FDA pilot aims to boost transparency for oncology tests

Editor's note: This article has been updated to clarify the regulatory framework for clinical laboratories and laboratory developed tests. 

The US Food and Drug Administration (FDA) is looking for up to nine drugmakers to join a pilot program intended to improve transparency for oncology drugs that rely on in vitro diagnostics to identify patients who may benefit from a particular treatment. Use of so-called companion diagnostics has increased with the proliferation of targeted therapies in recent years, especially in the oncology space.
 
Alongside its announcement of the pilot program on Monday, FDA released a final guidance detailing the program, which aims to establish minimum performance characteristics for tests meant to be used for patient treatment decisions.
 
Oncology drugs are often approved alongside an in vitro companion diagnostic, though the agency in some cases will approve a drug before a corresponding companion diagnostic is authorized, which creates a gap that is often filled by laboratory developed tests (LDTs). FDA details the circumstances in which it may approve treatments that require the use of a companion in vitro diagnostic when the test has not received marketing authorization in its guidance entitled In Vitro Companion Diagnostic Devices.
 
The agency said it has concerns about the reliability of LDTs that are not authorized by the agency, and said it hopes the new pilot program will help regulators have more confidence in future drug-device oncology combination products.
 
For years, FDA has raised concerns about LDTs, especially those used for diagnosing breast, ovarian, prostate and other cancers, and has called for a more modern framework for regulating such tests.
 
Jeff Shuren, director of the Center for Devices and Radiological Health (CDRH), has said that FDA has traditionally exercised enforcement discretion with regard to LTDs as they often carried low risks; however, the agency has said that the tests have grown more complex over time, are often high-risk and in some cases are mass manufactured. (RELATED: Shuren talks cybersecurity, calls for pre-cert and diagnostic reform legislation, Regulatory Focus 27 October 2022)
 
Shuren has previously stated that the agency needs a new framework for regulating LDTs. The labs that develop and perform such tests are overseen by the Centers for Medicare and Medicaid Services under the Clinical Laboratory Improvement Amendments (CLIA), though FDA has argued that it has the authority to regulate LDTs as medical devices under its existing regulations.
 
FDA Commissioner Robert Califf has also called for greater authority to regulate LDTs. While Califf has said he would prefer that Congress pass legislation making that authority explicit, he suggested that the agency would pursue rulemaking to establish regulations for LDTs if Congress does not act. In the latest Unified Agenda, FDA included a proposed rule that would amend the agency’s regulations to explicitly regulate LDTs as medical devices. (RELATED: Califf: FDA may use rulemaking for diagnostics reform if VALID isn't passed, Regulatory Focus 25 October 2022)

Pilot program
 
While it seeks legislative and regulatory fixes for LDTs, FDA said the new pilot program will enhance patient care and transparency by establishing minimum performance characteristics for tests used with participating products.
 
The pilot is voluntary, and FDA is clear in the guidance that it generally exercises enforcement discretion with regard to LDTs and that the guidance contains nonbinding recommendations and does not establish legally enforceable responsibilities.

“The agency has become increasingly concerned that some tests made by laboratories and not authorized by the FDA may not provide accurate and reliable test results or perform as well as FDA authorized tests,” the guidance states. “This may negatively impact treatment decisions. This pilot program is one step that may be helpful in reducing the risk of using LDTs for oncology drug treatment decisions while we continue to work on a broader approach for LDTs, including moving forward with rulemaking.”
 
According to Shuren, the guidance is aimed at addressing safety risks posed by “poorly performing” LDTs and set testing performance standards for labeling use if the drug is allowed on the market.
 
“The pilot aims to help by making transparent performance recommendations for diagnostic tests used to select certain oncology drug treatments,” he said.

While supportive of the goals of the pilot program, the American Clinical Laboratory Association (ACLA) said it felt LDT developers were unfairly maligned in FDA's announcement.

"FDA's proposed [companion diagnostic] CDx pilot program, though limited in scope, would share information about performance characteristics for companion diagnostics for important oncology products, thereby facilitating the development of tests by laboratories. At the same time, we are disappointed that FDA chose to disparage laboratory developed tests (LDTs) in its announcement of the program, rather than acknowledge and appreciate the critical and lifesaving role that LDTs play in our medical system," ACLA President Susan Van Meter told Focus.

"Every day, physicians and patients rely on innovative, high-quality LDTs to support patient access to the best available therapies. ACLA continues to support and applaud the work of its members who are developing groundbreaking tests in the service of patients and the public health," she added.
 
FDA details its expectations from pilot participants in the newly issued final guidance. Under the pilot, FDA will use information about the clinical trial assays (CTAs) used in the pivotal trial(s) to support drug approval to establish minimum analytical performance characteristics that would, “when established through properly conducted validation studies, … support extrapolation of the clinical validity of the CTA(s) to additional tests of the same type.” FDA said this could enable test makers to leverage the clinical validity of the CTAs and “streamline validation of additional tests.”
 
FDA said it will publish the minimum performance characteristics for tests used with approved drugs in the pilot on a dedicated website.
 
“This transparency aims to help facilitate better and more consistent performance of these tests, resulting in better drug selection and improved care for patients with cancer,” said FDA.
 
Drug developers who want to participate in the pilot program can submit a statement of interest alongside their investigational new drug (INDs) applications, new drug applications (NDAs) or biologic license applications (BLAs).
 
Sponsors should discuss the analytical validation data and performance characteristics of the diagnostics they plan to use in their trials with FDA before starting clinical trials. However, FDA will also consider trials that are already under way if the sponsor is able to collect the necessary data and provide sound justification for any missing validation data. The agency also cautions that if there is insufficient validation data on the assays used in the trials, they will likely deny participation in the pilot.
 
FDA has published templates on the CDRH website that oncology sponsors who want to participate in the pilot program can use to collect and provide performance characteristics and validation information for the clinical trial assays they intend to use.
 
“Based on the experience during the initial phase [of the pilot program], FDA intends to update this guidance to include more specific procedures with specific information to provide the agency and anticipates expanding the pilot to evaluate additional sponsors for acceptance into the pilot,” said FDA.
 
Final Guidance