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Advising the FDA: A Statistician’s Perspective Stephen L George, Ph.D.

This chapter discusses the role of FDA advisory committees, specifically the Oncologic Drugs Advisory Committee (ODAC), and the issues and examples related to accelerated approval. The author reflects on the membership of ODAC and the standards and challenges of accelerated approval.

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Advising the FDA: A Statistician’s Perspective Stephen L George, Ph.D.

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  1. Advising the FDA: A Statistician’s Perspective Stephen LGeorge, Ph.D. Duke University Medical Center NJ chapter of ASA Piscataway, NJ June 16, 2003

  2. Disclaimer The views expressed in this talk are those of the author. They do not necessarily represent those of the Food and Drug Administration.

  3. Outline • FDA advisory committees • Oncologic Drugs Advisory Committee (ODAC) • Accelerated approval: Issues and examples

  4. I. FDA Advisory Committees

  5. Federal Advisory Committee ActOctober 1972 • Purposes • To enhance the governmental decision-making process • To add credibility to the process • To provide a forum for public input • To open up the process (‘Sunshine’ law)

  6. Characteristics of Federal Advisory Committee Meetings • Open to the public • Advance notice • Public input • Public records, reports, transcripts

  7. Purposes of FDA Advisory Committees • To provide advice and recommendations to the FDA on regulatory matters related to specific applications • To provide general advice on regulatory issues not related to a specific application

  8. Key FDA Advisory Committee Points • Not all applications receive advisory committee review • Recommendations are not binding on the FDA

  9. II. Oncologic Drugs Advisory Committee (ODAC)

  10. Oncologic Drugs Advisory Committee (ODAC) • Review selected applications • Provide advice as requested • Established 1981? • Meets 3 or 4 times per year • 74 meetings through March 2003

  11. ODAC Membership(as of May 2003) • 9 academic medical oncologists • 1 medical oncologist in private practice • 1 pediatric oncologist • 1 statistician • 1 consumer representative • 1 industry representative (non-voting) • consultants, guests, speakers

  12. ODAC Statisticians1985-present • Thomas Fleming 1985 - 89 • Stephen Piantadosi 1989 - 93 • Richard Gelber 1993 - 97 • Richard Simon 1997-2001 • Stephen George 2001-2005

  13. Prior to Meetings • Public announcement of meeting and agenda • Conflict of interest screening • Materials sent 3 to 4 weeks before meeting • Sponsor briefing book • FDA review (medical, statistical, biopharm) • Other materials (papers, guidance, etc) • No contact with sponsor, media, or others

  14. Meeting Format • Public comments • Sponsor presentation • FDA presentation • Committee discussion • Voting on questions

  15. Some Reflections on Membership • Influence of statisticians • Time commitment • Laws, guidelines, precedents • Science vs regulations • Consistency in applying rules • Accelerated approval

  16. III. Accelerated Approval

  17. Standards for Approval of an NDA • Adequate, well-controlled studies • Substantial evidence of effectiveness • ‘Feel better or live longer’ criterion • Safety under conditions of proposed use • Assessment of whether benefits outweigh risks (risk : benefit ratio) • No consideration of costs

  18. Accelerated Approval(21CFR314.510; subpart H) • Serious or life-threatening illnesses • Appears to provide benefit over existing therapy • Basis for approval a) Effect on a surrogate endpoint, reasonably likely to predict clinical benefit; or b) Effect on a clinical endpoint other than survival or irreversible morbidity • Effective date: January 1993

  19. Accelerated Approvals in Oncology1995 - 2002

  20. Post-approval requirements • Additional well-controlled studies, usually already underway • Verify and describe clinical benefit: a) establish clinical benefit (if approval was based on a surrogate); or b) assess ultimate outcome (if approval was based on other clinical benefits) • Due diligence

  21. Withdrawal of Approval • Post-marketing studies: • Failure to verify clinical benefit • Lack of due diligence in conducting the studies • New safety concerns • Failure to adhere to approval restrictions • Misleading promotions • Other evidence on safety/effectiveness

  22. Issues in Accelerated Approval • Lower standard of evidence • Validity of surrogate • ‘reasonably likely’ to predict benefit? • No risk:benefit assessment is possible • Confirmatory studies • in different population of patients • accrual difficulties after AA • Due diligence

  23. Time from Accelerated to Full Approval, 1995 - 2002 • Four successful conversions: Taxotere (2.1 years), Camptosar (2.4 years), Xeloda (3.4 years), Zinecard (7.4 years) • Fifteen on-going: 0.5 to 7.6 years (median = 3.1 years)

  24. AA Example #1: Iressa • Advanced NSCLC • Third-line therapy for patients resistant or refractory to cisplatin and taxotere

  25. Iressa Study Design • Randomized phase II trial • Two dose levels of Iressa monotherapy: 250 mg po daily 500 mg po daily • Primary endpoints: • RR • Symptom improvement

  26. Iressa AA Results • RR: 14/139 (10%) [95% CI: 5%, 17%] • Symptom improvement: 40%? on FACT-L • Two negative first-line studies: • Randomized, placebo-controlled, double-blinded • Standard chemotherapy plus Iressa • Over 1,000 patients on each • No effect of Iressa on RR, TTP, or overall survival

  27. Public Comments, ODAC Meeting September 24, 2002 • Expanded access program: >20,000 patients • 14 presentations at ODAC meeting • A clash of expectations • Assumptions of presenters • Charge to the committee • Impact on decision-making

  28. ODAC Recommendations on Iressa • Primary vote: 11 yes, 3 no • Comments and recommendations: • Symptom improvement not adequately demonstrated (vote: 9 to 5) • No viable treatment options in third line setting, so 10% response rate is meaningful • Randomized trials are required to prove efficacy • No expanded access for patients eligible for trials

  29. Iressa Post-marketing Commitments • Initiate three new randomized studies Second line: Iressa vs Taxotere, 2003 – 2006 Third line: Iressa vs Placebo, 2003 – 2005 Third line: Iressa vs BSC, 2003 – 2005 • Complete two ongoing randomized studies Adjuvant, 2002 – 2008 Maintenance, 2002 - 2008

  30. AA Example #2: Oxaliplatin • Advanced colorectal cancer • Second-line therapy after failing 5-FU/LV and irinotecan • Randomized, open-label trial • Three treatments: A: 5-FU/LV B: Oxaliplatin C: Oxaliplatin + 5-FU/LV (FOLFOX4)

  31. Oxaliplatin Study Design • Primary endpoint: OS • Secondary endpoint: RR, TTP • Sample size: 786 patients (262/treatment) • Power = 0.88 (C: 11 mos vs A: 8 mos) • Targeted events: 393/524 (75%) on A & C • Interim analysis for AA: • 450 patients • RR and TTP only • A vs C only

  32. LV5FU2 FOLFOX4 Oxaliplatin LV 200 mg/m2 over 2 hrs  5-FU 400 mg/m2 bolus  5-FU 600 mg/m2 CIV x 22 hrs D1 & 2 , q 2 weeks . Oxaliplatin 85 mg/m2 IV D1 + LV 200 mg/m2 over 2 hrs  5-FU 400 mg/m2 bolus  5-FU 600 mg/m2 CIV x 22 hrs D1 & 2 , q 2 weeks . Oxaliplatin 85 mg/m2 IV q 2 weeks . Oxaliplatin Treatment Access Program 5-FU/LV vs Oxaliplatin vs 5-FU/LV/Oxaliplatin in Patients with Recurrent CRC following IFL Stage IV CRC Irinotecan/Bolus 5-FU/LV (IFL) PD on Rx or within 6 months of end of Rx Rothenberg et al: Proc ASCO 2003;22:252 (Abst 1011)

  33. Oxaliplatin AA Results • RR (A vs C): 0/151 vs 13/152 (8.6%) • TTP (A vs C): 2.7 mos vs 4.6 mos • No ODAC review • Approval: August 9, 2002 • Filing to approval: 46 days (a record!)

  34. Oxaliplatin Post-marketing Commitments • Complete AA study, 2004 • Complete other on-going randomized trials 3 First line, 2003 – 2005 2 Adjuvant, 2004 – 2007 1 Second line, 2005 2 Third line, 2004

  35. Efficacy: Response Rate Rothenberg et al: Proc ASCO 2003;22:252 (Abst 1011)

  36. FOLFOX vs 5-FU/LV: p < .0001 5-FU vs Oxaliplatin: p < .008 5.6 mo 1.9 mo 2.6 mo Time to Tumor Progression Independent Radiological Assessment Probability Rothenberg et al: Proc ASCO 2003;22:252 (Abst 1011)

  37. Relief of Tumor Related Symptoms Rothenberg et al: Proc ASCO 2003;22:252 (Abst 1011)

  38. 2-sided, stratified, log-rank FOLFOX vs 5-FU/LV: p = .07 Hazard Ratio: 0.84 (0.69 – 1.02) 9.8 mo 8.1 mo 8.7 mo Overall Survival Probability Rothenberg et al: Proc ASCO 2003;22:252 (Abst 1011)

  39. Efficacy Overall Survival * Death Hazard Ratio: 0.84 (95% CI: 0.69 – 1.02) Rothenberg et al: Proc ASCO 2003;22:252 (Abst 1011)

  40. Statistical Methods for AA • Shih, W. J., Ouyang, P., Quan, H., Lin, Y., Michiels, B., and Bijnens, L. Controlling type I error rate for fast track drug development programmes. Stat Med, 22: 665-675, 2003. • Sridhara, R., Yang, P. L., Chen, G., and Chi, G. Y. H. Design considerations in the accelerated approval process for new drug products. 2003. Unpublished. • Yang, P. L., Sridhara, R., Chen, G., and Chi, G. Y. H. Determination of optimal conditional power by controlling the false positive rate based on the surrogate endpoint. 2003. Unpublished.

  41. Design 1 Shih, WJ et.al. (2003) Stage 1Stage 2 |ZY1| > cY1,Y1? Yes Supports clinical benefit No Yes No |ZY2| > cY2,Y2? |ZS| > cS, ? No Yes Yes Fails to support clinical benefit Supports Accelerated Approval No |ZY2| > cY2,Y2?

  42. Design 2 Yang, P. et.al. (2002), Sridhara, R. et.al (2002) Stage 1Stage 2 ZY1 > cY1 , Y1? Yes Supports clinical benefit No Yes ZY2 > cY2, Y2? No cY1,a*< ZY1 < cY1,Y1 &ZS > cS, ? No Yes Fails to support clinical benefit Yes Supports Accelerated Approval No ZY2 > cY2,Y2?

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