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Real people. Real results.®
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
FDA’s Review of Reports
Real people. Real results.®
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 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
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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 HBVinfected 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/index
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Safety Study Considerations
• Objectives
– Identify previously unrecognized safety issues (hypothesisgeneration)
– 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, CDROMs, 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
functions…are 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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