FDA has announced its intention to issue draft guidances on the regulation of laboratory-developed tests—a controversial decision that could increase the burden of compliance and stifle innovation.
By Allyson B. Mullen
For decades, FDA has asserted that it has the authority to regulate laboratory-developed tests (LDTs). But on July 31, 2014, FDA took its biggest steps yet toward actively regulating such tests: FDA notified Congress of its intent to issue two draft guidance documents regarding oversight of LDTs, entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” and “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)”—referred to as the framework guidance and the notification guidance, respectively.
Under the draft guidance documents, FDA will take a risk-based approach to regulating LDTs. This means that there will be three groups of LDTs: LDTs subject to full enforcement discretion; LDTs subject to partial enforcement discretion; and LDTs subject to full FDA regulation.
For the first group, FDA plans to continue to exercise enforcement discretion with respect to LDTs that are used solely for forensic (law enforcement) purposes, and certain LDTs for transplantation when used in CLIA-certified, high-complexity histocompatibility laboratories.
The second group—those tests subject to partial enforcement discretion—encompasses a broader array of LDTs:
- Low-risk LDTs are those tests that are classified as Class I devices, are subject to partial enforcement discretion.?
- An LDT for a rare disease will follow the definition of a Humanitarian Use Device (HUD) in 21 C.F.R. § 814.3(n). Fewer than 4,000 people per year may be tested in order to qualify, compared with treated when this standard is applied to a therapeutic device)—thus, this group will rarely, if ever, be used.
- Traditional LDTs are, by FDA’s description: “IVD devices that reflect the types of LDT[s] available when FDA began its policy of generally exercising enforcement discretion over LDTs in 1976.” Essentially, traditional LDTs are the preamendment device equivalent. The draft framework guidance lists several factors that FDA will consider when determining if a test is a “traditional LDT,” including:
- Whether the LDT meets the definition of an LDT set out in the framework guidance
- Whether the LDT is manufactured and used at a single healthcare facility for a patient that is being treated in the same healthcare facility or healthcare system
- Whether the LDT is comprised of only legally marketed components—thereby excluding research-use only (RUO) and investigational-use only (RUO) products
- Whether the LDT is interpreted by a qualified healthcare professional, without use of software or automated instrumentation.
If a test is required to meet all of these criteria, it will significantly limit the number of tests that will fall into this category.
- LDTs for unmet needs are those tests for which there is no FDA-approved or FDA-cleared equivalent test available. As with its definition of “traditional LDTs,” the draft framework guidance lists several factors FDA will consider when determining whether an LDT addresses an unmet medical need. Two such factors are “whether there is [an] FDA-cleared or -approved IVD available for that specific intended use” and “whether the LDT is both manufactured and used by a healthcare facility laboratory (such as one located in a hospital or clinical) for a patient that is being diagnosed and/or treated at the same healthcare facility or within that facility’s healthcare system.”
?As mentioned above for traditional LDTs, if all of the stated criteria must be met in order to qualify as an LDT for an unmet need, then it is unlikely that many tests will meet this definition. For instance, some of the most novel and innovative tests are being provided by private companies as a service to healthcare providers—the tests are not being done at a healthcare facility.
Also, FDA will need to provide clarity regarding what it means by “intended use” in this context. Does a test have the same intended use if it measures the same analyte but for a different disease state?
FDA intends to exercise enforcement discretion over these categories of LDTs with respect to compliance with premarket submission and quality system requirements. Labs offering LDTs in this group, however, will be required to notify FDA of their test(s) and report adverse events, and corrections and removals.
The third group of LDTs spans high- and moderate-risk tests that FDA intends to fully regulate. The draft guidance defines the highest-risk devices as including:
- LDTs with the same intended use as a cleared or approved companion diagnostic
- LDTs with the same intended use as an FDA-approved Class III device
- Certain LDTs for determining safety and effectiveness of blood or blood products
Other high-risk LDTs will include tests classified as Class III devices. Moderate-risk LDTs are those that are classified as Class II devices. All LDTs in this third group will be subject to full regulation, including premarket notification or approval and compliance with the quality system regulation.
Change on the Horizon
With respect to LDTs in the second and third groups, FDA plans to exercise enforcement discretion regarding establishment registration for LDTs, provided that laboratories notify FDA of their LDTs within six months of FDA’s finalization of the guidance documents. No user fee will be associated with notification.
It is unclear what FDA will do with the information provided through the notification process, however. Based on the notification, for example, will FDA inform the laboratory as to what type of LDT it is running—a traditional LDT or an LDT for an unmet need, for example—or will laboratories self-identify their tests?
In addition, the notification guidance indicates that laboratories will be required to comply with the requirements for reporting medical device reports (MDRs) and corrections and removals pursuant to 21 C.F.R. Parts 803 and 806, respectively, just like any other medical device manufacturer.
Lastly, the draft guidance documents define an LDT as “an IVD that is intended for clinical use and designed, manufactured, and used within a single lab.” The draft framework guidance also identifies a number of laboratory tests that have been considered by industry to be LDTs in the past, but FDA believes are, in fact, IVDs. FDA says it will regulate all of these tests in the same way under the draft guidance documents.
FDA’s notice to Congress of the draft guidance documents stated that the guidance documents would not be issued until at least 60 days following the notification. Unless FDA opts to delay the timeline, the draft guidance documents will be issued for comment at the end of September. Generally, FDA allows 90 days for comment on draft guidance documents.
The agency has stated that it will hold a public hearing on these draft guidance documents. But given the difficulty in scheduling such a hearing at the end of the year, the hearing may not be held until early 2015. In addition, it is likely that FDA will receive a high volume of comments on the guidance documents, and thus, will take significant time to address them. It is also worth noting that any FDA redrafting will also require extensive internal vetting before it is issued to the public. Then, if the draft guidance documents are finalized, the requirements of the draft guidance documents will be phased in over approximately nine years.
Assessing the Potential Impact
The draft guidance documents have already drawn heavy criticism from several members of the House Committee on Energy and Commerce subcommittee during a hearing earlier this month. And there will likely be continued, extensive debate over these draft guidance documents during the coming months, given the significant effect that the burden of FDA regulatory compliance will place on laboratories.
After all, the draft guidance documentss, if finalized, will affect not only new LDTs, but also existing LDTs that are widely used in healthcare today. Moreover, the daunting regulatory oversight may deter new laboratories from even entering the field and threatens to slow adoption of innovative technologies in the diagnostic testing space.
To justify this significant change to laboratory regulation, FDA says that it needs to protect the public health because there are “inaccurate, unsafe, ineffective, or poor quality LDTs” currently on the market. However, FDA has yet to present evidence to support such a claim.
If finalized, these two draft guidance documents are poised to radically alter the way in which LDTs are regulated. These draft guidance documents would place significant burden on the approximately 2000 laboratories estimated to be affected, and will likely stifle innovation of new LDTs and modifications to existing tests. Ultimately, these controversial draft guidance documents present major questions and concerns for laboratories, as well as for the entire healthcare system.
Allyson B. Mullen is an associate at the law firm of Hyman, Phelps & McNamara, P.C., where she provides counsel to medical device and IVD manufacturers.