The document discusses the FDA's post-marketing study commitments and the evaluation of drug safety, highlighting the significant public health burden from serious adverse drug events that result in approximately 100,000 deaths annually. It emphasizes the need for improved pre-approval and post-marketing safety evaluations, including more rigorous trials and proactive monitoring of safety signals. The document also underscores the challenges faced by the FDA concerning compliance with safety commitments, approval processes, and the necessity for better enforcement tools to ensure drug safety.

1. FDA POST-MARKETING STUDY
COMMITMENTS FOR SAFETY
EVALUATION
Professor Peivand Pirouzi
2010
Food and Drug Administration Guidance
Publications

2. Outline
• Public health burden of serious adverse
drug events
• Reactions to drug safety systems
• Pre-approval drug evaluation
• Post-marketing safety evaluation
• Potential solutions

3. Serious Adverse Drug Events
The Magnitude
• Approximately 100,000 drug-induced deaths/yr
or the fifth leading cause of death
• Serious adverse drug events account for an
estimated 3-6% of all hospital admissions
• Approximately 700,000 patients go to an
Emergency Department for drug-induced,
related adverse events
• Enormous human and societal costs

4. Serious Adverse Drug Events
Time Trends
• From 1998 through 2005, 2.6-fold
increase (from 35,000 to 90,000)
• Reported events increased faster than
number of prescriptions
• Biotechnology products the worst
• 300 drugs accounted for 87% of all
reported events
Moore et al., Arch Intern Med 2007;167:1752-9

5. Sources of Drug Safety Information
Pre-approval
Phase 2 and 3 trials
Post-approval
Phase 4 trials
MedWatch (N = 422,889 in 2004)
Canada Vigilance
International data

6. Asymmetry in the Evaluation
• Approval is contingent on evidence of
efficacy from well-designed and adequately
powered clinical trials
• Such trials are generally not designed to
test specific hypotheses about safety
• The pre-market safety evaluation is often
exploratory

7. Pre-Approval Phases
Phase 1 Studies: Drug cautiously given to small
group of healthy volunteers (absorption,
metabolism, excretion, early indications)
Phase 2 Studies: Beneficial and adverse effects,
and dosing in a few hundred patients with the
targeted condition
Phase 3 Trials: Comparative trials to determine
benefit vs. harm involving thousands of patients.
Intended for regulatory approval and marketing

8. Pre-Approval Requirements
• New drugs intended for long-term use in
non-life threatening conditions:
• A minimum of 1,500 patients exposed
- 300 to 600 for 6 months
- 100 for a year
• Limits good evidence to: symptomatic
improvement, efficacy and common side
effects

9. Problems
• Insufficient patient safety information for
decision-making (approval
• Limited safety data for populations most
likely to be future users (elderly, those with
co-morbidities)
• Inadequate FDA review of design of studies
for NDAs to achieve optimal detection of
safety problems
• Safety signals, even when recognized, often
not actively pursued

10. Consequences
• Unsafe drug approved for marketing
• More than half have serious adverse drug events detected after
approval
• 10% have Black Box Warning added
• Average number of patients exposed prior to
withdrawal approximately 4 million
• Example: Vioxx exposed to 20 million patients before wirthdrawal

11. Vioxx
• A nonsteroidal anti-inflammatory drug (NSAID) that has now been
withdrawn over safety concerns. It was marketed by Merck & Co. to treat
osteoarthritis
•
• Approved as safe and effective by the Food and Drug Administration
(FDA) on May 20, 1999
• On September 30, 2004, Merck voluntarily withdrew rofecoxib from the
market because of concerns about increased risk of heart attack and
stroke associated with long-term, high-dosage use.
• In the year before withdrawal, Merck had sales revenue of US$2.5 billion from
Vioxx.
• FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart
attacks, 30 to 40 percent of which were probably fatal, in the five years the drug
was on the market.

12. Solutions – Pre-Approval
• More drug safety information -
- Larger and longer trials
- More relevant study populations
• More thorough FDA review of protocol
design
• Proactive FDA pursuit of safety signals
• Conditional approval, if safety problems
suspected

13. Post-market Commitments
• Today, 73% of new drugs have
commitments agreed to by sponsors
• Often multiple commitments by product
• First commitment was for levodopa (1970)
Therapeutic breakthrough for
symptomatic relief; no cure, so concerns
for long-term safety

14. Progress Report
# of open commitments 1,281
pending 911 (71%)
ongoing 173 (14%)
delayed 39 (3%)
submitted 157 (12%)
Federal Register, April 24, 2008

15. Problems
• Approval decisions rushed
• Unmet commitments for safety trials
• No penalties for failure to comply with post-approval
study commitments
• FDA lacks enforcement tools to leverage compliance
• FDA’s historic post-marketing safety surveillance
system is passive, insensitive and incomplete
• High threshold of safety threat needed before FDA
considers action (black box or withdrawal)

16. Solutions
• Unmet safety commitments by
manufacturers should be grounds for drug
withdrawal
• Authority to impose meaningful penalties
for failing to conduct safety trials
• Proactive post-marketing safety surveillance
• Lower threshold for FDA actions

17. New Authority and Enforcement
Tools
• FDA gets the authority to require post marketing studies
to identify or assess potential serious risks
• FDA can also initiate timely label changes or new post
marketing studies
• FDA may also use Risk Evaluation and Mitigation
Strategies to ensure benefits outweigh risks
• Failure to comply may result in a determination of
misbranding or escalating civil penalties
Psaty & Korn, JAMA 2007;298:2185-7

18. Risk Management and Regulation
Benefit Risk Balance
Risk identification
Risk Characterization
Recognized benefit
Adjustments
Revise tools to improve
Risk Minimization Tools
Benefit/risk balance
Risk reduction
Risk communication
Evaluation
Testing the tools
Reassess benefit/risk
balance

19. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInfor
mationforPatientsandProviders/ucm111350.htm

20. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsa
ndProviders/ucm129511.pdf

21. Access to Data and Active
Surveillance
• FDA required to establish an active post marketing
risk identification system
• The system is to include 25 million patients by July
1, 2010, and 100 million by July 1, 2012
• FDA to develop validated methods for the timely
identification of adverse events and potential drug
safety signals
• Congress allocated $25 million per year ($65
million in 2012)
Psaty & Korn, JAMA 2007;298:2185-7

22. Conclusions
• Current drug safety systems need
improvement - underway
• Proactive safety evaluations needed
• Retrospective - Database studies hold
promise
• Optimal compliance through understanding
of strategies and tools