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

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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).
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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
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Communication Dynamics between FDA and Industry
Industry
Project Team
Project Manager
Regulatory Affairs
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Interactions During Drug Development
Clinical Start
NDA/BLA Submission
NDA Review
Pre-clinical Research
Phase II
Phase III
Phase I
Pre-IND Meeting
EOP II Meeting
Pre-NDA Meeting
Labeling Meeting
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Good Meeting Management Practices

• GMMPs Facilitate input from review disciplines
• Prior to internal meeting (draft responses to
  industry questions)
• Internal meeting (preliminary comments to
  sponsor)
• Formal meeting (moderated discussion)
• Follow-up (meeting minutes, further discussion)

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Suggestions from CDER Statisticians(Good Meeting
Practices)

• Use a meeting with FDA as an opportunity to send
  in questions about statistical issues
• Ask good questions that will give you useful
  answers
• Provide sufficient detail to help us give useful
  statistical review comments
• Use the channels of communication to get a
  response from FDA statisticians about statistical
  issues

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Investigational New Drug Application (IND) Stage

• Special Protocol Assessment
• Statistical Analysis Plans

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Special Protocol Assessment
SPA Guidance 2002

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

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Suggestions from CDER Statisticians(Special
Protocol Assessment)

• Ask good questions that will give you useful
  answers
• Provide sufficient detail to help us give useful
  statistical review comments

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Statistical Analysis Plan (SAP)

• Prospective plan of statistical methods not
  detailed in the Protocol
• Protocol details design considerations vs. SAP
  details analysis considerations
• 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.

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Suggestions from CDER Statisticians(Statistical
Analysis Plan)

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

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Suggestions from CDER Statisticians(Statistical
Analysis Plan contd.)

• Identify 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,
• Commercial Sponsors should encourage co-operative
  trialists to write a Statistical Analysis Plan

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New Drug Application (NDA) Stage

• Integrated Summary of Efficacy
• Labeling

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Integrated Summary of Efficacy (Suggestions from
CDER Statisticians)

• Important component of New Drug Application
  Review
• Provide clinically meaningful and logically tight
  argument whether drug has necessary evidence for
  efficacy claim
• Provide side by side comparison of studies
• NOT necessarily pooled or meta-analysis of
  efficacy
• Discuss pooling study results with FDA

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Integrated Summary of Efficacy Example Can YoU
PRove Efficacy and Safety of curevir (CURES)
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Statistical Input on Labeling Text

• FDA Statisticians review labeling text
• Statistical support for study conclusions, claims
  and indications
• Description of study results, summary statistics
  and inferential language
• Information in tables and figures

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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).
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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,
  (AB) combination product, and A monotherapy.

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Labeling Example 3 Statistical Input Needed

• Proposed table The symbol was used for
  plt0.05, 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.

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Suggestions from CDER Statisticians(Labeling)

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

• Labeling Guidance, 2006
• Clinical Studies Section
• Adverse Reactions Section

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Improving Statistical Communication
Industry

• Provide statistical input at all stages
• Ask good questions
• Provide detailed, timely information
• Address critical statistical issues

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Acknowledgments

• FDA Statisticians from
• Divisions of Biometrics 1, Biometrics 2,
  Biometrics 3, Biometrics 4, and Biometrics 5
• Industry Statisticians /Programmers
• for their promptness in responding to FDA
  questions!