The US Food and Drug Administration last week issued a guidance intending to ease patient access to precision oncology drugs by outlining how test developers may achieve broader companion diagnostic indications.

The guidance is perhaps a bit late coming. After all, it has been long known that the one drug/one test paradigm is outdated in the present precision oncology era, where multiple drugs are approved for the same molecularly defined indication, and the FDA has approved several next-generation sequencing panels that are able to inform treatment strategies for many drugs at once.

Since the agency’s guidance seems very much in line with these market trends, the advice for sponsors in the FDA document is generally welcome news, said Susanne Munksted, managing director at Diaceutics, a diagnostics data analytics company that has also consulted on numerous Rx/Dx codevelopment projects. In Munksted’s view, tests that gauge DNA and RNA alterations associated with cancer drug response, particularly multigene NGS panels, may benefit from this guidance, since intellectual property is not owned by pharma in such cases.

“We already see broader panels being applied to several drugs, sometimes as post-launch commitments,” she said, In contrast, she noted that Dx companies may not be so free to pursue broader labeling for a immunohistochemistry-based CDx, where IP around the antibody is usually controlled by pharma. 

Industry observers also don’t see the guidance changing much in the way of regulatory requirements that CDx developers will have to meet in terms of demonstrating test performance. In fact, in seeking broader labeling, test developers will need to show their companion tests can reliably predict response (or non-response) to not just one cancer drug but to a group of drugs, potentially necessitating the involvement of multiple pharma companies.

In the past, when diagnostics developers have tried to pursue broader CDx labeling, it has been difficult to garner the cooperation of competing drug firms, and the FDA’s guidance doesn’t offer any solutions for this particular challenge. As such, it remains to be seen the extent to which diagnostics developers will pursue CDx labeling for a group of cancer drugs, Munksted said, and whether the guidance will encourage more precompetitive Rx/Dx deals between drug and diagnostics developers.

Broader labeling “not so simple”

In the early days of precision oncology, the relationship between a personalized drug and its companion test was a one-to-one relationship. When the FDA approved a drug for a molecularly defined patient population, the therapy label noted that the intended use population had to be identified using an FDA-approved test. The companion test referenced in drug labeling was usually used to identify best responders in the study that led to the approval of both the drug and the diagnostic.

Meanwhile, the FDA-approved label for the CDx would indicate that it could be used to predict response to that specific drug.

The standard Rx/Dx labeling practices have been useful for getting a drug and its CDx through regulatory review. However, now that there are multiple targeted drugs for BRAF V600E/K-mutated melanoma, ALK-positive and EGFR-mutated non-small cell lung cancer, and immunotherapies for PD-L1 expressing cancer indications, the older paradigm is no longer practical for patient care.

In its recently published guidance, the FDA illustrates the challenge using the example of EGFR inhibitors for NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitutions. The agency has approved five EGFR inhibitors for this molecularly defined subset of patients and four companion diagnostics. Qiagen’s Therascreen EGFR RGQ PCR Kit is indicated for use with afatinib (Boehringer Ingelheim’s Gilotrif), gefitinib (AstraZeneca’s Iressa), and dacomitinib (Pfizer’s Vizimpro). Roche’s Cobas EGFR Mutation Test V2 is indicated for use with gefitinib, erlotinib (Genentech’s Tarceva), and osimertinib (AstraZeneca’s Tagrisso).

Thermo Fisher Scientific’s Oncomine Dx Target Test is indicated for use with gefitinib, and Foundation Medicine’s FoundationOne CDx is indicated for afatinib, gefitinib, erlotinib, and osimertinib.

That means that a NSCLC patient who is tested on Qiagen’s test and learns of an EGFR exon 19 deletion, may be eligible for three of five FDA-approved EGFR inhibitors, according to the test’s FDA-approved label. And even though there are now several FDA approved NGS panels, such as FoundationOne CDx and Oncomine Dx, which can be used to guide therapy with multiple cancer drugs, as the EGFR inhibitor example shows, the labels of these tests still restrict their use to one or a few drugs in a molecularly defined category.

“[The] FDA is concerned that the current situation is not optimal for patient care because a clinician may need to order a different companion diagnostic (i.e. one that includes other therapeutic products on the label), obtain an additional biopsy(ies) from a patient, or both, to have additional therapy treatment options,” the agency acknowledged in the guidance.

The agency issued this guidance to help CDx developers pursue broader indications that would allow tests to be used alongside a therapeutic group. To achieve this, the sponsor will have to first define the therapeutic group its test will address. Specifically, there must be at least two cancer drugs with the same molecular indication in order to comprise a “therapeutic group,” and these drugs must already be approved with at least one companion test that analyzes the same sample type.

In defining the therapeutic group, the sponsors would have to demonstrate detailed understanding of the mechanism of action of the oncology drugs in the group, via clinical studies, retrospective analysis, or non-clinical data, and show that the companion test can detect the interaction between the drugs and the biomarkers of interest. Sponsors will also have to show that the CDx can analytically gauge the biomarkers of interest in the indication for the therapeutic group and establish the clinical validity in terms of being able to accurately predict who will or won’t respond to the drugs.

The FDA noted that a sponsor that already has a CDx approved alongside a drug in a potential therapy group will be able to leverage the data it has already generated. Sponsors that don’t have a companion test approved yet, but would like to pursue a therapy group indication, can demonstrate the test’s concordance with an already approved CDx in that indication, or analyze samples treated with drugs in the group retrospectively. Sponsors are also always free to do clinical studies from scratch to demonstrate analytical and clinical validity of a CDx in a therapeutic group.

While a therapeutic group indication won’t be appropriate for all companion tests, this pathway will be particularly attractive to providers of NGS cancer panels as they try to increase test adoption, in Munksted’s view. The more drugs an NGS panel is able to direct treatment to, the bigger their market advantage, she noted. 

Caris Life Sciences, for example, is in the midst of taking two NGS test panels, MI Transcriptome and MI Exome, through the FDA review process, and both will likely include CDx indications. The company “is pursuing discussions and seeking guidance from the FDA about this opportunity” for broader therapeutic group labeling, said Caris CSO David Spetzler. “Our tests include biomarkers where use of a broader label would be advantageous to both the treating physician and patient.”

However, achieving broader labeling will not be an easy task. “Labeling for such a broader use is not as simple as just matching diagnostic targets with therapeutic targets,” the agency told sponsors in its guidance.

Much of the regulatory burden will still fall on the diagnostics developer to demonstrate that the CDx can identify the population of patients that will be eligible for not just one drug, but a group of therapies. “Non-inferiority [or] concordance studies can be difficult, and often impossible, to perform if the test is not a commercially available kit for test developers, and access to pivotal clinical trial samples is limited as more tests and targeted therapies are codeveloped,” Spetzler said.

A spokesperson for Thermo Fisher Scientific, a company that garnered FDA approval in 2017 for its Oncomine Dx Target Test, also recognized that class labeling of the type described in FDA’s guidance could help CDx developers expand test claims, broaden patient access to targeted cancer drugs, and make it easier for physicians as they have to pick the right option for patients from an expanding menu of drugs. However, the guidance, also “does not eliminate the need to demonstrate performance and concordance,” the spokesperson added.

The Oncomine Dx NGS test gauges 23 genes associated with NSCLC, including three CDx markers for guiding cancer treatment, and assesses 46 genes in total. The company has been working with multiple pharma companies to expand the CDx indication for the test. The spokesperson noted that the latest guidance is in line with the interactions Thermo and the agency have had with regard to the various supplemental premarket approval applications that it is pursing for Oncomine Dx with different pharma partners. “Ultimately, we hope the guidance increases the utility of companion diagnostics and leads to improved patient outcomes,” the spokesperson said.

Even if the FDA’s guidance ushers in more companion tests with streamlined indications, the tests will likely still differ in terms of sensitivity and specificity, Spetzler noted. Even when tests gauge the same biomarker, if they have different sensitivity and specificity, they are identifying different groups of patients for the same drugs.

Aligning the performance of different CDx may be particularly challenging when they gauge gene expression or identify responders and non-responders based on a cut off, such as tests for PD-L1 expression and tumor mutational burden (TMB) for predicting immunotherapy benefit. The non-profit Friends of Cancer Research has been working with test providers to identify the variability between labs providing TMB estimates, and recently published a paper on the first phase of those harmonization efforts. If that paper is any indication, the work involved in understanding the differences between tests that gauge complex biomarkers, such as TMB, is not insignificant.

The FDA in its guidance discusses the impact on patients when tests have different cutoffs, but again it doesn’t offer any solutions in terms of harmonization other than to say, “Differing thresholds need to be resolved, for example, during the performance concordance testing and analysis.”

Implications for Rx/Dx deals

This patchwork of CDx labels also reflects the structure of Rx/Dx deals. Traditionally, within these deals, the drugmaker pays for the development and commercialization of the companion diagnostic that will enable FDA approval and marketing of its drug. But in the real world, especially while the FDA continues to exercise enforcement discretion over lab-developed tests, that one FDA approved CDx is not the only test that will be used to determine whether a patient should get that drug.

Firms like Diaceutics, which have helped companies ink these Rx/Dx deals, have found it difficult to get pharmaceutical companies to recognize the importance of supporting the broader diagnostics ecosystem, which includes local labs, pathologists, and oncologists. Because pharmas tend to focus narrowly on just getting their drugs through the FDA and to market, when the drugs enter the market, patient access and pharma revenues are stymied by the broader inefficiencies in the testing space.

A 2017 Diaceutics survey estimated that as many as 156,000 cancer patients in the US and Europe may be missing out on precision medicines due to delayed testing, poor sample management, and false-negative results. These inefficiencies translate to $16.6 billion in lost revenues for pharma annually.

Streamlining CDx test labels would also require drugmarkers to take a broader view of the precision oncology ecosystem. In the past, however, when diagnostics companies have tried to advance another FDA-approved CDx option for a drug that’s already come to market, often pharma companies haven’t been willing to share samples to facilitate the studies that would be needed to demonstrate test performance with regulators.

“The concern around sharing not only samples but commercially sensitive information will not create easy negotiations between Dx companies and multiple pharma companies,” Munksted predicted.

Meanwhile, CDx developers who still pursue broader therapeutic group indications may have to accept a lower level of pharma investment. The traditional Rx/Dx deal is predicated on the understanding that one drug company will fund the development and commercialization of the CDx that will be launched alongside its drug and drive sales of its therapy.

A pharmaceutical company may see a companion test with a broad indication, driving sales of all therapies in a group, including ones that its drug competes with, and may not be so inclined to support development of that test. “The incentive for pharma to be the sole sponsor for that test only really sustains if they have a significant first mover advantage on the competition,” Munksted said.

This may result in some pharmas arguing that because diagnostics companies can now make more money from the commercialization of their tests, they don’t need such big upfront development fees. In turn, “a big driver of CDx development and approval could be disrupted and reshaped in the near term,” she said.

On the positive side, over the longer term, this guidance may prod some drug companies to ink pre-competitive arrangements, which could improve somewhat the historically low returns diagnostics firms have seen from CDx sales. According to Diaceutics’ economic modeling, in the US NSCLC market, for example, diagnostics industry stakeholders comprising labs, data analytics firms, and marketing services extract only 2 percent of revenues generated downstream of these Rx/Dx deals, while 98 percent of revenues go to drug companies.

Although Diaceutics has tried to encourage precompetitive deals, pharma hasn’t been willing to engage in them when it comes to commercial-stage testing. These arrangements usually require the involvement of a third party to assure the drug firm that the diagnostics developer isn’t sharing its secrets, such as therapy and test launch strategies and timeframes, with competitors. Such tensions were particularly pronounced, Munkstead recalled, when drugmakers were competing for market share with their blockbuster immunotherapies and had to introduce PD-L1 testing in some indications.

“There is always tension in these precompetitive deals between what is truly shared and truly commercially sensitive,” Munksted said.

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