Rabies: Developing Monoclonal Antibody Cocktails for the Passive Immunization Component of Post-Exposure Prophylaxis Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 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 Stephanie Troy at 240-402-4656. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2021 Clinical/Antimicrobial 34605388dft.docx 07/13/21 Rabies: Developing Monoclonal Antibody Cocktails for the Passive Immunization Component of Post-Exposure Prophylaxis 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] https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2021 Clinical/Antimicrobial TABLE OF CONTENTS I. INTRODUCTION ........................................................................................... 1 II. BACKGROUND.............................................................................................. 2 III. DEVELOPMENT PROGRAM ....................................................................... 4 A. General Considerations ...................................................................................... 4 1 Nonclinical Virology Development Considerations ................................................... 4 a. Epitope mapping ............................................................................................ 4 b. Antiviral activity in cell culture ........................................................................ 4 c. Animal challenge studies................................................................................. 5 2. Early-Phase Clinical Development Considerations ................................................... 5 3. Efficacy Considerations ........................................................................................ 6 4. Safety Considerations ........................................................................................... 7 B. Phase 3 Efficacy Trial Considerations.................................................................. 8 1. Trial Design, Including Randomization, Stratification, and Blinding............................ 8 2. Trial Population and Location ............................................................................... 8 3. Entry Criteria...................................................................................................... 9 4. Dose Selection................................................................................................... 10 5. Use of Active Comparators.................................................................................. 10 6. Efficacy Endpoints ............................................................................................. 10 7. Trial Procedures and Timing of Assessments.......................................................... 11 8. Endpoint Adjudication ........................................................................................ 11 9. Statistical Considerations.................................................................................... 11 a. Analysis populations .................................................................................... 11 b. Efficacy analyses ......................................................................................... 11 c. Handling of missing data............................................................................... 12 d. Statistical considerations for a trial to support a first-line indication ..................... 12 10. Risk-Benefit Considerations ............................................................................ 13 C. Other Considerations ....................................................................................... 13 1. Nonclinical Safety Considerations ........................................................................ 13 2. Chemistry, Manufacturing, and Controls Considerations ......................................... 15 a. Candidate selection ...................................................................................... 15 b. Control strategy: potency assays..................................................................... 16 c. Control strategy: ratio of mAbs in cocktail ....................................................... 16 3. Labeling Considerations ..................................................................................... 16 4. Postmarketing Considerations ............................................................................. 16 REFERENCES ......................................................................................................... 17 Contains Nonbinding Recommendations Draft — Not for Implementation 1 Rabies: Developing Monoclonal Antibody Cocktails for the 2 Passive Immunization Component of Post-Exposure Prophylaxis 3 Guidance for Industry1 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 The purpose of this guidance is to help sponsors in the development of anti-rabies virus 18 monoclonal antibody (mAb) cocktails as an alternative to anti-rabies virus immunoglobulin 19 (RIG) as the passive immunization component of post-exposure prophylaxis (PEP) for the 20 prevention of rabies when given immediately after contact with a rabid or possibly rabid animal. 21 This draft guidance is intended to serve as a focus for continued discussions among the Division 22 of Antivirals, sponsors, the academic community, and the public.2 This guidance does not 23 address the development of rabies vaccines, products to treat rabies, or mAbs for other 24 indications. The recommendations in this guidance relate to studies to be submitted in support of 25 a biologics license application (BLA) submission under section 351 of the Public Health Service 26 Act (42 U.S.C. § 262) and implementing regulations at 21 CFR part 601. 27 28 This guidance does not address general issues of statistical analysis or clinical trial design. 29 Those topics are addressed in the ICH guidances for industry E9 Statistical Principles for 30 Clinical Trials (September 1998), E9(R1) Statistical Principles for Clinical Trials: Addendum: 31 Estimands and Sensitivity Analysis in Clinical Trials (May 2021), and E10 Choice of Control 32 Group and Related Issues in Clinical Trials (May 2001), respectively.3 33 34 The contents of this document do not have the force and effect of law and are not meant to bind 35 the public in any way, unless specifically incorporated into a contract. This document is intended 36 only to provide clarity to the public regarding existing requirements under the law. FDA 37 guidance documents, including this guidance, should be viewed only as recommendations, unless 1 This guidance has been prepared by the Office of New Drugs, Office of Infectious Diseases, Division of Antivirals in the Center for Drug Evaluation and Research at the Food and Drug Administration. 2 FDA encourages sponsors to contact the division to discuss specific issues that arise during the development of ra bies mAb cocktails. 3 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 1 Contains Nonbinding Recommendations Draft — Not for Implementation 38 specific regulatory or statutory requirements are cited. The use of the word should in Agency 39 guidance means that something is suggested or recommended, but not required. 40 41 II. BACKGROUND 42 43 Rabies has an almost 100% case fatality rate after clinical symptoms develop and there is no 44 proven treatment. However, timely administration of rabies PEP is nearly 100% effective in 45 preventing clinical rabies (WHO 2018). Globally, approximately 20 million people per year 46 receive PEP after potential rabies virus exposure (WHO 2013), including approximately 55,000 47 people in the United States (Pieracci et al. 2019). Despite available prophylaxis, approximately 48 59,000 people die from rabies worldwide each year (Hampson et al. 2015, WHO 2018), usually 49 either because PEP was not administered or because PEP was administered