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Efficacy Analyses – Alimta (NDA 21-677) Review

Presented by Yong-Cheng Wang at the 27 July 2004 meeting of the Oncologic Drugs Advisory Committee. Efficacy Analyses – Alimta (NDA 21-677) Review. Outline. Protocol specified primary endpoint analyses Post-hoc non-inferiority analysis of 50% retention Critical issues in Study JMEI

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Efficacy Analyses – Alimta (NDA 21-677) Review

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  1. Presented by Yong-Cheng Wangat the27 July 2004meeting of the Oncologic Drugs Advisory Committee

  2. Efficacy Analyses– Alimta (NDA 21-677) Review

  3. Outline • Protocol specified primary endpoint analyses • Post-hoc non-inferiority analysis of 50% retention • Critical issues in Study JMEI • Secondary endpoint analyses • Efficacy conclusions

  4. Protocol Specified Study Objectives • Primary Objective: • Superiority test to determine whether Alimta • is more effective than Docetaxel. • Ha1: HR(alimta/docetaxel) < 1 • Co-Primary Objective: • Fixed margin non-inferiority (NI) test if the • superiority test failed. • Ha2: HR(alimta/docetaxel) < 1.11

  5. Protocol Specified Primary Endpoint (OS) Analysis for ITT Population ITT: All randomized patients

  6. Protocol Specified Primary Endpoint (OS) Analysis for RT Population RT: All randomized and treated patients

  7. Post-hoc NI Hypothesisof 50% Retention • Post-hoc NI Hypothesis of 50% Retention: • To test that Alimta can retain 50% of control • (Docetaxel) effect. • Ha3: log HR(alimta/docetaxel) < • (0.5) log HR(BSC/docetaxel)

  8. Critical Issues in Study JMEI • Docetaxel effect can not be estimated from one small historical. • Can not assure the ability to repeat the results. • Can not reliably assess the magnitude of the Docetaxel effect. • Crossover of Alimta to Docetaxel.

  9. Historical Trial (TAX317) Used for Estimation of Control Effect * Survival data for RT population is not available.

  10. Crossover of Alimta to Docetaxel

  11. Exploratory Analyses of Secondary Endpoints

  12. Survival Rate for ITT Population

  13. Time to Progressive Disease

  14. Progression-Free Survival

  15. Tumor Response (Investigator-Determined) for Qualified Population Relative Risk (95% CI) for response = 1.04 (0.60, 1.78)

  16. Efficacy Conclusions • Study JMEI was a single, randomized, open-label, multi-center trial in advanced NSCLC patients treated with Alimta vs. Docetaxel. • Study JMEI failed to demonstrate superior efficacy of Alimta to Docetaxel. • Study JMEI also failed to demonstrate NI of Alimta to Docetaxel.

  17. Efficacy Conclusions • The estimate of Docetaxel effect based on a single small historical trial is neither reliable nor robust. • In the presence of crossover from Alimta to Docetaxel, the survival results are confounded and NI analysis is very difficult to interpret. • The result of 50% retention NI analysis is not interpretable.

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