During the past few weeks, I’ve been reporting on a letter that Bradley M. Thompson, JD, and James A. Boiani, JD, attorneys at Epstein Becker Green, recently sent to FDA Commissioner Margaret Hamburg. The attorneys sent this letter on behalf of the Combination Products Coalition (, an association of drug, biologic, medical device, and IVD manufacturers dedicated to working with FDA to improve the regulation of combination products. In the letter, they discussed the regulation of laboratory-developed tests (LDT) and made the argument for creating a single regulatory framework for IVDs and LDTs. This week’s blog presents further information from this letter.

According to the letter, the American Clinical Laboratory Association (ACLA) claimed in its citizen petition that the flexibility afforded by the Clinical Laboratory Improvement Amendments (CLIA) leads to the creation of tests that would otherwise go undeveloped in which: there is no financial incentive to perform clinical trials and seek FDA approval because the test will serve only a small patient population; there is a need to quickly develop tests for the diagnosis and assessment of emerging infectious diseases, among other diseases and conditions; or a kit has not yet completed the FDA approval process.

“None of these arguments support the continued unequal treatment of IVDs and LDTs, nor do they recognize that there are expedited FDA pathways for patient access to tests and other pathways being developed,” said the letter. “To the extent that these pathways are not as attractive to development as the LDT model, all stakeholders (labs and non-lab manufacturers) and FDA must work together to identify further efficiencies and develop a single system that allows valuable tests to reach the market more quickly.”

Read: Breaking Down the Regulation of LDTs: FDA Jurisdiction

Small Patient Populations
The letter stated that the Food, Drug, and Cosmetic Act provides an expedited pathway to market for medical devices that are used in small populations: the humanitarian device exemption (HDE). FDA approves HDE devices based on a demonstration of safety and probable effectiveness, which substantially reduces the requirements for approval versus premarket applications. The use of this pathway is one way of bringing IVD tests to smaller populations in a more cost effective manner.

“There are also economic incentives to develop HDE devices,” said the letter. “Congress lifted historical profit restrictions on the sale of devices used in the diagnosis of a disease or condition that occurs in pediatric patients or in a pediatric subpopulation, and diagnostics for which development is impossible, highly impracticable, or unsafe. In addition, even if sales of the device were subject to restrictions, laboratories could still profit from the services they provide (e.g., using the test to analyze a patient sample). Therefore, even without the current LDT pathway, laboratories will have profitable pathways to develop tests through the HDE process, and will be able to pursue approvals more quickly due to the HDE efficacy standard.”

Read: Breaking Down the Regulation of LDTs: FDA Authority

Emergency Use Authorizations
The letter also stated that in 2004, Congress approved a faster pathway to market for IVDs and other products in response to emerging infections and other events posing significant risks to public health. The Emergency Use Authorization (EUA) allows IVDs to come to market, provided they demonstrate probable effectiveness and safety, and are subject to certain FDA imposed controls. In 2013, Congress expanded the standards for EUAs to include not only responses to actual public health emergencies but also the potential for emergencies. FDA has interpreted the law to include responses to potential emerging infections (e.g., H7N9 flu and coronavirus) by authorizing several IVDs to address public health needs.

“Another process for faster approvals, which is being developed by FDA and stakeholders currently, is the transitional IVD process for emerging diagnostics, which the agency committed to exploring as part of the Medical Device User Fee Amendments (MDUFA) III,” said the letter. “Exactly what this process will look like is to-be-determined, but it could also play a role in addressing the access issues with which ACLA (and everyone else) is concerned.”

Read: Breaking Down the Regulation of LDTs: Public Health, First Amendment, and Innovation

Access to Investigational IVDs
In addition, the letter stated that just because an IVD is in the investigational phase of development does not mean it is inaccessible to patients. Patients can obtain access to investigational IVDs through several ways. For example, some patients may gain access by enrolling as subjects in clinical trials. Other avenues that allow patients early access to investigational IVDs for clinical use include the emergency use, treatment use, compassionate use, and continued use programs. These programs accommodate early access in a way that balances the patient’s need for the IVD with FDA review requirements.

“We understand this system will not provide the same level of freedom that the current CLIA framework does for LDT development because it will impose regulatory requirements,” said the letter. “Also, we fully acknowledge that there are areas for improvement in these programs. With a move toward equal regulation, FDA must continue to work with stakeholders, including the lab community, to improve the current regulatory framework to make access even better while ensuring the effectiveness and safety of diagnostics. But the move toward equal regulation also must proceed.”

Read: Breaking Down the Regulation of LDTs: Moving Forward

LDT Component Regulation
According to the letter, another point frequently raised by proponents of maintaining dual regulatory systems for IVDs and LDTs is the role of FDA in regulating LDT components. IVD manufacturers make many components that labs use to produce LDTs. These components are produced under quality systems, meaning labs that use them have greater assurance of making a higher quality test. While that is a good thing, the test is still something new, a combination of many components used in a specific way. Moreover, because the test is an LDT, it is not subject to FDA review. Conversely, if non-lab manufacturers did the exact same thing as labs (i.e., assembled the same components to make a specific test), they would be creating a Class II or III medical device subject to extensive premarket review requirements.

“However, if component level regulation is sufficient for labs, IVD manufacturers should be allowed to do what laboratories do: figure out ways to assemble components into new diagnostics for cancer, rare diseases, etc., and market them without FDA review,” said the letter. “Non-lab manufacturers are at least as expert in developing tests as high-complexity CLIA laboratories. Further, if component regulation is sufficient, a non-lab manufacturer should be able to help a laboratory design and/or validate a test method to ensure its proper operation. The end product would likely be even better than if the lab developed the test itself. Thus, if component regulation is sufficient for labs, there is no reasonable basis for restricting manufacturers from doing the same and assisting laboratories in this effort.”