Best Practices in Meeting Your Postmarketing Study Commitments

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Best Practices in Meeting Your Postmarketing
Study Commitments

• Cyndi Verst-Brasch, Pharm.D., M.S.
• Vice President, Late Phase, Kendle

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Postmarketing Commitment (PMC) Overview

• PMCs on the Rise
• PMC Costs on the Rise
• PMC Study Types
• PMCs Per Drug Classification
• PMCs Per Therapeutic Classification

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During 1998-03, 73 of NME Associated with PMCs
Source Tufts Center for the Study of Drug
Development Impact Report, Volume 6, Number 4,
July/August 2004
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PMC Patients, Numbers, and Costs on the Rise
Source Tufts Center for the Study of Drug
Development Impact Report, Volume 6, Number 4,
July/August 2004
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PMCs Per Drug Classification
Source Tuft Center for the Study of Drug
Development Impact Report, Volume 6, Number 4,
July/August 2004
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PMCs Per Drug Class
Source Tuft Center for the Study of Drug
Development Impact Report, Volume 6, Number 4,
July/August 2004
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PMC Study Types-Safety/ADR Increased Frequency
Source Tuft Center for the Study of Drug
Development Impact Report, Volume 6, Number 4,
July/August 2004
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Best Practices in Meeting Your PMCs

• Timely Submissions
• Reporting Requirements
• FDAs Review of Reports

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Timely Submissions

• Protocols
• Postmarketing Study Protocols
• Accelerated approval clinical benefit
  studies-submitted prior to application approval
• Other PMCs-submitted within three months after
  the date of the postmarketing study commitment
• Protocols for studies requiring an IND should be
  submitted to the appropriate IND, with copy of
  the cover letter to NDA, ANDA, or BLA
• Protocols for studies not requiring IND (e.g.,
  toxicology studies) should be submitted to NDA,
  ANDA, or BLA
• In all cases, final protocol should be
  accompanied by
• Proposed timelines for patient enrollment (or
  initiation of animal study), completion of study,
  and submission of the final report to FDA
• Guidance for Industry Reports on the Status of
  Postmarketing Studies-Implementation of Section
  130 of the Food and Drug Administration
  Modernization Act of 1997

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Reporting Requirements

• Postmarketing Study Status Reports
• Status reports for both human drugs and
  biological products should be submitted annually
  until a final study report submitted to FDA (21
  CFR 314.81(b)(2)(vii))
• Annual study reports are due within 60 days of
  the anniversary of the NDA, ANDA, or BLA approval
  in US once completed
• The FDA will notify Sponsor when the study
  commitment has been met
• Final Reports
• Submitted as a separate submission to NDA, ANDA,
  or BLA in original and 2 copies with form FDA
  356h and a cover letter attached
• Guidance for Industry Reports on the Status of
  Postmarketing Studies-Implementation of Section
  130 of the Food and Drug Administration
  Modernization Act of 1997

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Timeframes for FDAs Review of Reports

• Annual Status Reports
• FDA will review reports within three months of
  receipt
• If FDA disagrees with the categorization of the
  status of the study, Sponsor will be contacted
  for clarification
• Study Final Reports (FRs)
• Many FRs are submitted with supplemental
  application to modify product labeling
• FDA will review under established PDUFA timelines
• Those FRs not submitted for product labeling
  modification, the FDA will review within 1 year
  of receipt
• Guidance for Industry Reports on the Status of
  Postmarketing Studies-Implementation of Section
  130 of the Food and Drug Administration
  Modernization Act of 1997

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Safety/Pharmacovigilance-Focused PMCs

• Recent Examples of Safety-Focused PMCs
• Safety-Focused Study Considerations
• Operational Considerations
• Regulatory Considerations

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PMC Study Types-Safety/ADR Increased Frequency
Source Tuft Center for the Study of Drug
Development Impact Report, Volume 6, Number 4,
July/August 2004
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2005 Safety-Focused PMCs Examples
Drug Class Approval Date Commitment Description
Anti-Diabetic 03/16/2005 A multicenter, open-label, observational study to prospectively collect data that characterize the use of following introduction into the marketplace. This study will include non-targeted prescribers in the same approximate proportion as targeted prescribers.
Vaccine 01/14/2005 Conduct an open label, descriptive, epidemiological, safety surveillance study that enrolls 20,000 subjects or enrolls for 1 year, whichever results in the larger enrollment.
Hepatitis B Vaccine 03/29/205 a large simple safety study to assess the major clinical outcomes of death, progression of liver disease, and cancer in a broad population of HBV-infected patients using compared to standard of care over a period of 5 to 10 years of follow-up...

• http//www.accessdata.fda.gov/scripts/cder/pmc/ind
  ex

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Safety Study Considerations

• Objectives
• Identify previously unrecognized safety issues
  (hypothesis-generation)
• Investigating possible hazards (hypothesis-testing
  in order to confirm causal association)
• Confirming the expected safety profile under
  marketed conditions
• Design
• Prospective, open-label, observational, possible
  cohort comparison, real world,
  pharmacoepidemiological
• Inclusion/Exclusion Criteria
• Limited criteria representative of general
  population of intended users
• Intercurrent illnesses and concomitant
  medications permitted
• Statistical Plan
• Valid analyses with sample size justifications
  (typically large N)

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Safety Study Operational Considerations

• Investigator Mix
• Research savvy and community-based sites
• Flexible, simple approaches (protocol CRF
  design, data collection, data querying, etc.)
• Training of paramount importance (IM,
  web-conferencing, CD-ROMs, etc.)
• Drug Safety Monitoring Board (DSMB), Scientific
  Advisory Board (SAB) to help develop and monitor
  study
• Technology Mix
• Handling of voluminous data sets
• Simple, flexible (paper, fax, EDC)
• Real-time safety data availability
• Collection of patient-reported outcomes

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Safety Study Operational Considerations

• Cost Containment
• Site Management
• On-site monitoring
• Central monitoring
• (ICH/GCP 5.18.3 Extent and Nature of Monitoring)
• Remote monitoring
• Clinical Data Management
• Critical data focus
• Scientific programming of edit checks
• Data cleaning querying
• Project Management
• Efficient integrative technology
• Automated processes

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Safety Study Regulatory Considerations

• Office of Inspector General (OIG)
• Research Funding
• Post-marketing research activities should be
  especially scrutinized to ensure that they are
  legitimate and not simply a pretext to generate
  prescriptions of a drug
• Payments for research services should be fair
  market value for legitimate, reasonable, and
  necessary services
• Research contracts that originate through the
  sales or marketing functionsare particularly
  suspect
• OIG Compliance Program Guidance for
  Pharmaceutical Manufacturers, Federal Register,
  Vol.38, No. 86, May 5, 2003

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Safety Study European Regulatory Considerations

• Post-Authorisation Safety Study (PASS) Guidelines
• To provide studies of greater scientific
  credibility that could withstand peer-review
  scrutiny
• A formal investigation conducted for the purposes
  of assessing clinical safety of marketed
  medicines in clinical practice
• Pan-European guidance
• Very similar to Safety Assessment Marketed
  Medicines (SAMM)
• Developed in UK in 1994 by working group
  comprised of MCA (now MHRA), CSM, ABPI, BMA, and
  RCGP
• EMEA Notice to Marketing Authorisation Holders
  Pharmacovigilance Guidelines, 29 January 1999

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Safety Study European Regulatory Considerations

• Post-Authorisation Safety Study (PASS) Guidelines
  (cont.)
• The design of study depends on objectives
  (observational cohort studies, case-control
  studies, case surveillance, and clinical trials)
• Patients should be representative of general
  population of product users
• Regulatory requirements
• Sponsors encouraged to discuss draft protocol
  with authority
• Must submit finalized protocol and any proposed
  communications to doctors one month before study
  commencement
• Brief report on study progress every six months
• Ethic Committee approval required if patients are
  approached for information, additional
  investigations are performed, or treatment
  randomization is required
• EMEA Notice to Marketing Authorisation Holders
  Pharmacovigilance Guidelines, 29 January 1999

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Safety Study European Regulatory Considerations

• Post-Authorisation Safety Study (PASS) Guidelines
  (cont.)
• An independent advisory board should be appointed
  to oversee the study
• Decision to prescribe drug as part of routine
  clinical practice before patient is entered into
  study
• Study payment to doctors to recompense for time
  and expenses should be fair
• EMEA Notice to Marketing Authorisation Holders
  Pharmacovigilance Guidelines, 29 January 1999

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Summary

• PMCs are on the rise and likely here to stay
• Timely submissions of PMC protocols and study
  status reports are warranted
• Expectations from Agency delineated in guidance
  documents
• Safety/ADR postmarketing studies have been
  employed with increasing frequency
• Protocol, operational and regulatory
  considerations of large, pharmacoepidemiological
  studies
• Useful insight contained within the European
  Post-Authorisation Safety Study (PASS) Guidelines

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