FDA recently released two draft guidances on the regulation of laboratory-developed tests (LDT): Framework for Regulatory Oversight of LDTs and FDA Notification and Medical Device Reporting for LDTs. With the release of these guidances, the agency commenced a public comment period that will close on February 2, 2015. I asked IVD industry analysts for their impressions of and comments on the guidances.
Analysts were generally pleased with the LDT guidances and believed that releasing them for public comment is a significant step toward creating a single regulatory system for the oversight of IVDs.
“A single system with the right balance, one that provides assurances of safety, effectiveness, and quality while not creating unnecessary barriers to IVD innovation, will give patients the best access to the best IVD tests,” said Bradley M. Thompson, an attorney at Epstein Becker Green (Washington, DC). “FDA’s framework gets us a long way toward that goal.”
Analysts also thought that FDA properly identified what they would consider the primary gaps between the quality system regulations and the Clinical Laboratory Improvement Amendments (CLIA) regulation.
“I was pleased to see FDA put on paper its objectives and potential strategies for managing the questions about LDTs,” said Fred D. Lasky, principal consultant at Lasky Consulting (Sarasota, FL). “It has obviously been an area that the agency stated it was concerned about for many years. My hope is that the drafts will give exposure to the issues and provide feedback that will lead to potential solutions to all affected segments of the healthcare industry.”
However, some analysts had specific criticisms of the LDT guidances. For example, they are concerned that FDA has severely underestimated the extent of the work that will be required by both the laboratories and the agency. In their opinion, the likelihood that the agency will complete the review of all approvable Class III LDTs within the five-year goal is remarkably aggressive.
“In addition, the details regarding notifications for LDTs are lacking in addressing several questions,” said Lasky. “For example, when an LDT is performed on several pieces of equipment, does that constitute individual LDTs? When a change in the methodology that the lab would now consider routine takes place (e.g., a new model of an instrument or a new source of a standard material), does that require a new notification? When an analyte is examined by an LDT, how is the lab to become aware of a regulated IVD being available? When that occurs, how can the lab demonstrate that its test is substantially equivalent? Can a lab justify being different and not required to file a 510(k) if, for example, an assay detects or quantifies a different allele for the purpose of monitoring a specific disease?”
Lasky identified several other specific issues and concerns about the LDT guidances. According to Lasky, the definition of an LDT is both confusing and appears to be very narrow in scope. Larger academic and commercial clinical laboratories receive specimens for their specialized tests, which are frequently LDTs as more generally defined, but these entities seem to be excluded from the LDT guidances. However, the means of developing, validating, and offering such tests should not differ from the laboratories that provide LDTs only within their own venues, however they are defined.
“FDA states that it will use enforcement discretion based on patient risk,” said Lasky. “This is an often mentioned goal, but in my experience, it’s very difficult to define. In working with industry scientists, medical consultants, and regulators, agreement on risk rarely occurs. The most commonly used definition is when therapy based on the laboratory result has consequences that can lead to significant morbidity or mortality. Otherwise, the debates go on. I am skeptical about agreement being reached that will help labs or IVD manufacturers, for that matter, know if an LDT is eligible for enforcement discretion.”
Lasky was pleased to see FDA call for the use of medical device reporting (MDR) requirements if a test result might lead to death or serious injury. He also hopes the agency provides more guidance to laboratories on how to implement this regulation for its LDTs. Proper use of this regulation has always been an important focus of FDA audits. Moreover, based on the many warning letters that the agency issues, it appears that many manufacturers have not developed processes that meet FDA’s expectations.
“It was not clear to me how and when, after the LDT rule becomes final, FDA would require laboratories to comply with the rules related to MDR as well as removals and corrections, which are mentioned in the FDA notification draft,” said Lasky. “The information that the agency requires of industry to include in its notifications of field corrections is very useful but not included as a reference.”
Other analysts believe that what also needs to happen in tandem with the activity around LDTs is taking a close look at regulatory reforms that will help speed up the IVD development process. Right now, the LDT guidance continues to extend enforcement discretion to LDTs for unmet medical needs (i.e., diagnostic needs that are not being met because FDA has not approved an appropriate IVD test). Stakeholders need to ask why are there unmet needs and what barriers are there in the regulatory framework that may be holding back test development, and then develop solutions that let all innovators, whether IVD manufacturers or laboratories, use their expertise to make the best products for patients under a single regulatory system.
“Bringing all the stakeholders together, such as FDA, the Centers for Medicare and Medicaid Services (CMS), IVD manufacturers, clinical labs, patient groups, etc., will be important to all the work that will be going on in the months and years ahead,” said Thompson. “FDA’s LDT draft guidance provides some opportunity for that through the comment process, public meetings that the agency has scheduled, etc. However, having a more formal and comprehensive process, similar to what Congress mandated for health information technology, to bring everyone together to talk about how we can make the best system for all IVDs, and not just LDTs, would help in developing the optimal regulatory system to give patients the best IVD tests.”