Implementation of Pharmacogenomics in Clinical Practice: Barriers and Potential Solutions

Transcription

1 Molecular Pathology : Principles in Clinical Practice Implementation of Pharmacogenomics in Clinical Practice: Barriers and Potential Solutions KT Jerry Yeo, Ph.D. University of Chicago [email protected] Presented by AMP & AACC May 7-8, 2010 Chicago, IL

2 Disclaimer Received reagent support from GenMark Dx

3 Objectives By the end of this presentation participant should be able to: 1. Describe the Promise of PGx in Personalized Drug Therapy 2. Appreciate the current barriers in clinical adoption of PGx 3. Discuss potential solutions to enhance the adoption of PGx in clinical practice

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6 The Promise of PGx 4Rs:Right drug,right patient, right dose, right time! Maximise drug efficacy Decrease ADRs Salvage failed drugs

7 Resurrect 3 failed drugs?

8 Barriers to PGx adoption

9 Translation Issues Cost-Effectiveness of PGx/Reimbursements Issues Controversial Trials Results (e.g. Cyp2C19 PGx-Clopidogrel) Paucity of large Randomized Controlled Trials Need for Consensus Guidelines Physician Awareness/Understanding Wu, Babic & Yeo. Person Med 2009;6:315

10 Translation Issues Patient Awareness vs Physician Readiness: Education efforts needed Laboratory Issues/Preparedness to adopt PGx/Informatics Lack of in-house expertise for consultations/interpretations: Opportunity for leadership by teaching hospitals Wu, Babic & Yeo. Person Med 2009;6:315

11 Reimbursement Issues

12 Reimbursement CPT Codes Extraction of highly purified nucleic acid Multiplex PCR for first 2 sequences Multiplex each additional sequence * Mutation Identification by ASPE * Interpretation and Reporting Pathologist Interpretation if performed Currently no specific CPT codes for PGx panels makes tests appear less important to 3 rd party payors Lack of standardization in test-billing is a deterrent and barrier to implementation Wu, Babic & Yeo. Person Med 2009;6:315

13 Guidelines against Warfarin PGx At the present time, for patients beginning [vitamin K antagonist] therapy, without evidence from randomized trials, we suggest against the use of pharmacogenetic-based initial dosing to individualize warfarin dosing (Grade 2C) (Hirsh J, et al. Chest. 2008;71S 109S). American College of Medical Genetics Working Group reached a more ambivalent conclusion: [T]here is insufficient evidence, at this time, to recommend for or against routine [genetic] testing in warfarin-naive patients. The ACMG statement also said, Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing (Flockhart DA, et al. Genet Med. 2008;10: ).

14 CMS Ruling for PGx testing for Warfarin (May 4, 2009) CMS believes that the available evidence does not demonstrate that pharmacogenomic testing to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries. Therefore, we are proposing that pharmacogenomic testing to predict warfarin responsiveness is not reasonable and necessary under 1862(a)(1)(A) of the Social Security Act. Pharmacogenomic testing to predict warfarin responsiveness is covered only when provided to Medicare beneficiaries who are candidates for anticoagulation therapy with warfarin and only then in the context of a prospective, randomized, controlled clinical study.

15 ACCF/AHA 2010 Recommendations for Antiplatelet Rx Practice Careful clinical judgment to assess the importance of the variability in response to clopidogrel Clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel metabolism.can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel has been associated with adverse patient outcomes. The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined (e.g. CYP 2C19 *2 vs *3 or *4 ) Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies. The selection of the specific test, as well as the issue of reimbursement, are both important additional considerations.

16 Recommendations (Cont) The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time. No information that routine testing improves outcome in large subgroups of patients Clinical course of the majority of patients treated with clopidogrel without either genetic testing or functional testing is excellent...genetic testing may be considered in patients believed to be at moderate or high risk for poor outcomes JACC 2010;56:

17 Solutions-Randomized Trials

18 COAG Trial Study will last about four years ~1200 patients who are beginning warfarin treatment. Conducted at 12 US medical centers funded by the NHLBI Primary outcome is time within therapeutic INR in first 4 weeks of anticoagulation

19 Trials Evaluating Antiplatelet Rx JACC 2010;56:

20 JACC 2010;56: Trials (cont)

21 JACC 2010;56: Trials (cont)

22 Some Good News

23 Mayo-Medco Warfarin Study Controls PGx (30% reduction) Controls For patients on Warfarin: 900 patients followed over 6 months for hospital utilization rates based on genotypeguided dosing 2500 patients control-no genotype performed Hospitalization rates decreased by 30% when genotype information was available PGx grp Epstein et al., JACC 2010,;55:2804

24 Medco also plans new services for genetic tests it s launching a service for health insurers that would administer coverage for high-tech lab tests..

25 Meta-Analysis by Mega et al JAMA 2010;304:1821

26 Risk of Stent Thrombosis Mega et al.jama 2010:304:1821

27 Correlation of CYP genotypephenotype Holmes et al. JAMA 2011:306:2704

28 RESET Gene Study (Sardella) ~1/3 of patient on clopidogrel (loading dose 600mg or maintenance dose 75 mg/d) show high on platelet reactivity (HTPR) Prasugrel 10mg significantly decreased platelet reactivity compared to high-dose clopidogrel (150 mg/d maintenance) for HTPR patients High clopidogrel dose is largely ineffective in the presence of Cyp2C19 *2 allele; in noncarriers both drugs have similar effects

29 Clin Pharm Consortium Guidelines for Clop PGx Scott et al. CPT 2011;90:

30 Scott et al. CPT 2011;90: CYP2C19 guided Rx

31 Scott et al. CPT 2011;90: Suggested Algorithm

32 FDA Initiatives

33 Personalized Medicine Coalition A Victory for Personalized Medicine and Patients Washington, DC - March 24, 2010 The Personalized Medicine Coalition (PMC) praised the landmark health care reform legislation signed into law this week, noting that it represents the first time the principles of personalized medicine were formally voted on and passed by both houses of Congress and signed into law by a president. Also significant is the bill s alignment of personalized medicine with the conduct and use of comparative effectiveness research (CER).

34 Education Efforts

35 Need for Education

36 Education

37 We need DNA Twist!

38 Web-based PGx Education

39 PGx Example

40 Summary-Solutions More evidence-based studies; many underway Consensus guidelines on clinically relevant PGx biomarkers and interpretations Better definitions of genotype-phenotype relationships (e.g. Cyp 2C19, 2D6) Standardization of dosing algorithms (Warfarin) Institutional expertise and leadership Major educational efforts for all health-care professionals; update medical school curriculum to include PGx Stronger FDA drug labeling & other initiatives Advocacy group like PMC Reimbursement by CMS

41 Conclusions Pharmacogenetics will increasingly be used more in clinical decision making in the near future Quantitative measures of the relative risk of toxicity or poor outcome is needed to convince health systems, health professionals, and patients that genome-guided prescribing is important. There is a real need for robust economic analyses of pharmacogenetics testing. Guidelines, standardized PGx panels, physician education, reimbursements are some of the critical factors in assisting adoption of PGx testing.

42 The Future Genomics, Transcriptomics, Proteomics & Metabolomics Interrelationships Gerszten et al Nature 451:949

43 The future is at our doorstep.

44 Collaborators: Nikolina Babic, PhD Loren Joseph, MD Soma Das, PhD Christine Lee, AB Alan Wu, Ph.D., UCSF Acknowledgements

45 Self-Study Questions List the current major barriers to the implementation of pharmacogenomics in clinical care. What is the current controversy in adoption of PGx for clinical use? What are the potential solutions required to facilitate wider adoption of pharmacogenomics?