In response to congressional pressure, FDA has released a copy of its long-awaited draft guidance covering regulation of LDTs. FDA seems to have addressed many if not all of the concerns regarding negative impacts from LDT regulation, at least in writing the guidance. Actual implementation will be interesting to watch, but several things about the proposed regulatory framework give hope that negative impacts will be minimized:

Test developers can continue to offer tests during review.
While FDA is retaining the right to shut down tests that it deems patently unfit due to inadequate validation, indication, etc, it is allowing test developers to continue to offer tests while the review process is underway. Since the review of tests is staged based on risk, and the periods for each stage are relatively long, it will be almost a decade before some test developers have their tests reviewed.

Review of tests will utilize literature validation.
In FDA’s own words, “Use of clinical literature to support a demonstration of clinical validity, which FDA expects would reduce the need for additional clinical studies to show
clinical validity for LDTs where the analytes/markers that are measured/assessed
have had their clinical validity established in the literature.”

FDA will not review low risk tests and tests for rare diseases and unmet needs.
The possibility that FDA review could limit the availability of tests for rare diseases, by making it cost ineffective to offer such tests, was a major concern for lab directors and others. Granted, FDA is continuing its enforcement discretion for such tests, so review could be applied at some point in the future, or in selected cases.

Third party review of tests will be facilitated for moderate risk tests.
This is an interesting point in the guidance, wherein FDA states that it will expand the third party review program for Class II devices to facilitate faster review. This isn’t actually a FDA program with which I am familiar, and it will be interesting to learn more about the details of the proposed expansion. How big is it currently in terms of tests reviewed, and how much bigger is FDA proposing to make it? Are we merely talking about expanding the review capabilities of accredited CAP and CLIA inspectors?

The guidance does raise at least a couple more interesting questions:

How are review phases being defined?
FDA makes mention multiple times to certain phases beginning when review of tests in the prior phase has been “completed.” It is not clear what the cutoff will be for each cohort of tests, as presumably such a cutoff must exist in an environment wherein new tests will be submitted regularly, and in volumes one would presume will be significantly larger than anything FDA has had to deal with to-date.

How will FDA classify tests according to risk?
Existing guidelines will be utilized, along with input from “advisory panels.” The latter is in response to “industry’s expressed interest in participating in the discussion of the classification process.” The concept of “risk” is central to FDA’s proposed framework, and a big part of FDA’s strategy for minimizing the potential for negative impacts from regulatory review, so it will be interesting to see how much contention arises in evaluating risk for each test.

Will LDT review practices be applied to device review standards?
FDA states that LDTs will be reviewed for PMA and 510(k) clearance as for devices, but will they be reviewed in the same ways? Will device manufacturers be able to make increasing use of literature validation? Will devices be reviewed increasingly by thirty party reviewers? FDA’s track record for review period lengths is improving, but still historically not good, so if implementation of new policies for LDTs could have a positive impact on device review periods that would be a very positive side effect.

Will the guidance be implemented as written?
It is still not clear, at least to me, whether the guidance will be implemented as written. This current release of the guidance was in response to congressional pressure, and it is my understanding that the guidance still sits in review at the Office of Management and Budget (OMB). Whether OMB has the authority to withhold or modify the guidance is unclear. Many stakeholders have also questioned FDA’s basic authority to regulate LDTs, and while FDA certainly has a strong and consistent position on the issue, at least one lawsuit has been filed challenging this authority, and leading lab directors believe the authority is lacking.

There is clearly much still to understand, but at least FDA’s position is now known.