During the past couple of 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 (CPC), 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.

Read: Breaking Down the Regulation of LDTs: FDA Jurisdiction

History of FDA Authority
According to the letter, FDA has publicly expressed for many years its belief that LDTs pose risks to patients due to the potential for improper validation of LDTs. At an FDA public meeting on the oversight of LDTs in July 2010, agency officials stated that these “risks include risk of missed diagnosis, wrong diagnosis, and failure to receive appropriate treatment.”

“When one considers many LDTs are intended for use in diagnosing serious or life-threatening diseases, and the widespread use of LDTs, the potential for serious harm to patients (if FDA is right) is clear,” said the letter. “In that case, how can FDA maintain a dual system of regulation that provides no FDA oversight of LDTs?”

The letter stated that much of FDA’s authority has historically come from laws enacted in response to public tragedies, which it had previously lacked sufficient authority to respond to. The letter cited the following laws as examples:

  • The 1906 Pure Food and Drugs Act. Before the 1906 law, the U.S. faced an epidemic of harms from patent medicines. These so-called snake oil remedies were purported cure-alls, but they often harmed or even killed patients. An exposé on the dangers of patent medicines (i.e., the addictions, injuries, and deaths they were causing) was published in late 1905 and played a key role in securing passage of the 1906 legislation.
  • The 1938 Food, Drug, and Cosmetic Act (FDCA). The 1938 law was passed in response to the Elixir of Sulfanilamide tragedy in 1937, which claimed the lives of more than 100 people in 15 states. This tragedy was the motivation behind new drug safety requirements included in the 1938 legislation.
  • The 1962 Kefauver-Harris Amendments to FDCA. The Kefauver amendments added the effectiveness and clinical trials requirements for new drug approvals. They were passed as a response to the tens of thousands of birth defects caused by the use of thalidomide.
  • The 1976 Medical Device Amendments. These amendments gave FDA clear authority to regulate IVDs, LDTs, and other medical devices. They were passed in response to pacemaker failures and the thousands of injuries resulting from the use of the Dalkon Shield intrauterine device.
  • The 1990 Safe Medical Device Amendments. These amendments introduced post-market surveillance and reporting requirements as a response to the market withdrawal of a heart valve in 1986.
  • The 2013 Compounding Quality Act. In response to a compounding-related fungal meningitis outbreak that claimed the lives of more than 60 people and injured 760 others, Congress passed this legislation to expand FDA’s authority over drug compounding.

“In the LDT case, FDA says it has identified risks and claims it has the authority to prevent risks that could lead to misdiagnosis or mistreatment of disease,” said the letter. “However, the FDAs of seven Presidential administrations have chosen not to exercise this authority. In light of history, it is difficult to imagine how FDA’s findings and inaction can be reconciled.”

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

Disputing Clinical Lab Claims
The letter stated that in its citizen petition, the American Clinical Laboratory Association (ACLA) tried to change FDA’s mind about the risks of LDTs. ACLA claimed that many LDTs are the accepted gold standard tests for Gaucher disease, breast cancer, colon cancer, and many other serious illnesses. ACLA also suggested that the absence of documented cases of patient harm from LDTs demonstrates their safety. In addition, ACLA explained that FDA regulation over LDTs could leave patients without diagnostic options. The letter considered each of these points.

First, is every LDT a gold standard test? The letter stated that there are approximately 20,000 high complexity laboratories that conduct LDTs. If each of these labs is running an LDT for breast cancer, for example, there are 20,000 LDTs for that one disease. Thus, when ACLA refers to LDTs for a disease, it is talking about 20,000 different LDTs.

“Also, given that laboratories may run 1000s of LDTs, as stated by ACLA, there are potentially millions of distinct tests with different designs and validations,” said the letter. “How many of these tests have been designed and validated properly? Under the current regulatory framework, we have no way to answer that question. Without that answer, the gold standard status of certain LDTs is not a good reason to maintain a dual regulatory system.”

Second, does the apparent absence of documented cases of patient harm indicate LDT safety? According to the letter, ACLA claimed that “even though laboratories are not required to report adverse events, litigation or other publicity would have revealed” harms to patients. This is not a persuasive argument. Although catastrophic and identifiable harms may spur litigation or publicity, many other problems will not be identified through these means.

Breaking Down the Regulation of LDTs: Access to Innovative IVDs

“For example, with FDA-regulated products, the vast majority of safety reports that FDA receives are not the result of lawsuits or publicity,” said the letter. “They are issues identified through a company’s post-market surveillance and complaint investigation systems (systems that laboratories are not currently required to have, as ACLA acknowledged in its petition).”

Third, is the potential disruption of testing a reason not to regulate LDTs? The letter stated that new regulations always have the potential to create some amount of disruption. In the past, when bringing historically marketed but unapproved products within the scope of FDA regulation, the agency has balanced the potential for disruption and the need for regulation through judicious use of enforcement discretion (i.e., enforcement discretion would be exercised for some finite period to transition currently marketed products into a new regulatory structure).

“If there are situations where there are no FDA-approved alternatives to an LDT, and a specific LDT does not appear to pose unreasonable risks to patients based on existing validation data, some period of FDA enforcement discretion would of course be reasonable,” said the letter. “But the indefinite enforcement discretion FDA is now exercising for LDTs is not.”

In the coming weeks, I’ll continue to discuss how the attorneys explain why FDA can and should 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 establish equal regulation.

Read: Breaking Down the Regulation of LDTs: Moving Forward