1. Ginger Clasby - EVP, Business Development
Ethical Considerations Associated with Investigator Payments & Patient Recruitment
Ginger Clasby - EVP, Business Development
Promedica International
Costa Mesa, CA
x 25

2. 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:

3. 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:

4. 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:

5. 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 ( ) to 7.2 yr ( )**
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:

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. 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

8. 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)

9. 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:

10. 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:

11. 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:

12. 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:

13. 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:

14. 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:

15. 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:

16. 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:

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

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

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
Points to make:

20. 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. 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:

22. 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:

23. 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:

24. 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:

25. 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:

26. 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: