Two-Stage Adaptive Design in
Late-Stage Trials
M. Scott Harris, MD
Middleburg Consultants, Inc.
Professor of Medicine
Geor...
ADVENT Trial
• Multicenter trial initiated by Napo Pharmaceuticals in 2007
• Limited pool of potential patients
• One pivo...
Three Options to Consider
1. Single Four-Arm Trial: Run a single Phase 3 four-arm trial;
four dose groups vs. placebo
2. T...
Sample Sizes Required for 80% Power
Method Sample Size
Bonferroni (4-arm) 540
Two Separate Trials 416
Phase 2/3 Posch-Baue...
Active
X mg p.o. b.i.d.
Active
Y mg p.o. b.i.d.
Active
Z mg p.o. b.i.d.
placebo
p.o. b.i.d.
n 50 50 50 50 200
total
Active...
Outcome
• A statistical plan was developed to guarantee control of
type-1 error, employing Posch et al 2005.
• The SAP was...
Take Home Messages for Pivotal Trials
• A Special Protocol Assessment (SPA) should be conducted.
• The Statistical Analysi...
Regulatory Guidance
Guidance for Industry: Adaptive Design Clinical Trials for Drugs
and Biologics , February 2010
http://...
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Scott Harris

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Scott Harris

  1. 1. Two-Stage Adaptive Design in Late-Stage Trials M. Scott Harris, MD Middleburg Consultants, Inc. Professor of Medicine Georgetown University School of Medicine harris@middleburgconsultants.com Making best use of scarce resources
  2. 2. ADVENT Trial • Multicenter trial initiated by Napo Pharmaceuticals in 2007 • Limited pool of potential patients • One pivotal trial sufficient for approval • Phase 2 trials have identified three potential doses • Uncertain dose-response relationship
  3. 3. Three Options to Consider 1. Single Four-Arm Trial: Run a single Phase 3 four-arm trial; four dose groups vs. placebo 2. Two Separate Trials: Run a four-arm Phase 2 trial to select the best dose, then run a second independent Phase 3 two-arm trial 3. Seamless Phase 2/3 Trial: Start with four arms, select the best dose at an interim analysis, continue with two-arms, and pool the data from both stages.
  4. 4. Sample Sizes Required for 80% Power Method Sample Size Bonferroni (4-arm) 540 Two Separate Trials 416 Phase 2/3 Posch-Bauer 350
  5. 5. Active X mg p.o. b.i.d. Active Y mg p.o. b.i.d. Active Z mg p.o. b.i.d. placebo p.o. b.i.d. n 50 50 50 50 200 total Active * mg p.o. b.i.d. placebo p.o. b.i.d. 75 75 Interim analysis 150 50 + 75 = 125 50 + 75 = 125 350 Stage I: Dose selection Stage II: Dose assessment XYZ = 125 mg, 250 mg, or 500 mg Primary and secondary efficacy analyses n Study Stages and Interim Analysis
  6. 6. Outcome • A statistical plan was developed to guarantee control of type-1 error, employing Posch et al 2005. • The SAP was approved by FDA through Special Protocol Assessment. • The trial completed enrollment in 2010. • The lowest of the three active doses was selected by the Interim Analysis Committee. • The p-value achieved was 0.0096. • An NDA (Fulyzaq®, crofelemer) was submitted to FDA in 2011 and approved in December 2012
  7. 7. Take Home Messages for Pivotal Trials • A Special Protocol Assessment (SPA) should be conducted. • The Statistical Analysis Plan should be submitted to the Agency before the trial commences, assuring that that overall type-1 error is preserved. • The entire adaptive strategy must be pre-specified in an Interim Analysis (IA) Charter. • An independent statistical center should oversee the IA in accordance with this charter. • Procedures must be instituted to assure rigorous preservation of blinding.
  8. 8. Regulatory Guidance Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics , February 2010 http://www.fda.gov/downloads/Drugs GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf

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