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My Personal Thoughts on SMARTs

My Personal Thoughts on SMARTs. Christy Chuang-Stein Pfizer Inc The views expressed here are completely my own. They do not reflect those of Pfizer’s or of any other group I am associated with. 6 th UPenn Conference Statistical Issues in Clinical Trials. SMART.

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My Personal Thoughts on SMARTs

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  1. My Personal Thoughts on SMARTs Christy Chuang-Stein Pfizer Inc The views expressed here are completely my own. They do not reflect those of Pfizer’s or of any other group I am associated with. 6th UPenn Conference Statistical Issues in Clinical Trials

  2. SMART • Intuitive, interesting and innovative • Some pharma companies have employed certain aspects of the SMART concept. • The SMART idea is being explored to determine the strategies for a development program by an academic-industry subteam of the Adaptive Design Working Group.

  3. CATIE • Clinical Antipsychotic Trials of Intervention Effectiveness (in patients with chronic schizophrenia) • The largest, longest, and most comprehensive independent trial to examine existing therapies for schizophrenia, conducted between Jan 2001 and Dec 2004 • Funded by the National Institute of Mental Health with drugs donated by the manufacturers in identical-looking capsules • The objective was to determine which medications provided the best treatment for schizophrenia. • 1,493 subjects were initially randomized to one of five drugs. Patients were to receive the drug for 18 months. 74% of patients discontinued the initial treatment early.

  4. R Phase I Olanzapine Quetiapine Risperidone Ziprasidone Perphenazine Atypical antipsychotics (2nd generation) Responded Phase II (543 patients) Discontinued - lack of efficacy Discontinued - side effect Continue R R Clozapine A diff atypical Ziprasidone A diff atypical

  5. A Possible Application: Targeted Therapy If respond, continue New TT If fail, receive SOC R If respond, continue SOC If respond, continue New TT If fail, receive SOC If fail Among patients with the targeted characteristics R If respond, continue SOC, 2nd line New TT If fail R SOC, 3rd line

  6. Another Possible Application: POC Enrichment After washout Responders New candidate Enrichment : likely responders Placebo R A marketed product in the same class Non-responders New candidate Enrichment: non-responders R Placebo FDA draft guidance: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, issued in Dec 2012.

  7. SMART Concept at the Program Level • Consider Phase II and Phase III as two contiguous stages of the development program. We want to choose the best strategy for each stage. • We know the type of information we want to have at the end of Phase III. Can we back-engineer to identify the optimal dose-finding strategy for Phase II? • An academe-industry subteam has been looking at this for the past 2 years. Technical solutions proved to be challenging. • The subteam is part of the “Adaptive Program” workgroup. The latter is part of an extensive academe- industry-government “Adaptive Design Working Group”. ADWG has been active since 2005.

  8. Final Thoughts • Pharmaceutical industry has always been looking for better and more efficient ways to develop products, maintaining high quality for the evidential basis under the constraints of time and cost. • CATIE is unique in its scope and objective (and 43 million USD, 10 years ago). Many comparisons between active treatments are being carried out either indirectly or based on non-RCT data sources. • Forming collaboration and partnerships is a great way forward to pilot-test the concept and generate interests among different stakeholders.

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