Best Practices in Meeting Your Postmarketing Study Commitments

1. Best Practices in Meeting Your Postmarketing Study Commitments Cyndi Verst-Brasch, Pharm.D., M.S. Vice President, Late Phase, Kendle

2. Postmarketing Commitment (PMC) Overview • PMCs on the Rise • PMC Costs on the Rise • PMC Study Types • PMCs Per Drug Classification • PMCs Per Therapeutic Classification

3. 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

4. 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

5. PMCs Per Drug Classification Source: Tuft Center for the Study of Drug Development Impact Report, Volume 6, Number 4, July/August 2004

6. PMCs Per Drug Class Source: Tuft Center for the Study of Drug Development Impact Report, Volume 6, Number 4, July/August 2004

7. 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

8. Best Practices in Meeting Your PMCs • Timely Submissions • Reporting Requirements • FDA’s Review of Reports

9. 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

10. 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

11. Timeframes for FDA’s 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

12. Safety/Pharmacovigilance-Focused PMCs • Recent Examples of Safety-Focused PMCs • Safety-Focused Study Considerations • Operational Considerations • Regulatory Considerations

13. 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

14. 2005 Safety-Focused PMCs Examples http://www.accessdata.fda.gov/scripts/cder/pmc/index

15. 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)

16. 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

17. 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

18. 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 functions…are particularly suspect” OIG Compliance Program Guidance for Pharmaceutical Manufacturers, Federal Register, Vol.38, No. 86, May 5, 2003

19. 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

20. 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

21. 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

22. 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