Friday, November 18, 2016

FDA Will Not Finalize LDT Guidance

On November 18, 2016, Genomeweb broke an important new announcement: that FDA will not finalize its 2014 proposal to regulate laboratory developed tests (LDTs).   Genomeweb's story is here (subscription required).  See a rapid press release from ACLA, here.  AMP thanked the FDA for its decision here.  Further coverage at WSJ, here, and RAPS and STAT, open access here and here; Bloomberg here.

As I had noted to clients earlier this week, the election sharply raised this outcome.  If anything were to happen in the next year, it would resemble the Senate proposal to upgrade clinical utility review under CAP (or other outsourced bodies like New York State) - but even this is unlikely, following the reasoning below.

There had been four alternatives for LDT regulation:
  1. For the FDA to implement its phased-in LDT guidance, proposed in July 2014, with some revisions based on public comments.
  2. A House bill (also called the Diagnostic Tests Work Group Proposal, DTWG) that involved massive FDA reform with the creation of a new center for diagnostic tests.
  3. Senate proposals to create "enhanced CLIA."  Clinical validity would be reviewed, but likely outsourced from CMS CLIA itself.
  4. Nothing happens.  (Bet here).  
The new administration under President Trump will be anti-regulation - for example, he has proposed that no agency can release a regulation unless it cancels two old ones.  But other factors are also in play.  The system has continued to function well for 2-3 years under no FDA regulation.  This reduces the pressure to do anything, and reduces arguments (from the FDA or others) that something must be done urgently.   The FDA and CMS probably used Theranos as a media opportunity for LDT-related problems.   Other than that, there is less pressure to do anything from most stakeholders.

In the ten days between the election and today's announcement, it was unlikely that the FDA would put out the regulation as a "lame duck" activity.  For one thing, both draft and final LDT guidance required  60 days notice to Congress*, and an announcement of the FDA guidance after about now would already place the implementation date after President Trump's inaugural.   Even further, the Congressional Review Act gives Congress special leverage to overturn recent regulations (here, here.)  Except from some Democrats, support for FDA LDT regulation was not visible on the Hill in September 2016 hearings (as reported by Bloomberg, here; for transcript, here).

But what else happens?  Absent anything coming from FDA, the pressure for a massive overhaul via the House legislation is less likely.   This is not to say anything critical of the House plan; it's a very interesting one; but hundreds of bills are introduce for each major bill that passes, so it takes a lot of flags blowing in the right direction for something to pass.   

This leaves the Senate approach for "enhanced CLIA," and while this is a smaller initiative, it too is less likely to pass given that the FDA has backed down and the status quo has been working for another two years.   However, the administration could go ahead with this if it wanted to.  In November 2015 hearings, Dr Jeff Shuren of FDA and Dr Patrick Conway appeared shoulder-to-shoulder for a lengthy House hearing.   To panel questions, Dr. Shuren emphasized and re-emphasized that FDA LDT implementation would go smoothly, while Dr Conway emphasized and reimphasized that enhanced CLIA was impossible.  On that score Conway stayed especially close to a very short list of talking points and fixed phrases.   But under a new and hypothetically pro-CLIA administration, a new CMS chief medical officer could have an opposite list of talking points (we welcome enhanced CLIA, it will be easy to outsource enhanced CLIA, etc.)  

I think the status quo will remain in place.  Notably, more genomic tests are already entering FDA's review - such as gene panel tests from Thermo Fisher, Foundation Medicine, Illumina, and others.   The FDA may continue to roll out innovative and adaptable forms of review, as it did for the 23andMe carrier genetic tests last year


For a detailed (subscription) interview with FDA expert Jeff Gibbs, Genomeweb November 29, here. _____

Sidebar: A Year Can Make a Difference
The FDA's back-away comes almost one year to the day after FDA released, with some fanfare, a hastily written white paper "on the real patients" from LDTs. (here and here).  At least in parts, the white paper was below the FDA's usually high standards for credibility in regulatory assessment and regulatory science.  


Sidebar: Clinical Validity Review Not Trivial
As noted above, if anything happens, it might be Enhanced CLIA, the Senate's approach.  Clinical validity analyses could be added to CLIA review, mostly likely outsourced to medical expertise at organizations like CAP and NY State.   However, simply "adding clinical validity review" is not trivial at all.  Imagine that after a wide genomic fishing expedition, a special gene-disease association is found.  This would have to be reconfirmed independently, because it could be statistically significant only by change (a few of 100 genes will hit p<.05 by chance).  How large the confirmation study has to be, under what conditions,  with what special considerations relative to the gene and disease, are not trivial checkmark questions.  This is just a for-example that clinical validity is not trival. 


* Under FDASIA 2012, Section 1143.  Here, here
In the