Friday, December 11, 2015

Are Pharmacogenetics a "Culture Shock" Zone for Payers, FDA, and Labs?

This entry discusses why pharmacogenetic information (like recommendations for CYP gene testing) proliferate on FDA labeling but are rarely covered by payers.   At the FDA pharmacokinetics, dosing, pharmacogenetics, are fundamentals of every drug approval.  On the other hand, for doctors who are medical directors (including active physicians) pharmacokinetic data and equations may be at most a rare or incidental part of their thinking and practice.  

This fall I had a chance to read The Culture Map: Breaking Through the Invisible Boundaries of Global Business, by Erin Meyer (here).   Piecing together several different facts about pharmacogenetic testing, I think they outline in part a culture difference between the FDA and payers that contribute to the ongoing disagreements on how much coverage should be available in a fee for service system for CYP and other pharmacogenetic genes.

An entry point is an article last year in JAMA Internal Medicine, arguing that while pharmacogenetic references proliferate on FDA drug labeling, there was not enough evidence for the "clinical utility" of the FDA statements (article by Wang et al., here; letter by Burke, here).   {Not to be outdone, Annals of Internal Medicine argues there isn't even enough evidence provided for black box warnings on FDA labels - here.)

Concordant with Wang's skeptical view of the "value" of pharmacogenetic relationships with drugs, Genomeweb recently published two articles on pharmacogenetic test providers and their efforts with payers (here and here).

Nonetheless, CYP genetic tests dominate Medicare-paid services for genetic CPT codes (here).

Recently the MolDX program released a narrow LCD for limited coverage of pharmacogenetic testing (here).   Reflecting of the MolDX program's many interchanges with laboratory stakeholders on the narrowness of coverage, MolDX also published a companion article on its rationale for narrow coverage of pharmacogenetic testing (here at CMS or in the cloud here).   MolDX states:
     MolDX recognizes the abundant literature available regarding the pharmacokinetic and pharmacodynamic CYP association with drugs, and that experts, including the FDA, mention and recommend CYP genotyping. However, the MolDX LCD CYP2D6, CYP2C19, CYP2C9 and VKORC1 Genetic Testing limits coverage to specific populations where the evidence supports genotyping will lead to proven clinical management changes and result in improved patient outcomes.
     Although MolDX does not dispute the associations between certain genotypes and drug responses or reactions, there is very limited guidance in the published literature regarding whom to test and when. The majority of guidelines reference dosing recommendations without commentary on when the genetic testing is appropriate. In fact, the most recent CPIC guideline [*]addressing CYP2D6 and CYP2C19 and SSRIs states that “clinical variables that may influence SSRI therapy as well as genotyping cost-effectiveness are beyond the scope of this document” [Hicks 2015].
     The guideline continues to state there are many influencers, including drug interactions and clinical factors, that should be taken into account when prescribing and dosing medications. For this reason clinical utility of pharmacogenomic testing is difficult to establish.  The authors are careful to recommend dosing based on existing CYP2D6 and/or CYP2C19 genotype results, rather than recommend pre-prescribing genetic testing.  
     MolDX agrees that, if available, this information may be considered as one component in the decision regarding which medication to use or which dose to prescribe. However; that does not establish clinical utility for the test in the Medicare population.
     In the consideration of prospective pre-medication genotyping across the entire Medicare population, further studies addressing clinical practicality, logistics, and cost-effectiveness are necessary to establish clinical utility. The MolDX LCD addresses the clinical indications for genotyping. The policy does not define what to do with that information once it is known. In addition, the FDA labels recommend genotypes prior to use, suggesting that this information may be useful but not necessary. ["recommend"]
Medicare is required to use public health dollars towards interventions that are proven to be effective. At this time there is limited data to support the clinical utility of CYP2D6 and CYP2C19 genotyping beyond the indications outlined in the LCD.
MolDX also publishes a "Response to Comments" regarding the draft LCD, at CMS here, in the cloud here.  To get all three documents - the LCD, the CYP Evidence Analysis, and the LCD Comment Period Q&A - download this ZIP file from the cloud, here.

The Conundrum

Why is the FDA information on pharmacogenetic biomarkers so omnipresent, detailed, and enthusiastic (here and here) while the payer response so tepid?

I think one factor may be cultural differences - meaning, differences in background, exposure, daily work, and experiences.   P

harmacogenetic considerations, including pharmacokinetics, drug interactions, and dosing decisions are the very fabric of new drug approvals and occupy a very large amount of time during FDA review, trial data analysis, and advisory committee data presentions, where this type of data goes on for slide, after slide, after slide, after slide and occupies many pages in the FDA review documents.  (Metaphorically, if Eskimos have 50 words for snow, the FDA has 50 words for pharmacokinetics, so to speak).

On the other hand, a typical physician (whether vintage 1980 or 2010) spends relatively little time, on these considerations when writing a drug prescription.  He certainly doesn't have 50 pages of fine print pharmacokinetic data tables in his head, as the FDA review had.   This extreme difference in work exposure and subject matter is one aspect that underlies the salience, the "pop," of information for an individual.

Assumptions are pivotal in driving the scope, style, and framework of communications.  For example, I saw a payer's comment in regards to CYP testing, "We either get short overenthusiastic testimonials to the great value of CYP testing, or, we get 200 PDF publications dumped on that we don't have time to review."  There couldn't be a more explicit picture of the existence of a communications gap between the parties on the two sides of that exchange.

The very first blog at this website, in February 2014, was on the potential high value of better utilizing generic genes to choose, dose, and optimize generic drugs (here).  The paradox, of course, is that nobody is incented to research generic genes or generic drugs.

[*] CPIC is the Clinical Pharmacogenetics Implementation Consortium, here.  See also the European Consortium, here.