Enrollment Challenges in Cardiothoracic Surgical Clinical Trials

Transcription

1 Enrollment Challenges in Cardiothoracic Surgical Clinical Trials Robert E. Michler, M.D. Surgeon-in-Chief Samuel I. Belkin Chair Professor and Chairman Department of Surgery Department of Cardiothoracic Surgery Co-Director, Montefiore-Einstein Heart Center

2 Patricia Friedmann, M.S. Director Clinical Research Design & Biostatistics Departments of Surgery & Cardiovascular and Thoracic Surgery Albert Einstein College of Medicine Deborah Ascheim, M.D. Associate Professor Dept of Health Evidence & Policy / Cardiovascular Institute Clinical Director of Research, InCHOIR Mount Sinai School of Medicine Annetine C. Gelijns, Ph.D. Professor of Health Policy Co-Chair Department of Health Evidence and Policy Mount Sinai School of Medicine Thank you to CTSN, REMATCH and STICH trial investigators, coordinators and study participants.

3 Consequences of Not Reaching Target Enrollment Numbers May need to abandon trial Insufficient statistical power Reputation and credibility Clinicians Institutions

4 NCI-funded Trials 1 Trial initiation and completion too slow Launch period often exceeds 2 years Trial concept to 1 st patient enrolled Most trials do not meet enrollment targets Over-ambitious timelines and enrollment predictions 60% of NCI-sponsored trials are completed and published Only 3% of cancer patients in clinical trials Underrepresentation of women, elderly, and minorities Impacts generalizability 1. A National Cancer Critical Trials System for the 21 st Century. IOM 2010

5 Enrollment Challenges in Surgical Clinical Trials Protocol Site Surgeon/Physician Patient Funding/Reimbursement

6 Three Major Clinical Trials REMATCH STICH I & II NHLBI- CT Surgery Network Trials MR Trials 6

7 REMATCH Trial Design Hypothesis: Long-term treatment with LVAD will reduce 2-yr mortality by 1/3-1/2 compared to optimal medical management with the same or better quality of life Target Population: need but ineligible for cardiac transplant (primarily Medicare patients) Planned sample size: 140 patients Dates of enrollment: May July 2001

8 Patients Rematch Trial Enrollment Enrollment Original Projection TC $ Actual Enrollment Time (quarter years)

9 STICH Surgical Treatment for IsChemic Heart Failure * Multicenter international randomized trial Two primary hypotheses CABG + MedRx is better than MedRx alone Surgical Ventricular Reconstruction (SVR) in pts w/lv dysfunction is better than CABG alone Enrollment Dates: July 2002 May 2007 NHLBI sponsored * CAD Class I-IV EF 35%

10 STICH Trial Enrollment 1 32 sites selected (2002) Incremental expansion to 171 sites (up to 2005) 44 sites deactivated without enrolling any patients 1. Jones R.H., White H., Velazquez E.J. et al. STICH (Surgical Treatment for Ichemic Heart Failure) Trial Enrollment. J of Am College Cardiology 2010; 56(6):

11 All Enrolling Sites 2136 patients 127 clinical sites 26 countries 1747 days

12 2136 Patients Enrolled at 127 Clinical Sites in 26 Countries over 1747 Days

13 Enrollment Time Interval and Total Patients by Country

14 NHLBI/CT Surgery Network MR Trials Design Objectives are to evaluate efficacy & safety MMR: CABG with MV Repair vs. CABG alone SMR: Replacement versus Repair Primary endpoint is LVESVI (by TTE) at 12 months Sample Size: 250 (SMR) and 300 (MMR) Dates of enrollment: Dec to present

15 MR Trials Enrollment NHLBI CTSN Experience 3.3 pts/month % eligible/ randomized: 36% 14.0 pts/month % eligible/ randomized: 47% Total Enrollment SMR: 182 MMR: 148

16 Enrollment Challenges in Surgical Clinical Trials Protocol Site Surgeon/Physician Patient Funding/Reimbursement

17 Protocol Specific Is the Investigational Arm Available Outside of the Trial? REMATCH STICH I & II MR Trials NO YES YES

18 Protocol Specific Trial Design STICH imaging studies Pre-Trial Enrollment Estimates CT Surgery Network Over estimates Eligibility Criteria STICH stratum B Equipoise

19 Enrollment Challenges in Surgical Clinical Trials Protocol Site Surgeon/Physician Patient Funding/Reimbursement

20 Site Specific Site-specific Clinical-Trial culture Communication issues Logistical issues Eligibility Criteria

21 Enrollment Challenges in Surgical Clinical Trials Protocol Site Surgeon/Physician Patient Funding/Reimbursement

22 Surgeon/Physician Equipoise REMATCH/STICH/CT Surgery Network Procedures available outside of trial Physician tool kits Burden and Burnout

23 Engagement of Referring Physicians Lack of awareness/equipoise of referring physicians and colleagues Importance of communication/feedback Physician tool kits Descriptive materials Eligibility criteria Rationale for trial

24 Enrollment Challenges in Surgical Clinical Trials Protocol Site Surgeon/Physician Patient Funding/Reimbursement

25 Why do Patients Participate in RCT s? 1 Altruism Perceived earlier access to experimental treatment Closer Monitoring 1. Sawka and Pritchard. Can improved communication increase patient participation in randomised clinical trials? European Journal of Cancer 2001; 37:

26 Patient-Related Challenges Randomization Study protocol Treatment preference Comparator Arm Procedures available outside of trial Patient Burden Cultural & language barriers Lack of awareness & mistrust

27 Enrollment Challenges in Surgical Clinical Trials Protocol Site Surgeon/Physician Patient Funding/Reimbursement

28 REMATCH Original Funding Structure NHLBI, Thoratec NHLBI Thoratec HCFA Hospitals Patients Data collection & analysis OR cost Devices Treatment costs, excluding implant hospitalization implant hospitalization Unethical to charge

29 REMATCH:Financial Liability of Participating Hospitals (2001 $) Average Cost Per Patient - $63,113 (without device & OR cost) Resource Category Average LVAD $67,085 Professional Paymt $23,935 ±10,897 Length of Stay 17.2 ±5.3days Special Care Days $14,765 ±10,874 Regular Floor $7,071 ±7,376 Operating Room $10,818 ±1,725 Diagnostics $3,900 ±3,574 Laboratory $3,407 ±1,767 Blood Products $2,873 ±2,562 Drugs $3,257 ±3,229 Miscellaneous $3,235 ±1,695 Rehabilitation $670 ±423

30 Device Reimbursement for Trial Costs Economic burden of implant hospitalization has caused centers to decline participation and impose restrictions on patient enrollment New CMS Policy, September 2000 cover Rx costs of Medicare patients in NIH clinical trials: Type B Device How will other insurers respond? Ad hoc and laborious for the investigator

31 STICH Funding NIH paid $10,000 per site at outset Completion of documents and IRB approval Prior to any patients enrolled 44 sites deactivated for lack of enrollment Site costs exceeded NIH budget NIH agreed to pay bonuses but only for enrolling patients

32 Lessons Learned BEFORE TRIAL: Refine eligibility criteria BEFORE trial starts Quickly thereafter Run-in time IRB/legal Require Screening logs for predicting recruitment numbers Training Lessons for Investigators Number of recruitment sites

33 Lessons Learned THROUGHOUT TRIAL: Use logs to ascertain reasons for nonparticipation Add Sites Toolkit for investigators Patient-targeted information (toolkit & web) Active Communication between sponsor, coordinating center and investigators Regular meetings with investigators Frequent Site visits- meet with Institutional leadership

34 Lessons Learned Partnership between referring physicians and surgeons Multiple Principal Investigators? SITE CHAMPION