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Societies raise concerns over FDA’s draft guidance on laboratory developed tests
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On Oct. 3, 2014, the FDA released draft guidance proposing a regulatory framework for laboratory developed tests, or LDTs. These in vitro diagnostic devices, which have been condoned by the agency for decades under an enforcement discretion policy, are often developed and validated by individual labs to provide prompt detection or quantification of pathogens in situations where commercial assays are unavailable.
Johan S. Bakken
The proposed guidance would assess current LDTs using a risk-based approach, with nonexempt high-risk tests and then moderate-risk tests requiring mandatory oversight during a 9-year adoption period. Despite the draft’s designation of regulation exemptions — including tests for rare diseases, tests addressing unmet clinical needs and “traditional LDTs” resembling those used during the late 1970s — representatives from the Infectious Diseases Society of America (IDSA), the American Society for Microbiology (ASM) and the Pan American Society for Clinical Virology (PASCV) have noted several points within the guidance that present unique problems to infectious disease diagnostic labs.
“Our societies are concerned that ID LDTs, which have little evidence of providing unreliable results that lead to harmful patient care decisions, are not being appropriately considered by the FDA’s proposed regulations,” IDSA President Johan S. Bakken, MD, PhD, FACP, FIDSA; ASM President Lynn W. Enquist, PhD; and PASCV President Gregory A. Storch, MD, wrote in a letter to FDA Commissioner Robert M. Califf, MD. “Many ID LDTs have a long history of safe and effective use in patient care, and our societies firmly believe the risks posed by ID LDTs are dwarfed by their advances and benefits to patient care.”
Regulatory oversight could settle diagnostic quality, market issues
According to the FDA, the issue of unregulated LDTs is a long-standing concern. While early tests used across several medical specialties were relatively simple and had limited availability, newer LDTs, which are not subject to premarket review, are comparatively more involved and potentially susceptible to error.
Robert M. Califf
“Modern LDTs are now commonly used in patient care; they are more complex, have a nationwide reach and have higher-risk uses,” the FDA told Infectious Disease News. “The FDA is aware of faulty or unproven LDTs that could cause patients to be over- or undertreated for health diseases; cancer patients to be exposed to inappropriate therapies or not get effective therapies; incorrect diagnosis of autism; unnecessary antibiotic treatments; and exposure to unnecessary, harmful treatments.”
The agency said it first identified the regulatory gap in the 1990s along with advisory committees to the Secretary of the Department of Health and Human Services, and that previous actions to expand oversight have been unsuccessful. While the FDA said the current proposal is primarily motivated by patient safety, Angela M. Caliendo, MD, PhD, professor and vice chair of medicine at Alpert Medical School of Brown University, also viewed the oversight as an opportunity to encourage a fair diagnostic market.
Angela M. Caliendo
“[Over time] there were more and more of these LDTs being run in laboratories, and that put the laboratories at a competitive advantage over commercial companies,” Caliendo told Infectious Disease News. “Commercial companies, in order to sell their product, had to take them through the FDA, but the individual laboratories did not. The companies felt they were at a competitive disadvantage compared to the laboratories for marketing or providing this sort of testing.”
Current proposal presents financial, administrative issues for clinical labs
According to Bakken, Enquist and Storch, however, the current proposals would place clinical labs at a severe disadvantage. Subjecting labs to the diagnostic device requirements initially designed for commercial manufacturers would “create an impossible challenge, both in financial and administrative resources,” they wrote in the letter to Califf. The three societies elaborated on this point in a joint commentary published in Clinical Infectious Diseases, and argued that most clinical labs and health care institutions do not have the regulatory expertise to “navigate complex FDA regulations” and cannot afford the estimated $2 million to $5 million necessary for 510k submission of a single diagnostic test.
“Commercial companies have an entire department to do the regulatory side of this and to deal with the FDA — hospital-based laboratories don’t have those sorts of resources,” Caliendo said. “This is going to shut down LDTs in hospital-based laboratories, and we’re going to be forced to send tests out to a reference laboratory.”
The FDA said these concerns will be mitigated by the outlined regulatory exceptions, as many of the LDTs developed and used by labs should be considered “traditional” or rare disease LDTs. In addition, regulation requirements would not be applied to tests satisfying an “unmet clinical need,” for which cleared or approved tests do not exist.
While Caliendo and colleagues applauded these distinctions, they expressed concern over the proposed 12-month phase-in period for when a new commercial test fulfilling an unmet need is cleared. Because the capital budget cycles for many labs are also 12 months long, directors could find themselves unable to acquire the appropriate commercial diagnostic and conduct testing within the 12-month period, Caliendo explained.
“If they modified this requirement a little bit and were a little bit more flexible — give labs 2 years instead of 1 year to adopt the new test, and wait to remove unmet need status until two or three tests were cleared instead of one test being cleared — I think these changes could be very helpful,” she said. “But the way it’s written right now, with one test cleared and a requirement to use it within a year, is very problematic for labs.”
Well-established diagnostic capacity, in-house expertise at risk
Although many of these issues would extend across specialties, the experts noted that several aspects of the proposed guidance are especially pertinent to ID.
Bakken, Enquist and Storch wrote that because many patients’ infectious illnesses are time-sensitive, any potential delays or unavailabilities imposed by the oversight process could severely impact treatment.
“Time is of the essence in ID patient care, where even a few hours’ delay can negatively impact a patient’s outcome,” they wrote in their letter. “ID diagnostics also play a critical role in the public health response to outbreaks, hospital infection prevention, and the stewardship of antimicrobial drugs to limit the development of drug resistance.”
Caliendo said the expertise many clinical facilities have with these LDTs also provides clinicians with a local resource in case a consultation is necessary, which could be lost if a hospital is forced to send its specimens to a remote facility.
Furthermore, several of the LDTs characterized as high-risk by the FDA are frequently used and have a well-reported history of clinical validity, according to Caliendo and colleagues. These LDTs — which include viral load tests for transplant-associated opportunistic infections such as cytomegalovirus, Epstein-Barr virus and BK virus — may be classified as high-risk under the proposed guidance, and thus be unavailable to labs until submission and acceptance of an application through the premarket approval process.
“These tests are really the standard of care; they are widely used in clinical practice,” Caliendo said. “I think we will actually be causing harm if we don’t find a way to keep these types of tests in clinical use.”
Final guidance expected later this year
These concerns and others were submitted to the FDA in 2015 by the IDSA, ASM and PASCV, who expect the final guidance to be released later this year. The FDA said that comments from public meetings and letters were used to refine the draft, and it will make final decisions based on its best judgment with the provided information.
“FDA has, in developing its LDT guidances, taken into account comments and suggestions from a wide variety of stakeholders on important factors to consider in its proposed oversight of LDTs,” the agency said. “FDA applies its regulations of in vitro diagnostics according to what is necessary and sufficient to assure safe and effective devices. What ultimate controls are needed depend on many factors including the maturity of the technology and what is known about it.”
Caliendo also acknowledged the utility of FDA-approved assays in clinical care and said that a wide provision of readily available commercial tests would reduce the field’s reliance on LDTs. However, reaching this goal will require regulatory guidance that is able to keep commercial and clinical interests in balance.
“The issue of a fair and level playing field did need to be addressed, and we have to come to an understanding that works for everybody,” Caliendo said. “If we can find a way to incentivize the companies to get these tests FDA-cleared and into clinical use, that helps everybody.” – by Dave Muoio
- References:
- Caliendo AM, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw260.
- FDA. Framework for regulatory oversight of laboratory developed tests (LDTs) Draft Guidance. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.pdf. Accessed May 11, 2016.
Disclosures: Caliendo reports compensation for scientific advisory board participation at Abbott Molecular, BioMérieux, Cepheid, Nanosphere, Quidel and Roche Molecular, as well as a grant from Hologic T2 Biosystems. Infectious Disease News was unable to confirm disclosures for Bakken, Enquist and Storch. Please see the full commentary for a list of all other authors’ relevant financial disclosures.