POSTMARKETING SAFETY STUDIES

1
POST-MARKETING SAFETY STUDIES -- NEED FOR
IMPROVEMENT
Curt D. Furberg, MD, PhD Professor, Division of
Public Health Sciences Wake Forest University
School of Medicine Winston-Salem, NC
2008
2
Outline

• Public health burden of serious adverse drug
  events
• Reactions to our drug safety system
• 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 20071671752-9
5
Sources of Drug Safety Information

• Pre-approval
• Phase 2 and 3 trials
• Post-approval
• Phase 4 trials
• MedWatch (N 422,889 in 2004)
• 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 and measure
  adverse events (AEs) with any pre-specified level
  of sensitivity
• The pre-market safety evaluation is often
  exploratory

7
Major Commentaries

• Drug Safety Improvement Needed in FDAs
  Postmarket Decision-Making and Oversight Process,
  United States GAO
• FDAs Monitoring of Postmarketing Study
  Commitments, DHHS Office of Inspector General,
  2006
• IOM report - Washington, DC National Academies
  Press, 2006.
• Congressional Hearings and Bills

8
Assessment of the US Drug Safety System (the IOM
Report)

• Recommendations (n25)
• A culture of safety (n5)
• The science of safety (n13)
• Regulatory authorities for drug safety (n4)
• Communication about safety (n2)
• Resources for the drug safety system (n1)

Institute of Medicine of the National Academies
Press, Washington, DC, 2006
9
(No Transcript)
10
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

11
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, surrogate efficacy and common side
  effects

12
Problems

• Insufficient patient safety information for
  decision-making (approval) the norm
• 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

13
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
• Vioxx exposed to 20 million patients
• Strained resources

14
Prescription Drug User Fee Act (PDUFA)

• In 1992, PDUFA authorized user fees to speed up
  the drug approval process
• FDA prohibited from using fees for all drug
  safety activities until 2002
• Under PDUFA, median review times declined -
  Review goals 90 of priority NDAs lt 6 months, lt
  10 months for standard
• US is now the first country of launch - 2 (1980)
  to 60 (1998)

15
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

16
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

17
Progress Report
Federal Register, April 24, 2008
18
Problems

• Approval decisions rushed
• Unmet commitments for safety trials the norm
• No penalties for failure to comply with
  post-approval study commitments
• FDA lacks enforcement tools to leverage
  compliance
• FDAs 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)

19
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

20
New Authority and Enforcement Tools

• FDA gets the authority to require postmarketing
  studies to identify or assess potential serious
  risks
• FDA can also initiate timely label changes or new
  postmarketing 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 20072982185-7
21
Access to Data and Active Surveillance

• FDA required to establish an active postmarketing
  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

Psaty Korn, JAMA 20072982185-7
22
Resources
Although the IOM committee expressed a strong
preference for increased resources from general
revenues, Congress retained the user-fee approach
and provided the agency with additional fee
revenues for drug safety, increasing from 25
million in 2008 to 65 million in 2012.
Psaty Korn, JAMA 20072982185-7
23
Opportunities at WFUBMC

• An established data warehouse at WFUBMC would
  allow studies to
• Investigate associations between genetic markers
  and treatment effects
• Improve quality of care (identification of
  patients taking disease-inducing drugs)
• Verify potential safety signals
• Collect long-term safety data

24
Conclusions

• Current drug safety system inadequate
• Modest improvements underway
• Proactive safety evaluations needed
• Database studies hold promise