FDA POST-MARKETING STUDY COMMITMENTS FOR SAFETY

EVALUATION

Professor Peivand Pirouzi 2010

Food and Drug Administration Guidance Publications

Outline

• Public health burden of serious adverse drug events

• Reactions to drug safety systems • Pre-approval drug evaluation • Post-marketing safety evaluation • Potential solutions

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

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

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

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

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

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

• 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

Problems

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

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.

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

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

Progress Report

# of open commitments 1,281 pending 911 (71%) ongoing 173 (14%) delayed 39 (3%) submitted 157 (12%)

Federal Register, April 24, 2008

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)

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

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

Risk Management and Regulation

Risk Minimization Tools Risk reduction

Risk communication

Evaluation Testing the tools

Reassess benefit/risk balance

Adjustments Revise tools to improve

Benefit/risk balance

Benefit Risk Balance

Risk identification Risk Characterization Recognized benefit

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm

http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm129511.pdf

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

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