Dr. Jack Snyder, RAC, DABT, CPI, CPE
CATO Research Washington
“Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” and “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)” (issued Oct. 3, 2014)
On October 3, 2014, FDA issued draft guidance entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs).” If the guidance is finalized, laboratories seeking to maintain their ability to offer LDTs will be required to submit applications for premarket review as medical device manufacturers – a complex, time consuming and costly process.
FDA appears to be taking the position that the agency doesn’t have to go through full APA (Administrative Procedures Act) rulemaking procedure (including economic analysis) because FDA is not actually issuing a binding rule. Rather, FDA is asserting that the agency has always had regulatory authority over LDTs, and they’re just being transparent about when and how they’re going to exercise it. According to an FDA spokesperson, “We believe that LDTs serve an important role in health care and that there are many good tests on the market. Unfortunately, FDA is also aware of faulty or unproven LDTs, including problems with several high-risk LDTs . . . FDA is concerned that people could initiate unnecessary treatment, or delay or forego treatment altogether, for a health condition, which could result in illness or death.”
In its Federal Register notice, FDA said it expects approximately 650 laboratories will be required to provide notification about 17 LDTs each in the first year after guidance is finalized. In New York alone, 565 labs submitted 9,800 lab-developed tests for review under that state’s law in 2014. FDA also noted that the National Institutes of Health Genetic Test Registry includes about 7,600 tests that are not FDA-approved or -cleared. Assuming genetic tests represent roughly 70 to 80 percent of all LDTs, FDA estimated a total of 11,050 LDTs as the total annual response in the first year. By contrast, CMS says more than 11,000 CLIA-certified labs perform high-complexity testing, including LDTs, and some lab directors estimate that dozens of molecular markers are offered as LDTs by hundreds, if not thousands, of laboratories across the country, translating into potentially tens of thousands of premarket submissions to the FDA.
According to the draft guidance, when deciding whether to require premarket review for laboratory-developed tests, the FDA will consider:
- Whether the test is intended for use in high-risk diseases, conditions, or patient populations
- Whether it is used for screening or diagnosis
- The nature of the clinical decision made based on the test result
- Whether a clinician or pathologist would have information beyond the LDT result to help guide diagnosis or treatment
- What alternative testing and treatment options would be available to the patient
- The potential consequences of erroneous results
- The number and types of adverse events associated with the LDT.
Proponents of enhanced FDA oversight of LDTs have advocated as follows:
- FDA should review novel and/or high-risk tests, regardless of who develops them, as a critical step to help assure test accuracy and patient safety.
- In contemporary oncology practice, a patient’s treatment options are increasingly driven by detection of molecular abnormalities in the tumor that drive treatment selection. LDTs used to detect those abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients.
By contrast, expressions of concern (or opposition) from healthcare professionals and organizations (as reflected in publications from the College of American Pathologists and other organizations representing laboratory professionals) have included the following:
- FDA may not have the statutory authority to regulate LDTs.
- FDA seeks to convert almost all clinical laboratories into manufacturers.
- Laboratories currently use a lot of FDA-approved kits but without following the standard operating instructions that come with those kits. Rather, the kits are modified to make them better.
- If 510(k) submissions are required, the sponsor would have to state an LDT’s intended use. Frequently, however, an LDT’s intended use changes with time. As knowledge accrues, more intended uses arise. For many LDTs, it is hard to pre-specify the intended labeling and then never deviate from it.
- A rulemaking (rather than guidance) process would require FDA to explain how FDA regulation of laboratories would be harmonized with current CLIA regulation of laboratories.
- Risk-benefit balancing will vary significantly among the LDTs used for cancer (CA), infectious disease (ID), and genetic (GENE) testing.
- Risks raised by most LDTs are dwarfed by the benefits to patient care.
- Proposed oversight of LDTs may threaten innovation and impede patient access to existing high quality or state-of-the-art tests, especially in major medical centers that lack the financial and administrative resources for 510(k) or PMA (pre-market approval) submissions.
- Many clinical laboratories will forsake LDTs and adopt commercial and/or reference testing, with rising costs, increased turnaround time, and increased investment in new instruments.
- Clinical laboratories will lose the flexibility needed to make improvements to already approved or cleared tests, essentially freezing outdated tests in time.
- FDA should convene experts to identify LDTs that have appropriate information that establishes safety and clinical validity.
- Tests for transplant-related viruses should be moved from “high-risk” to “moderate risk” category.
- “High-risk” LDTs should be compared to “high-risk approved devices” as predicates.
- Clinical laboratories should not be precluded from testing patients being treated at a facility outside a laboratory’s healthcare system.
- FDA should delay regulatory oversight of LDTs for unmet medical needs for at least 2 years and until at least 2 commercial tests are approved.
- The need to test non-intended specimens represents an unmet need.
- FDA should propose a simple regulatory mechanism to allow validation and unhindered access to databases other than FDA-approved options.
- Proposed oversight of LDTs interferes with the practice of medicine, since board-certified professionals use emerging medical knowledge and patient care needs to continuously monitor every stage of the development, performance, and interpretation of LDTs.
- Patient access to Laboratory Developed Procedures (LDPs) should not be impaired by implementing guidance or regulations that duplicate the role of CLIA, MDA, proficiency testing, accreditation, and other quality measures in routine use by clinical laboratories. LDPs have been defined as “professional services that encompass and integrate the design, development, validation, verification, and quality systems used in laboratory testing and interpretative reporting in the context of clinical care.”
- “Devices” and “articles,” as defined in the Medical Device Act, may not be the same as, and may not encompass “clinical laboratory testing services.”
FDA held a public workshop on January 8-9, 2015 to discuss the agency’s draft guidance on LDTs. The workshop highlighted various areas of discussion, including: components of a test and LDT label considerations; clinical validity and intended use; categories for continued enforcement discretion; notification and adverse event reporting (MDRs); public process for classification and prioritization; and quality system regulation. Comments on the draft guidance were due to the agency by February 2, 2015.