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The Good Review Management
Practice Guidance -- A Statistical
Reviewer’s Perspective
Steve Wilson, Dr.P.H., CAPT USPHS
Deputy Director, Division of Biometrics II,
CDER/FDA
ASA Biopharmaceutical Section -FDA/Industry Workshop
Marriott Wardman Park, Washington, DC
September 16 , 2005
Disclaimer
Views expressed in this
presentation are those of the
speaker and not, necessarily, of
the Food and Drug
Administration.
Acknowledgements
• Dave Christiansen
• Ruthie Davi
• Ed Nevius
• ADaM Workgroup
Outline
• Statistical Review
• Good Review Management Practice
Guidance
• Time for Change
– Pre-NDA Statistics Meeting
– Meta-Data Standards for Analysis
– Statistical Guidance
Statistical Review
• Assess quality / completeness of data
• Assess compliance with protocol / blinded
analysis plans -- conduct of the study
• Check appropriateness of statistical models and
conclusions
• Verify results reported in the NDA
• Answer new review-related questions
• Examine individual patient experience during
clinical trial
A Review Tale
New Guidance
Guidance for Review Staff and Industry
Good Review Management Principles and
Practices for PDUFA Products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
April 2005
Procedural
GRMP: Operational Principles
• The foundation for good review
management is created during product
development.
• The applicant is responsible for submission
of a complete marketing application to
maximize the efficiency of the review
process and reduce the need for multiple
cycle reviews.
• Effective and efficient management of the
review process is primarily an FDA
responsibility.
GRMP : Operational Principles (cont.)
• Active applicant involvement is important
during the review process.
• Good review management increases first
cycle approvals.
• Effective and timely communication
between the FDA and applicants enhances
the review process
GRMP: Fundamental Values
• Quality
• Efficiency
• Clarity
• Transparency
• Consistency
• Mom
• Apple Pie
• No Surprises
GRMP:
FDA Reviewing Steps
• Application completeness
• Pre-submission
• Application receipt
• Filing
• Review Planning
• Review
• Advisory Committee
• Wrap-up and Labeling
• Action
Guidance for Good Review Management
Principles for PDUFA Products
Application Receipt
CDR assigns NDA/BLA no.
EOP2 Mtg. Pre-NDA Mtg.
Presubmission
Filing
Fileabiliy Evaluation
Encourage Regular Mtgs.
Acknowledgement Letter
Scientific & Reg. Advice
Assignment of Review Team, Review Priority,
Signature Authority
Request Consults
Inform of Filing Deficiencies
Background
Packages
Submit
App &
User
Fee
Respond to Filing Deficiencies
Davi, 2005
Guidance for Good Review Management
Principles for PDUFA Products
Labeling
Negotiations
Filing
Final Division
& Office Eval.
& Action
AC Mtg.
Application Filed and Under Review
Primary & Secondary Review
IR/DR Letters
Schedule AC
AC Backgrounder,
Questions, & Prep.
Schedule AC
AC Preparations
Planned Amendments (safety update)
Respond to IR/DR Letters
Evaluate &
Incorporate
AC advice
Labeling
Negotiation
Labeling
Negotiation
Davi, 2005
The Shoe is on the Other Foot
Time for a Change?
Is the GRMP another annoying
regulatory/management
burden?
or
“An OPPORTUNITY disguised
as a PROBLEM*”?
J. Michael
Industry/FDA Statisticians:
Like an Old Married Couple?
Changes/Opportunities
• Can we change?
• What do we change?
• How do we change?
• Can we get better?
If I Ran the Zoo
If I Ran the Zoo:
Some of the Changes That I
Would Like to See
• Earlier/Better Communication: A Pre-NDA
Statistics Meeting
• Metadata Standards for Data and Analysis
• More Guidance Relating to Statistics for
Therapeutic Areas
• Required Electronic Submission using the
e-CTD (IND and NDA/CTD)
• Technology-supported Tools for the IR/DR
Process
• “Adult Conversation” -- Sponsors
submissions including reviews
GRMP: Earlier/Better
Communication
Labeling
Negotiations
Filing
Final Division
& Office Eval.
& Action
AC Mtg.
Application Filed and Under Review
Primary & Secondary Review
IR/DR Letters
Schedule AC
AC Backgrounder,
Questions, & Prep.
Schedule AC
AC Preparations
Planned Amendments (safety update)
Respond to IR/DR Letters
Evaluate &
Incorporate
AC advice
Labeling
Negotiation
Labeling
Negotiation
Davi, 2005
GRMP: A Pre-NDA Statistics Meeting
Application Receipt
CDR assigns NDA/BLA no.
EOP2 Mtg. Pre-NDA Mtg.
Presubmission
Filing
Fileabiliy Evaluation
Encourage Regular Mtgs.
Acknowledgement Letter
Scientific & Reg. Advice
Assignment of Review Team, Review Priority,
Signature Authority
Request Consults
Inform of Filing Deficiencies
Background
Packages
Submit
App &
User
Fee
Respond to Filing Deficiencies
Davi, 2005
Pre-NDA Statistics Meeting
• Why not include in existing Pre-NDA
meeting?
– Wrong audience – (The bored and the lost)
– No time – technical issues get moved to the
end of the agenda
– Timing - may be too early or too late
• Will it add value?
– Yes – it is necessary
• How will it affect reviewers/sponsors
processes and procedures?
Pre-NDA Statistics Topics
• Review proposed primary analyses
• Review proposed ADaM and SDTM
datasets
• Discuss what additional analyses and
ADaM datasets might be useful (“Review
Analysis Files”)
• Discuss submission of programs
– Analysis dataset creation programs
– Analysis generation programs
– Timing and functionality of submission of
programs
• Evaluate “test data” – “pre-e-Submission”
Pre-e-Submission Data and
Metadata
• Provides valuable feedback to sponsor
• Allows agency to test compatibility with
standard tools and databases
• Tests content and structure of metadata,
documentation and programs
• Identifies technical problems early
• Highlights possible areas of misunderstanding
and differences in interpretation
• “Tunes” in the reviewer
How to Provide “Clear
Communication”
• Use the eCTD to provide a common
organization and structure to the document.
– Makes components easy to find
– Allows standard tools to be used for navigation,
browsing
• Use ADaM and SDTM dataset standards and
metadata to describe the submitted data
– Common look and feel for data, both within and
across submissions
– Allows standard tools to be used for navigation,
browsing and analysis
Metadata Standards for Data
and Analysis
• Enable reviewers to understand, replicate,
explore, confirm, reuse, etc.
• Clear, unambiguous communication of
decisions, analysis and results
• Underlying principles:
– Can a reviewing statistician understand?
– Can a reviewing statistician efficiently:
• Quality Assure?
• Validate?
• Analyze?
Metadata Standards for Data and
Analysis
1.
2.
3.
4.
Analysis
Analysis Datasets
Analysis Variables
Programs
More Statistical Guidance:
General Principles & Therapy-Specific
GRMP: Motivates All of Us to Wear
the Same Better \Faster Shoes