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FDA to Rethink Enforcement Discrection Policy Over LDTs at July Public Meeting

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By Turna Ray

In a step toward squelching the confusion around the US Food and Drug Administration's regulatory oversight of laboratory-developed tests, the agency announced it would hold a public meeting next month on the controversial topic.

Recognizing that the complexity, business landscape, and medical application of laboratory-developed tests have changed since the implementation of the Medical Device Amendments of 1976, the FDA said in a Federal Register notice this week that due to "public health concerns, the agency believes it is time to reconsider its policy of enforcement discretion over LDTs."

The meeting will be held July 19-20 in Washington, DC.

The FDA has practiced enforcement discretion over the majority of LDTs, which are assays developed and analyzed at laboratories that have been accredited under the Centers for Medicare and Medicaid Services' Clinical Laboratory Improvement Amendment. Although laboratories are certified to develop and analyze these tests, the assays themselves do not hold 510(k) clearance or a premarket approval from the FDA.

Meanwhile, the FDA has focused its regulatory muscle on diagnostic kits, analyte-specific reagents used in LDTs, or certain high-risk LDTs called in vitro diagnostic multivariate index assays.

The FDA said in this week's notice that it has practiced enforcement discretion over LDTs since in the past these types of tests "were generally relatively simple," "well-characterized," "low risk," and used to diagnose rare diseases in a limited patient population. However, in recent years, the use of LDTs has grown, particularly in the context of medical decision-making in the area of personalized medicine, which necessitates a change in the way the agency weighs the risks and benefits associated with these assays.

"Today, while these tests are still performed in laboratories with high-complexity certificates, they often use components that are not regulated individually by FDA, and they are often used to assess high-risk but relatively common diseases and conditions and to inform critical treatment decisions and are often performed in geographically distant commercial laboratories instead of within the patient's healthcare setting under the supervision of a patient's pathologist and treating physician, or may be marketed directly to consumers," the FDA noted.

"In addition, even when FDA-approved tests are available for a disease or condition, laboratories often continue to use LDTs that have not been reviewed by the agency," according to the FDA. "Finally, an increasing number of LDT manufacturers are corporations rather than hospitals or public health laboratories, which represent a significant shift in the types of tests developed and the business model for developing them."

The last public meeting FDA held regarding its intent to regulate IVDMIAs — lab-developed multiplex tests that employ mathematical algorithms to interpret a person's genetic risk for disease or likelihood of response to a drug — was highly contentious and, some would assert, left the diagnostics industry with more questions than definitive answers.

At the 2007 meeting on IVDMIAs, LDT developers asserted that FDA's selective regulation of IVDMIAs created more regulatory uncertainty in the industry, as well as overly burdensome requirements for small companies developing tests for rare diseases, which would hinder innovation. After input from the industry at the meeting, the FDA updated its 2006 draft guidance on IVDMIAs, but the second version still didn't seem to satisfy laboratory test developers (PGx Reporter 08/01/07).

Meanwhile, device manufacturers who haven't taken the less rigorous regulatory pathway by marketing LDTs, but have invested in clearing tests for medical use through FDA's lengthy regulatory process, have criticized FDA's selective approach toward LDTs as creating an uneven playing field. These firms, spurred by a Citizen Petition issued by Genentech, have urged FDA to end its longstanding practice of enforcement discretion and regulate all LDTs (PGx Reporter 12/17/08).

In December 2008, Genentech petitioned the FDA to take make its in vitro diagnostics regulations more consistent by extending its oversight over LDTs in a risk-based manner. Genentech "believes that FDA should exercise its regulatory authority over all in vitro diagnostic tests pursuant to the risk-based classification system it uses for medical devices," the company stated in its Citizen Petition. "Based on the current classification system, Genentech anticipates that many [laboratory-developed tests] will be considered low risk and would not require significant regulatory oversight."

In the Federal Register notice, FDA for the first time publicly acknowledged that its regulatory practices may have given uneven market advantages to LDT developers. "FDA recognizes that while the absence of FDA oversight may make it easier for laboratories to develop and offer tests on a rapid timeline, the absence of a level playing field creates a competitive disadvantage and potential disincentive to innovation by other manufacturers whose tests are approved or cleared by the agency for similar indications," the agency states in the notice. "In addition, as set out above, it means that some diagnostics critical for patient care may not be developed in a manner that provides a reasonable assurance of safety and effectiveness."

Referencing a 2008 report from the HHS Secretary's Advisory Committee on Genetics Health and Society, which recommended that the FDA should regulate all LDTs (PGx Reporter 02/20/08), the agency said it "believes that a risk-based application of oversight to LDTs is the appropriate approach to achieve the desired public health goals."

Although the Federal Register notice issued by FDA this week is only an invitation to stakeholders to provide input, it's an indication that the agency is trying to figure out a risk-based regulatory strategy that would allow it to extend oversight over all LDTs without being overly burdensome to smaller laboratory test developers and simultaneously fostering innovation in rare disease markers.

"It is important that FDA provide a reasonable, predictable, and consistent regulatory policy for ensuring the safety and effectiveness of LDTs and provide sufficient time for implementation," the agency noted. "Therefore, this policy should encourage innovation, improve patient outcomes, strengthen patient confidence in the reliability of these products, and help reduce health care costs."

According to the agency, after the July meeting and a subsequent comment period ending Aug. 15, the agency is planning to "develop a draft oversight framework for public comment to provide predictability as quickly as possible." The FDA added that it "also intends to phase in such a [regulatory] framework over time based on the level of risk of the test."

The announcement regarding this meeting follows FDA's recent regulatory action against direct-to-consumer genomics firms. Letters sent to five firms last week suggest that the agency considers these tests and services medical devices and not LDTs (PGx Reporter 06/11/10).

The FDA has been expressing its definitive intent to take a more consistent regulatory approach toward LDTs in publicized comments, as well as in a recently published commentary in the New England Journal of Medicine.

This week, NIH Director Francis Collins and FDA Commissioner Margaret Hamburg published an NEJM editorial, "The Path to Personalized Medicine," in which they outlined how the two HHS entities are working together to advance research and adoption of genomically-guided medicine.

With regard to FDA's role in overseeing the safety and efficacy of personalized medicine products, Collins and Hamburg note that "increasingly ... the use of therapeutic innovations for a specific patient is contingent on or guided by the results from a diagnostic test that has not been independently reviewed for accuracy and reliability by the FDA."

As an example, the authors site the availability of an LDT that claims to predict the 20 percent of patients who will not respond to the oncologic Rituxan. "The FDA has not reviewed the scientific justification for this claim, but health care providers may use the test results to guide therapy," the editorial cautions. "This undermines the approval process that has been established to protect patients, fails to ensure that physicians have accurate information on which to make treatment decisions, and decreases the chances that physicians will adopt a new therapeutic–diagnostic approach."

Collins and Hamburg go on to say that the FDA is clarifying the process for manufacturers so they know, for instance, when a companion diagnostic must be approved or cleared before or at the same time as the therapy. "The agency will ensure that claims that a test will improve the care of patients are based on solid evidence, and developers will get straightforward, consistent advice about the standards for review and the best way to demonstrate that the combination works as intended," Hamburg and Collins write.

Furthermore, since LDTs are increasing in use in the medical setting, the article points out several troubling adverse events linked to LDTs that have not been greenlighted by the FDA. For example, there have been cases where women were erroneously told they were negative for a mutation conferring a "very high risk" of breast cancer; an ovarian cancer test, marketed before the completion of an NIH-funded study, gave false results reportedly causing the removal of women's ovaries; and flawed data for a Down's syndrome test were discovered a few days before the test was to go on the market.

"Through a process that includes opportunities for public input, the FDA will work to ensure the quality of key diagnostic tests, helping to protect patients and giving clinicians confidence that personalized medicine will lead to real health improvements," Collins and Hamburg assured in the article.

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