9-9-2013 - BioCentury - Friends of Cancer Research Proposing Breakthrough Companion Diagnostics | Friends of Cancer Research

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9-9-2013 - BioCentury - Friends of Cancer Research Proposing Breakthrough Companion Diagnostics

9-9-2013 - BioCentury - Friends of Cancer Research Proposing Breakthrough Companion Diagnostics

September 9, 2013

By Steve Usdin

Friends of Cancer Researhc, the advocacy organization that conceived of and persuaded Congress to enact FDA's breakthrough therapies program, last week unveiled a proposal to expedite development of companion diagnostics that are intended for use with a breakthrough drug.

In contrast to the breakthrough therapies program, which was incorporated into the FDA Safety and Innovation Act, FOCR's new proposal focuses on steps the agency and diagnostics companies can take to streamline development and review within existing law.

Senior agency officials, including Jeffrey Shuren, director of the Center for Devices and Radiological Health (CDRH), and Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), made it clear they support the proposal in principle at a Sept. 6 meeting sponsored by FOCR.

Shuren suggested, however, that supporting the breakthrough diagnostics program may require additional funding.

CDRH wasn't at the table when the breakthrough therapies program was developed, and the center has not received any additional funds to help it speed the review of breakthrough companion diagnostics applications, he noted.

Shuren said the center has been able to handle the added workload, but "resources are a challenge." In addition, he said budget sequestration "has thrown a terrible monkey wrench" into CDRH's finances.

All or most of the breakthrough diagnostics proposals could be implemented without legislation. Many of them echo steps CDRH has already implemented on an informal basis and plans to codify in formal guidance documents, Shuren said.

Rational Exuberance

Drug companies, patients and investors have responded enthusiastically to the breakthrough therapies program: as of Aug. 23, CDER had received 82 requests for breakthrough designation. It had granted 25, and 25 were pending.

The program is intended to speed the development of drugs when there is dramatic clinical evidence of efficacy.

The first approval of a breakthrough drug is likely to come this fall, according to FDA officials.

Marketing applications are pending for at least three breakthrough therapies.

Obinutuzumab to treat previously untreated chronic lymphocytic leukemia (CLL), from Roche and its Genentech unit, has a Dec. 20 PDUFA date. Ibrutinib from Pharmacyclics Inc. and Johnson & Johnson has a Feb. 28, 2014, PDUFA date for previously treated mantle cell lymphoma (MCL) and previously treated CLL/small lymphocytic lymphoma (SLL).

The PDUFA date is not disclosed for serelaxin from Novartis AG to treat acute heart failure (AHF). In its January earnings announcement, the pharma said it expected a U.S. submission in 2Q13 but it has not disclosed precisely when the application was submitted.

FDA frequently beats PDUFA goals for cancer drugs that, like obinutuzumab and ibrutinib, could provide dramatic improvements over standard care.

The flood of breakthrough designations is a reflection of the progress the biopharma industry has been making in creating targeted therapies, according to Woodcock (see BioCentury, June 24).

At the same time, the rapid development of diagnostics is a prerequisite to speeding the deployment of these breakthrough therapies, said Michael Pacanowski, associate director for genomics and targeted therapy in the Office of Clinical Pharmacology at CDER.

Indeed, about two-thirds of the applications FDA has accepted for its breakthrough therapies program include a companion diagnostic.

Woodcock noted the use of targeting strategies to enhance efficacy in products that have breakthrough designations is not limited to cancer and monogenic hereditary diseases, but also include "other diseases where the biomarkers are more fuzzy."

Woodcock added that she hopes to see targeting in antibiotic drug development based on improved diagnostic technology.

Despite this central role in targeted medicine, diagnostics were not explicitly included in the breakthrough therapy legislation.

"There is pressing need to clarify the pathways to make both [drugs and companion diagnostics] come to market in a timely fashion," Pacanowski told the meeting.

In the absence of a process for expediting development of companion diagnostics, "in many cases the co-development of a diagnostic may lag behind" development of a breakthrough therapy, warned Howard Scher, chief of the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center.

FOCR's Proposal

In an interview on BioCentury This Week television, FOCR Executive Director Jeff Allen said the group and its collaborators has been working to identify "particular strategies for keeping the development time of the diagnostic in line with the compressed development time of an associated breakthrough therapy" (see BioCentury This Week, Sept. 8).

Prior to the advent of breakthrough therapies, FDA stated that it will not allow delays in approving an in vitro diagnostic (IVD) to delay access to an important new drug.

In a 2011 draft guidance on IVD companion diagnostics, the agency said it "may decide to approve a therapeutic product even if its IVD companion diagnostic device is not yet approved or cleared when the therapeutic product is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and the benefits from the use of the therapeutic product with an unapproved or uncleared IVD companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared IVD companion diagnostic device."

The FOCR proposal, which hasn't been publicly released, uses this statement as a point of departure for recommendations for streamlining administrative processes, instituting a risk-based review system, and speeding the uptake of newly approved companion diagnostics for breakthrough therapies.

The administrative proposals include automatically assigning Priority Review designation to a breakthrough companion diagnostic and applying the "all hands on deck" approach CDER uses for breakthrough therapies.

Shuren told the meeting that CDRH already assigns companion diagnostics Priority designation, "which means they move to the top of the queue for PMAs."

He added that CDRH has piloted an "innovation pathway" that provides extensive collaboration and involvement of senior management for breakthrough medical devices.

"It has been successful for the companies; it has helped them reduce the time and cost to come to market. The challenge for us is it is very resource intensive," Shuren added.

FOCR's proposal calls for CDRH to use "risk-based processes to determine required analytical studies for each assay type at the time of PMA filing."

This could involve working with sponsors to determine what data could be supplied postmarket, and in some cases allowing approvals based on premarket submission of data that can be obtained rapidly.

For example, the FOCR proposal suggests that "contrived samples," such as cell lines, plasmids and serum spiked with recombinant protein could be used instead of actual patient samples for initial assessment of assay performance.

Supplementing patient samples with contrived samples could be particularly helpful for low-prevalence diseases and in instances when specimens are rare, Tracy Bush, director of companion diagnostic regulatory affairs at Roche, said at the meeting.

The most challenging recommendations - and potentially most consequential -involve streamlining reviews of quality systems.

For example, it might be possible to determine when some quality systems review requirements can be deferred to the postmarket. FOCR's proposal suggests this approach could be applied "when a device manufacturer is developing an assay for 'distribution' to a single lab such as for a rare indication."

The proposals also suggest FDA could defer some manufacturing process validation to the postmarket, such as for manufacturers that have PMAs for the same or highly similar manufacturing processes.

FOCR also is proposing that CDRH allow sponsors to take steps prior to approval that would speed the deployment of breakthrough companion diagnostics.

"Under current regulations, devices cannot be shipped to laboratories until they are approved and laboratories are verified to perform the testing," according to the FOCR proposal.

Labs that participated in clinical trials can start offering a companion diagnostic as soon as it is approved, but it can take months for other labs to complete the necessary training, establish standard operating procedures and verify test methods, said Christine Gathers, senior director for regulatory affairs for diagnostics at Eli Lilly and Co.

According to FOCR, CDRH has authority to allow sponsors to ship tests to labs prior to approval, which would allow the labs to set up SOPs and do the necessary training.

Elizabeth Mansfield, director of personalized medicine in CDRH's Office of In Vitro Diagnostics Device Evaluation and Safety, confirmed FDA could allow such shipments if the labs do not use the tests to report data to physicians.

FDA's Response

"The set of proposals is incredibly on point, incredibly helpful; it echoes a lot of things we have been thinking about internally or have implemented," Mansfield told the meeting.

She added that the implementation of the specific elements of the risk-based approach "will probably be context dependent," but the proposals are an "excellent jumping-off point" for internal FDA deliberations.

Shuren said FOCR's proposal is consistent with CDRH's goal of having medical devices approved and available to patients in the U.S. before other countries.

He added that CDRH doesn't have a formal program like CDER's accelerated approval, but it has implemented an ad hocprocess that is intended to accept a greater degree of uncertainty in order to get high priority devices approved more rapidly.

Instead of surrogate endpoints, CDRH's approach involves "shifting requirements from pre- to postmarket," Shuren said. The center is working on a formal policy on pre- and postmarket data requirements and "will consider folding the FOCR white paper into the framework."

CDRH can do a lot to expedite co-development of diagnostics under its existing authority, Shuren said, but he left the door open to asking Congress for additional authority.

"At the present time there is a lot we can do with our current authority. A push from Congress to do things can be helpful, but we are looking at how far we can take this with our current authority and whether we can take it further with an extension of the law."

Woodcock stressed the importance of close collaboration between CDER and CDRH, and argued that regulators and sponsors need to change their approach to facilitate breakthroughs.

Reviewers and companies need to understand that breakthrough products are a "very different game," she said, one in which "patients are willing to accept much more risk" and are telling regulators "don't dot all the Is and cross all the Ts, get the products out to us."

But as the agency starts to approve breakthrough therapies based on less data than is traditionally available, attention will shift to coverage and reimbursement of drugs and companion diagnostics - topics that are not addressed by FOCR's proposals.

On reimbursement in particular, the value of innovator diagnostics has yet to be hashed out with Medicare and private payers.

Speaking on BioCentury This Week television, Robert McCormack, head of Technology Innovation at Janssen Diagnostics, and Kate Claessens, senior director of health policy and reimbursement at Roche Diagnostics, argued that reimbursement should be tied to evidence of clinical utility - that the use of the diagnostic actually can be shown to improve patient outcomes.

"I think the price a test receives should be incumbent upon the evidence behind it," said McCormack.