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The FDA’s LDT Report Provides a Clear View of the Agency’s Concerns

On November 16, the FDA appeared before Congress to make the case for greater regulation of laboratory developed tests (LDTs) and issued a report of specific examples that illustrate its view of the real and potential harms to patients from certain LDTs

Historically, the FDA has used enforcement discretion and has not enforced IVD requirements on LDTs. LDTs are currently regulated under the Clinical Laboratory Improvement Amendments (CLIA), which is overseen by the Centers for Medicare and Medicaid Services (CMS).

There are significant differences in how CMS and FDA approach the oversight of LDTs and IVDs. For example, clinical validation is not part of the CMS review, whereas it is a part of the FDA’s premarket review. Furthermore, the FDA’s adverse reporting databases do not document any issues associated with a result that was generated from an erroneous LDT. Marketing claims are also not specifically regulated.

The FDA has exercised enforcement discretion for LDTs because they were considered relatively simple tests that were used for rare conditions. However, due to the increasing complexity of current LDTs and their availability to be used to diagnose serious medical conditions, including cancer and heart disease, the FDA feels that regulatory oversight has a potentially greater impact on patients.

The FDA put together the 20 case studies not to undermine the value of LDTs, but to show how lack of LDT oversight is, in its view, inadequate and has failed to prevent significant harm to patients.

In anticipation of the FDA’s expansion of LDT oversight in the coming months, LDT manufacturers should assess regulatory strategies to address comprehensively the potential concerns the agency may raise — as well as the viable evidence strategies to address those concerns while also providing a viable commercial path forward.

 

Critical Case Studies to Read

1. False Positive Results (see page 8)

Even though the patient doesn’t have Lyme disease, the LTD gave a positive result causing unnecessary treatment and delaying diagnosis of the true underlying condition.

In two cases, some false positives results for ovarian cancer were observed. These can be even more detrimental because they prompted unnecessary surgeries for women to remove healthy ovaries.

Some patients with Pertussis (whooping cough) were also incorrectly diagnosed and incorrectly treated.

2. False Negative Results (see pages 14 and 15)

For newly diagnosed stage I and II breast cancer patients and HPV patients, some tests may suggest that a patient does not have the disease, when in fact they do. The patients did not receive the appropriate treatment and the disease progressed.

3. False Positive and False Negative Results (see page 16)

Non-invasive pre-natal testing, which are tests to identify fetal chromosomes abnormalities in maternal blood from cell-free DNA, gave many false positive and false negative results. Women may abort the pregnancy or deliver the child with unanticipated genetic syndrome.

4. Disproven Scientific Concepts (see page 23)

The FDA estimated a total public health cost of the inaccuracy of the CARE Clinics BioMarkers test for autism alone to be $66.1 million. With this test children have undergone inappropriate and harmful treatment based on test results.

 

Beyond these Four Concerns

The report also lists tests that have no clear relevance to the disease being tested, tests with unsupported claims that may mislead patients and providers, and tests with inadequate labeling to allow for interpretation of the test result or determination of follow-up testing is required. The FDA also identifies risk to clinical trial validity when LDTs are used to determine enrollment, treatment, or treatment efficacy without validation tests of the LDT, which has led to inaccuracies or inconsistencies in results.

Should the FDA no longer exercise enforcement discretion, LDTs would now be regulated and distributed the same way as an in vitro diagnostic test. All LDTs would be subject to basic IVD requirements such as adverse event reporting, and many would be subject to FDA premarket review, either a 510(k) or a PMA.

This would drive up costs, may discourage some laboratories from investing in the development of new diagnostic tests, and some laboratories may be forced out of business. This would be unfortunate. LDTs provide patients and clinicians with more information than ever before.

FDA’s role in regulating LDTs may benefit some companies seeking investors in new diagnostic technology. By providing the regulatory framework in the draft guidance document, the FDA has continued to display their willingness to balance their goals of safety and efficacy. Both FDA and industry must work together to protect public health.

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