1. Improving Accrual to Clinical Trials Saving patients and $aving Time Daniel Weisdorf October 2011 Thanks to Mary Horowitz

2. Clinical Research Basic Biomedical Research Human Studies of Safety/ Efficacy – Clinical Trials Clinical Science and Knowledge Clinical Practice and Health Decision Making Improved Health From: Sung et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278-87. E ffectiveness vs. Efficacy Quality/ Access Improvement Impaired Health

3. Major frequent problems in Clinical Trials 1. Bad idea 2. Poor study design--masks true test of a good idea competing hazards, co-variates, wrong patient group 3. Too few patients--statistically invalid. May not observe great response in subset. 4. Too short a trial. 5. Wrong analysis. ,ß...….. errors

4. CLINICAL TRIALS ARE DIFFICULT  2003 Institute of Med Report  High research costs/lack of funding  Regulatory burden  Fragmented infrastructure/ incompatible databases  Lack of willing participants (informed consent issues+ )  Lack of qualified investigators  Career disincentives  True for all disciplines – but especially in HCT

5. Distribution of Transplant Volumes among 181 US Centers Reporting Data to CIBMTR-2008 Distribution of Transplant Volumes among 181 US Centers Reporting Data to CIBMTR-2008 Mmh06_6.ppt 29% >100/y HCT is really uncommon

6. Distribution of Allogeneic Transplant Volumes among 181 US Centers Reporting Data to CIBMTR -2008 Distribution of Allogeneic Transplant Volumes among 181 US Centers Reporting Data to CIBMTR -2008 Mmh06_6.ppt Individual centers treat relatively few heterogeneous patients. Many patient & treatment factor affect outcomes. 23% >100/y Allogeneic HCT is even more uncommon

7. ALLOGENEIC TRANSPLANTS ELIGIBLE FOR A TRIAL OF AN INTERVENTION FOR AML-CR1 For Phase III trial needing 200 patients over 2 years, 25% of all eligible patients must be enrolled – Most definitive trials will require multicenter participation 7,000 2,0005,000 AMLOther disease 8001200 HLA-ident sib Other donor 400 in ~200 centers 400 CR1Not CR1

8. HCT Trials are difficult  Complex therapy for life-threatening diseases  Long, involved informed scary consent documents  Patients are very sick Everyone [patient/referring MD/transplant MD] wants to believe they know the best treatment  Competing risks complicate the primary endpoint  How do you interpret patients who die before reach a primary endpoint? Death before engraftment or GVHD  Need more patients to make up for drop-out  Two subjects – donor and recipient  Increases complexity and costs  Decreases numbers eligible for studies

9. BMT endpoints occur at varying times Engraftment at 20-45 days; GVHD by 100+ days; Chronic GVHD 2-24 months Relapse 1-2 years; Survival long term. Quit for early endpoint likely makes sample too small to see late endpoint. Followup is costly but well designed early trial can be informative later on

10. DBV06_21.ppt Small Numbers  Tests our willingness to collaborate.  Large collaborative observational databases – a unique feature of our field CIBMTR EBMT Usable for study planning—control and eligible pts  Collaboration for clinical trials –2001 – Blood and Marrow Transplant Clinical Trials Network BMT CTN – infrastructure for large Phase II and III trials –2005 – Resource for Clinical Investigations in BMT RCI BMT – smaller Phase I/II trials

11. What makes a good Protocol?  Important question  Can the result change practice?  How many people might it affect?  What is a realistic effect size?  How to estimate baseline outcomes and treatment effects  Affects target enrollment  How many patients are there that might be eligible to enroll?  Who is treating them now and how?

12. What makes a good Protocol?  Important question  Can the result change practice?  How many people might it affect?  What is a realistic effect size?  What are realistic baseline outcomes and treatment effects  Determines target enrollment  How many patients are there that might be eligible to enroll?  Who is treating them now and how?

13. What makes a good Protocol?  Important question  Can the result change practice?  How many people might it affect?  What is a realistic effect size?  How to estimate baseline outcomes and treatment effects  Affects target enrollment  How many patients are there eligible to enroll?  Who is treating them now; and how?  Are they interested in a new HCT trial?

14. Baseline Outcomes and Effect Sizes  Publication bias – results may be misleading  Single center study – examine your own data  Multicenter study – CIBMTR database

15. TCP99_30.ppt 95% CONFIDENCE INTERVALS FOR STUDIES PRODUCING 50% SURVIVAL SAMPLE SIZE, N 0203040506070809010010 PROBABILITY, % 0 50 100 300200 Publish + Don’t Publish + most papers

16. TCP99_30.ppt SAMPLE SIZE, N 0203040506070809010010 PROBABILITY, % 0 50 100 300200 Publish + Don’t Publish + Most trials 95% CONFIDENCE INTERVALS FOR STUDIES PRODUCING 50% SURVIVAL

17. Not all have equipoise

18. Baseline Outcomes and Effect Sizes  Publication bias – results may be misleading  Single center study – examine your own data  Multicenter study – CIBMTR/EBMT databases  Consider randomized Phase II study Allows consideration of broader eligiblity and selection to judge worthiness for followup study  Can use pick the winner design- not the best, but the best to study

19. Randomized Phase II Trials  Single arm Phase II designs assume historical rate is “fixed” and efficacy based on a one sample comparison to that a fixed rate  A randomized control arm may be helpful if historical rate is uncertain  Especially useful when inclusion criteria are variable: VOD syndrome, high risk GVHD  BMT CTN 0302 – randomized 4 arm Phase II of treatment for high-risk acute GVHD  Response rate in eligible population was not well understood—and 4 agents were promising

21. Cautions when you write the protocol  Treatment regimen –  How closely does it mimic practice?  Is it unnecessarily complex?  Supportive care  Fussy (single institution habit) requirements can prevent centers from participating  Too many restrictions can prevent patients from participating

22.  Treatment regimen –  How closely does it mimic practice?  Is it unnecessarily complex?  Supportive care  Fussy (single institution habit) requirements can prevent centers from participating  Too many restrictions can prevent patients from participating  Collect only what you need for Safety; analysis; planning next trial Cautions when you write the protocol

23. BMT CTN Protocol 0302 Randomized Phase II Trial of Combined Therapy with Prednisone with Either MMF, Etanercept, Pentostatin or Ontak for Newly Diagnosed AGVHD Looser eligibility Easier start 72 not 48h Wider Pred dose range

24. Writing a good protocol  How many patients are there that might be eligible to enroll?  Who is treating them now and how?

25. Approximate Annual Number of US Transplants Fulfilling Eligibility Criteria for BMT CTN Trials Rapid accrual

26. % of Eligible US Transplants Enrolled on BMT CTN Trials Unique trials

27. Understanding the Potential Patient Population  Is the study feasible?  Does accrual require capture of 10% [or 50%] of all transplants  Number of centers  Collaboration  Timeline  Accrual goal  Are there competing protocols?

28. CALGB 100104 Revlimid After Autotransplant Monthly Accrual Launched 18 months into accrual of BMT CTN 0102 (auto-auto vs auto-allo transplants) which targeted same patient population

29. CALGB 100104 Revlimid After Autotransplant Monthly Accrual Complete accrual 2009; results released early

30. Don’t design protocol to fail  Eligibility criteria  Balance between maximizing accrual and minimizing heterogeneity that confounds outcomes  Examine the impact of specific criteria

31. Easy enrollment Unbiased population

32. EXAMPLE – INCLUSION CRITERIA % of patients100 Day survival Acute leukemia, CR121%16% Acute Leukemia, CR211%21% CML, CP111%13% CML, AP5%22% MDS1%22% MPS1%22% NHL / HD, CR12%17% Acute leukemia, Rel 19%30% NHL / HD, PIF6%33% NHL / HD, Rel 17%30% NHL / HD, CR21%30% NHL / HD, Rel 22%33% NHL / HD, Other4%40% CLL3%35% Multiple Myeloma8%40% OK NOT OK

33. Biological assignment trial-sometimes necessary for a successful trial  Randomized trial: A random method is used to assign the treatment group,  All patients must be eligible to receive either treatment  Balances unknowns that influence outcome  Biological assignment trial: Treatment group is assigned by availability of therapy  HLA-identical Sib vs. Auto  Sib vs. alternative donor  Related vs. unrelated  Related vs. auto

34. Biological assignment – WHY?

35. BIOLOGIC ASSIGNMENT: Why For Phase III trial needing 200 patients over 2 years, 25% of all eligible patients must be enrolled 7,000 2,0005,000 AMLOther disease 8001200 HLA-ident sib Other donor 400 in ~200 centers 400 CR1Not CR1

36. BMT CTN 0102: Auto-auto vs auto-allo HCT for Myeloma NEED a Sib donor % With Donor Trial Design Annual Accrual Sample Size Required Years of Accrual 20% Randomized trial (Matched sibling donors only) 514629.1 Biological Assignment (all patients) 2547202.8 25% Randomized trial (Matched sibling donors only) 634627.3 Biological Assignment (all patients) 2546152.4 30% Randomized trial (Matched sibling donors only) 764626.1 Biological Assignment (all patients) 2545502.2

37. BIOLOGIC ASSIGNMENT – WHY NOT?  Donor availability may influence outcome  eg., very young patients may not have siblings  eg., Older patients’ may not have healthy available siblings  Planned assessment and adjustment for major prognostic factors  Unblinded study: Physician or patient knowledge of donor availability may differentially affect enrollment  Influence referral if donor availability known early  Subtle pressure for or against enrollment  Need to monitor for enrollment bias

38. Biologic Assignment: 0102 Number of Living Siblings P value 0-1≥2 Age0.001 ≤55 45%59% >55 55%41% Race0.3 Caucasian 82%78% Other 18%22%

39. AFTER YOU OPEN THE PROTOCOL  Cheerleading – an essential element  Personal communication is powerful  Get others to champion your protocol  Acknowledge that accrual is difficult and needs focused attention  Figure out how to provide help  Balance praise, cajoling, enticements, appeal to higher calling Accrual Plan

40. Accrual Plan Assessment Target Accrual and Accrual Period---monitor steps & progress Number of Sites Number of Committed Sites Optimal Number of Sites Potential High Value Sites Solicit cooperative group or special collaborators Seek Patient Advocacy support Anticipated Accrual Barriers Competing Protocols Competing Treatment Preference/Bias Recruitment Focus: Transplant centers Referring MDs Patients

41. Never forget Avoid the most annoying CROs Tend to press detail over quality If they don’t like the trial, they won’t enroll Work on inclusiveness prior to opening Anticipate accrual barriers Pay enough to cover the costs Slow accrual is more costly than more $$/patient Don’t be complacent; Ongoing communication helps. Guilt helps too

42. AFTER YOU OPEN THE PROTOCOL  Pay attention  Identify problems early and correct them quickly  Trial success is collaborative  Listen to centers—before & after trial opens  Limit amendments  Only those needed for safety or accrual

44. Confirmatory trials are essential !!! -Reduce likelihood of false + -Verify original results -Expands the number of observations, perhaps allowing subgroup effects to be seen in combined analysis (Meta-analysis) BUT-- only one trial doesn’t teach us the truth