Louis B. Jacques, MD Director Coverage & Analysis Group

1. WSMOS 2012 Louis B. Jacques, MD Director Coverage & Analysis Group

2. Topics • Coverage Process • FDA and CMS • MOU • Parallel Review • Targeted Therapies and Molecular Diagnostics • MolDx

3. Social Security Act 1862(a)(1) Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services— (A) which, except for items and services described in a succeeding subparagraph or additional preventive services (as described in section 1395x(ddd)(1) of this title), are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member, *** (E) in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section, ***

4. MEDICARE NATIONAL COVERAGE PROCESS PreliminaryDiscussions Reconsideration Benefit Category 6 months or 9 months Final Decision Memorandum and Implementation Instructions Proposed Decision Memorandum Posted National Coverage Request StaffReview Public Comment External Technology Assessment Departmental Appeals Board Staff Review MEDCAC

5. The Preferred Road to Therapeutic Coverage • Provide adequate evidencethat • A treatment strategy using the new therapeutic technology compared to alternatives • Leads to improved clinically meaningful health outcomes • In Medicare beneficiaries

6. The Preferred Road to Diagnostic Coverage • Provide adequate evidencethat • The incremental information obtained by new diagnostic technology compared to alternatives • Changes physician recommendations • Resulting in changes in therapy • That improve clinically meaningful health outcomes • In Medicare beneficiaries

7. Health Outcomes of Interest Longer life and improved function/participation Longer life with arrested decline Significant symptom improvement allowing better function/participation Reduced need for burdensome tests and treatments Quality of life Longer life with declining function/participation Improved disease-specific survival without improved overall survival Surrogate test result better Image looks better Doctor feels confident More Persuasive* Less Persuasive * If based on methodologically robust evidence

8. CMS and FDA

9. Things we hear… • “FDA approved it so CMS must cover it.” • “Just because FDA didn’t approve it…CMS should cover it anyway.” • “We don’t think the Boxed Warning is really relevant to this indication.” • “FDA won’t allow us to include clinical outcomes in our trial.” • “We can’t share (our own) data with you without getting FDA approval.”

10. How do our review processes compare?

11. FDA CMS MOU http://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/ucm217585.htm

12. Why Parallel Review? • Sponsors focus on FDA, Medicare coverage is • Not on the radar screen at all • Presumed (erroneously) to come automatically with FDA approval/clearance • Door has been open to sponsors for ad hoc engagement of CMS and FDA, particularly with devices. • CMS input on inclusion of Medicare-relevant outcomes • Enrollment of older subjects in trials

13. FDA-CMS Parallel Review Pilot • Soliciting nominations from sponsors of innovative medical device technologies to participate in a pilot program for concurrent review of certain FDA premarket review submissions and CMS national coverage determinations • Sets procedures for voluntary participation and guiding principles that the agencies will follow • Published October 17, 2011, (76 FR 62808) • Effective November 10, 2011 • http://www.gpo.gov/fdsys/pkg/FR-2011-10-11/html/2011-25907.htm

14. Cancer

15. How does a cancer diagnosis affect patients and their loved ones? • Everything has changed. My friends and co-workers treat me differently. • When people don’t know what to say, sometimes they say nothing – which can be worse. • She took care of me for 50 years – I have to do everything possible for her now, no matter what. • He’s clueless without me; he can’t even pay a bill on time. • This treatment will kill me if the cancer doesn’t get me first. • If I’d known it was going to turn out like this I would have just stayed home. It would have been better that way. • Thank you for listening to me. Things I’ve heard…

16. What is in the Oncology Space? • Tumor-specific clinical care with curative intent • Tumor-specific clinical care with palliative intent • Treatment-specific clinical care with any intent, e.g. neuropathy, lymphedema • Biomarker development in the context of drug/biologic development

17. PATIENT Workup + New Test Usual Workup Usual Therapy Different Therapy Better Outcome Usual Outcome Worse Outcome

18. Molecular Testing and BiomarkersChallenges • “Home brew” laboratory developed tests have largely avoided FDA review (to date.) • Biomarker tests might not be commercially available for clinical use. • Receptor promiscuity creates risk for unintended effects • Different markers (e.g. CYP2C9 and VKORC1) and different techniques (e.g. SNPs and sequencing) on different proprietary platforms make it difficult to generalize or compare results. • The evidence base is sparse and uneven.

19. ACCE • Analytic Validity: the ability of a genetic test to accurately and reliably measure the genotype (or analyte) of interest in the clinical laboratory, and in specimens representative of the population of interest. It includes analytic sensitivity and specificity, reliability and assay robustness. • Clinical Validity: the ability of a genetic test to accurately and reliably predict the clinically defined disorder or phenotype of interest. It includes clinical sensitivity and specificity, and positive and negative predictive values (taking into account the prevalence of the phenotype or disorder of interest in the tested population). • Clinical Utility: the evidence of improved measurable clinical outcomes; the genetic test’s usefulness and added value to patient management decision-making. It encompasses effectiveness and net benefit (the balance of benefits and harms); and • In the ACCE model, the E refers to ethical, legal, and societal implications which may reflect non-quantifiable political and moral judgments rather than outcomes of clinical trials.

20. Pharmacogenomics in CancerJanuary 17, 2010 MEDCAC For those items where you have at least intermediate confidence that there is sufficient evidence to address the question, how confident are you that pharmacogenomic testing improves health outcomes for patients with cancer whose anticancer treatment strategy is guided by the results of testing as described below? 1 = No confidence; 5 = High confidence

21. Desirable Characteristics of Evidence for Diagnostic TestingMEDCAC February 25, 2009 There was broad consensus that CMS should expect a high evidentiary standard for genetic and genomic tests. The evidence base regarding the clinical use of these tests is immature, and the true harms and benefits that may accrue from the use of these tests are uncertain. https://www4.cms.hhs.gov/mcd/viewmcac.asp?where=index&mid=47

22. MEDCAC Recommendations • Direct patient clinical outcomes: mortality, functional status, adverse events. • Consider the clinical context: what are the consequences of being wrong if the test proves to be misleading? • Endorsed the EGAPP/ACCE framework. • The complexity of issues related to genetic and genomic testing speak for the need for stronger evidence than what might be considered for other types of diagnostic testing. • Ethical concerns compel scientifically robust clinical trials and should not be an excuse to support uninformed care