Interest Continues in CDx Codevelopment, But Clinical Utility Focus Needed

A recent string of announcements of partnerships aimed at expanding companion diagnostic (CDx) codevelopment reflects the commitment of pharmaceutical companies to develop targeted therapeutics, particularly for their cancer product pipelines. Yet for these tests to be commercially successful, experts say test developers must incorporate a steadfast focus on the tests’ clinical utility during all stages of development. The 1998 Herceptin/HercepTest approval for metastatic breast cancer marked the beginning of the era of CDx codevelopment. While there has been tremendous hope that such targeted therapeutics will increase the efficacy of cancer treatment and improve survival outcomes, there remains a limited number of approved CDx on the commercial market. “People said [HercepTest] was heralding in a new age—the way of the future. But another decade passed and right now we have relatively few CDx, leaving a lot of people asking what happened,” Kenneth Emancipator, M.D., a board member of the American Society for Clinical Pathology, explains to DTET. “But when you look at pharmaceutical companies’ current pipelines, I predict an explosion of CDx within five years.” Experts say demonstration of a test’s clinical utility is key to overcoming several large hurdles, namely reimbursement and regulatory approval, on the path to clinical adoption of companion diagnostics. CDx codevelopment was the topic of a special focus issue of Clinical Cancer Research (CCR) published online March 14. The authors of one of the articles stress that demonstration of clinical utility should be incorporated into the early stages of assay development and trials “by anticipating what types of questions will need to be answered and what kinds of data need to be generated to supplement routine analytical and clinical validation studies.” According to David Parkinson from New Enterprise Associates (Menlo Park, Calif.) and colleagues, the best practices for demonstration of clinical utility incorporate these steps:

• Define the intended use of the assay along and understand the clinical context of the test;
• Begin outlining what evidence will be needed early in assay development and project planning;
• Evaluate potential regulatory pathways and accompanying business strategy needs;
• Integrate all steps needed to demonstrate clinical utility (both pre- and post-approval) into the development plan;
• Design clinical trials to begin gathering evidence of clinical utility even before approval and commercialization; and
• Assemble the chain of evidence.

This additional evidence needed to establish clinical utility is, of course, costly to produce and adds to the inherent risk in developing CDx products. “A CDx is a low-margin profit that assumes pharmaceutical risk in development,” says Emancipator. “Pharmaceutical risk with a diagnostic [financial] reward is not a good deal. . . . Even with pharmaceutical companies paying for a portion of the research and development, there is an opportunity cost for the diagnostic company. What if the drug fails and doesn’t make it to market?” Even if the drug-CDx pair does make it to the market, test reimbursement can remain a challenge. Diagnostic tests are notoriously undervalued by payers and are not reimbursed according to the value of the information they provide.

2014 Announcements of CDx Partnerships
Diagnostic Co.	Pharmaceutical Co.	Partnership Details
Agendia	Daiichi Sankyo	The Japanese drug maker announced in late April it will use Agendia’s oncology biomarker technology to evaluate new drugs in clinical trials.
Diaxonhit	InnaVirVax	Diaxonhit received $2.4 million to develop a CDx for an AIDS vaccine and personalized care of AIDS patients from InnaVirVax, in conjunction with the Strategic Industrial Innovation Program (France), in late April.
Ventana (a Roche company)	Genmab	Ventana will develop an immunochemistry CDx that could be used for screening tissue factor from solid tumor samples in patients participating in clinical trials for investigational drug HuMax-TF-ADC.
Prestizia (France)	Splicos and CNRS	In collaboration with the French National Center for Scientific Research, Prestizia will develop a microRNA CDx for the investigational HIV treatment SPL-464.
Eutropics	Tolero Pharmaceuticals	Eutropics announced in January it will use its Praedicare-Dx biomarker platform to support the development of Tolero’s alvocidibm, in Phase III trials, for patients with two forms of leukemia.
Dako collaborations (an Agilient company)	Amgen	Early in the year, Dako announced several with Amgen to work on a CDx for a drug candidate for an undisclosed form of cancer.
Source: Compiled by DTET from press releases and news reports

“Recognition of the importance of establishing the clinical utility of a test can be reinforced by payer resistance to tests lacking this level of evidence, or by a tiered reimbursement system which rewards clinical tests with superior levels of clinical utility information,” writes Parkinson in CCR. “Absent a rewards system that recognizes the value of this information, complex tests of high predictive value will not be developed with the needed frequency.” Also impeding test development and adoption is a less than clear regulatory framework. The future regulatory environment for laboratory-developed tests remains uncertain, while the U.S. Food and Drug Administration’s (FDA’s) Elizabeth A. Mansfield describes the agency’s approach to CDx approval as a “still-evolving regulatory paradigm.” “To date, no two co-development activities have been exactly the same, so the learning curve for all parties has been steep,” admits Mansfield in the CCR special focus issue. “In its efforts to be as flexible as possible within the bounds of regulatory constraints, FDA has considered each situation individually. Although this approach allows the greatest flexibility in development, it does not lend itself easily to defining a prescriptive or predictable pathway. FDA continues to believe that although predictability is important, flexibility must take precedence.” Advances in technology are further confounding the evolving regulatory and reimbursement paradigms as next-generation sequencing (NGS) makes it possible to examine multiple genomic alterations simultaneously, seemingly making the one-test, one-drug model appear dated. “It seems almost inevitable that a consolidation of diagnostic testing should take place, to enable a single test or a few tests to garner all the necessary information for therapeutic decision making,” writes Mansfield. Yet expanded NGS, in the short term, will not dominate CDx testing. “There are a lot people talking about next-gen as a panacea,” says Emancipator, who currently works for Merck Research Labs as director of CDx. “There is definitely a place for it, as it is a way around the one-test, one-drug phenomenon, but there are other types of biomarkers that are important, too, that are not immediately available to NGS.” Takeaway: Pharmaceutical companies and test developers will keep an eye on new technologies, including NGS, to possibly improve the efficiency and cost-effectiveness of CDx testing. Regardless of the platform, CDx development needs to focus on clinical utility. Side Box: Questions to Evaluate Clinical Utility

• Does the test improve clinical and health outcomes because of the result’s subsequent effect on diagnosis and intervention?
• Do the results provide information useful for decisionmaking?
• Do the benefits outweigh the harms when the test results are considered in patient management?
• Is there a chain of evidence demonstrating that the test results can change patient management decisions and improve net health outcomes?

Source: Adapted from “Evidence of Clinical Utility: An Unmet Need in Molecular Diagnostics for Patients With Cancer” by David R. Parkinson, Robert T. McCormack, Susan M. Keating, et al., published in Clinical Cancer Research online March 15.