Ethical Considerations Associated with Investigator Payments & Patient Recruitment Ginger Clasby - EVP, Business Dev

1. 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

2. Popular Media HeadlinesWhat 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

3. Background – Drug Development Climate1990’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

4. Background - Drug Development ClimateIndustry’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

5. Background - Drug Development ClimateInteresting 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

6. 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

7. 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

8. And SoIn 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)

9. Investigator ManagementFDA’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

10. Investigator ManagementSponsor’s Toolbox • Appropriate financial agreements • Formal investigator training programs • Study monitoring activities • Internal auditing program • Investigator termination from study

11. Investigator ManagementInvestigator 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

12. Investigator ManagementFDA 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

13. Investigator ManagementFDA 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

14. Investigator ManagementFDA 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

15. Investigator ManagementInvestigator 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

16. Investigator ManagementStudy 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

17. Investigator ManagementInternal Audits by Sponsor • Perform interim site audits by trained auditors uninvolved in study Be suspicious Expect fraud

18. Investigator ManagementInvestigator Termination by Sponsor • Terminate shipment of investigational product • Terminate investigator participation in study • Report investigator to FDA

19. 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

20. 21 CFR 50.25Consent 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

21. 21 CFR 50.25Add’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

22. Subject Recruitment ProgramsWANTED – 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

23. Subject Recruitment ProgramsPrint 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

24. Subject Recruitment ProgramsResearch 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

25. IRB Review of Subject Recruitment MaterialsProhibited 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

26. Integrity In Corporate PracticesWhat 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