Charting a Path to Personalized Medicine: Regulatory Challenges Loom for Companion Diagnostics
By Marie Powers
The biotech industry's interest in companion diagnostics has grown in concert with the recognition that those tests can offer an approval pathway for narrowly effective and costly biologics targeting specific biomarkers. To date, the FDA has offered scant guidance on the development of companion diagnostics, but that's about to change, potentially rearranging the landscape for biotechs and pharmas considering how to develop companion diagnostics internally or to partner with diagnostics firms.
Speaking Wednesday during a webcast sponsored by the Regulatory Affairs Professionals Society, Christine Gathers, senior director of regulatory affairs and diagnostics for Eli Lilly and Co., laid out the regulatory challenges facing drug developers and suggested partnering strategies that may allow them to move their therapies to the head of the class.
The time is ripe to consider companion diagnostics, as the industry is closer than ever to understanding the biological basis to disease, Gathers pointed out.
"We better understand molecular signaling pathways, and we're honing in on targets – especially in the oncology area, but we are seeing progress in other therapeutic areas," she said, adding that the goal of personalized medicine is to provide improved outcomes for patients "as opposed to drugs that only work for 50 percent of the patient population. Diagnostics are the tools that enable us to identify the right drug for each patient."
This could be a bellwether year for that effort. The FDA is set to issue a series of guidances, including a final guidance on in vitro companion diagnostic devices as early as this month.
"A lot of questions came up in the review of that guidance last year, and generally, the industry thought there were more questions generated than answers," Gathers said. (See BioWorld Today, July 18, 2011, Aug. 3, 2011, and Oct. 6, 2011.)
The FDA also is expected to issue final guidance on research-use only diagnostics as well as a series of draft guidances for laboratory-developed tests, diagnostics co-development and pre-investigational device exemption meetings. Despite some additional clarity, drug developers still will have to feel their way forward in developing companion diagnostics.
"Even with these new guidances, the FDA has commented that it remains behind relative to the pace of innovation," Gathers said. "As a result, there is significant ambiguity for the industry on a number of topics."
For starters, companion diagnostics have no clear regulatory process. The FDA remains a maze of multiple centers and divisions, and it's difficult for a drug or diagnostic company to know where to start when submitting those regulatory requests and how to link the different review groups.
The FDA has been slow to provide guidance on co-development globally, Gathers said. In addition, the industry is looking for more direction on bridging studies.
"It's not really clear what a company should do if it has a test in Phase III and wants to establish concordance with a commercial test that it plans to forward as a [pre-market approval] application," she observed.
Drug developers also are seeking greater direction about clinical utility – the key driver behind companion diagnostics – instead of guessing what standards the agency will measure. A public workshop in April in which FDA officials and industry experts sparred on the merits of minimal residual disease as a surrogate endpoint in acute lymphoblastic leukemia offered little assurance the agency is moving with any speed to address a raft of technical implementation issues. (See BioWorld Today, April 19, 2012.)
So far, the FDA's one clear message to developers is to submit applications for companion diagnostics along with drug applications for simultaneous review – a move that requires companies to develop those diagnostics prior to Phase II.
The industry has asked for greater flexibility, Gathers pointed out, since biomarkers are more likely to emerge at the end of Phase II studies or during Phase III. For the time being, however, she urged drug developers to develop biomarkers early in the game so they can mitigate risk, partner more quickly with a diagnostics manufacturer and collaborate with regulatory bodies globally.
"As time goes on, it becomes much more difficult to coordinate across regulatory bodies and also achieve that simultaneous submission," increasing the prospect of a delayed drug launch, Gathers said.
To maximize the opportunity for companion diagnostics, Gathers advised pharmas and biotechs to seek early interactions with regulatory bodies. In the U.S., that means bringing together senior managers from the FDA's Center for Devices and Radiological Health and Center for Drug Evaluation and Research from the outset. That prospect is fraught with its own set of challenges, since the two agencies have entirely different review processes in terms of the formality of review, frequency of interactions, initiation of investigation labeling, approval mechanisms and postmarketing studies.
Nevertheless, it's critical "to have the right players present so you can follow each Center's meeting format along with their preferences," Gathers maintained.
In terms of the level of evidence required for a companion diagnostic, "the intended use drives the data requirements," as do end users, she said. Regulators are examining factors such as the presence of an established cutoff point, the sensitivity of the test, the comparison to a gold standard and whether reported results represent a composite score or individual analytes.
Specificity and sensitivity also are key drivers for the FDA in evaluating biomarker effectiveness and weighing benefit compared to risk. For example, what is the strength of association between test results and a particular treatment response? What is the amount of difference in the treatment response between the tested and untested group? Will the marker identify patients for treatment or exclusion to treatment? Do exploratory data exist to support a prospective study?
Obviously, addressing those and a multitude of complex issues requires a careful partnering strategy.
Gathers advised drug developers to consider a potential partner's track record, the number of filed pre-market approvals and supplements, the duration of review times, experience of staff for individuals, capacity based on project-specific needs and the organization's working model, development approaches and regulatory interactions.
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