Ginger Clasby - EVP, Business Development Ethical Considerations Associated with Investigator Payments & Patient Recruitment Ginger Clasby - EVP, Business Development Promedica International Costa Mesa, CA 714-799-1617 x 25 gclasby@promedica-intl.com

Popular Media Headlines What the Public Hears… “Drug Trials Hide Conflicts for Doctors” – NY Times, 1999 “Research for Hire: A Doctor’s Drug Studies Turn into Fraud” - NY Times, 1999 “Safety Concerns Halt Oklahoma Research” – NY Times, 2000 “Probes Targeted UCI Researcher” – LA Times, 2006 Points to make:

Background – Drug Development Climate 1990’s Forward Managed care’s strong emphasis on cost containment Increased industry emphasis on new drug development (to preserve/increase revenues) FDA reforms improve product review efficiencies Points to make:

Background - Drug Development Climate Industry’s Tactical Changes Med school research inefficiencies & patient enrollment timetables at odds with industry drug development timelines Industry develops private practitioner researchers & provides significant subject enrollment incentives Subject recruitment programs become increasingly sophisticated Points to make:

Sources: *Business Week, **Thomson CenterWatch Background - Drug Development Climate Interesting Statistics Industry investment in biomedical R&D increased from 32% in 1980 to 62% in 2000* Ave. time from IND to product approval dropped from 9.2 yr (1987 -1989) to 7.2 yr (1999-2001)** Investigator grants paid by PhRMA member companies increased from $3.2 billion (1993) to $12.2 billion (projected 2005)** Currently ~ 50,000 clinical trials taking place in US** Sources: *Business Week, **Thomson CenterWatch Points to make:

Typical Investigator Compensation Programs $$$$$$$$! Flat fee for each subject enrolled Covers cost of exams, treatments, staff time, overhead Bonuses paid for subjects enrolled within accelerated timeframe or above target numbers Finder’s fees or gifts for eligible subjects Medical writing support

Fast Track Systems: Industry Study Cost Trends, October 2003 Median US Cost/Patient $$$$$$$$! $9,800 Oncology trials $9,000 CNS trials $8,900 Anti-infective trials $4,500 Hematology trials $6,900 Endocrine trials $6,500 Gastrointestinal trials Fast Track Systems: Industry Study Cost Trends, October 2003

And So In the Rush to Enroll… Subject disqualification criteria may be overlooked Subjects may not be given full disclosure regarding trial objectives Subjects may not be given full disclosure regarding associated risks Subjects may be rushed to participate (without given time to think it over)

FDA does not have authority to review financial agreements Investigator Management FDA’s Toolbox Investigator Agreement – Form 1572 Financial Disclosure by Clinical Investigators FDA Bioresearch Monitoring Program – Clinical Sites, Sponsors, IRBs Application of sanctions in association with violative behaviors BUT - FDA does not have authority to review financial agreements Points to make:

Investigator Management Sponsor’s Toolbox Appropriate financial agreements Formal investigator training programs Study monitoring activities Internal auditing program Investigator termination from study Points to make:

Disregard to terms of agreement may be considered a criminal offense Investigator Management Investigator Agreement – FDA Form 1572 Commits to conduct study in accordance with protocol, FDA regulations & IRB conditions Commits to ensure informed consent requirements are met for all subjects (including controls) Commits to ensure that IRB reviews & approves study initially & on a continuing basis Disregard to terms of agreement may be considered a criminal offense Points to make:

Investigator Management FDA Investigator Financial Disclosure Applies to FDA-directed marketing applications only No financial arrangements where study outcome may affect investigator compensation Investigator has no proprietary interest in tested product Investigator has no significant equity interest in company Investigator has not received significant payments of other sorts Points to make:

Investigator Management FDA Bioresearch Monitoring Program Comprehensive program of on-site inspections & data audits to monitor all aspects of conduct & reporting of FDA-regulated research Inspections typically include clinical investigators, IRBs, sponsor &/or CRO Points to make:

Investigator Management FDA Sanctions Exclusion of questionable quality or integrity data Restriction of parties corrupting process through misconduct of malfeasance Notification to affected parties to implement corrective action Points to make:

Investigator Management Investigator Training Programs by Sponsor Provide detailed training on protocol implementation, study-related documentation & GCP Provide periodic training throughout study based on protocol or procedural amendments Training should be documented Points to make:

Address nonconformities appropriately Investigator Management Study Monitoring Activities by Sponsor Perform study initiation visits Perform interim study visits at appropriate intervals Perform appropriate study data review to ID protocol deviations, data inconsistencies, unreported safety events Review IRB submissions & responses Get technical Fill in the blanks Don’t be intimidated Address nonconformities appropriately Points to make:

Investigator Management Internal Audits by Sponsor Perform interim site audits by trained auditors uninvolved in study Be suspicious Expect fraud Points to make:

Investigator Management Investigator Termination by Sponsor Terminate shipment of investigational product Terminate investigator participation in study Report investigator to FDA Points to make:

The Role of the IRB Responsible for subject rights & welfare May insist on documentation of GCP training Reviews/approves study protocol & consent documents Reviews/approves most subject recruitment materials Reviews periodic study progress reports Reviews serious adverse event reports Points to make:

21 CFR 50.25 Consent Document Must Include Study involves “research”; explains research purpose Known risks/benefits Alternative treatments or procedures Extent to which confidentiality will be maintained Compensation & medical tx available in event of injury or illness Contact(s) to discuss study/subject rights Participation is voluntary Points to make:

21 CFR 50.25 Add’l Consent Document Language Tx may involve unforeseeable risks Anticipated circumstances when participation may be terminated w/o regard to consent Additional costs to subject for participation Consequences associated with withdrawal of consent Commitment to provide info on significant new findings during study that may affect willingness to participate Approximate # of subjects involved Points to make:

Subject Recruitment Programs WANTED – Study Subjects NOW! Study websites Call centers Professional referrals Community outreach In-office awareness materials Direct to patient media advertising – newspaper, radio, TV, bulletin boards, posters, flyers, etc. Financial compensation Points to make:

Subject Recruitment Programs Print Recruitment Advertising Should Include Name & address of investigator or research facility Condition under study or purpose of research Summary of criteria used to determine study eligibility Brief list of participation benefits (including cash) Time or other commitment required of participants Location of research & who to contact for further information Points to make:

Subject Recruitment Programs Research Subject Payments Payment amount & schedule must be approved by IRB Payment amount should be reasonable – not coercive Payment schedule should accrue - not contingent on study completion Points to make:

IRB Review of Subject Recruitment Materials Prohibited Practices Coercive language “New treatment” “Free medical treatment” “Make $100!” Stated or implied certainty of favorable outcome Claims of safety or effectiveness Claims of equivalence/superiority to other products Points to make:

Integrity In Corporate Practices What Industry Can Do Be thoughtful about patient eligibility criteria Be realistic with respect to enrollment timetable Provide appropriate investigator training & oversight Follow-up promptly & appropriately on complaints Points to make: