Guidance for Investigators Subject Recruitment & Retention

Guidance for Investigators Subject Recruitment & Retention Meeting of Investigators supported by the NHLBI Clinical Trials Planning Studies for Rare Thrombotic and Hemostatic Disorders (U34) program Sreelatha Meleth, PhD May 22, 2015 RTI International is a trade name of Research Triangle Institute. www.rti.org

CONTENTS 1. Getting Started Guidelines and Regulations International Conference on Harmonisation (ICH), FDA, NHLBI, AccrualNet 2. The Recruitment Plan Benchmarks Strategies Barriers to participation & subject withdrawal 3. Recommendations 4. References 2

GETTING STARTED The Investigator should be familiar with both International Conference on Harmonisation 1 and FDA guidelines for Good Clinical Practice and human subject protection. The Investigator should understand and apply the NIH/NHLBI guidelines and procedures for recruitment and retention. 3

International Conference on Harmonisation Good Clinical Practices Sections Covered by GCP: Institutional Review Board (IRB) Sponsor Protocol Regulatory Documents Investigator 4

International Conference on Harmonisation (ICH) Good Clinical Practices Investigator Responsibilities Under GCP Education and Experience Commensurate with disease process studied Comply with GCP Human subject protection Complete FDA 1572 (if applicable) Investigator Agreement (Form 1572 2 and 1572 Guidance 3 ) Adequate Resources Institutional support, appropriate personnel, etc. Medical Care Appropriate care available Communicate with IRB Submission and approvals, reporting obligations, etc. Comply with Protocol Other 5

FDA - CODE OF FEDERAL REGULATIONS (CFR) Human Subject Protection and Institutional Review Boards (IRB) The Code of Federal Regulations (CFR) is an annual collation of guidelines and rules that are published in the Federal Register. Title 21 (food and drug) and Title 45 (human subject protection) contain information that is essential for conducting clinical trials.) Title 21 Part 50 - Human Subject Protection 4 FDA regulated trials, requirements of informed consent, vulnerable populations (employees, prisoners, pregnancy, fetuses & neonates, children, etc.) Title 21 Part 56 Regulations & Guidelines for IRB 5 IRB organization, membership, and function Title 45 Part 46 DHHS Protection of Human Subjects 6 IRB functions, operations, and records, etc. 6

NHLBI Guidelines All studies for which the success of the overall grant or contract depends on the timely recruitment of human subjects should have accrual monitoring plans Principal Investigator (PI) and Institution Business Official (BO) will receive a letter reminding them of NHLBI s milestone accrual policy Thirty days to provide policy 7

NHLBI GUIDELINES Investigator develops recruitment plan with benchmarks (may collaborate with NHLBI) NHLBI review of benchmarks and compatibility with the budget Not uncommon for request for revisions Investigator attaches recruitment plan to the proposal submission Failure to submit the plan will likely delay the approval of NHLBI funding 8

NHLBI GUIDELINES NHLBI will review recruitment & retention 25%, 50%, and 75% of the projected recruitment period Suboptimal Performance Zones 7 : Yellow Zone: accrual > 75% but less than 100% NHLBI may increase monitoring frequency and may request a corrective action plan realistic enough to meet enrollment criteria by end of enrollment period. 9

NHLBI GUIDELINES Amber Zone - accrual is <75% but still at or above the minimally acceptable levels. The investigator may be required to submit an analysis of recruitment, identified barriers, and an associated corrective action plan. The NHLBI may also request a budget review. Red Zone - accrual is below minimally acceptable levels: <25% of the benchmark at the 25% time point OR <25% of the benchmark at the 50% time point OR <50% of the benchmark at the 75% time point NHLBI will consider restricting, Withholding or discontinuing funds. 10

NHLBI GUIDELINES Investigators applying for or having been approved for NHLBI funding are required to establish and monitor adherence to recruitment benchmarks 11

RECRUITMENT FIRST STEP STUDY DESIGN Previous presentation demonstrates the value of alternatives to the standard two arm RCT 12

Recruitment Review Preparatory to Research (RPR) Networking Advertisements Informed Consent Understanding Barriers 13

RECRUITMENT PLAN Review Preparatory to Research (RPR) Method to identify prospective study subjects prior to commencement of study enrollment. This may help Investigators to get a head start. With IRB approval, the Investigator may use the RPR to review patient information to evaluate inclusion/exclusion criteria, disease history, etc. Patient information obtained during this review must be destroyed once eligibility is determined. This information may not be used for any data to be collected for purposes of the research study. 14

RECRUITMENT PLAN Networking Others interested in the disease to be studied Find resources to conduct the clinical research Professional associations Attend conferences and conventions Advertisements Investigators may or may not find advertisements to be helpful for the study of rare hematological diseases. If used, it is important for the Investigator to understand the regulations regarding advertisement for research, such as: Information that may be included Where and how the advertisements displayed IRB approvals 15

RECRUITMENT PLAN Highlights of Recruitment Plan: 1. Determine Investigators role in recruitment 2. Evaluate feasibility of sample size and Availability of eligible participants 3. Establish referral sources and networking 4. Establish Benchmarks 5. Determine Strategies 6. Begin Enrollment 7. Evaluate effectiveness of recruitment and retention metrics 8. Adjust and implement recruitment & retention efforts accordingly 16

RECRUITMENT PLAN Understanding Barriers to Research Important in order to proactively reduce or eliminate impact from some of the following: Belief that standard therapy is best Lack of awareness of clinical trials Fear, distrust, suspicions, apprehensions, and skepticism Individual values and beliefs Logistical barriers Socioeconomic barriers 17

RECRUITMENT STRATEGIES: NETWORKING Accessing, Assessing and Utilizing Patient Databases Keeping Patients Informed and Engaged Partnering with Patient Support Groups 18

NETWORKING: UTILIZING PATIENT DATABASES Staff in specialty clinics crucial resource Their relationship with patients can help Buy in from them on the benefits of the proposed trial important Their access to patient data bases is invaluable Clinic patient database can be used to flag patients who may be recruit-able based on age, disease stage and / or stated interest in participating in trials Identify patients who have expressed interest in trials that address a specific research question Identify referring physicians and informing them about a prospective trial 19

NETWORKING : INFORMED & ENGAGED PATIENTS Top recruitment strategy for trials with rare disease (DeWard et al (2012) Make discussion of clinical studies routine part of clinic visit Using IRB/ REB approved materials (flyers, letters, emails, web postings) or add a Research Corner to newsletter to keep patients aware of current trials Live events to bring patients, especially those who have not been seen for a while, into clinics to talk about current thought and research directions 20

NETWORKING:PATIENT SUPPORT GROUPS Regular engagement with national and local support groups Developing educational materials about the trials and distributing to support group Social Media Advocacy groups using social networking more and more. Some success stories of the use of social networking to recruit patients For profit organization http://www.patientslikeme.com/ maybe a useful resource to identify patients 21

PLEASE NOTE.. Regardless of the recruitment strategy The Investigator (or any research study staff) may not approach a prospective subject until the research study is introduced to that patient by a member of his or her health care team. 22

STRATEGIES FOR RETENTION Assess Patients ability to participate Logistics & Support 23

CRUCIAL FIRST STEP: ASSESSING PATIENT S ABILITY TO PARTICIPATE Consent Process - An opportune time to begin relationship building between the study staff and the study subject. May result in better study compliance and higher retention rates. Review the requirements of the trial and ensure feasibility Number of assessments Duration Timing of Clinic Visits ( frequency & length) Identify potential obstacles Transportation sponsors sometimes provide funds or there maybe help from support groups Child Care Try to arrange based on convenience of childcare or identify resources such as support groups to pay for Travel / Vacation logistics plan ahead for sample collection / mailing etc. 24

RETENTION: LOGISTICS & SUPPORT Letters to employers or schools to explain the importance of the patient s participation in the study Determine whether family dynamics are a barrier to participation and attempt to help resolve them Assess compliance regularly Send reminder text message or email on day before visit Ensure timely reimbursement to subjects 25

AccrualNet 8 The National Cancer Institute s resource for the process of recruiting and retaining participants to clinical trials Integrating recruitment & retention during protocol design Guidance for selecting investigative site How to maximize enrollment and retention (https://accrualnet.cancer.gov/) 26

RECOMENDATIONS 1. Review and apply regulatory guidelines and regulations (e.g., ICH GCP, FDA, IRB) 2. Understand and follow the NHLBI requirements 3. Submit a recruitment plan with the proposal 4. Use AccrualNet as a source for information 5. Be creative with recruitment techniques or strategies. 27

REFERENCES 1. ICH Harmonised Tripartite Guideline - Guideline For Good Clinical Practice E6(R1). Available at: http://www.ich.org/fileadmin/public_web_site/ich_products/guidelines/efficacy/e6_r1/step4/e6_r1 Guideline.pdf. Updated June 10, 1996. Accessed 4-SEP-2013. 2. Food and Drug Administration, FDA Forms - 1572. Available at: http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm074728.pdf. Updated July, 2013. Accessed March 4, 2014. 3. Food and Drug Administration, FDA Forms 1572 Guidance. Available at: http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm223432.pdf. Updated July, 2013. Accessed march 4. 2014. 4. Food and Drug Administration. Title 21, Part 50 Protection of Human Subjects. Code of Federal Regulations. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=50. Updated January 6, 2013. Accessed September 4, 2013. 5. Food and Drug Administration. Title 21, Part 56-Institutional Review Boards. Code of Federal Regulations. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=56. Updated June 1, 2013. Accessed September 19, 2013. 6. U.S. Department of Health & Human Services. Title 45, part 46-Portection of Human Subjects. Code of Federal Regulations. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html. Revised January 15, 2009. Accessed September 19, 3013. 7. National Heart, Lung, and Blood Institute, Guidance and Implementation for Monitoring Adequacy of Accrual of Participants to NHLBI Supported Human Subject Research. Available at http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm. Accessed September 19, 2013. 28

REFERENCES 8. National Cancer Institute: Strategies, Tools and Resources to Support Accrual to Clinical Trials (AccrualNet ). Available at: https://accrualnet.cancer.gov/. Accessed September 4, 2013. 9. US National Library of Medicine National Institutes of Health, The National Center for Biotechnology Information Canadian Journal of Surgery. How to optimize patient recruitment. June 2010. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2878987/, Accessed 29-JAN-2014. 10. International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use. 10-JUN-1996. Available at ICH Harmonised Tripartite Guideline - Guideline For Good Clinical Practice E6(R1) SECTION 4.8, Accessed 4-SEP-2013. 11. U.S. Department of Health & Human Services, Can the preparatory research provision of the HIPAA Privacy Rule at 45 CFR 164.512(i)(1)(ii) be used to recruit individuals into a research study?. 14-MAR-2006. Available at: http://www.hhs.gov/hipaafaq/permitted/research/317.html, Accessed 20-SEP-2013. 12. DeWard, SJ, Wilson A, Bausell H, Volz AS and Mooney K, Practical Aspects of Recruitment and Retention in Clinical Trials of Rare Genetic Diseases: The Phenylketonuria (PKU) Experience, Journal of Genetic Counselling, (2014),23: 20-28 29