Ethical Considerations Associated Ethical Considerations Associated with Investigator Payments & Patient with Investigator Payments & Patient RecruitmentRecruitment

Ginger Clasby - EVP, Business DevelopmentGinger Clasby - EVP, Business DevelopmentPromedica InternationalPromedica International

Costa Mesa, CACosta Mesa, CA714-799-1617 x 25714-799-1617 x 25

gclasby@promedica-intl.comgclasby@promedica-intl.com

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

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

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

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

Typical Investigator Compensation Programs$$$$$$$$!

• Flat fee for each subject enrolledCovers 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

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 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)

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

Investigator ManagementSponsor’s Toolbox

• Appropriate financial agreements• Formal investigator training programs• Study monitoring activities• Internal auditing program• Investigator termination from study

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

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

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

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

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

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 technicalFill in the blanks

Don’t be intimidatedAddress nonconformities appropriately

Investigator ManagementInternal Audits by Sponsor

• Perform interim site audits by trained auditors uninvolved in study

Be suspicious

Expect fraud

Investigator ManagementInvestigator Termination by Sponsor

• Terminate shipment of investigational product• Terminate investigator participation in study• Report investigator to FDA

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

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 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

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

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

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

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

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