Laboratory-developed tests may be misidentifying patients for treatment with targeted therapies. Under a new initiative, the FDA will work with sponsors to develop minimum performance characteristics for LDTs that may be used with an approved cancer drug in clinical practice.
The US Food and Drug Administration’s pilot program for oncology drugs and in vitro diagnostic tests is aimed at bringing the regulatory paradigm closer to the widespread use of laboratory-developed tests in clinical practice.
The new program also is intended to bolster patient safety by ensuring patients who receive a targeted cancer therapy actually are positive for the genetic mutation or marker at which the therapeutic is directed, agency officials said.
Richard Pazdur, director of the Oncology Center of Excellence, and Harpreet Singh, director of the Division of Oncology Products II, discussed the new pilot program at an 11 July Friends of Cancer Research meeting.
The FDA described the initiative in a 20 June final guidance, “Oncology Drug Products Used With Certain In Vitro Diagnostic Tests: Pilot Program.” Pazdur had previewed plans for the program at a meeting in November. (Also see “US FDA Oncology, Device Centers Developing Public Diagnostic Standards” – Pink Sheet, 5 Dec, 2022.)
Currently, the FDA may decide to approve a life-saving treatment that requires use of an in vitro companion diagnostic, even if a corresponding companion diagnostic has not yet received marketing authorization. In those situations, lab-developed tests are used for deciding which patients receive treatment in clinical practice.
The agency generally has exercised enforcement discretion for LDTs, meaning that it has not enforced regulatory requirements, the guidance states.
The pilot is intended “to provide greater transparency regarding performance characteristics that certain tests for oncology biomarkers should meet,” the guidance states. “Through this transparency FDA seeks to support better and more consistent performance of certain LDTs used to identify patients for treatment with certain oncology drug products, resulting in better drug selection and care for patients with cancer.”
‘Incongruence’ Creates Safety Concerns
Singh discussed the current “incongruence in the regulatory paradigm and what’s actually happening.”
“It is the regulatory expectation that for each drug that is approved, that there’s one diagnostic test used to identify select patients for safe and effective use of that drug,” she said. However, “practically speaking, this is incongruent with what’s actually happening in the real world in academic settings and community settings in oncology practice.”
Data often are lacking to bridge from the various LDTs used for clinical trial enrollment to one central diagnostic test. If a drug is approved without a companion diagnostic, the problem is magnified, Singh said.
“We’ve put this drug out into the world absent a companion diagnostic, 40 times we’ve done this, and how the patients are selected for these approved drugs are based again on these unregulated, locally developed tests.”
Patients “are being potentially subjected to tests which may not actually be properly identifying them,” Singh said. “So it’s about patient safety. We think it’s a public health issue.”
The pilot program is aimed at “trying to bring the regulatory paradigm closer to what we know is actually happening and keep patients safe.”
Minimum Performance Characteristics As A Benchmark
Under the pilot, if the FDA concludes that a drug product should be approved, it will rely on the same pivotal clinical trials that supported drug approval to establish the clinical validity for the clinical trial assays (CTAs) used in those studies.
“Further, FDA intends to recommend minimum analytical performance characteristics for other tests that, when established through properly conducted validation studies, FDA believes would support extrapolation of the clinical validity of the CTA(s) to additional tests of the same type,” the guidance states.
“If FDA approves an oncology drug product enrolled in this pilot program, FDA expects that at the time of drug product approval, it will recommend minimum performance characteristics for in vitro diagnostic tests to be used to identify patients for treatment with that drug product.” – FDA Guidance
“If FDA approves an oncology drug product enrolled in this pilot program, FDA expects that at the time of drug product approval, it will recommend minimum performance characteristics for in vitro diagnostic tests to be used to identify patients for treatment with that drug product.”
These minimum performance characteristics, which will be posted on the Center for Devices and Radiological Health’s website, are intended to serve as a benchmark for developers seeking to design accurate and reliable tests.
“Test developers would be able to leverage the clinical validity of the CTAs established through the drug trial to help streamline validation of additional tests for the same use,” the guidance states. “Ultimately, this may bring new treatment options to appropriate patients sooner.”
The agency anticipates labeling for approved drugs in the pilot program will state the product is indicated for patients identified as exhibiting a named biomarker by in vitro diagnostic tests that have the agency’s recommended performance characteristics. The approved drug labeling and CDRH’s website also are expected to specify relevant test characteristics for the in vitro diagnostics for use with the drug, such as the biomarker detected, test method and specimen type.
Nine Sponsors Sought
In the pilot’s initial phase, which will last up to one year, the FDA is seeking participation of up to nine sponsors. The program will be periodically evaluated based on various experiences and comments to the docket. A public meeting will be held within three years.
“This does not limit us to nine drug development programs,” Singh said. “There’s just nine companies that we’d like to work with, big and small, based on the characteristics of their programs.”
The agency also is looking for a variety of tumor types and technology.
“Ideally, you would come to us prospectively with your biomarker-driven drug and associated clinical trial and your diagnostic strategy, and we would work together to establish minimal performance characteristics that will be used with these locally developed tests,” Singh said.
“With the drug approval will come basically a set of characteristics that providers can use and labs can use to ensure that the patients they are selecting are in fact meeting these characteristics and are appropriate for use with these drugs.” – FDA’s Harpreet Singh
“The locally developed test that we’ll be using, plan to use, you would work with the lab to make sure that they meet these minimal performance characteristics,” Singh added. “And at the time of drug approval, all of these characteristics will be transparently publicized on OCE and CDRH’s website.”
“Therefore, with the drug approval will come basically a set of characteristics that providers can use and labs can use to ensure that the patients they are selecting are in fact meeting these characteristics and are appropriate for use with these drugs,” she said.
Although the guidance allows for sponsors to enter the program on a retrospective basis, meaning that their clinical trials already have enrolled, the focus is really on prospective application of this program.
“If this is a successful pilot, it will be rolled out into a prospective discussion with the sponsors at the time that they come in to discuss their clinical trials, what will be the minimal performance criteria, and then this will be applied forward in the clinical trial,” Pazdur said. “So there’s not this bridging that has to happen between what was used in the clinical trial versus what an approved test would be.”
The pilot program does not preclude a sponsor from coming in for an approved companion diagnostic, he said. However, a sponsor that is accepted into the pilot would not be required to develop a companion diagnostic.
“If you’re working with us prospectively … within a clinical trial, a biomarker-driven strategy that would otherwise call for a singular companion diagnostic, by acceptance into the pilot … you would pursue ensuring that the locally developed tests meet minimal performance characteristics that we would help you establish,” Singh said.
“At the time of drug approval, you would not have a companion diagnostic. You would have listed on the website, OCE and CDRH, the minimal performance characteristics used in the plethora of locally developed labs … That would be how providers would, in turn, select patients to be treated with this drug.”
Interim Step Ahead Of LDT Rulemaking?
In announcing the pilot program, the FDA said it may help reduce the risk of using LDTs for oncology treatment decisions as the agency works on a broader approach for such diagnostics, “including moving forward with rulemaking.”
The VALID Act, which would give the agency comprehensive oversight of in vitro diagnostics and move LDT oversight from the Center for Medicare and Medicaid Services, failed to make it into the final user fee reauthorization package or the year-end omnibus appropriations law in 2022.
Although the legislation recently was reintroduced in Congress, the FDA has suggested it is considering taking regulatory action on its own. (Also see “Shuren: ‘You Can’t Be Expecting Us To Just Sit Back’” – Medtech Insight, 18 May, 2023.)
