Biomarker-driven cancer care relies on precision companion diagnostics co-developed with targeted therapies in clinical trials. A one-drug/one-test strategy has been the norm in such co-development. But as biomarker-defined subsets of patients get smaller and smaller, what happens to patients with rare diseases or conditions?

A new white paper from the Friends of Cancer Research (FOCR) states that, today in oncology, next-generation sequencing technologies can query many biomarkers in one test. Thus, the traditional co-development approach of one drug/one test is “less ideal and poorly aligned with clinical and laboratory practice and patient needs,” as the paper puts it. The white paper defines rare in this case as a threshold of 10,000 patients.

Because of the small patient numbers, drug developers may not have an incentive for developing an approved companion diagnostic for a therapy for patients with a very rare disease or rare variant. Thus, for these small clinical trial subpopulations, the paper suggests that it seems prudent to allow diagnostic biomarker tests from multiple laboratories, as long as the tests meet an acceptable level of accuracy and comparability.

Released during an FOCR webinar, the white paper sets forth a new way of rethinking and adjusting regulatory requirements at the FDA for the development of a companion diagnostic for a therapy for patients who fall into a rare biomarker category. The goal is to bring targeted therapies sooner to patients with these rare diseases and conditions.

The white paper, Expedited Development of Diagnostics for Therapies Targeting Rare Biomarkers or Indications, comes at a time when legislation in Congress would reform the regulation of diagnostic products and provide oversight on laboratory-developed tests. The Verifying Accurate Leading-edge IVCT Development (VALID) Act of 2021 provides definitions of relevant terms for the acquisition and analysis of human specimens. It also establishes a program to evaluate and expedite the development of an in vitro clinical test (IVCT) that addresses an unmet need in patients. The act clarifies that an IVCT shall follow and adhere to certain FDA regulatory requirements.

If the U.S. learned one thing from the COVID-19 pandemic, it was the importance of accurate diagnostic tests, said U.S. Rep. Diana DeGette (D-CO), a co-sponsor of the VALID act. Speaking during the FOCR webinar, she noted that the VALID act provides a “breakthrough” framework within the FDA that offers a new way to evaluate diagnostic tests for rare diseases and conditions.

The time for Congress to clarify the rules on diagnostic tests is now, said Rep. Larry Bucshon, MD (R-IN), a co-sponsor of the VALID act who spoke during the webinar. He noted that the VALID act “balances patient safety while supporting innovation.” What drove Bucshon to help draft the VALID act was his experience as a physician before coming to Congress. “I’m working all the angles, as is Diana,” to get Congress to hold hearings on the VALID act.

The FOCR white paper states that the type and extent of information required by the FDA to support its approval of diagnostic tests for rare diseases “may need to vary based on the benefit/risk balance for the individual test and its intended use.” The white paper notes that the FDA “has generally not applied differing requirements for levels of evidence or certainty” when a companion diagnostic test addresses rare biomarkers. The purpose of the white paper’s suggested framework aims to improve patient access to clinical trials for rare diseases/biomarker therapies via the expanded use of local diagnostic tests, and to lower the risk and streamline the development of a companion diagnostic for rare cancers to align with a drug.

“We’re not asking for statutory change or new rules,” emphasized Rasika Kalamegham, PhD, a co-author of the FOCR white paper who is Executive Director and Head of US Regulatory Policy at Genentech. The regulatory adaptations are needed because patients with rare variants need them, she added. Speaking during the webinar, she said the white paper is not asking for changes in the evidentiary bar for companion diagnostics in the rare disease space, but what she would like to see is somewhat more formal guidance from the FDA.

Agreeing on the need for meaningful change was white paper co-author Jochen Lennerz, MD, PhD, Associate Professor of Pathology at both Massachusetts General Hospital and Harvard Medical School. Speaking during the webinar, he stressed the importance of scientific evidence in driving meaningful policy changes.

The white paper recognizes the inherent problems in using multiple local diagnostic tests because of laboratory variability. It states that “diagnostic tests have varying underlying designs and methodologies, and laboratories use different analyses, which can lead to discordance across tests.” But the paper states that “the benefits of identifying and accruing patients using multiple local tests, particularly when identifying rare variants, may outweigh the risk of variability in the clinical trial population.”

To address the diagnostic test/variability problem, the white paper suggests the alignment of minimum performance standards and variants/variant classes to help standardize biomarker measurement, “which in turn could reduce barriers to patient enrollment and ensure homogeneity in the trial population.” It contains a table of proposed minimum requirements to support the use of tests detecting rare variants.

Clinical trial sponsors could articulate, prior to patient enrollment, the minimum performance standards needed to accrue patients based on the particular study needs. Then local laboratories with individual tests could provide evidence that they meet the minimum performance standards required if they intend to enroll patients into trials. Previously, the FOCR published a white paper containing recommendations for proposed minimum performance standards called Blueprint for Breakthrough: Research and Reimbursement in the Age of Precision Medicine.

Current FDA guidance allows clinical trial enrollment using multiple local diagnostic tests; FDA recommends that the drug sponsor evaluate the comparability of test results among potential sites prior to beginning trial testing at those sites.

FDA staffers have been thinking along the lines of the authors of the FOCR white paper, said Soma Ghosh, PhD, a biologist and Regulatory Scientist in the FDA’s Center for Devices and Radiological Health (CDRH). She said the agency is “definitely open to flexibilities” in the evaluation of companion diagnostics for therapies designed for patients with rare disease variants. The white paper includes a table of regulatory flexibilities that could be applied. The table addresses analytical and clinical validation, and suggests allowing for post-marketing collection of real-world evidence.

The new FOCR white paper recommends the following ideas.

• CDRH staff and a companion diagnostic drug developer could engage in a dialogue earlier in the development process to explore flexibilities that could be applied to development of a companion diagnostic for patients with a rare biomarker.
• CDRH should commit to an expedited review timeline of 75 days for companion diagnostics for rare indications to ensure contemporaneous approval of the co-diagnostic and the drug, since drugs for rare indications are typically reviewed in a compressed timeline.
• A core set of validation data should be submitted to FDA pre-approval for all diagnostic tests.

If these recommendations are adopted, the winners will be patients with rare cancers. The white paper states: “Modifications to the development process can maximize patient access by not restricting the screening requirements to a single test, provide for rapid access to clinical trials by alleviating the need for repeat biopsy and analysis, expedite clinical drug development by identifying additional eligible patients, and ensure consistency between different tests with the same intended use.”