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1 Improving FDA/Industry Interactions: Suggestions from FDA/CDER Statisticians Rafia Bhore, Ph.D. Janice Derr, Ph.D. FDA / CDER / Office of Biostatistics.

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Presentation on theme: "1 Improving FDA/Industry Interactions: Suggestions from FDA/CDER Statisticians Rafia Bhore, Ph.D. Janice Derr, Ph.D. FDA / CDER / Office of Biostatistics."— Presentation transcript:

1 1 Improving FDA/Industry Interactions: Suggestions from FDA/CDER Statisticians Rafia Bhore, Ph.D. Janice Derr, Ph.D. FDA / CDER / Office of Biostatistics The views expressed in this presentation are those of the speakers and not necessarily of the U.S. Food and Drug Administration (FDA).

2 2 CDER Office of Biostatistics DB1 Cardiovascular & Renal; Neurological; Psychiatric DB2 Pulmonary & Allergy; Metabolism & Endocrine; Analgesics & Anesthetics DB3 Gastrointestinal; Reproductive & Urologic; Dermatologic & Dental DB4 Anti-Infective & Ophthalmology; Anti-Viral; Special Pathogen & Transplant DB5 Oncology Biologics; Oncology Drugs; Imaging & Hematology DB6 Generic; Pharmacology & Toxicology; Chemistry & Manufacturing; Safety; Special Projects & Clinical Pharmacology

3 3 Communication Dynamics between FDA and Industry Project Manager Clinical Stats Micro Clin Pharm Chem Pharm/ Tox Regulatory Affairs Project Team

4 4 Interactions During Drug Development Pre-clinical Research Phase IIPhase III Clinical Start NDA/BLA Submission Phase I Pre-IND Meeting EOP II Meeting Pre-NDA Meeting Labeling Meeting NDA Review

5 5 Good Meeting Management Practices GMMPs Facilitate input from review disciplines uPrior to internal meeting (draft responses to industry questions) uInternal meeting (preliminary comments to sponsor) uFormal meeting (moderated discussion) uFollow-up (meeting minutes, further discussion)

6 6 Suggestions from CDER Statisticians (Good Meeting Practices) uUse a meeting with FDA as an opportunity to send in questions about statistical issues uAsk good questions that will give you useful answers uProvide sufficient detail to help us give useful statistical review comments uUse the channels of communication to get a response from FDA statisticians about statistical issues

7 7 Investigational New Drug Application (IND) Stage Special Protocol Assessment Statistical Analysis Plans

8 8 Special Protocol Assessment uSponsors can submit certain types of protocols with specific questions prior to start of study (Guidance recommends 90 days). uFDA determines if SPA process applies to the request, and if so, responds to questions within 45 days (PDUFA goal). uProtocol agreements under SPA are part of the administrative record. Regulations describe the circumstances under which the agreements can be changed. SPA Guidance 2002

9 9 Suggestions from CDER Statisticians (Special Protocol Assessment) uAsk good questions that will give you useful answers uProvide sufficient detail to help us give useful statistical review comments

10 10 Statistical Analysis Plan (SAP) uProspective plan of statistical methods not detailed in the Protocol uProtocol details design considerations vs. SAP details analysis considerations Design: Endpoints, type of control, planned comparisons, multiple testing, interim analyses Design: Endpoints, type of control, planned comparisons, multiple testing, interim analyses Analysis: Statistical models, handling of missing data, nature of censoring, analysis populations, repeated measurements over time, study windows, etc. Analysis: Statistical models, handling of missing data, nature of censoring, analysis populations, repeated measurements over time, study windows, etc.

11 11 Suggestions from CDER Statisticians (Statistical Analysis Plan) uStatistical Analysis Plan (SAP) should be detailed and prospectively written uProspectively submit to FDA for Phase 3 studies and Phase 2 supportive studies Open-label studies submit before study begins Open-label studies submit before study begins Blinded studies submit prior to last patient enrolled or first interim analysis (whichever comes first) Blinded studies submit prior to last patient enrolled or first interim analysis (whichever comes first)

12 12 Suggestions from CDER Statisticians (Statistical Analysis Plan contd.) uIdentify critical issues at protocol design stage or at least Statistical Analysis Plan writing Examples: adjustment for multiplicity, interim analysis plan, non- inferiority evaluation, missing data, … Examples: adjustment for multiplicity, interim analysis plan, non- inferiority evaluation, missing data, … uCommercial Sponsors should encourage co- operative trialists to write a Statistical Analysis Plan

13 13 New Drug Application (NDA) Stage Integrated Summary of Efficacy Labeling

14 14 Integrated Summary of Efficacy (Suggestions from CDER Statisticians) uImportant component of New Drug Application Review uProvide clinically meaningful and logically tight argument whether drug has necessary evidence for efficacy claim uProvide side by side comparison of studies uNOT necessarily pooled or meta-analysis of efficacy Discuss pooling study results with FDA Discuss pooling study results with FDA

15 15 Integrated Summary of Efficacy Example: C an Yo U P R ove E fficacy and S afety of curevir (CURES)

16 16 Statistical Input on Labeling Text FDA Statisticians review labeling text: uStatistical support for study conclusions, claims and indications uDescription of study results, summary statistics and inferential language uInformation in tables and figures

17 Labeling Example #1: Statistical Input Provided CLINICAL STUDIES … The NAGLAZYME-treated group showed greater mean increases in the distance walked in 12 minutes (12- minute walk test, 12-MWT) and in the rate of stair climbing in a 3-minute stair climb, compared to the placebo group (Table 2).

18 18 Labeling Example #2: Statistical Input Needed Proposed text: The combination of A and B is effective in lowering LDL-C levels beyond that achieved by either agent alone. Statistical issue: The study was not designed to support this conclusion. The study had two arms, (A+B) combination product, and A monotherapy.

19 19 Labeling Example #3: Statistical Input Needed Proposed table: The symbol * was used for p<0.05, and ** was used to indicate no statistically significant difference between the active treatment arm and the placebo arm. Statistical issue: This is not a typical way to depict this outcome and may be confusing to some readers.

20 20 Suggestions from CDER Statisticians (Labeling) uProvide your statistical perspective in the development of labeling text. Labeling Guidance, 2006: Clinical Studies Section Clinical Studies Section Adverse Reactions Section Adverse Reactions Section

21 21 Improving Statistical Communication Clinical Stats Micro Clin Pharm Chem Pharm/ Tox Provide statistical input at all stages Provide statistical input at all stages Ask good questions Ask good questions Provide detailed, timely information Provide detailed, timely information Address critical statistical issues Address critical statistical issues

22 22 Acknowledgments uFDA Statisticians from Divisions of Biometrics 1, Biometrics 2, Biometrics 3, Biometrics 4, and Biometrics 5 Divisions of Biometrics 1, Biometrics 2, Biometrics 3, Biometrics 4, and Biometrics 5 uIndustry Statisticians /Programmers for their promptness in responding to FDA questions! for their promptness in responding to FDA questions!


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