A couple of weeks ago, I reported 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 (CPC), an association of drug, biologic, medical device, and IVD manufacturers dedicated to working with FDA to improve the regulation of combination products. In this letter, the attorneys 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.

Read: Breaking Down the Regulation of LDTs: FDA Authority

FDA’s Jurisdiction Over LDTs
According to the letter, FDA’s jurisdiction over LDTs is unquestionable. More than ten years ago, Thompson raised this issue with FDA’s Office of Chief Counsel and provided a detailed legal analysis, which explained how the Federal Food, Drug, and Cosmetic Act (FDCA) gave the agency authority to regulate LDTs. The agency agreed with this analysis and has consistently reaffirmed such authority over the years. Borrowing from that analysis, the following summarizes why LDTs are medical devices that are introduced into interstate commerce for commercial distribution, and are thus subject to FDCA.

“First, an LDT is a medical device, not a service,” said the letter. “Under FDCA, medical devices include any article comprised of ‘reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease.’ IVDs meet this definition, as do LDTs, which are collections of reagents, instruments, and systems assembled into an article for these same intended uses. The only difference between IVDs and LDTs is that the assembly of LDTs takes place at a lab instead of a traditional factory, which is irrelevant to jurisdiction, because it depends on what the article is, not where it is made.”

The letter stated the American Clinical Laboratory Association (ACLA) has argued that the act of assembling IVD-cleared products in the laboratory does not make a medical device, but is a service provided by the laboratory. However, FDA has long held that even the simplest assembly of two or more medical devices is an FDA-regulated device manufacturing activity. Even basic co-packaging of two finished devices creates a new medical device that is subject to FDA regulation. What labs are doing when they assemble devices to create LDTs goes beyond simple co-packaging. They are integrating their know-how and creativity into those combinations of components, which creates a new medical device.

“Second, LDTs are in interstate commerce,” said the letter. “The U.S. Constitution empowers the federal government to regulate commerce among the states. In enacting FDCA, Congress relied on this authority when it authorized FDA to regulate medical devices in interstate commerce. LDTs are in interstate commerce even though they do not physically cross state lines. It is well-settled law that products which have a substantial effect on interstate commerce are themselves in interstate commerce. There is no question that both elements are met for LDTs.”

The letter made the following points to demonstrate that LDTs are in interstate commerce: LDTs generate billions of dollars in revenue and play a fundamental role in managing the diagnosis and treatment of disease across the country; many laboratories advertise and promote their LDTs using instruments of interstate commerce (e.g., email, Internet, roads), often across state lines, and receive samples throughout the U.S.; and many LDTs are often constructed using components that were themselves in interstate commerce.

“Third, LDTs are being introduced into interstate commerce for commercial distribution,” said the letter. “Commercial distribution is defined as ‘any distribution of a device intended for human use which is held or offered for sale.’ The courts have found that a product is ‘held for sale’ and in commercial distribution when it is used in providing a medical service, but never sold in a commercial sense.”

The letter also stated that in its citizen petition, ACLA made arguments that have been previously considered and rejected by FDA: LDTs are services, not medical devices; LDTs are not in interstate commerce; and LDTs are not held for sale in commercial distribution. There have not been changes in the law that would result in FDA reaching a different conclusion than it has before.

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

Both Regulatory Systems for IVDs and LDTs Cannot Be Correct
“The IVD and LDT systems represent two completely different approaches to diagnostics regulation,” said the letter. “Yet, both IVDs and LDTs are diagnostic tests, informing physician diagnosis and treatment decisions, and having an equal impact on patients. A right result may save a life, and a wrong result may do serious harm. LDTs are subject to regulation under the Clinical Laboratory Improvement Amendments (CLIA), whereas IVDs are subject to both FDCA and CLIA. If CLIA by itself provides sufficient regulatory controls, because IVDs are also subject to CLIA just like LDTs, what value does FDA regulation provide? Can both systems be right?”

The letter stated that another way to look at the issue is to compare the different controls provided under FDCA and CLIA, differences that result from the complementary functions the two statutes are intended to serve. FDCA was created to regulate products, while CLIA regulates services.

“FDCA regulates the development, approval, manufacture, marketing, and post-market surveillance of IVDs,” said the letter. “Generally, IVDs start with early development under design control requirements, proceed through preclinical testing and clinical studies, and are submitted for review and approval by FDA. IVDs are manufactured under a robust quality system that governs all phases of production, and includes post-market surveillance through a complaint handling system. When potential safety events are identified, IVD manufacturers report these events through the medical device reporting system or, if the problem warrants, initiate a recall to correct the product or remove it from the market.”

Breaking Down the Regulation of LDTs: Access to Innovative IVDs

On the other hand, according to the letter, CLIA regulates laboratory practices and assures a laboratory’s competency to conduct a test by establishing requirements for personnel expertise, proficiency testing, facility requirements, and quality control testing to ensure on-going test performance. As a result of these differences, the controls that FDA places on IVDs under its FDCA authority do not exist under CLIA.

“There is an optimal system for regulation that balances oversight of IVD manufacturing with flexibility that allows for innovation,” said the letter. “Striking the right balance is crucial to the public health. Yet, the current system does not offer balance, but treats two indistinguishable products, LDTs and IVDs, completely differently, and imposes a number of extra requirements on IVDs beyond those for LDTs. In light of this, both systems cannot be right.”

In the coming weeks, I’ll continue to discuss how the attorneys explain why FDA can, should, and must create a single regulatory system that treats manufacturers equally, whether they call themselves a lab, an IVD company, or something else. I’ll also discuss their proposed actions that FDA should take to move toward equal regulation.

Read: Breaking Down the Regulation of LDTs: Moving Forward