CLINICAL DEVELOPMENT Track IA: A Focus on Drug Safety

1. CLINICAL DEVELOPMENTTrack IA: A Focus on Drug Safety Dara Corrigan & Ben Martin Arnold & Porter LLP

2. 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

3. 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

4. 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)

5. 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

6. 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)

7. 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

8. 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

9. 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”

10. “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”

11. “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

12. 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

13. “Risk Management” “Risk management is an iterative process of (1) assessing a product’s benefit-risk 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 benefit-risk balance.” • Two Components: • “Risk Assessment” • “Risk Minimization”

14. 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

15. “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”

16. “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)

17. 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

18. 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

19. 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

20. 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

21. Part II:OIG Oversight & Related Issues

22. 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

23. 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

24. 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

25. 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

26. State Involvement . . . and the Media • Data concerning negative clinical studies • Theory of fraud in failing to tell doctors about negative studies • Violation of New York consumer protection laws • Marketing data inconsistent with clinical studies June 3, 2004 SPITZER SUES A DRUG MAKER, SAYING IT HID NEGATIVE DATA

27. COMPARISON OF POTENTIAL DRUG SAFETY CASES TO THE NEURONTIN PROSECUTION

28. 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 theoryto recover money • Very high damageslinked to safety issues • Thomas the Tank Engine

29. 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