抗癌新藥研發、轉譯醫學於臨床方面之法規科學考量

1. 抗癌新藥研發、轉譯醫學於臨床方面之法規科學考量抗癌新藥研發、轉譯醫學於臨床方面之法規科學考量 賴怡君 醫師 醫藥品查驗中心 1

2. DISCLAIMER • This presentation was not officially cleared, and the views offered here do not necessarily reflect official positions of DOH, including TFDA.

3. Outline • Introduction • Biomarker • Prognostic / Predictive • Combo Guidance • How to prove clinical utility? • Conclusion 3

4. Introduction 4

5. Translational Medicine Translating progress in basic research into products and procedures that benefit patients Discover a important gene in oncogenesis A drug that inhibit the deregulated gene Translate into Richard Simon. Expert Reviews in Molecular Medicine. Vol. 12;e32; Oct 2010

6. Why Oncology is Leading the Way? • Easy access to the tissue • Better understanding of the complex patho-physiological mechanism. • Lack of stigma • Lethality combined with high toxicity and high cost of oncological drug. de Leon. Pharmacol Res 2009;59: 81-89 6

7. Example: RCC von Hippel-Lindau (VHL) syndrome RCC VHL gene was identified in 1993 VHL protein HIF VEGF Bevacizumab (anti-VEGF Ab) Sunitinib, sorafenib (TKI target VEGFR-1& VEGFR-2) Temsirolimus, everolimus (mTOR inhibitor, upstream of HIF) Harzstark AL. Small EJ. Where Do We Need to Go with Clinical Trials in Oncology. In: Kelly WK. Halabi S, editors. Oncology Clinical Trials. New York: DemosMedical , 2010:357-361

8. Iressa in NSCLC Adenocarcinoma, Asian, female, never-smoker 8

9. Biomarker - Prognostic - Predictive 9

10. Prognostic Marker Affects clinical outcome regardless of treatment MammaPrint, Oncotype DX Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

11. Predictive Marker Affect the effect of a specific treatment ER(+) good response to tamoxifen or AI Her2-neu overexpression good response to Herceptin Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

12. Combo Guidance- Drug-Device codevelopment 12

13. Potential of Drug/Test Combinations To provide many clinical benefits: - Differential diagnosis of a disorder - Identification of a patient subset - Identification of potential responders to a specific drug - A way to target therapy - An approach to identifying individuals at risk for adverse events - An adjunct tool for monitoring responses to drugs - A way to individualize therapy

14. Drug-Device Co-Development Concept Paper Review procedure issues processes and procedures for submitting and reviewing a co-developed drug-test product. Analytical test validation the in-vitro ability to accurately and reliably measure the analyte of interest, including analytical sensitivity and specificity, and focuses on the laboratory component of drug/test development. www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/UCM116689.pdf

15. Drug-Device Co-Development Concept Paper Clinical test validation the ability of a test to detect or predict the associated disorder in patients and includes clinical sensitivity and specificity, and/or other performance attributes of testing biological samples. Clinical test utility when evaluating the patient risks and benefits in diagnosing or predicting efficacy or risk for an event (drug response, presence of a health condition). www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/UCM116689.pdf

16. FDA “Combo” Concept Paper 2005 16 www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/UCM116689.pdf

17. Questions about “Co-development Concept Paper” from the sponsors • Different timelinesfor development of IVDs and drugs. • Most common starting points of biomarker development are Phase 2 or even Phase 3. • The diagnostic test is rarely developed de novo in complete parallel with a therapeutic. • Multiple testsare developed in parallel with a drug product and additional biomarkers could be added later. • An approved PMA is currently required for all medical device with claims of clinical utilities. “Burden” [less burdensome pathway de novo 510(k)] • Lack of Transition processfrom VGDS to Co-development • Lack of implications for cross-labelings. 17 http://www.fda.gov/ohrms/DOCKETS/dockets/04n0279/04N-0279-EC2-Attach-1.pdf

18. How to proveclinical utility? 18

19. Possible methods to prove clinical utility Prospective Enrichment designs All-comers or Unselected designs Marker based strategy Marker by treatment interaction Retrospective/Prospective designed Utilize data collected from previously conducted RCT Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

20. Screens for the presence or absence of a marker (or a panel of markers) Then only includes patients who either have or do not have a certain marker characteristic or profile Enrichment design Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542 20

21. Enrichment design Base on Not all patients will benefit from the study treatment the benefit will be restricted to a subgroup of patients who either express or do not express a specific molecular feature Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542

22. Example - Herceptin Careful assay validation and substantial preclinical evidence suggested that only HER2 + breast cancer patients would benefit from treatment with Herceptin. Enroll Her 2+ only patients in NSABP B-31 & NCCTG N9831 http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp [assessed 19 Aug, 2011]

23. Combined analysis: Herceptin significantly improves disease free survival • Approved for Her2+ as adjuvant therapy (Clinical Utility) 23 Romond EH, et al. NEJM 2005;353:1673-1684

24. Enrichment design Pros Clear and quick success Reduced sample size (Her 2+: about 20%) Cons predictive utility of HER2were left unanswered due to the issues of assay reproducibility and inclusion of only biomarker defined subgroups Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542

25. All comers or Unselected designs All patients of a specific disease type and stage are eligible for the clinical trial, regardless of their actual marker status Marker based strategy Marker by treatment interaction Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542

26. Marker-based Strategy Randomize subjects to treatment either base on or independent of the marker status

27. Marker-based Strategy 27 Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542

28. Example MammaPrint (clinical validation) MINDACT trial (clinical utility) Prospective, randomized controlled Node negative breast cancer Expect to recruit 6000 patients within 3 years

29. MINDACT Trial 29 Cardoso F, et al. Molecular Oncology, 1:246-251, 2007

30. Also called biomarker-stratified design Use the marker status as a stratification factor when randomizing subjects to treatment Marker by treatment interaction 30

31. Marker by treatment interaction 31 Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542

32. Example: story of erlotinib and EGFR NSCLC maintenance study Randomized trial in unselected patientswith advanced NSCLC comparing erlotinib to placebo group. 32 Tarceva US FDA Label, April 2010

33. Better OSthan placebo Approved for maintenance therapy Tarceva US FDA Label, April 2010

34. Subgroup analysis PFS & OS HR in EGFR positive 0.69 (95% CI:0.58, 0.82) & 0.77 (95% CI:0.64, 0.93) PFS & OS HR in EGFR negative 0.77 (95% CI:0.51, 1.14) & 0.91 (0.59, 1.38) Tarceva US FDA Label, April 2010

35. Test EGFR before erlotinib? Survival benefit due to erlotinib in the EGFR− subset cannot be excluded. US FDA Labeling: only show demographic of EGFR IHC, no recommendations of testing prior to choose Tarceva therapy.

36. MARVEL- Marker Validation for Erlotinib in Lung Cancer Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

37. MARVEL Hypothesis The primary comparisons will be PFS for patients on erlotinib compared with pemetrexed within the FISH+ and FISH− subgroups. Null Hypothesis I FISH+ subgroup:Erlotinib is not superior to pemetrexed. Null Hypothesis II FISH− subgroup:Pemetrexed is equally effective as erlotinib. Mandrekar SM, Sargent DJ.Journal of Clinical Oncology. 2009;27(24):4027-4034

38. MARVEL possible results E: Erlotinib, P: pemetrexed Mandrekar SM, Sargent DJ.Journal of Clinical Oncology. 2009;27(24):4027-4034

39. Utilize data collected from previously conducted RCT Samples must be available on large majority of patients to avoid selection bias (some patients may not have samples) Hypotheses, analyses techniques…etc. must be stated prospectively Prospectively designed retrospective 39 Mandrekar SM, Sargent DJ. Journal of Biopharmaceutical Statistics. 2009;19(3):530–542

40. Example: KRAS & Panitumumab Vectibix, IgG2 monoclonal antibody against EGFR Study 20020408: III, R, Open, EGFR-expressing mCRC progressed after standard chemotherapy 10 endpoint: PFS Custem EV, et al. Journal of Clinical Oncology. 2007;25:1658-1664

41. Study 20020408 Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

42. Got accelerated approval by US FDA in 2006 KRAS hypothesis Pre-specified statistical analysis plan to evaluate outcome by KRAS status Custem EV, et al. Journal of Clinical Oncology. 2007;25:1658-1664

43. Prospectively designed retrospective “Prospective retrospective” analysis plan was finalized prior to any KRAStesting of tissue samples for KRAS mutation status Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

44. Statistical analysis Primary objective: to assess if the effect of panitumumab on PFS was significantly greater in patients with wild type KRAS compared to patients with mutantKRAS Sumithra J.Mandrekar. FDA-IDSA Workshop, Nov 12-13, 2009

45. Mutant KRAS subgroup: PFS by treatment Amado RG, et al. Journal of Clinical Oncology. 2008;26:1626

46. Wild-type KRAS subgroup: PFS by treatment Amado RG, et al. Journal of Clinical Oncology. 2008;26:1626

47. Revise Label July 2009, US FDA label Indication and Usage: Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. (clinical utility)

48. Conclusion Novel & validated biomarkers + streamlining clinical trials: move drug development from a population-based to personalized medicine. One size dose not fit all! Collaboration with regulatory agency, academia and industry is the key to success.

49. Thank you for your attention!