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)CongressState 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