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Roche Molecular Medicine Laboratories Biomarkers in Personalized Health Care: Opportunities, Challenges, Approaches Klaus Lindpaintner Roche Molecular.

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Presentation on theme: "Roche Molecular Medicine Laboratories Biomarkers in Personalized Health Care: Opportunities, Challenges, Approaches Klaus Lindpaintner Roche Molecular."— Presentation transcript:

1 Roche Molecular Medicine Laboratories Biomarkers in Personalized Health Care: Opportunities, Challenges, Approaches Klaus Lindpaintner Roche Molecular Medicine Laboratories

2 Case Report 1: Ms. Silvia R., 28 Started on imipramine 25 mg tid No improvement 3 weeks later Dose increased to 50 mg tid No improvement 3 weeks later Switched to paroxetine 20 mg qd No improvement 3 weeks later One week later admitted to hospital in critical condition after attempted suicide Depression

3 Patient w/ pneumonia treated w/ antibiotics and w/ codeine for cough On treatment day 4 patient was found unresponsive Transfer into ICU, life support: intubation, respirator Supportive care was successful – patient recovered fully Case report 2: Joon C., MD, 34 Pneumonia

4 1997 Diagnosis: breast cancer Prognosis: 3 years to live On her 55. birthday… On January 12, 2006 Case Report 3: Ms. Regula S Breast Cancer

5 Case Report 4: Patient #45 Day 15 Baseline Metastatic malignant melanoma

6 Proper treatments – improper dose Gene test for CYP450- 2D6, indicates ultra-rapid variant in both patients Resulting in Ineffective dose in case 1 Effective overdose in case 2

7 Drug metabolism Inherited differences affect drug effects

8 Pro-drug activation Same principle – turned on its head Ineffective Adverse events

9 nl HER2 HER2 Personalized Approach to the patient Example: breast cancer, Herceptin® Breast cancer facts: 700,000 new cases in Europe and the US -- 200,000 deaths One in 10 women will contract breast cancer in her life-time Breast cancer facts, updated: 2/3 of all patients: 7 years survival 1/3 of all patients: 3 years survival growth factor Her2 - growth factor Her2 + Diagnosis for Ms Regula S.: (1) Biopsy: + (2) HerCep-Test: + Herceptin® therapy initiated

10 BRAF Kinase An Important Mediator of Cellular Proliferation Membrane RTK Y-P Ras GTP Other Effectors Growth Factors RAF MEK ERK P P Nuclear Translocation Gene Expression BRAF V600E MEK ERK P P Abnormal Cellular Proliferation Normal signaling Oncogenic signaling Arrested

11 Personalized health care Two fundamentally different concepts, one consequence Genetic Concept – Archibald Garrod, (sulphonal-induced porphyria) –Molecular variant is immaterial to disease –Inherited susceptibilities to xenobiotics (drugs, nutrients) –Generally affects pharmacokinetics –Static –Example; CyP450, UGT Molecular Concept – Disease Cause-Effect Targeting –Molecular variant fundamentally important to disease pathology –rewriting the textbook of medicine based on molecular understanding –Generally affects pharmacodynamics, causation-driven treatments –Dynamic –Example: Her2, BRAF

12 Case Report 5: State of the Pharmacopoeia A call for more effective and safer drugs 1 Spears et al., Trends Mol Med, 2001; 2 Lazarou et al., JAMA, 1998 Drug Response Rate, % Analgesics 0 20 40 60 80 Cancer Efficacy Safety

13 Case Report 6: NME track record Step-change needed in pharmaceuticals development Sources: FDA/CDER Data, PhRMA data, Price Waterhouse Coopers analysis, Pharma 2020 R&D spend New Molecular Entities (NME) $ 47 bn $ 17 bn 17 53 19962007

14 Case report 7: New technologies Expanding our understanding of diseases IHC/ISH Benchmark Microarray analysis AmpliChip Sequencing Real-time PCR TaqMan Multiplex proteins Impact Elecsys ELISA

15 Healthcare Pressures: Benefit-Risk Ratio Economic Pressures: Benefit-Cost Ratio New Technologies: Expanded Capabilities Need for highly differentiated medicines that have a clear impact on individual and public health Only truly innovative medicines will find acceptance Innovative ~ Personalized PHC as Key Driver of Change Key to enabling highly differentiated medicines

16 Messages: Personalized Healthcare Essential to progress in individual patient care Conceptually nothing new Requires thoughtful, differentiated consideration: Context and Information Content

17 Personalized Healthcare General considerations Qualification and Utility of Biomarkers Study Design Considerations Economical and Ethical Considerations Opportunities & Challenges

18 Personalized Healthcare General considerations Qualification and Utility of Biomarkers Study Design Considerations Economical and Ethical Considerations Opportunities & Challenges

19 Personalized Health Care A definition Discovery and development of pharmaceuticals and diagnostics that better account for human variation and for the diverse molecular basis of disease. Use of biomarkers expected to be critical to facilitate this differentiation.

20 Personalized Medicine, Biomarkers Pharmacogenetics: An altogether new concept?? Finding the optimal treatment for every patient is as old as medicine: differential diagnosis 530 BC: Pythagoras observes that some people tolerate the ingestion of fava-beans, others not 1960 AD: glucose-6-phosphate-dehydrogenase deficiency recognized as the cause 1990 AD: SNPs in the G6PD gene characterized Tailoring treatments to drug-specific test results is nothing new. Example: antibiotics –Gram-positive bacteria: e.g. penicillin derivatives –Gram-negative bacteria: e.g. aminoglycosides –M. tuberculosis: isoniazid/rifampin/pyrazinamide

21 Biomarkers and Personalized Health Care What is new – and why now? Since~1980: Availability of powerful, highly parallel new screening methods (omics) makes hypothesis-free search for new biomarkers and for new treatment approaches a reasonable proposition. Since ~2000: Paradigm shift(?): maturation of these basic cell and molecular biology tools makes them newly applicable to later-stage R&D and clinical practice as robust, reliable diagnostics Translation of extant, older as well as newly emerging knowledge into clinical practice

22 Complexity of Science A biomarker might be more difficult to find than a drug Biomarker = Any biological parameter used as indicator of disease process or drug response Potentially valuable Early stage assessment Clinical use Exploratory

23 Biomarker Development – Requirements Significant hurdles Generation of a biomarker hypothesis Develop prototype assay Identification of candidate markers Discovery Clinical validation of candidate markers using assay Assay refinement & development IVD test Regulatory test approval Validation Distribution to laboratories Auditing for result consistency Commercialisation Clinician/Lab education

24 Confirmatory Phase Dx launch/ Post-launch assessment Biomarker development Making PHC happen A complex undertaking Target Selectio n Exploratory Phase Discover y Phase Research Companion diagnostic feasibility & attractiveness Tailored prescribing & monitoring Target identification Patient selection Research assay Technically validated assay Clinically validated IVD assay DevelopCommercialise Lead Generation/ Optimisatio n Phase 0Phase IPhase IIPhase IIIFiling Market Phase IV PoC

25 Personalized Healthcare General considerations Qualification and Utility of Biomarkers Study Design Considerations Economical and Ethical Considerations Opportunities & Challenges

26 Responders, Non-Responders Reality Check 31% 43% 22% Regulatory agency benchmark: 35% improvement/response (hypothetical) AN

27 Biomarker test performance, qualification Diverse considerations Analytical performance: QC and accreditation of labs Clinical validity: retrospective/observation studies Clinical utility: prospective intervention trials Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

28 Biomarker test performance, qualification Diverse considerations Analytical performance: QC and accreditation of labs Clinical validity: retrospective/observation studies Clinical utility: prospective intervention trials Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

29 Analytical performance … not a foregone conclusion

30 Biomarker test performance, qualification Diverse considerations Analytical performance: QC and accreditation of labs Clinical validity: retrospective/observation studies Clinical utility: prospective intervention trials Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

31 Study Design Justifying the (implicit) conclusions? Patients and Methods Chemotherapy-naive patients with advanced NSCLC with 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. Conclusions First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

32 Biomarker test performance, qualification Diverse considerations Analytical performance: QC and accreditation of labs Clinical validity: Proper study design essential retrospective/observation studies Clinical utility: prospective intervention trials Note: Prior probability (i.e. context): critical for test performance (i.e. information content), esp. screens (sensitivity/specificity, PPV/NPV)

33 labeled DNA target Oligonucleotide probe * * * * * The Roche CYP450 Amplichip Pioneering technology and the challenge of clinical utility Broad allelic coverage of known variants, for many ethnic groups (CYP2D6 and CYP2C19) Introduced micro-array technology to diagnostics CE, FDA Certified – first-in-class device Analytical Performance (new gold standard) Clinical Validity Clinical Utility (psychiatry, CVD): t. b. d. Ultimately: need to demonstrate incremental cost-effectiveness ratio acceptable to payers a new era of ph III studies in Dx

34 Context: Tamoxifen and CYP450 2D6 Testing prior to treatment? N-desmethyl-tamoxifen (NDM) Tamoxifen CYP3A4/5 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) CYP2D6

35 Personalized Healthcare General considerations Qualification and Utility of Biomarkers Study Design Considerations Economical and Ethical Considerations Opportunities & Challenges

36 Study Design Considerations (1) Context: Nature of illness, aim of marker Biomarker Target Product Profile: First, do no harm! Serious (life-threatening) illness Default: dont withhold in error; If in doubt: treat Less serious illness Default: dont treat in error; If in doubt: dont treat

37 Biomarker Target Product Profile Efficacy marker: High sensitivity Safety marker: High specificity Efficacy marker: High specificity Safety marker: High sensitivity Less serious illness: dont prescribe inappropriately Serious illness: dont withhold inappropriately Determined by Context and Information Content

38 Study Design Considerations (2) 2 fundamentally different Objectives –Advancing fundamental understanding, but clinically not necessarily actionable p-value-driven –Finding clinically actionable biomarkers: information content in given context! magnitude-of-effect-driven; p essential but not sufficient Indication Efficacy vs. Safety Phase of trial Effects on Study Design: –Type of specimens –Number of specimens Defining the Target Product Profile – Controlling Costs – Debunking Myths

39 Lost in Translation OR = 1.5 OR =1.15 OR = 9 sens/spec = 55% sens/spec = 51% sens/spec = 75% Different scientific terminologies in research and clinic

40 Lost in Translation Posit: significance 0.05, power 85% Different scientific terminologies in research and clinic

41 Lost in Translation n = 936 n = 7456 n = 42 Different scientific terminologies in research and clinic Consequences: OR = 1.5 OR =1.15 OR = 9 sens/spec = 55% sens/spec = 51% sens/spec = 75%

42 Personalized Healthcare General considerations Qualification and Utility of Biomarkers Study Design Considerations Economical and Ethical Considerations Opportunities & Challenges

43 Personalized Medicine – Challenges Economic Exhaustive pharmacogenetic research efforts have narrowed your niche market down to Harry Finkelstein of Newburg Heights here.

44 Economics of stratification drive PHC Creating patient benefits and commercial incentives Unstratified Medicine Stratified Medicine Reduced Eligible Patient Population Patient benefit: Optimal efficacy Avoid unnecessary treatment / side effects Decreased uncertainty Penetration Market share Duration of therapy Adherence Line extensions

45 Economics of stratification drive PHC Creating patient benefits and commercial incentives Unstratified Medicine Stratified Medicine Reduced Eligible Patient Population Payer Acceptance

46 The Tightening Reimbursement Climate Biomarker strategies may be essential Elkin et al; J Clin Oncol 2004; 22:854 ff ($/£ conv. rate 1/1/2003, not PPP-adjusted) NB: National Institute for Clinical Excellences (NICE) threshold for approving reimbursement through NHS believed to be ~UK £ 30,000 per QUALY (quality-adjusted life year)

47 Biomarker Adoption Evidence counts Results: In the base case, genotype-guided dosing resulted in better outcomes, but at a relatively high cost. Overall, the marginal cost-effectiveness of testing exceeded $170 000 per QALY…

48 A friendly nudge…

49 Ethical, Legal, Societal Considerations Do we need to reinvent the wheel? Autonomy: privacy and respect Confidentiality –Patient protection more important than data protection – GINA –Information content, not type counts: counter genetic exceptionalism Beneficence: do good No Maleficence: dont do harm

50 Biomarkers - Personalized Medicine Summary Conceptually nothing new – nothing to be afraid of! Essential to progress in individual patient care –Only more differentiated understanding of patients/disease will allow progress in health care Requires thoughtful, differentiated consideration –Avoid black-and-white thinking: complex disease pathology is complex – context counts –High demand on information-content of test: Evidence-based implementation –Essential: create win-win scenarios with payers –Not a panacea: we will not always find a biomarker, but we must always try. Motto: Robust (aggressive?) optimism – paired w/ realism and modesty!

51 No 1-on-1 custom tailoring, but towards a much better fit … 38 40 39 39½ 37 3 / 4 Remember: All medical decisions/knowledge are based on group-derived (aggregate) data analysis – individual data are anecdotal and cannot be validated.

52 We Innovate Healthcare


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