Recruitment and Remuneration of Phase I Subjects

May 14, 2014

Presented by:Theresa Cummings RN, MSSchulman Associates IRB

About Schulman Associates IRB

Established in 1983

US and Canadian boards fully accredited by the

Association for the Accreditation of Human Research

Protection Programs (AAHRPP)

Superior audit history with FDA—five consecutive audits

with no findings.

21 CFR Part 11 compliant electronic systems

Compliant with FDA, OHRP and Health Canada

requirements

About Schulman Associates IRB

Full board meetings five days a week

Dedicated daily expedited review of qualifying minimal

risk protocols

Phase I Board with streamlined processes tailored to

Phase I timelines

Oncology Review Board for all phases of oncology

research

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CROs, institutions and sites

About Schulman Associates IRB

Clinical Quality Assurance (CQA) and Human Research

Protection (HRP) consulting services provided by

Provision Research Compliance Services

www.provisionrcs.com

Provision is a joint venture between

Schulman Associates IRB and Falcon Consulting Group

www.sairb.com

About Today’s Presenter

Theresa Cummings RN, MS

Schulman Associates IRB BS in Nursing from Georgetown University

MS in Nursing Education from University of

Maryland

Extensive experience on the operational side of

clinical research

• CCRC in CNS phase I-III trials for 4 years

• Clinic Director for over 12 years for several

Phase I clinics

Joined Schulman Associates in early 2013

Objectives of this webinar include:

Review regulatory guidelines and their application when recruiting subjects into Phase I trials

Differentiate between clinical practice and research

Review principle of Justice as it relates to recruitment of subjects

Review regulatory guidelines and their application when paying subjects for participating in a Phase I trials

Introduction to Recruitment and Remuneration

Two key regulations govern how advertising and

recruiting of subjects can occur

• 21 CFR 56.111(a)(3)

• 45 CFR 46.111(a)

These regulations outline expectations of sites involved

in the conduct of research as well as IRBs overseeing

research.

The IRB is your experienced guide to help ensure

these regulations are followed.

Recruitment of Phase I Subjects/Volunteers

Clinical Practice refers to interventions that are

designed with the sole purpose of enhancing

well-being and has a reasonable expectation of

success.1

Physicians swear to follow the Hippocratic Oath

and uphold the ethical principles of beneficence

and non-maleficence – ensuring benefits of care

outweigh the possible burdens.

Purpose of Clinical Practice

1. Extracted from the Belmont Report

http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html#xbound

Research is an activity designed to test a hypothesis, permit conclusion to be drawn and thereby develop or contribute to generalizable knowledge.1

Phase I research specifically:

• Conduct tests on a molecule to establish safety and tolerability data using study designs such as MTD, QT studies, DDI studies and Food effect studies.

• Generally conducted in Healthy Normal Volunteers (HNV), although more and more studies are designed with a patient arm or include a limited subset of patients.

Purpose of Research

1. Extracted from the Belmont Report

http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html#xbound

Therapeutic Misconception – occurs “when a research

subject fails to appreciate the distinction between the

imperative of clinical research and of ordinary

treatment and therefore inaccurately attributes

therapeutic intent to research procedures.”1

Similarities and Differences

(1) Clinical Trials and Medical Care: Defining the Therapeutic Misconception

Gail E. Henderson, Larry R. Churchill, Arlene M. Davis, Michele M. Easter, Christine

Grady, Steven Joffe, Nancy Kass, Nancy M. P. King, Charles W. Lidz, Franklin G. Miller,

Daniel K. Nelson, Jeffrey Peppercorn, Barbra Bluestone Rothschild, Pamela Sankar,

Benjamin S. Wilfond, Catherine R. Zimmer

PLoS Med. 2007;4(11):e324

When the form is signed?

At the time the ad is placed?

When the subject arrives at the clinic?

When the phone rings in the recruitment center?

When Does Consent Begin?

Advertising methods for a single study should be spread across a diverse platform to ensure equal opportunity exists for all to be exposed to the ads and respond. If only the internet will be used, you will exclude opportunity to many.

Belmont Report emphasizes fairness in distribution of burden and benefit of research.

Principle of Justice & the Belmont Report

Key direct advertising modalities include

• Newspaper, radio, TV, flyer, bulletin board postings

• Database e-blasts and warm calls

• Social media outlets (Twitter, web pages, Facebook)

Key with social media: same rules apply. Cannot place undue

influence on a person or emphasize the stipend in the

recruitment materials.

Use of testimonials in advertising: does it provide information

that prospective subjects need to determine their eligibility and

level of interest?

How Can You Recruit for Phase I HNV and Patient Populations?

When you want to consider something outside

the box to facilitate recruitment, communication

and providing the context of the concept under

consideration is key.

• Context memo

• Consultation /draft review

Communication with IRB Is Key

Do’s• Include name and address of the

facility and/or PI

• Indicate the condition under study

• List participation benefits (if any)

• Time and other commitment

requirements

• Whom to contact for more

information

• Keep size and type of font the

same throughout the ad

Print Advertising (Flyers, Ads, Web Postings, etc.)

Don’ts• Advertise “Free Medical

Treatment”

• Use terms such as “New

Medication” or “New Treatment”

without explaining it as

investigational

• Explicitly or implicitly claim the

drug is safe or effective or

equivalent or superior to any other

drug

• Use misleading language

• Highlight payment – flashing $$

Internal databases – characterize individuals who call-in on numerous data points (age, gender, medical history, etc.) in response to an ad to establish eligibility for a specific study or for future consideration.

The more sensitive the information being loaded into the database, the tighter the site’s procedures must be to protect human subjects.• What happens if a caller hangs up?• Names of non-eligible stored for later?• Paper notes – shred or store?

Use of Internal Databases for Recruitment

External databases – from pharmacies or

purchased mailing lists limit recruitment efforts

to a much more narrow focus (only those taking

metformin, for example).

• Materials being mailed to subjects must be IRB approved

Use of External Databases for Recruitment

Development of a program to expand database must

be described in detail for IRB consideration as part of

review of generic recruitment materials.

• Lunch and Learn concept

• Free giveaways for those who attend or complete database form

Generalized Database Expansion Is Possible

Private Practice Physicians CAN serve as a consultant

on a study (for the site or the sponsor) and get paid

for these services (or other bona fide professional

services). They can also refer their patients to

participate in a study.

Private Practice Physicians CANNOT get paid a fee

SOLELY for the referral.

Physician Involvement in Research

Consultant vs. Sub-Investigator

• If they will be conducting study related procedures

that support an endpoint of the study, sub-investigator

is the safest route to take (i.e. Lumbar puncture for

collection of CSF for Pharmacokinetic evaluation).

• If they will be treating emergent side effects that may

or may not ever occur then consult would make more

sense (i.e. Dermatologic exam of a rash or liver

biopsy and w/u for a DILI).

Physician as Sub-Investigator

Payment of a stipend is NOT considered a benefit of

participation in a research trial.

Payment of a stipend for participation IS considered

a recruitment incentive.

Payment of a stipend CANNOT be coercive or present

undue influence on a person to say yes to the

research.

Remuneration of Phase I Subjects

Time and Inconvenience

• Removing the individual from their daily

routine & confinement for a period of

time – sometimes extended

• Prohibiting them from earning money in

another way

• Restricting access to certain things

(smoking, alcohol, etc)

• Requiring certain dietary limitations

(high fat, low fat, no grapefruit, etc.)

What Are You Paying For?

Study specific procedures

• Cannot pay extra to the arm of the study getting

IV dosing vs. SQ or PO dosing

• Cannot call out payment for “high risk” procedures

(muscle biopsy or lumbar puncture as examples)

What Are You Not Paying For?

Should be avoided if possible in Phase I research.

Follow due diligence in your planning stages to ensure

your initial submission includes stipend amounts that

are commensurate with the effort you think it will take

to recruit the study.

Very few “do-overs” in Phase I for recalculation of

stipend later if recruitment is suffering.

Alteration of Stipend Amounts After IRB Approval

FDA is accepting of study completion payments;

HOWEVER, the amount must be reasonable and not

unduly influence subjects to stay in the study when they

otherwise would have withdrawn.

IRB Considerations:

• Ideal to accrue payment, even completion bonuses

• IC must be reflective of amount and distribution plan

• Interim payments are acceptable and standard for studies of long duration

Study Completion Payments

Transportation• Airfare

• Taxi vouchers

• Pay for mileage

Housing outside of protocol requirements• Extended stay in the clinic for logistic reasons (other than

safety concerns)

• Hotel room nearby – discounted rate

IRB considerations:• Offered to all subjects

• Communicated during initial submission

• What services will include (max. value of each)

Fair and Equitable Services Offered to All

Recruitment should focus on information subjects need to determine interest in this study and eligibility

Recruitment should be multifaceted and share benefit and burden of research to all

Recruitment methods may differ for Phase I studies and later phase studies

Remuneration amounts should be consistent and fair for time and inconvenience associated with participation

Communicate with your IRB

Conclusion

Recruitment and Remuneration of Phase I Subjects

May 14, 2014

Presented by:Theresa Cummings RN, MSSchulman Associates IRB