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Practical Implementation of Multi-Arm Multi-Stage Trials Mahesh Parmar Director

Practical Implementation of Multi-Arm Multi-Stage Trials Mahesh Parmar Director MRC Clinical Trials Unit. Structure of presentation. MAMS Designs MAMS application in STAMPEDE Issues in implementation Conclusions. MAMS Designs MAMS application in STAMPEDE Issues in implementation

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Practical Implementation of Multi-Arm Multi-Stage Trials Mahesh Parmar Director

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  1. Practical Implementation of Multi-Arm Multi-Stage Trials Mahesh Parmar Director MRC Clinical Trials Unit

  2. Structure of presentation • MAMS Designs • MAMS application in STAMPEDE • Issues in implementation • Conclusions

  3. MAMS Designs • MAMS application in STAMPEDE • Issues in implementation • Conclusions 1. MAMS Designs

  4. Why Multi-Arm, Multi-Stage trials? • More often than not ‘new’ is not better • Academia • 624 NCI sponsored phase III trials (Arch. Int Med, 2008) • ~30% of trials ‘statistically significant’ • ~40% of trials ‘new’ therapy preferred • Industry • Agents successful at phase I: only 10-20% receive a marketing authorisation • Success rate of phase III trials ~30-40%

  5. Why Multi-Arm, Multi-Stage trials? • Typical (academic) Phase III trial • Hundreds or thousands of patients • 5 to 10 years from idea to result • Hundreds of research staff • Cost millions in development • Years of investment from the key players • High chance of finding new treatment is not superior

  6. Principles of a New Strategy • Need better mechanism • than single arm phase II trial to decide • Test as many new promising treatments as possible • in the same timescale • maximise potential for a “positive trial” • Potential to discontinue unpromising arms • quickly and reliably • Start to randomise as quickly as possible • Multi-Arm, Multi-Stage (MAMS) trials

  7. Activity (phase II stages) • Asks the question • Are there reasons why we should not continue testing this treatment? • Testing for a lack-of-activity • Emphasis not testing for activity but for lack-of-activity or lack-of-sufficient-benefit

  8. Activity phase II stages • Assume definitive outcome measure is most clinically relevant • eg overall survival in cancer trials • In Activity Stages focus on an earlier outcome measure • eg “failure-free survival” (FFS) in cancer trials

  9. Multi-Arm, Multi-Stage Trials R A N D O M I S E Con-trol Test 1 Eligible patient Test 2 Test 3 Test 4

  10. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Test 1 Eligible patient Test 2 Test 3 Test 4

  11. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Test 1 Yes Eligible patient Test 2 Yes Test 3 Yes Test 4 Yes

  12. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Control Test 1 Sufficient activity Yes Eligible patient Test 2 Yes Test 3 Yes Test 4 Yes

  13. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Control Test 1 Sufficient activity Yes Yes Eligible patient Test 2 Yes Test 3 Yes Test 4 Yes

  14. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Control Test 1 Sufficient activity Yes Yes Eligible patient Test 2 Insufficient activity Yes Test 3 Yes Test 4 Yes

  15. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Control Test 1 Sufficient activity Yes Yes Eligible patient Test 2 Insufficient activity Yes No Test 3 Yes Test 4 Yes

  16. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Control Test 1 Sufficient activity Yes Yes Eligible patient Test 2 Insufficient activity Yes No Test 3 Sufficient activity Yes Test 4 Sufficient activity Yes

  17. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Control Test 1 Sufficient activity Yes Yes Eligible patient Test 2 Insufficient activity Yes No Test 3 Sufficient activity Yes Yes Test 4 Sufficient activity Yes Yes

  18. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Control Control Test 1 Sufficient activity Sufficient activity Yes Yes Eligible patient Test 2 Insufficient activity Yes No Test 3 Sufficient activity Yes Yes Test 4 Sufficient activity Yes Yes

  19. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Yes Control Control Test 1 Sufficient activity Sufficient activity Yes Yes Yes Eligible patient Test 2 Insufficient activity Yes No Test 3 Sufficient activity Yes Yes Test 4 Sufficient activity Yes Yes

  20. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Yes Control Control Test 1 Sufficient activity Sufficient activity Yes Yes Yes Eligible patient Test 2 Insufficient activity Yes No No (N/A) Test 3 Sufficient activity Yes Yes Test 4 Sufficient activity Yes Yes

  21. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Yes Control Control Test 1 Sufficient activity Sufficient activity Yes Yes Yes Eligible patient Test 2 Insufficient activity Yes No No (N/A) Test 3 Sufficient activity Insufficient activity Yes Yes No Test 4 Sufficient activity Yes Yes

  22. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Yes Control Control Test 1 Sufficient activity Sufficient activity Yes Yes Yes Eligible patient Test 2 Insufficient activity Yes No No (N/A) Test 3 Sufficient activity Insufficient activity Yes Yes No Test 4 Sufficient activity Sufficient activity Yes Yes Yes

  23. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Yes Control Control Control Test 1 Sufficient activity Sufficient activity Primary analysis Yes Yes Yes Eligible patient Test 2 Insufficient activity Yes No No (N/A) Test 3 Sufficient activity Insufficient activity Yes Yes No Test 4 Sufficient activity Sufficient activity Primary analysis Yes Yes Yes

  24. Multi-Arm, Multi-Stage Trials Stage 1 accrual Intermediate analyses 1 Stage 2 accrual Intermediate analyses 2 Stage 3 accrual Final analyses R A N D O M I S E Con-trol Yes Yes Yes Control Control Control Test 1 Sufficient activity Sufficient activity Primary analysis Yes Yes Yes Eligible patient Test 2 Insufficient activity Secondary analysis Yes No No (N/A) Test 3 Sufficient activity Insufficient activity Secondary analysis Yes Yes No Test 4 Sufficient activity Sufficient activity Primary analysis Yes Yes Yes

  25. Advantages of MAMS • Fewer patients • Less overall time • Randomised from the start • Concurrent (not sequentially) • No delay between phase II and phase III • Fewer applications for finance and approvals • one grant application • one protocol • one CTA submission (per country) • one ethics submission (per country) • one R&D approval (per site) • Saves many years!

  26. Advantages of MAMS • Fewer patients • Less overall time • Increased flexibility • Reduced costs

  27. MAMS Designs • MAMS application in STAMPEDE • Issues in implementation • Conclusions 2. MAMS application in STAMPEDE

  28. Impact • Most common male cancer • UK diagnosis: 34,000 in 2005 • UK deaths: 10,000 in 2006 • Global deaths: 250,000 in 2000 • Rising rates of diagnosis • Aging population, awareness, PSA screening • Modest treatment effect = big impact

  29. Needs in prostate cancer • Urgent need to improve outcomes for men starting hormone therapy with prostate cancer • Median survival ~4 years • Median failure-free survival ~2 years • No new therapies improving survival for this group of men for many years

  30. Design rationale • Many interesting agents • Different classes and modes of action • No obvious reason to choose one • Many used in later stages of disease • Don’t want to choose arbitrarily • Quicker and efficient to use MAMS design

  31. Control Control Hormone Therapy (HT) Androgen suppression (AS) A A arm arm R R A A B B HT + zoledronic acid AS + zoledronic acid N N D D C C HT + docetaxel AS + docetaxel O O M M D D HT + celecoxib AS + celecoxib I I S S E E AS + zoledronic acid + docetaxel HT + zoledronic acid + docetaxel E E F F HT + zoledronic acid + celecoxib AS + zoledronic acid + celecoxib Trial Design

  32. Trial Design Stages Stage Outcome Measures Primary Secondary Pilot Safety Feasibility Activity I-III Failure-free survival Overall survival (phase II) (PSA-driven) Toxicity Skeletal-related events Efficacy IV Overall survival Failure-free survival (phase III) Toxicity Skeletal-related events Quality of life

  33. Design Assumptions: for all stages • Pairwise comparison of each research arm against control • Hazard ratios for design • 10% improvement in FFS: 50 to 60% at 2 yr

  34. Significance level and power

  35. Cutpoints in STAMPEDE 95% power 95% power 95% power

  36. MAMS Designs • MAMS application in STAMPEDE • Issues in implementation • Conclusions 3. Issues in implementation

  37. Groups to convince – 1 • Medical community • Mostly seen by urologists • Trial treatments need to be given by oncologists • Would it appear complex in clinics? • Or in MDT meetings? • Previous multi-arm trials • Excellent recruitment to: • FOCUS – colorectal cancer – 5 arms • ICON5 – ovarian cancer – 5 arms

  38. Groups to convince – 2 • Men with prostate cancer • Involved patient groups • Two patients on Trial Management Group • Very positive opinions • Patient involvement has been excellent for trial • Two-part PIS • General information (few pages) – prior to randomisation • Arm-specific information • All before randomisation or • Only relevant one after randomisation (few pages) • Patient choice – as informed as patient would like to be

  39. Groups to convince – 3 • Funding bodies • Regulatory and ethical committees • Hospital governance • Potential for conservative reviewers • No precedent for such approaches • Approved – after a bit of ‘discussion’

  40. Groups to convince – 4 • Industry partners • 3 industry partners in STAMPEDE • All keen on design because… • Not primarily comparing their drugs head to head • Efficient design • Early “get-out” if agent not so beneficial • More companies = more negotiations • More contracts • More time • …

  41. Recruitment • How many patients are required? • Total N dependent on: • Observed accrual rates • Observed event rates • Do we have the predicted mix of patients? • # arms recruiting in each Activity & Efficacy Stage • Likely 2300 to 3600 patients • Over 5.5 to 7.5 years • Faster recruitment: • Requires more patients • Takes less time

  42. STAMPEDE Accrual

  43. Pilot Phase • Assessing safety & feasibility • Particularly for the combination arms • Target: 210 patients in 18 months • Limited centres • Completed: Oct-2005 to Spring-2007 • On schedule • IDMC recommended continuing all arms • None stopped because of clear safety signals

  44. Stage 1 • Completed ahead of schedule • IDMC recommended continuation of all arms

  45. Hurdles • Funding • Finalising choice of drug • Discussions with pharma • Funding (revisited) • EU Clinical Trials Directive • Vioxx • Increased number of stages • Continuity of staff • Pilot phase

  46. Funding – main grant • Outline Application to MRC – May 2001 • Accept for Full Application • Novel design & novel drugs vs conservatism • Advised to submit to CTAAC instead • New at time – for cancer trials, incl. MRC funds • Outline Application to CTAAC – November 2001 • Accept for Full Application • Full Application to CTAAC – November 2002 • Accepted for partial funding – Feb 2003 • Agreements/funding needed from industry partners

  47. Funding – industry partners • Novartis – zoledronic acid • Research grant • Free drug • Drug distributed to sites • Sanofi-Aventis – docetaxel • Research grant • Discounted drug (buy 1, get 2 free) • Sites to buy drug & claim back • Pfizer – celecoxib • Free drug • Research grant, including distribution costs

  48. Negotiations • Discussions required in many trials • More difficult if many companies? • Different pace • Different contracts • Different comments on protocol • Flagged plans for future discussions • International expansion planned • All agreements made with UK affiliates

  49. Changes in CTU Personnel

  50. Future hurdles • Recruitment rates • Contracts revisited • Moving through MAMS stages • Dropping arms • Completing recruitment • Adding arms

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