2. Subject Recruitment & Retention Joyce A. Cramer Associate Research Scientist, Yale Univ School of Medicine President, Epilepsy Therapy Project Former National Project Director, VA Cooperative Studies Program

3. Patient Recruitment in Clinical Trials Written from personal experience Published in 1992 My first RCT 1977 My last RCT 2007 Little change over 30 years, except web-based methods

4. Take Away Points Have a plan Review it regularly Revise as needed to reach targets

5. 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)

6. 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?

7. 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

9. 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

10. 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 ⅩInadequate trials of other meds for this dx ⅩMultiple other medical issues ⅩCannot describe traumatic events ⅩFrequent admissions Ⅹ Unable to complete assessments independently ⅩCognitive ability ⅩDepression

11. 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

12. 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.

13. 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

14. 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. 

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

16. 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

17. 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

18. Site Progress Review The funnel effect… Site progress is monitored monthly –# pre-screened – # full screening – # evaluated for eligibility – # randomized – # assessments completed – # completed –Dropouts

19. Site Progress Review The 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

20. Site Progress Review The 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

21. 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 !

22. 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.

23. 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.

24. 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.

25. Take Away Points Have a plan Review it regularly Revise as needed to reach targets