Subject Recruitment& Retention

Joyce A. CramerAssociate Research Scientist, Yale Univ School of

MedicinePresident, Epilepsy Therapy Project

Former National Project Director, VA Cooperative Studies Program

Patient Recruitment in Clinical Trials Written from personal experience

Published in 1992

My first RCT 1977My last RCT 2007

Little change over 30 years, except web-based methods

Take Away Points

•Have a plan•Review it regularly•Revise as needed to reach targets

3 PLAGUES:Endemic to clinical trials

Recruitment

Retention

Finding appropriate patients Keeping them active for the duration of the study

Baseline

Appropriate BL assessments (reduce placebo responders)

RECRUITMENT IS A SCIENCE

• Like Sisyphus, Researchers are doomed to start at the bottom if they do not learn how to develop and implement a recruitment strategy

• Recruitment problems can severely affect a clinical trial if not well managed

How do I do it?

ELEMENTS OF A RECRUITMENT STRATEGY

• Methods• Chart review• posters• Letters to pt & MD• calls• direct advertising• internet

• Sources• your own patients• referrals from within

your center• referrals from outside

your center• direct contacts with

patients

The Strategy

•Develop a recruitment strategy NOW

–Start screening quickly and continue to screen until the study closes

Study Sponsor / Principal Investigator

• Need personal ‘ownership” of the study

• Need to connect with every Investigator & Coordinator

• Need to train all site staff– Learn at start which sites have

weaknesses; monitor closely

RECRUITMENT CONSIDERATIONS for Sites

Current non-response to another med for this dx

Willing to try another type of medication

Able to describe events

Able to attend follow-up for 6 months

Ⅹ Inadequate trials of other meds for this dx

Ⅹ Multiple other medical issues

Ⅹ Cannot describe traumatic events

Ⅹ Frequent admissions

Ⅹ Unable to complete assessments independently

Ⅹ Cognitive ability

Ⅹ Depression

Avoiding high placebo responses

• Avoid inappropriate baseline data– If patients are having an exacerbation of

symptoms/events when enrolled, all will improve.

• Insist on stability before enrollment (e.g., sev months)

– If recruiters explain too much about eligibility criteria, patients may endorse what they think you want to hear

• Overstate number of symptoms/events

SET TARGETS

• Target: 400 patients

• Timetable: 24 Months

• Sites: 20• Site Goal:

– 20 patients total – 10 patients per year

• Low enrollment means the site never learns the protocol!

• Every site must enroll 1 patient every month for the next 2 years– Sites unable to meet these

requirements will be placed on probation.

– Rapid improvement will be necessary to demonstrate capacity to remain a study site.

– Non-performing sites will be replaced.

0

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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Cumulative Total Monthly Total

Example of a Study That Enrolled “On-Target” and “On-Time”

Exceed Target of 600 (627) randomized patients on schedule

VA CSP #425

Randomized an average of 25 patients per month for 24 months, final month = 46

Monitored compliance to assure studying

drug

0

20

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ENROLLED

Re-Engage Sites in Your Study

Reach Target (120) three months after probation

Re-engage Sites

at Month 14 (N=60)

Very low recruitment for >12 months; Study “on probation” at month 12.

Yes, it is a “battle” to the end, with many headaches and casualties

Case Report Forms

• If site staff do not keep pace with case report forms every day, they pile up.

• This impedes recruitment because they don’t have time to be searching

Conference Calls & Problem Calls

• Schedule monthly conference calls to continue training, inform everyone about updates.

• Urge sites to call with any questions.– If you cannot find an

answer in the Operations Manual within 5 minutes, call the monitor

Site Progress ReviewThe funnel effect…

• Site progress is monitored monthly– # pre-screened– # full screening– # evaluated for eligibility– # randomized– # assessments completed– # completed– Dropouts

Site Progress ReviewThe funnel effect of Lasagna’s Law for Tx studies

• Monitor progress monthly– 10 pre-screened– 5 full screening– 4 evaluated for eligibility– 3 randomized– 2 assessments

completed– 1 completed– Minus dropouts

Site Progress ReviewThe funnel effect of Cramer’s Corollary for non-Tx studies

• Monitor progress monthly– 40 pre-screened– 5 full screening– 4 evaluated for eligibility– 3 randomized– 2 assessments

completed– 1 completed– Minus dropouts

Set Targets and Timelines

• Example:• Have 24 months to

enroll 400 patients.• 20 sites=20

patients/site• 10 patients/yr/site• Every site needs 1

enrollment every month for the next 2 years

Every month costs $$

There should be no extensions !

Mistakes Happen…

• Subjects erroneously considered not eligible

• Subjects erroneously considered eligible

• Subjects complete screen and decline randomization

• Subjects enroll, attend one visit (or take one dose of study medication) and withdraw

• Subjects complete part, but not all of the study before withdrawing

• BUT..analyses must consider every person.

Consider patient burden

to enhance recruitment

• Schedule appointments at the convenience of the patient - not you!

• Don’t overwhelm patients with too much at one time.

• Give patients a coffee/lunch break as needed– Provide vouchers for food,

parking– Place for family to wait

• Check self-report forms for completion BEFORE the patient leaves for the day.

Recommendations:

• INCLUDE RECRUITMENT MATERIALS IN INITIAL IRB SUBMISSION

– Update immediately when plan changes– Consider national and local needs

• All sponsor and site staff should perform a full “mock” evaluation with all CRFs

• This will give everyone the “look and feel” of issues for sites and patients.

Take Away Points

•Have a plan•Review it regularly•Revise as needed to reach targets