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Evolving Regulatory Landscape For Companion Diagnostics

By Deborah Borfitz 

July 19, 2022 | It is now the expectation if not the reality that companion diagnostics (CDx) be approved concurrently with their corresponding therapeutic product. Multiple countries are quickly adopting policies and regulations for drug-diagnostic co-development and common themes are emerging about how a CDx should be clinically validated, according to Eunice Lee, Ph.D., vice president of global regulatory affairs at Guardant Health.  

One big unknown in the U.S. stems from the Verifying Accurate Leading-edge IVCT Development (VALID) Act, which proposes that the Food and Drug Administration (FDA) regulate laboratory-developed tests (LDTs) as it does other in vitro diagnostic (IVD) products, she says. The FDA has generally not enforced premarket regulatory requirements because LDTs were historically relatively simple lab tests with limited distribution. The clinical labs where they’re made receive oversight under the Clinical Laboratory Improvement Amendments of the Centers for Medicare & Medicaid Services. 

After more than a decade of attempts at regulatory reform, the VALID Act is closer to enactment than ever before, says Lee. If passed, high-risk LDTs would need to start undergoing a clinical validation assessment as part of the FDA’s premarket approval process just as IVDs currently do. 

The FDA has played a pioneering role in shaping the global regulatory landscape for CDx overall, says Lee. Guidances published by the agency are in many respects well aligned with similar documents more recently issued by its counterparts in China, Australia, and the European Union (EU).  

The latest EU IVD regulation (IVDR) frequently references CDx whereas in the previous IVD directive there were none, she notes. “That’s showing a real trend toward this co-development.” 

When it comes to regulatory policies surrounding CDx in the U.S. and the EU, perhaps the most striking difference is that in the former there is an “explicit expectation” that such products be approved concurrently with approvals of the drugs whereas in the latter there is no clear policy regarding concurrent diagnostic certification and drug approval, says Lee. This may be related to the fact that IVDs in the EU get reviewed by various third-party “Notified Bodies” as part of the regulatory process. These are organizations designated by an EU country to carry out conformity assessment procedures to demonstrate that products comply with requirements set forth in the applicable legislation, such as IVDR. 

Despite its clear preference for concurrent approvals, she adds, in several recent instances, the FDA has departed from its stated guidance and issued a post-marketing commitment with a drug approval to bring the associated CDx forward.  

At the upcoming Next Generation Dx Summit, Lee will be presenting an overview of the evolving global regulatory landscape for diagnostics and the impacts on co-development programs, as well as strategies for navigating the changing environment. She is also serving as chairperson for the larger conference track on the latest regulatory and policy updates for CDx. 

Validation And Reach 

In general, emerging regulatory policies globally seem to favor clinical validation of CDx products in tandem with investigative studies on their corresponding drug, says Lee. For example, one of the CDx-related technical review guidelines released by China’s National Medical Products Administration is focused on clinical trials where CDx reagents and anti-tumor drugs are being co-developed.  Demonstration of product safety and clinical performance are also highlighted in an EU directive to the In Vitro Diagnostic Medical Devices Regulation.  

In Australia, IVD companion diagnostics were first defined in medical device guidance issued by the Therapeutic Goods Administration in 2020, she continues. Notably, clinical evidence for a CDx requires simultaneous appraisal of the clinical evidence for the associated medicine and consideration of that drug product in the risk/benefit profile of the device.  

Strategy-wise, Lee advises early planning regarding the countries where the CDx will be registered to enable pertinent information on the product labeling to be applicable region to region, to the extent possible. Understanding the differing timelines between geographies could also inform launch priorities since, irrespective of regulatory policies on concurrent approvals, “from a commercial perspective it is still important to have two products be commercially available in close timing to each other.” 

The registration strategies of large pharmaceutical companies are typically considered early on in clinical development programs involving CDx partnerships, says Lee, since it’s important for them to know if their global reach is matched by would-be diagnostic providers. With LDTs, which are usually single-site tests, a key discussion point is how to make such products available in those regions outside the country.  

The overall percentage of targeted therapy approvals for indications that rely on a specific biomarker status have held steady over the past few years, she adds. In a report Lee gave at the 2020 Next Generation Dx Summit, personalized medicines accounted for roughly 20% of all new molecular entities approved by the FDA. 

Now Trending 

Among other happenings on the CDx front are advocacy efforts by Friends of Cancer Research around the co-development of drugs and diagnostics intended for rare patient populations, a topic addressed in a white paper recently published by the group, says Lee. It makes the point that next-generation sequencing (NGS) technologies can query many biomarkers in a single test, making the traditional one drug/one test approach “less ideal and poorly aligned with clinical and laboratory practice and patient needs.” Given the small clinical trial subpopulations, the paper argues, it would be prudent to allow diagnostic biomarker tests from multiple laboratories.  

Interest in developing relatively noninvasive liquid biopsy assays as companion diagnostics is also high, Lee says, with circulating tumor DNA solutions quickly penetrating the market and paving the way toward clinical translation across the cancer continuum. These will be a “powerful tool” in oncology to enable patient selection for therapy, the monitoring of disease progression, and timely access to the latest treatments. 

Few such tests have been FDA-approved to date, Lee notes. The first blood-based CDx was developed by Roche for the drug erlotinib (Tarceva, Astellas) for the treatment of non-small cell lung cancer (NSCLC).  

In 2020, Guardant Health’s Guardant360 CDx assay became the first liquid biopsy assay approved for comprehensive genomic profiling across all solid cancers. The test was also approved as a companion diagnostic to identify patients with specific types of mutations of the epidermal growth factor receptor gene in a deadly form of metastatic NSCLC, Lee says. Last year, the test became the first CDx approved to identify patients with locally advanced or metastatic NSCLC who harbor the KRAS G12C mutation and may benefit from sotorasib (Lumakras), developed and manufactured by Amgen.  

As technology advances, the regulatory framework needs to respond flexibly, says Lee. She cites the introduction of NGS, when marketing approvals still required validation of every single marker for an indication. The number of genes that can be simultaneously sequenced with NGS made it impractical if not unfeasible to validate every potential mutation that might be detected, so the regulatory paradigm had to evolve to allow for platform-level validation of high-throughput sequencing. 

With liquid biopsies and NGS of complex biomarkers, the same sort of flexibility is needed with respect to validation strategies if these products are to be reviewed efficiently and come to market in a timely manner, she adds.    

Editor’s Note: In addition to Eunice Lee, speakers addressing companion diagnostics at the 2022 Next Generation Dx Summit include Mark Stewart, Ph.D., vice president of science policy at Friends of Cancer Research; and Jennifer S. Dickey, Ph.D., vice president, regulatory and quality, at Personal Genome Diagnostics. A panel discussion will follow on whether the CDx regulatory paradigm is keeping up technology. 

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