LDTs: FDA Does an End Run on Regulatory Proposal Lab Industry Helped Create

A couple of years ago, the lab industry played an active role in the drafting of the Diagnostic Accuracy and Innovation Act (DAIA), a bill designed to establish a new regulatory regime for laboratory developed tests (LDTs). But last month, without consulting anybody, the FDA sent a 59-page Technical Assistance document (TA) to a pair of US Congressional Representatives (Larry Bucshon, R-Ind. and Diana DeGette D-Colo.) pretty much re-writing the DAIA. Predictably, the industry was none too pleased and roundly condemned the TA proposal.

Here’s a rundown of the situation.

Background: How FDA Clears Lab Tests
New diagnostics currently come to market via two FDA regulatory pathways:

• In vitro diagnostics are approved or cleared before coming to market and must prove clinical evidence of validity;
• LDTs undergo no pre-market regulatory review.

Critics contend that LDTs are often inaccurate and unreliable. And because they’re not subject to adverse event reporting, there’s no way to determine if patients are harmed. The DAIA was intended to resolve these issues by creating a new category of tests called in vitro clinical tests (IVCTs).

FDA Tinkers in the Name of ‘Public Health’
But now the FDA is apparently unhappy with the DAIA it helped to create. We’re all for creating streamlined paths to market for IVCTs, and getting rid of over-regulation that thwarts innovation, notes the agency in the opening of its August TA. However, it continues, safeguarding public health must be a priority. And to serve it, the FDA says it needs authority to request raw data and take corrective action against test developers which the current DAIA doesn’t provide. In particular, the agency wants to make clear it has the power to remove tests that put public health at risk from the market.

FDA’s 5 Proposed DAIA Changes
Among the notable differences between the current DAIA and the FDA’s new TA proposal:

1. Definition of IVCTs

The DAIA defines IVCTs as a laboratory test protocol or finished product, which is used in disease detection, screening, prediction, and monitoring, and for selecting treatment based on analysis of human samples. The TA definition would also consider test platforms and software used for these same purposes to be IVCTs. The FDA doesn’t specifically mention “finished product,” “laboratory test protocol” or “laboratory-developed test” in its IVCT definition.

2. Risk Categories

The DAIA establishes a process for determining whether a test is low-risk, moderate-risk or high risk, and outlines regulatory requirements consistent with a test’s risk level. The TA defines high and low risk tests but leaves out moderate-risk.

3. Timelines

The DAIA contains strict review timelines. Should the FDA fail to meet the deadlines, test would be automatically approved. The TA version of the bill contains no timelines for review.

4. Regulation of IVCTs

The DAIA would create a new center for IVCTs within the FDA. The TA proposes the creation of collaborative communities of private and public stakeholders who advise the FDA on mitigating measures and performance standards for IVCTs.

5. Raw Data

The TA makes explicit that raw data should be submitted for high-risk, cross-referenced, or first-of-a-kind tests, and that the U.S. Department of Health and Human Services secretary can request raw data for any other test.

FDA Pre-Certification
Another notable difference between the DAIA and TA is the latter’s proposed framework for pre-market approval, provisional approval and pre-certification of tests, with a substantial portion of tests being exempt from pre-market review and other requirements.

Basic outline: The FDA scheme would:  

1. Exempt manual, public health surveillance, law enforcement and investigational tests from notification, pre-market review, adverse event reporting, quality systems and labeling requirements.

2. Require low volume test developers to report adverse events and include labeling.

3. Require grandfathered tests to notify FDA and report adverse events.

4.  Exempt tests for rare diseases from pre-market review but subject them to other requirements.

5. Require pre-market review of high-risk tests, and subject them to labeling, quality systems, adverse event reporting and notification requirements.

6. Provisionally approve tests that use breakthrough technology or address an unmet need, allowing developers to bring them to market on an expedited time frame and remain on the market as long as they complete and submit post-market studies within the specified time frame.

7. Establish “mitigating measures,” where, by following FDA requirements, test developers can limit the risk for patient harm from an erroneous result.

8. Allow test developers to apply for pre-certification for groups of IVCTs using a single technology or test method, and have other elements in common. After achieving pre-certification, developers could launch new tests that fall in that group without having to garner pre-market review.

6 Things the Lab Industry Hates about the FDA Proposal

Almost immediately after the FDA issued the TA, the ACLA wrote a response letter raising 6 objections to the proposal:

1. The FDA lacks the legal authority to regulate LDTs;

2. IVCTs should be subject to their own regulatory framework separate from medical devices;

3. The transition provision could subject IVCTs to regulation “immediately after enactment”;

4. The agency could use the grandfathering provision “to ‘claw back’ grandfathered tests at its discretion without basis in meaningful standards”;

5. Eliminating the moderate-risk category for IVCTs will create confusion and lead to more tests being classified as high risk; and

6. The definitions of “analytical validity” and “clinical validity” give the FDA “unprecedented discretion in determining whether an IVCT is analytically or clinically valid.”

Backing for the FDA Proposal

While the lab industry hates it, the FDA approach does have its backers. On Aug. 20, the Pew Charitable Trusts submitted its own comments regarding the FDA’s TA (Pew Comments). After outlining criteria that policymakers should consider, Pew came out in favor of the FDA’s TA’s oversight regime approach stating that it “would establish regulatory requirements based on a test’s risk” while providing broad exemptions to maximize access. Pew also applauded the FDA’s approach to gathering and reviewing information on exempted tests to ensure public health.