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Improving FDA/Industry Improving FDA/Industry Interactions: Interactions: Suggestions from Suggestions from

FDA/CDER StatisticiansFDA/CDER Statisticians

Rafia Bhore, Ph.D.Rafia Bhore, Ph.D.

Janice Derr, Ph.D.Janice Derr, Ph.D.

FDA / CDER / Office of BiostatisticsFDA / 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).

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CDER Office of BiostatisticsCDER Office of Biostatistics

DB1DB1 Cardiovascular & Renal; Neurological; PsychiatricCardiovascular & Renal; Neurological; Psychiatric

DB2DB2 Pulmonary & Allergy; Metabolism & Endocrine; Pulmonary & Allergy; Metabolism & Endocrine; Analgesics & AnestheticsAnalgesics & Anesthetics

DB3DB3 Gastrointestinal; Reproductive & Urologic; Gastrointestinal; Reproductive & Urologic; Dermatologic & DentalDermatologic & Dental

DB4DB4 Anti-Infective & Ophthalmology; Anti-Viral; Anti-Infective & Ophthalmology; Anti-Viral; Special Pathogen & TransplantSpecial Pathogen & Transplant

DB5DB5 Oncology Biologics; Oncology Drugs; Imaging & Oncology Biologics; Oncology Drugs; Imaging & HematologyHematology

DB6DB6 Generic; Pharmacology & Toxicology; Chemistry Generic; Pharmacology & Toxicology; Chemistry & Manufacturing; Safety; Special Projects & & Manufacturing; Safety; Special Projects & Clinical PharmacologyClinical Pharmacology

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Communication Dynamics Communication Dynamics between FDA and Industrybetween FDA and Industry

Project Manager

ClinicalStats

Micro

ClinPharm

Chem

Pharm/Tox

Regulatory Affairs

Project Team

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Interactions During Drug Interactions During Drug DevelopmentDevelopment

Pre-clinical Research

Phase II Phase III

Clinical Start NDA/BLA Submission

Phase I

Pre-IND Meeting

EOP II Meeting

Pre-NDA Meeting

Labeling Meeting

NDA Review

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Good Meeting Management Good Meeting Management PracticesPractices

GMMPs Facilitate input from review GMMPs Facilitate input from review disciplinesdisciplines

Prior to internal meeting (draft responses to Prior to internal meeting (draft responses to industry questions)industry questions)

Internal meeting (preliminary comments to Internal meeting (preliminary comments to sponsor) sponsor)

Formal meeting (moderated discussion)Formal meeting (moderated discussion)

Follow-up (meeting minutes, further discussion)Follow-up (meeting minutes, further discussion)

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Suggestions from CDER Suggestions from CDER StatisticiansStatisticians

(Good Meeting Practices)(Good Meeting Practices) Use a meeting with FDA as an opportunity to Use a meeting with FDA as an opportunity to

send in questions about statistical issues send in questions about statistical issues

Ask good questions that will give you useful Ask good questions that will give you useful answers answers

Provide sufficient detail to help us give useful Provide sufficient detail to help us give useful statistical review commentsstatistical review comments

Use the channels of communication to get a Use the channels of communication to get a response from FDA statisticians about response from FDA statisticians about statistical issuesstatistical issues

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Investigational New Drug Investigational New Drug Application Application (IND) Stage(IND) Stage

Special Protocol AssessmentSpecial Protocol Assessment

Statistical Analysis PlansStatistical Analysis Plans

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Special Protocol AssessmentSpecial Protocol Assessment

Sponsors can submit certain types of Sponsors can submit certain types of protocols with specific questions prior to start protocols with specific questions prior to start of study (Guidance recommends 90 days).of study (Guidance recommends 90 days).

FDA determines if SPA process applies to the FDA determines if SPA process applies to the request, and if so, responds to questions request, and if so, responds to questions within 45 days (PDUFA goal).within 45 days (PDUFA goal).

Protocol agreements under SPA are part of Protocol agreements under SPA are part of the administrative record. Regulations the administrative record. Regulations describe the circumstances under which the describe the circumstances under which the agreements can be changed. agreements can be changed.

SPA Guidance 2002SPA Guidance 2002

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Suggestions from CDER Suggestions from CDER StatisticiansStatisticians

(Special Protocol Assessment)(Special Protocol Assessment) Ask good questions that will give you useful Ask good questions that will give you useful

answers answers

Provide sufficient detail to help us give useful Provide sufficient detail to help us give useful statistical review commentsstatistical review comments

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Statistical Analysis Plan (SAP)Statistical Analysis Plan (SAP) Prospective plan of statistical methods not Prospective plan of statistical methods not

detailed in the Protocoldetailed in the Protocol

Protocol details design considerations vs. Protocol details design considerations vs. SAP details analysis considerationsSAP details analysis considerations

Design: Endpoints, type of control, planned Design: Endpoints, type of control, planned comparisons, multiple testing, interim analysescomparisons, multiple testing, interim analyses

Analysis: Statistical models, handling of missing Analysis: Statistical models, handling of missing data, nature of censoring, analysis populations, data, nature of censoring, analysis populations, repeated measurements over time, study repeated measurements over time, study windows, etc.windows, etc.

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Suggestions from CDER Suggestions from CDER StatisticiansStatisticians

(Statistical Analysis Plan)(Statistical Analysis Plan) Statistical Analysis Plan (SAP) should be Statistical Analysis Plan (SAP) should be

detailed and prospectively writtendetailed and prospectively written

Prospectively submit to FDA for Phase 3 Prospectively submit to FDA for Phase 3 studies and Phase 2 supportive studiesstudies and Phase 2 supportive studies Open-label studies submit before study Open-label studies submit before study

beginsbegins

Blinded studies submit prior to last patient Blinded studies submit prior to last patient enrolled or first interim analysis (whichever enrolled or first interim analysis (whichever comes first)comes first)

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Suggestions from CDER Suggestions from CDER StatisticiansStatisticians

(Statistical Analysis Plan contd.)(Statistical Analysis Plan contd.) Identify critical issues at protocol Identify critical issues at protocol

design stage or at least Statistical design stage or at least Statistical Analysis Plan writingAnalysis Plan writing

Examples: adjustment for multiplicity, interim analysis Examples: adjustment for multiplicity, interim analysis plan, non-inferiority evaluation, missing data, …plan, non-inferiority evaluation, missing data, …

Commercial Sponsors should Commercial Sponsors should encourage co-operative trialists to encourage co-operative trialists to write a Statistical Analysis Planwrite a Statistical Analysis Plan

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New Drug Application New Drug Application (NDA) Stage(NDA) Stage

Integrated Summary of EfficacyIntegrated Summary of Efficacy

LabelingLabeling

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Integrated Summary of Efficacy Integrated Summary of Efficacy (Suggestions from CDER (Suggestions from CDER

Statisticians)Statisticians) Important component of New Drug Application Important component of New Drug Application

ReviewReview

Provide clinically meaningful and logically tight Provide clinically meaningful and logically tight argument whether drug has necessary evidence for argument whether drug has necessary evidence for efficacy claimefficacy claim

Provide side by side comparison of studiesProvide side by side comparison of studies

NOT necessarily pooled or meta-analysis of efficacyNOT necessarily pooled or meta-analysis of efficacy

Discuss pooling study results with FDADiscuss pooling study results with FDA

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Integrated Summary of Efficacy Integrated Summary of Efficacy Example: Example:

CCanan YoYoUU PPRRove ove EEfficacy and fficacy and SSafetyafety of curevirof curevir (CURES)(CURES)

Treatment Success Rate by Study and for Pooled Studies

41%

15%

29%

22%18% 20%

0%5%

10%15%20%25%30%35%40%45%

CURES 1 study CURES 2 study CURES

TestPlacebo

p

p-value < .0001

p-value < .0001

p-value = .380

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Statistical Input on Labeling Statistical Input on Labeling TextText

FDA Statisticians review labeling text:FDA Statisticians review labeling text:

Statistical support for study conclusions, Statistical support for study conclusions, claims and indicationsclaims and indications

Description of study results, summary Description of study results, summary statistics and inferential languagestatistics and inferential language

Information in tables and figuresInformation in tables and figures

Labeling Labeling Example Example

#1: #1: Statistical Statistical

Input Input ProvidedProvided

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).

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Labeling Example #2: Labeling Example #2: Statistical Input NeededStatistical Input Needed

Proposed textProposed text: “The combination of : “The combination of AA and and BB is is effective in lowering LDL-C levels beyond effective in lowering LDL-C levels beyond that achieved by either agent alone.”that achieved by either agent alone.”

Statistical issueStatistical issue: The study was not designed : The study was not designed to support this conclusion. The study had to support this conclusion. The study had two arms, two arms, (A+B)(A+B) combination product, and combination product, and AA monotherapy. monotherapy.

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Labeling Example #3: Labeling Example #3: Statistical Input NeededStatistical Input Needed

Proposed tableProposed table: The symbol “: The symbol “**” was used for ” was used for p<0.05, and “p<0.05, and “****” was used to indicate ” was used to indicate nono statistically significant difference between statistically significant difference between the active treatment arm and the placebo the active treatment arm and the placebo arm.arm.

Statistical issueStatistical issue: This is not a typical way to : This is not a typical way to depict this outcome and may be confusing to depict this outcome and may be confusing to some readers. some readers.

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Suggestions from CDER Suggestions from CDER StatisticiansStatisticians(Labeling)(Labeling)

Provide your statistical perspective in Provide your statistical perspective in the development of labeling text.the development of labeling text.

Labeling Guidance, Labeling Guidance, 2006:2006:Clinical Studies SectionClinical Studies Section

Adverse Reactions SectionAdverse Reactions Section

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Improving Statistical Improving Statistical CommunicationCommunication

ClinicalStats

Micro

ClinPharm

Chem

Pharm/Tox

Provide Provide statistical input statistical input at all stages at all stages

Ask good Ask good questions questions

Provide detailed, Provide detailed, timely timely informationinformation

Address critical Address critical statistical issuesstatistical issues

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AcknowledgmentsAcknowledgments

FDA Statisticians fromFDA Statisticians from

Divisions of Biometrics 1, Biometrics 2, Divisions of Biometrics 1, Biometrics 2, Biometrics 3, Biometrics 4, and Biometrics 5Biometrics 3, Biometrics 4, and Biometrics 5

Industry Statisticians /Programmers Industry Statisticians /Programmers

for their promptness in responding to FDA for their promptness in responding to FDA questions!questions!