2. Best Practices for Investigator and Staff Selection/Training Lori Ann Post, PhD Associate Professor and Research Director Yale University School of Medicine A Presentation for Missing Data in Clinical Trials Forum March 16-17, 2015 Philadelphia

3. Patient Recruitment in Clinical Trials Written from personal experience Published in 1992 My first RCT 1995 to present Little change over 20 years, except web-based methods

4. Take Away Points Good employees do not necessarily translate into good recruiters but all recruiters must be good employees. Upfront training = better sampling so spend the money and effort on training. You cannot fix a failed enrollment Track overall recruitment rates by site and by recruiter daily. Discriminate when recruiting recruiters for variations in: –Context –Study Subject –Patient Population

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 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 Failure to recruit < 85% means your results are meaningless in Phase II-IV CTs 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 Recruiters 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. Context of Study Site Patients may not feel well. Patients may be facing difficult decisions. Travel to patient Social context of patient Medical Facilities Emergency Department Community Agency Location

11. Study Subject Recruiters must be comfortable with the subject matter e.g. HIV/Crack study Bunnies Recruiters must reflect the study subject No relationship between recruiters area of interest and success as a recruiter Some patients are terminally ill, have health conditions such as cancers, STI, or are embarrassed eg. Victims of violence

12. Training Recruiters Review study subject matter Review study local Review study protocol Visit the site Role playing with each other Piloting with real patients with observers Provide recruiters with a fail safe enrollment plan when something goes wrong and something always goes wrong. –E.g. patient is suicidal, too ill,

13. SET TARGETS Target: 90% Enrollment Timetable: 1 Week Failure to meet target needs to be remediated immediately HIT supports careful monitoring of recruiters Check recruitment rate by site weekly Check recruitment rate by investigator. Investigators below the 85% mark should receive additional training and observation to improve recruiting skills Failure to reach 85% in one week results in termination.

14. Appearance How should recruiters behave? Unremarkable Clean Non-judgmental Able to connect Boring Not a lot of make up No sexy attire – e.g. leather hot shorts Tattoos, ear spreaders and piercings – not likely. Traditional Uniform

15. Authority Name badgeClinical jacket

16. Know your population Yale New Haven Health 1/3 White 1/3 Latino 1/3 African American Recruiters should match target population – Some examples of prior studies Gangs Elderly Substance Addicts Battered Women

17. Train Recruiters on behavior Always introduce self to attendings and nurses before each shift Don’t interfere with healthcare Don’t hover around doctors, nurses, EMTs or other consults Stop interview if problem arises. Discuss with study coordinator

18. Train Recruiters on building rapport Get patient a blanket Get patient a drink if physician says ok Shake hands with patient and proxies Introduce topic Ask if there are questions Calm any fears

19. Safety of Recruiters Offsite Bring cell phone Send two recruiters if possible - - especially if it is a more risky topic. Send photo of recruiter Use phone and snail mail to confirm meeting Onsite Introduce yourself by first name but refer respectfully to patient as Mr., Mrs., Ms Don’t give out personal contact info Provide patient with study contacts and study phone and study email and address, IRB, PI

20. Example of Elderly Disability Study That Enrolled “On-Target” and “On-Time” Exceed Target of 600 (627) randomized patients on schedule Randomized an average of 60 patients per month for 24 months  Monitored compliance to assure studying drug

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

22. 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

23. 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

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

25. 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

26. 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

27. 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 !

28. 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.

29. 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.

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

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

33. Conclusion Methods used to encourage recruitment and retention were categorized as: –patient contact, patient convenience, support for recruiters, monitoring and systems, incentives, design, resources, and human factors. Interventions felt to merit investigation by respondents fell into three categories: training site staff, communication with patients, and incentives.