Transcript CLINICAL DEVELOPMENT Track IA: A Focus on Drug Safety

CLINICAL DEVELOPMENT
Track IA: A Focus on Drug Safety
Dara Corrigan & Ben Martin
Arnold & Porter LLP
Government Oversight
Part I: Ben Martin
 Food & Drug Administration (FDA)
Part II: Dara Corrigan
 HHS Office of the Inspector General (OIG)
 Congress
 State Attorneys General, Other Agencies
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Part I: FDA Oversight
 What We Will Cover:
• Use of Pre-Marketing Clinical Studies in Developing a
Drug’s Safety Profile
• Post-Marketing Communication of Information in a Drug’s
Safety Profile
• Potential Consequences of Non-Compliance
 What We Will NOT Cover:
• Post-Marketing Surveillance/Pharmacovigillance
Activities
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Sources of Authority
 Current IND Regulations
• 42 C.F.R. pt. 312
 FDA Guidance Documents Related to Clinical Studies
• http://www.fda.gov/oc/gcp/default.htm
 ICH Guidelines Related to Clinical Studies
• http://www.ich.org/cache/compo/276-254-1.html
 Proposed Revisions to IND Regulations
• 68 Fed. Reg. 12,406 (Mar. 14, 2003)
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Drug Safety: The Big Picture
 Intense scrutiny recently on drug safety issues
• New players on the scene (addressed in Part II)
 Recent attention should not obscure the focus
historically given to drug safety issues
• In 1980s, three criminal prosecutions (Oraflex, Selacryn, &
Merital) alleging that drug companies withheld or failed to
report properly AE information
 Still, FDA has made drug safety a renewed priority
• Organizational restructuring, proposed revisions to its
regulations, new guidance documents, and other initiatives
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Developing a Safety Profile
 Three sources from which a drug sponsor acquires data
used to develop a drug’s safety profile:
 Controlled clinical studies (pre- and post-marketing)
 Post-marketing spontaneous AE reports from ANY source
• Clinical studies, literature, MedWatch, other contacts
from physicians/patients, lawsuit depositions
 Epidemiological analysis of safety database
 Clinical data have limited utility in identifying risks
• Average # total participants (investigational and placebo) (4000)
vs. low rate of occurrence of some serious risks (1/1000)
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Development of Clinical Safety
Information
Pre-Clinical Data
 Investigator’s Brochure
 Receipt, Evaluation, & Reporting of AEs
 Clinical Study Reports
 Product Labeling
 BOTTOM LINE: Process for developing safety information is
extremely complex; companies must have adequate organization
(personnel and procedures) in place to perform this function
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Learning from Experience
 Drug A: Majority of study population received short-
term dosing; ADE related to extended dosing was not
observed in pooled data
 Drug B: AEs treated individually as minor ADEs later
concluded to be symptoms of more serious syndrome
 Drug C: Phenomenon thought to indicate efficacy later
discovered to be a safety signal
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FDA’s Safety-Related Initiatives
 “Critical Path” Initiative
 “Drug Watch” for Emerging Drug Safety
Information
 Proposed Revision of AE Reporting
Requirements in IND/NDA Regulations
 Emphasis on “Risk Management”
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“Critical Path” Initiative
 The “Critical Path” refers to the therapeutic product
development process
 FDA’s March 2004 Report
• Addressed recent slowdown in innovative medical therapies
submitted for approval, despite advances in biomedical research
• Called for modernization of tools to access the safety and
effectiveness of potential new products earlier and more
accurately
 “Critical Path Opportunities List”
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“Drug Watch”
 Goal: Greater transparency and quicker access for
physicians and patients to safety information
 Draft guidance issued
 Dedicated page on FDA’s website
• FDA will post emerging drug safety information it is evaluating
• Could include data in which causation has not been established
 Drug Safety Oversight Board (DSB)
• Membership includes representatives from CDER offices, CBER,
CDRH, other HHS and non-HHS agencies
• Will designate information to be posted on “Drug Watch” and
track safety issues through resolution
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Reporting Requirements
 Proposed revisions:
• Would conform FDA’s reporting requirements to ICH
guidelines
• Would adopt terminology codifying the presumption
of a causal relationship between AEs and the drug
• Would expand the number of AE reports subject to
expedited reporting
• For post-marketing safety reports, would impose new
standard for investigating such reports
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“Risk Management”
“Risk management is an iterative process of (1) assessing a product’s benefitrisk balance, (2) developing and implementing tools to minimize its risks
while preserving its benefits, (3) evaluating tool effectiveness and
reassessing the benefit-risk balance, and (4) making adjustments, as
appropriate, to the risk minimization tools to further improve the benefitrisk balance.”
 Two Components:
• “Risk Assessment”
• “Risk Minimization”
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Pre-Marketing “Risk Assessment”
“Risk assessment consists of identifying and characterizing the nature,
frequency, and severity of the risks associated with the use of a product.”
 No “one size fits all” methodology
• Consider safety issues when designing and conducting
“efficacy” clinical studies
• Preclinical research, similarity to approved treatments, known
metabolic pathways?
• Population size and diversity, effect of dose and duration, potential
unexpected interactions?
• Adjust existing studies or design new studies based on new
information
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“Risk Assessment” (cont.)
 Adopt a standardized terminology for all studies
• Increase likelihood that data could be pooled by avoiding
mixing “apples with oranges”
• Verify coding of investigators
• Be consistent and accurate when coding AEs
 Follow-up with individuals who withdraw
 Analyze data thoroughly and “creatively” for expected
and unanticipated safety signals
• Play the “devil’s advocate”
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“Risk Minimization”
“The goal of risk minimization is to minimize a product’s risks while
preserving its benefits.”
 Prescription requirement, product labeling usually
adequate
• Consider accepting some “labeling risks” in face of unknown
drug risks
 Risk Minimization Action Programs (RiskMAPs)
• Drug-specific activity based on: nature and rate of known risk(s)
vs. benefit(s), population most at risk or likely to benefit most,
existence and risk(s)/benefit(s) of alternatives, reversibility of
AE(s), preventability of AE(s), and probability of benefit(s)
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RiskMAPs
 RiskMAP Elements
• Specific goal(s), stated in absolute terms
• Specific objective(s) that result in processes or behaviors likely to
achieve goal(s)
• Specific tool(s) to obtain objective(s)
• Method for evaluating effectiveness of tools
 RiskMAP Tools
• Should maintain widest access to product with least burden on
health system, while achieving risk minimization goal(s)
• Three basic categories
• Targeted Education & Outreach
• Reminder Systems
• Performance-Linked Access Systems
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Communication of Safety Profile
 Safety claims, like efficacy claims:
• Must not be “false or misleading in any particular”
• Must be “based on competent and reliable scientific evidence”
 Standard applies to all product labeling and advertising
 Oral statements attributable to sponsor must be
consistent with product label
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Consequences of Non-Compliance
 Withdrawal of IND/NDA
 Product Recall
 Product Seizure; Disgorgement of Profits
 Criminal Prosecution (company and individuals)
• Consent Decree; Fines
 Product Liability Litigation
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Summary of Part I
 UNDERSTAND COMPLEXITY OF PROCESS FOR
DEVELOPING A DRUG’S SAFETY PROFILE
 DESIGN CLINICAL STUDIES WITH SAFETY ISSUES
IN MIND
 ANALYZE DATA THOROUGHLY FOR SAFETY
SIGNALS; EXPECT THE UNEXPECTED
 CHARACTERIZE THE SAFETY DATA ACCURATELY
An ounce of prevention may be worth a pound of cure
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Part II:
OIG Oversight & Related Issues
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OIG’s Relationship to FDA
 Beginning in 2000, after the election of President Bush,
OIG did not focus on FDA
 Similar to OIG’s relationship with CMS, coordination
between OIG and FDA is not a routine practice
 OIG has traditionally focused on internal reviews of
FDA
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The 2005 OIG Work Plan
 11 FDA-related projects in the work plan
 Focus primarily on FDA’s internal processes,
e.g., monitoring post-marketing studies,
oversight of off-label drug promotion
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The Guidant CIA
 New focus on FDA regulatory requirements
 Analogous to OIG’s efforts with respect to drug
pricing issues
 New fraud theories likely to emerge
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Congressional Scrutiny of FDA
 Sen. Grassley’s focus on drug safety and
whistleblowers
 Sen. Grassley’s recent requests for information
related to Guidant
 Close relationship between Sen. Grassley and
OIG
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State Involvement . . . and the Media
June 3, 2004
SPITZER SUES A DRUG MAKER, SAYING
IT HID NEGATIVE DATA
 Data concerning negative clinical studies
 Theory of fraud in failing to tell doctors about negative
studies
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
Violation of New York consumer protection laws
Marketing data inconsistent with clinical studies
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COMPARISON OF POTENTIAL
DRUG SAFETY CASES TO THE
NEURONTIN PROSECUTION
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Aggressive Prosecution
 Neurontin Case

Ghost-written articles, trips, sham “educational” session and
grants

Example of the type of case that law enforcement likes—
potentially high damages and egregious conduct that could put
patients in jeopardy

Law enforcement uses legal theory
to recover money
 Very
high damages
linked to safety issues
 Thomas the Tank Engine
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Summary of Part II
 UNDERSTAND THE OIG/LAW ENFORCEMENT
VIEW OF THE PHARMACEUTICAL INDUSTRY
 REMEMBER THE SUCCESS OF LAW ENFORCEMENT
IN PURSUING THE IMPLIED CERTIFICATION
THEORY IN THE DRUG PRICING CASES
 DEVELOP A COMPREHENSIVE STRATEGY TO DEAL
WITH OIG/LAW ENFORCEMENT/CONGRESS/
STATES/MEDIA
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