Louis B. Jacques, MDDirector

Coverage & Analysis Group

WSMOS 2012

Topics• Coverage Process• FDA and CMS– MOU– Parallel Review

• Targeted Therapies and Molecular Diagnostics– MolDx

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

Staff Review

ProposedDecision

Memorandum Posted

National Coverage Request

MEDCAC

External Technology Assessment

6 months or 9 months

Reconsideration

Staff Review

Public Comment

Final DecisionMemorandum

andImplementation

Instructions

Benefit Category

Departmental Appeals Board

MEDICARE NATIONAL COVERAGE PROCESS

Preliminary Discussions

The Preferred Road to Therapeutic Coverage

Provide adequate evidence thatA treatment strategy using the new

therapeutic technology compared to alternatives

Leads to improved clinically meaningful health outcomes

In Medicare beneficiaries

The Preferred Road to Diagnostic Coverage

Provide adequate evidence thatThe incremental information obtained by

new diagnostic technology compared to alternatives

Changes physician recommendationsResulting in changes in therapyThat improve clinically meaningful health

outcomes In Medicare beneficiaries

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

CMS and FDA

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.”

How do our review processes compare?CMS FDA

+++ Data Transparency ±+ Advisory Committees +++

Yes Public Comment on Decisions No

Yes Proposed Decisions Published No

No Brand Name Product Specific Decisions Yes

No User Fees Yes

FDA CMS MOU

http://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/ucm217585.htm

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

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

Cancer

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…

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

PATIENT

Usual Workup

Usual Therapy

Usual Outcome

Workup + New Test

Different Therapy

Better Outcome

Worse Outcome

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.

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.

Pharmacogenomics in CancerJanuary 17, 2010 MEDCAC

a) CYP2D6 for breast cancer patients who are candidates for tamoxifen NA

b) UGT1A1 for colon cancer patients who are candidates for irinotecan NA

c) HER2/neu for breast cancer patients who are candidates for trastuzumab 4.55

d) BCR-ABL for chronic myelogenous leukemia patients who are candidates for imatinib

1) Diagnosis and Monitoring 2) Point to detect treatment failure

4.27NA

e) K-ras for metastatic colorectal cancer in patients who are candidates for cetuximab and/or panitumumab

4.36

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

Desirable Characteristics of Evidence for Diagnostic Testing

MEDCAC 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

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