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FDA Guidance for Clinical Trial Sponsors

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FDA Guidance for Clinical Trial Sponsors Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees For questions on the content of this guidance, contact the Office of Communication, Training, and Manufacturers Assistance (CBER) at 800-835-4709 or 301-827-1800. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research (CBER) Center for Drug Evaluation and Research (CDER) Center for Devices and Radiological Health (CDRH) March 2006 OMB Control No. 0910-0581 Expiration Date: 10/31/2021 See additional PRA statement in Section 8 of this guidance Contains Nonbinding Recommendations Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees Additional copies of this guidance are available from: 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 Phone: 800-835-4709 or 301-827-1800 Internet: http://www.fda.gov/cber/guidelines.htm or Office of Training and Communication Division of Communications Management Drug Information Branch, HFD-210 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Rockville, MD 20857 Phone: 301-827-4573 Internet: http://www.fda.gov/cder/guidance/index.htm or The Division of Small Manufacturers, International, and Consumer Assistance (DSMICA) Center for Devices and Radiological Health Food and Drug Administration 1350 Piccard Drive, Rockville, MD 20850 Phone: 800-638-2041 or 301-443-6597 Internet: http://www.fda.gov/cdrh Email: [email protected] Facts-on-Demand (faxback): 800-899-0381 or 301-827-0111 Contains Nonbinding Recommendations Table of Contents 1. INTRODUCTION AND BACKGROUND .................................................................... 1 1.1. History of DMCs ........................................................................................................... 2 1.2. Current Status ............................................................................................................... 3 2. DETERMINING NEED FOR A DMC ........................................................................... 3 2.1. What is the Risk to Trial Participants? ...................................................................... 4 2.2. Is DMC Review Practical? ........................................................................................... 4 2.3. Will a DMC Help Assure the Scientific Validity of the Trial? ................................. 5 3. DMCs AND OTHER OVERSIGHT GROUPS ............................................................. 5 3.1. Institutional Review Boards ......................................................................................... 6 3.2. Clinical Trial Steering Committees ............................................................................. 6 3.3. Endpoint Assessment/Adjudication Committees ....................................................... 7 3.4. Site/Clinical Monitoring ............................................................................................... 7 3.5. Others with Monitoring Responsibilities .................................................................... 7 4. DMC ESTABLISHMENT AND OPERATION ............................................................ 8 4.1. Committee Composition ............................................................................................... 8 4.2. Confidentiality of Interim Data and Analyses.......................................................... 10 4.2.1. Interim Data .......................................................................................................... 10 4.2.2. Interim Reports to the DMC ................................................................................. 11 4.3. Establishing a Charter Describing Standard Operating Procedures .................... 12 4.3.1. Considerations for Standard Operating Procedures .............................................. 12 4.3.1.1. Meeting Schedule and Format ...................................................................... 12 4.3.1.2. Meeting Structure.......................................................................................... 13 4.3.1.3. Initial Meeting ............................................................................................... 13 4.3.1.4. Format of Interim Reports to the DMC and Use of Treatment Codes.......... 14 4.3.2. Statistical Methods ................................................................................................ 15 4.4. Potential DMC Responsibilities ................................................................................. 16 4.4.1. Interim Monitoring................................................................................................ 16 4.4.1.1. Monitoring for Effectiveness ........................................................................ 17 4.4.1.2. Monitoring for Safety ................................................................................... 17 4.4.1.3. Monitoring Study Conduct ........................................................................... 20 4.4.1.4. Consideration of External Data ..................................................................... 20 4.4.1.5. Studies of Less Serious Outcomes ................................................................ 22 4.4.2. Early Studies ......................................................................................................... 23 4.4.3. Other Responsibilities ........................................................................................... 24 4.4.3.1. Making Recommendations ........................................................................... 24 4.4.3.2. Maintaining Meeting Records....................................................................... 24 5. DMC RECOMMENDATIONS AND REGULATORY REPORTING REQUIREMENTS .......................................................................................................... 25 6. INDEPENDENCE OF THE DMC ................................................................................ 26 6.1. Desirability of an Independent DMC ........................................................................ 27 6.2. Value of Sponsor Interaction with the DMC ............................................................ 27 6.3. Risks of Sponsor Exposure to Interim Comparative Data...................................... 28 6.4. Statisticians Conducting the Interim Analyses ........................................................ 29 6.5. Sponsor Access to Interim Data for Planning Purposes.......................................... 31 i Contains Nonbinding Recommendations 7. SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION OF DMCs ......................................................................................................................... 32 7.1. Planning the DMC ...................................................................................................... 32 7.2. Accessing Interim Data............................................................................................... 32 7.2.1. DMC Recommendations to Terminate the Study ................................................. 33 7.2.2. FDA Interaction with DMCs ................................................................................ 33 7.3. DMC Recommendations for Protocol Changes ....................................................... 34 8. PAPERWORK REDUCTION ACT OF 1995 .............................................................. 34 ii Contains Nonbinding Recommendations Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 1. INTRODUCTION AND BACKGROUND This guidance discusses the roles, responsibilities and operating procedures of Data Monitoring Committees (DMCs) (also known as Data and Safety Monitoring Boards (DSMBs) or Data and Safety Monitoring Committees (DSMCs)) that may carry out important aspects of clinical trial monitoring. This guidance is intended to assist clinical trial sponsors in determining when a DMC may be useful for study monitoring, and how such committees should operate. We recognize that in many clinical trials the sponsor delegates some decision-making regarding the design and conduct of the trial to some other entity such as a steering committee (see Section 3.2) or contract research organization (CRO) (see 21 Code of Federal Regulations (CFR) 312.3(b)). This document, while pertaining primarily to the sponsor with regard to trial management and decision-making, may also be relevant to any individual or group to whom the sponsor has delegated applicable management responsibilities (see Section 3). This guidance finalizes the draft guidance entitled "Guidance for Clinical Trial Sponsors: On the Establishment and Operation of Clinical Trial Data Monitoring Committees" dated November 2001. Sponsors of studies
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