Evidence Generation for Genomic Diagnostic Test Development Health Care Provider Perspective

Transcription

1 IOM Genetics Workshop Evidence Generation for Genomic Diagnostic Test Deveopment Heath Care Provider Perspective Danie F. Hayes, M.D.

2 A Question of Vaues: Is it worth it Patient care Improved cancer outcomes, by focusing the right therapy on the right patient - increase chance of: Cure Surviva Paiation Decrease exposure to toxicity of useess therapy

3 Incorporation of Tumor Marker Into Cinica Care What evidence is required from stakehoders? How is evidence currenty being generated? Are there innovative ways to generate higher quaity evidence more efficienty? What are the barriers to generating this evidence and how can they be overcome?

4 Incorporation of Tumor Marker Into Cinica Care What evidence is required from stakehoders? How is evidence currenty being generated? Are there innovative ways to generate higher quaity evidence more efficienty? What are the barriers to generating this evidence and how can they be overcome?

5 Definitions: Semantics Regarding Evidence for Tumor Markers Anaytica Utiity Does the assay accuratey and reproduciby measure what you say? Cinica Vaidity Does the assay actuay identify a bioogic difference ( pos vs. neg ) that may or may not be cinicay usefu? Cinica Utiity Do resuts of the assay ead to a cinica decision that has been shown with high eve of evidence to improve outcomes? Teutsch S.M., et a. Genet Med. 11:3-14, 2009

6 Recent decrease in UK and USA breast cancer mortaity at ages years Adj CTX Adj HT Screening Modified from Peto et a. Lancet 355:1822, 2000 Berry D.A., et a. N Eng J Med. 353: , 2005

7 Adjuvant Systemic Therapy Shoud A Patients Receive A Therapy? If pt is wiing to accept ANY toxicity for ANY benefit: then treat her with everything If pt is wiing to forego SOME benefit to avoid SOME toxicity, OR If patient and society are wiing to forego SOME benefit to avoid cost: then seect therapy carefuy Depends on: We -defined subgroups that do or do not benefit from therapy Patient s, Doctor s, and Society s Perspectives Regarding Risks, Benefits, and Costs of Therapy

8 ASCO Tumor Marker Guideines Pane Recommended Markers for Breast Cancer ER, PgR Seect Endocrine Therapy HER2 Seect Trastuzumab/Lapitinib UPA/PAI -1 Avoid Chemo if ER+/Node neg Oncotype DX Avoid Chemo if ER+/Node neg Harris L., et a. J Cin Onco. 2007

9 ASCO Tumor Marker Guideines Why Are the Guideines So Conservative? Recommended ony those markers for which resuts woud change cinica decisions Evidence-based Lack of Leve of Evidence I or II studies: A Tumor Marker Utiity Grading Scae Hayes, et a; J Nat Cancer Institute 88:1456, 1996

10 TMUGS: Leves of Evidence Leve I Definition Prospective, Marker Primary Objective, We-powered OR Meta-anaysis II III IV V Prospective, Marker Secondary Objective Retrospective, Outcomes, Mutivariate Anaysis Retrospective, Outcomes, Univariate Retrospective, Correation with Other Marker, No Outcomes Hayes, et a; J Nat Cancer Institute 88:1456, 1996

11 TMUGS: Leves of Evidence Leve I II Definition Prospective, Marker Primary Objective, We-powered OR Meta-anaysis MOST TUMOR MARKER STUDIES Prospective, Marker Secondary Objective III IV V Retrospective, Outcomes, Mutivariate Anaysis Retrospective, Outcomes, Univariate Retrospective, Correation with Other Marker, No Outcomes Hayes, et a; J Nat Cancer Institute 88:1456, 1996

12 TMUGS: Leves of Evidence Leve I Definition Prospective, Marker Primary Objective, We-powered OR Meta-anaysis II III IV V Prospective, Marker Secondary Objective Retrospective, Outcomes, Mutivariate Anaysis Retrospective, Outcomes, Univariate Retrospective, Correation with Other Marker, No Outcomes Hayes, et a; J Nat Cancer Institute 88:1456, 1996

13 When is a Diagnostic Cinicay Usefu? It is either prognostic or predictive of cancer outcomes or predicts toxicity The magnitude of effect is sufficienty arge that cinica decisions based on the data resut in outcomes that are acceptabe Greater chance for benefit Smaer toxicity risk The estimate of magnitude of effect is reiabe Assay is reproducibe Cinica tria/marker study design is appropriate Resuts are vaidated in subsequent we-designed studies (Leves of Evidence I or II) Henry N.L., Hayes DF; Oncoogist. 11:541-52, 2006

14 Vaue of Cancer Diagnostics: Identify Those Patients for Whom Benefits Do NOT Outweigh Risks, and Therefore We Can Safey Recommend Withhoding that Treatment Prognosis Prediction 100% cure P r o g 50% cure n o s I s 10% cure Factor 1 Neg Factor 2 Neg No Therapy Factor 1 Pos Factor 2 Pos Therapy P=<0.05 No Therapy Factor 1 Pos Factor 2 Pos Factor 2 Neg Factor 1 Neg Therapy P=<0.05

15 Cancer Diagnostics: Why Use Them? Identify patients who woud FOREGO or DISCONTINUE therapy to AVOID toxicities. A are exposed to cost and toxicity Some but not a positive patients wi benefit Few if any negative patients wi benefit

16 Tamoxifen vs. Not RECURRENCES Effect of ER POOR POSITIVE Eary Breast Cancer Triaists' Coaborative Group. Lancet. 365: , 2005

17 Incorporation of Tumor Marker Into Cinica Care What evidence is required from stakehoders? How is evidence currenty being generated? Are there innovative ways to generate higher quaity evidence more efficienty? What are the barriers to generating this evidence and how can they be overcome?

18 Tumor Markers: Determination of Cinica Utiity Strategies to Test the Test and Generate LOE I data: Prospective Cinica Trias: Marker is Primary Objective! Sargent D.J., et a. J Cin Onco. 23:2020-7, 2005 Freidin B., et a. J Nat Cancer Inst. 102:152-60, 2010 At present, very few such trias are ongoing in N.A. For exampe, in breast cancer, there are 3: Tria Disease Test Num pts Status TaiorRx Adj Breast 21-gene RS ~6500 Fuy accrued S0500 Met Breast CeSearch ~120 Ongoing

19 Incorporation of Tumor Marker Into Cinica Care What evidence is required from stakehoders? How is evidence currenty being generated? Are there innovative ways to generate higher quaity evidence more efficienty? What are the barriers to generating this evidence and how can they be overcome?

20 Tumor Markers: Determination of Cinica Utiity Strategies to Test the Test and Generate LOE I data: Prospective Cinica Trias: Marker is Primary Objective! Sargent D.J., et a. J Cin Onco. 23:2020-7, 2005 Freidin B., et a. J Nat Cancer Inst. 102:152-60, 2010 Is a Prospective Tria Aways Necessary For Marker Utiity? NO! But use of archived tissue must be done with rigor Simon R.M., Paik S, Hayes DF. JNCI 101: , 2009

21 Use of Archived Tissues To Determine Cinica Utiity of Tumor Markers Category A B C D Tria Design Prospective Prospective using archived sampes Prospective /observationa Retrospective/observationa Cinica tria PRCT designed to address tumor marker Prospective tria not designed to address tumor marker, but design accommodates tumor marker utiity. Accommodation of predictive marker requires PRCT Prospective observationa registry, treatment and foow up not dictated No prospective aspect to study Patients and patient data Prospectivey enroed, treated, and foowed in PRCT Prospectivey enroed, treated, and foowed in cinica tria and, especiay if a predictive utiity is considered, a PRCT addressing the treatment of interest Prospectivey enroed in registry, but treatment and foow up standard of care No prospective stipuation of treatment or foow up; patient data coected by retrospective chart review Specimen coection, processing, and archiva Specimens coected, processed and assayed for specific marker in rea time Specimens coected, processed, and archived prospectivey using generic SOPs. Assayed after tria competion. Specimens coected, processed, and archived prospectivey using generic SOPs. Assayed after tria competion. Specimens coected, processed and archived with no prospective SOPs Statistica Design and anaysis Study powered to address tumor marker question. Study powered to address therapeutic question; underpowered to address tumor marker question. Focused anaysis pan for marker question deveoped prior to doing assays Study not prospectivey powered at a. Retrospective study design confounded by seection of specimens for study. Focused anaysis pan for marker question deveoped prior to doing assays Study not prospectivey powered at a. Retrospective study design confounded by seection of specimens for study. No focused anaysis pan for marker question deveoped prior to doing assays Vaidation Resut unikey to be pay of chance Athough preferred, vaidation not required Resut more ikey to be pay of chance that A, but ess ikey than C. Requires one or more vaidation studies Resut very ikey to be pay of chance. Requires subsequent vaidation studies Resut very ikey to be pay of chance. Requires subsequent vaidation Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

22 Use of Archived Tissues To Determine Cinica Utiity of Tumor Markers Category Tria Design Cinica tria A Prospective PRCT designed to address tumor marker Patients and patient data Specimen coection, processing, and archiva Statistica Design and anaysis Vaidation Prospectivey enroed, treated, and foowed in PRCT Specimens coected, processed and assayed for specific marker in rea time Study powered to address tumor marker question. Resut unikey to be pay of chance Athough preferred, vaidation not required Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

23 Use of Archived Tissues To Determine Cinica Utiity of Tumor Markers Category Tria Design B Prospective using archived sampes Cinica tria Patients and patient data Specimen coection, processing, and archiva Statistica Design and anaysis Prospective tria not designed to address tumor marker, but design accommodates tumor marker utiity. Accommodation of predictive marker requires PRCT Prospectivey enroed, treated, and foowed in cinica tria and, especiay if a predictive utiity is considered, a PRCT addressing the treatment of interest Specimens coected, processed, and archived prospectivey using generic SOPs. Assayed after tria competion. Study powered to address therapeutic question; underpowered to address tumor marker question. Focused anaysis pan for marker question deveoped prior to doing assays Vaidation Resut more ikey to be pay of chance that A, but ess ikey than C. Requires one or more vaidation studies Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

24 Use of Archived Tissues To Determine Cinica Utiity of Tumor Markers Category Tria Design Cinica tria Patients and patient data Specimen coection, processing, and archiva Statistica Design and anaysis Vaidation C Prospective /observationa Prospective observationa registry, treatment and foow up not dictated Prospectivey enroed in registry, but treatment and foow up standard of care Specimens coected, processed, and archived prospectivey using generic SOPs. Assayed after tria competion. Study not prospectivey powered at a. Retrospective study design confounded by seection of specimens for study. Focused anaysis pan for marker question deveoped prior to doing assays Resut very ikey to be pay of chance. Requires subsequent vaidation studies Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

25 Use of Archived Tissues To Determine Cinica Utiity of Tumor Markers Category Tria Design Cinica tria D Retrospective/observationa No prospective aspect to study Patients and patient data Specimen coection, processing, and archiva Statistica Design and anaysis Vaidation No prospective stipuation of treatment or foow up; patient data coected by retrospective chart review Specimens coected, processed and archived with no prospective SOPs Study not prospectivey powered at a. Retrospective study design confounded by seection of specimens for study. No focused anaysis pan for marker question deveoped prior to doing assays Resut very ikey to be pay of chance. Requires subsequent vaidation Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

26 Revised LOI Scae: Use of Archived Tissues Leve of Evidence Category from Tabe 1 Vaidation Studies Avaiabe I A None required I B One or more with consistent resuts II B None or Inconsistent resuts II C 2 or more with consistent resuts III C None or 1 with consistent resuts or Inconsistent resuts IV-V D NA Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

27 Incorporation of Tumor Marker Into Cinica Care What evidence is required from stakehoders? How is evidence currenty being generated? Are there innovative ways to generate higher quaity evidence more efficienty? What are the barriers to generating this evidence and how can they be overcome?

28 Undervaue of Tumor Markers: Muti-factora Tumor Marker Research is not perceived to be as exciting or important as new therapeutics, especiay the cinica component Less Academic credit Breast Cancer Steering Committee Review of New Concept: of course, the secondary randomization to new drug is the exciting part Less Funding Cancer Center Support Grants: ack of investigator initiated THERAPEUTIC Trias is significant weakness Less Rigor Less evidence required for cinica use FDA Guideines Panes Less QC/QA/Proficiency testing (test dependent) Less reimbursement

29 Undervaue of Tumor Markers: A Vicious Cyce Marker Utiity is Poory Vaued Less Certainty of Data; Less Vaue for Tumor Marker Cinica Utiity Few Recommendations for Cinica Use Poor Leve of Reimbursement Lower Funding for Tumor Marker Research Lower Leve of Evidence (Private, Pubic) Litte Incentive to do Propery Designed and Controed Cinica Studies Poor Reguatory Organization Regarding Cinica Data Needed to Approve Test CLIA/LDTs

30 Acceptance of Tumor Markers: Baance of Carrots and Sticks Rapid Cinica Acceptance Patient and cinician desire Financia and academic benefits Vaidated Cinica Utiity LOE I studies Financia burden/low Payoff

31 Highy Vaued Tumor Markers: A Virtuous Cyce FDA/Guideines Panes/Tech Assessment Panes SOCIETY Marker Advocacy Utiity Community is Highy Vaued CMS/BCBS/ etc Leve I Data; High Vaue for Tumor Marker Cinica Utiity Strong Recommendations for Cinica Use High Leve of Reimbursement Leve I Evidence Higher Funding for Tumor Marker Research (Private, Pubic) Huge Incentive to do Propery Designed and Controed Cinica Studies Unified FDA and Guideines Approva/Recommendations Cooper Groups, Cancer Centers, Industry NCI/Industry/ DOD/Phianth

32 Increase Vaue of Tumor Markers: Proposas Recom ns for cinica tumor marker use be evidence-based for cinica utiity Increase reimbursement for tumor markers IF cinica utiity Increase funding for tumor marker research = to that for therapeutics. Reform reguatory review of tumor markers. Organize Oncoogic Product Line incuding ODAC and OIVD FDA criteria shoud require anaytica vaidity and cinica utiity Eiminate aboratory deveoped test discretion Require new drug registration trias have biospecimen bank Enhance academic credit for tumor marker studies Increase rigor of tumor marker pubications (severa pubications- REMARK, etc) = Therapeutic Trias

33 Thanks to Many Coeagues ASCO TM Guideines Committee Richard Schisky; U. Chicago Doug Bayney; U. Michigan Steve Gutman; Formery FDA, now U. Centra Forida Finey Austin; Roche Diagnostics Craig Henderson; U.C.S.F. Richard Simon; NCI Steve Shak; GHI Gerry Doye; Immunicon/Veridex Robert McCormack; Veridex Ted Lawrence, Gary Lyman, Cindy Stephens, Mark Somerfied; ASCO Jeff Aen; FOCR COBRA: David Fockhart, Vered Stearns, James Rae, others

34 Tamoxifen and 2D6: Case Study Theoretica Background: Tamoxifen may be a pro-drug Parent is weak SERM Tamoxifen is metaboized to two active moieties: 4-hydroxy tamoxifen 4-hydroxy N-desmethy tamoxifen (Endoxifen)

35 Tamoxifen is Activated and Inactivated by Poymorphic Enzymes Weak anti-e2 Weak anti-e2 Potent anti-e2 Inactive Known Genetic Variants Rae, J.M.

36 CYP2D6 variant genotype and CYP2D6 inhibitors ower Endoxifen Concentrations Figure P= P=0.007 Pasma endoxifen concentration (nm) P= WT/WT EM/EM (18) (18) WT/Vt EM/PM (7) (7) PM/PM Vt/Vt (2) (2) EM/EM WT/WT (12) EM/PM WT/Vt (7) (2) No Cyp 2D6 Inhibitors No CYP 2D6 Inhibitors CYP 2D6 genotype groups With With Cyp CYP 2D6 2D6 Inhibitors Jin et a; JNCI 97:30, 05

37 North Centra Cancer Treatment Group Adjuvant Breast Cancer Tria ER + Newy diagnosed Breast cancer 5 years tamoxifen 5 years tamoxifen + 1year fuoxymesterone OVERALL: no difference in DFS or OS for addition of fuoxymestrone to tamoxifen Inge JN, et a. Cancer 67: , 1991

38 Disease-Free Surviva (CYP2D6 *4) 100 % Wt/Wt Wt/* P= Years after randomization *4/*4 Goetz, MP, et a. J Cin Onco. 23:9312, 2005 CP

39 Category A B Tria Design Prospective Prospective using archived sampes Cinica tria Patients and patient data Specimen coection, processing, and archiva Statistica Design and anaysis Vaidation PRCT designed to address tumor marker Prospectivey enroed, treated, and foowed in PRCT Specimens coected, processed and assayed for specific marker in rea time Study powered to address tumor marker question. Resut unikey to be pay of chance Athough preferred, vaidation not required Prospective tria not designed to address tumor marker, but design accommodates tumor marker utiity. Accommodation of predictive marker requires PRCT Prospectivey enroed, treated, and foowed in cinica tria and, especiay if a predictive utiity is considered, a PRCT addressing the treatment of interest Specimens coected, processed, and archived prospectivey using generic SOPs. Assayed after tria competion. Study powered to address therapeutic question; underpowered to address tumor marker question. Focused anaysis pan for marker question deveoped prior to doing assays Resut more ikey to be pay of chance that A, but ess ikey than C. Requires one or more vaidation studies

40 Revised LOI Scae: Use of Archived Tissues Leve of Evidence Category from Tabe 1 Vaidation Studies Avaiabe I A None required I B One or more with consistent resuts II B None or Inconsistent resuts II C 2 or more with consistent resuts III C None or 1 with consistent resuts or Inconsistent resuts IV-V D NA Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

41 CYP2D6 pharmacogenomics: Discordant Resuts Swedish study-postoperative radiotherapy vs. adjuvant chemo, w/ (n=112) or w/o (n=114) 40 mg tamoxifen for 2yrs CYP2D6 *1/*1 WT CYP2D6 *1/*4 or *4/*4 Tam + Tam + Tam - Tam - Just the opposite of expected!!

42 CYP2D6 and Tamoxifen Since origina Goetz paper at east 15 separate studies suggesting that for women taking tamoxifen for prevention or treatment of breast cancer: That CYP2D6 var/var OR inhibitors = WORSE outcome That CYP2D6 has NOTHING to do with outcome That CYP2D6 = BETTER outcome

43 Revised LOI Scae: Use of Archived Tissues Leve of Evidence Category from Tabe 1 Vaidation Studies Avaiabe I A None required I B One or more with consistent resuts II B None or Inconsistent resuts II C 2 or more with consistent resuts III C None or 1 with consistent resuts or Inconsistent resuts IV-V D NA Simon R.M., Paik S, Hayes DF. J Nat Cancer Inst. 101: , 2009

44 Tamoxifen PKG Definitive Vaidation Studies and New Directions Int Tam Pharm Coa ATAC SABCS 2010 BIG98 SABCS 2010 NSABP P1 and P2 SABCS 2010 (SABCS 2009: No interaction) UK Prev n tam vs pac Competed Bayor (pop n based) SABCS 2010 IES Work in Progress E3108 Prosp tria/metastatic ER Pos Metaboism Distribution ER pathway/co-activators/repressors Tota >9,000 patients

45 Tumor Marker evaluation What is the probem? There appears to be an Inconsistent/Uncear path to cinica acceptance: FDA criteria for cearance/approva may not consider specific cnica utiity FDA cearance does not mean an assay shoud be used cinicay Laboratory Deveoped Tests (LBT): Home Brew rue - An assay can be marketed without FDA cearance Disagreement about what outcomes need to be improved, and how to measure them There is a disconnect among Guideines Panes and between them and FDA Low reimbursement Entrepreneurs cannot afford to deveop new markers if cost of doing so is substantiay increased

46 Increase Vaue of Tumor Markers: Proposas Increase research $$ for cinica trias directed towards markers Cinica trias in which marker is primary objective of study Cinica trias in which marker is secondary endpoint Co-deveopment; or at the east- Coection and storage of specimens in association with PRCTs Consoidate a Oncoogy Reguatory activities within FDA Create an ODAC -ike committee for tumor markers Maintain CLIA as mediator of QA/QC; but eiminate home brew designation A LDTs? Seected assays? New assays? Have FDA stipuate that no registry tria be accepted without prospective pan for specimen bank: Prospective co-deveopment pan; or at the east Coection/storage Transparent system to access specimens Independent peer review Adequate IP protection Increase rigor of tumor marker approva to meet a criteria needed for cinica adoption of a tumor marker Severa Pubications Increase reimbursement commensurate with increased rigor in approva process (as for therapeutics) Fundamentay change method of care-giver reimbursement, so that doctors get paid for doing the right thing, and not for recommending their gimmick