Controls That Can Resolve Ethical, Practical, or Inferential Problems (2.3.5).................................................................................................................................... 22 i 6. Advantages of Dose-response Trials (2.3.6)................................................................................................ 22 a. Efficiency (2.3.6.1) ............................................................................................................................................. 22 b. Possible Ethical Advantage (2.3.6.2) ................................................................................................................... 23 7. Disadvantages of Dose-response Study (2.3.7)............................................................................................ 23 D. ACTIVE CONTROL (SEE SECTION 1.3.4) (2.4) ...................................................................................................