9-16-2013 - Gray Sheet - Companion Diagnostics For Breakthrough Drugs Also Getting Swift Attention, FDA Says

9-16-2013 - Gray Sheet - Companion Diagnostics for Breakthrough Drugs Also Getting Swift Attention, FDA Says

September 16, 2013

By Sue Sutter

Device center officials cite a host of formal and informal actions available under existing legislative authority to ensure that development and review of companion diagnostics do not hinder the ability of FDA-designated breakthrough therapies from coming to market.

FDA’s Center for Devices and Radiological Health is using its regulatory flexibility to ensure that development and evaluation of companion diagnostics for “breakthrough” therapies keep pace with the speedier timelines envisioned for such drugs under the FDA Safety and Innovation Act.

Speaking at a Sept. 6 conference on drug/diagnostic co-development for breakthrough therapies, CDRH officials highlighted a number of formal and informal actions they are taking or potentially could take to prevent development of companion diagnostics from dragging down the speed at which breakthrough therapies can reach the market.

Some of the actions, such as designating companion diagnostics for priority review and taking a risk-based approach to determining the amounts and types of data needed pre- and post-approval, resemble draft proposals developed by a stakeholder working group for expediting development of in vitro diagnostics intended for use with breakthrough therapies.

While agency officials said CDRH has been able to keep up with the breakthrough-related workload to date, they nevertheless acknowledged the program’s resource strains on the device center, whose role was not reflected in the statutory language creating the expedited regulatory pathway.

Streamlining coDx Development

Created by FDASIA, the breakthrough therapy designation is aimed at expediting development of drugs and biologics intended to treat serious conditions and for which preliminary clinical evidence indicates the product may demonstrate substantial improvement on a clinically significant endpoint compared to available therapy.

FDA laid out the qualifying criteria, features and submission and response timelines for the breakthrough program in its June draft guidance on expedited pathways ("FDA Expedited Programs Guidance: “Available Therapies” Depends On U.S. Standard Of Care" — "The Pink Sheet," Jul. 1, 2013).

Drugs that receive the breakthrough designation also qualify for fast-track status, and sponsors will receive intensive guidance on an efficient drug development program and an organizational commitment that involves FDA senior managers.

The program, which is just a year old, has proven immensely popular with sponsors thus far. As of Sept. 6, the Center for Drug Evaluation and Research had received 85 requests for breakthrough designation, granting 27 and denying 35. The Center for Biologics Evaluation and Research had received 10 requests as of Aug. 31, granting none and denying eight. Many of the drugs for which breakthrough designation has been granted include a companion diagnostic, according to agency officials.

However, industry stakeholders and others have raised concerns that the development of companion diagnostics could become a rate-limiting factor for breakthrough therapies. There is no comparable and express statutory provision for breakthrough diagnostics, and the development, validation and approval of a companion diagnostic may not be able to keep pace with a breakthrough drug’s abbreviated clinical development program ("“Breakthrough Therapy” Development Speed May Be Tempered By Manufacturing Hurdles" — "The Pink Sheet," Nov. 26, 2012).

Stakeholders have sought more details from FDA regarding how CDER/CBER will coordinate with CDRH in ensuring that a companion diagnostic’s development does not slow the breakthrough drug’s march to approval ("A “Breakthrough” Reality Check: Sponsors Seek FDA Flexibility On Manufacturing, Diagnostics" — "The Pink Sheet," Jul. 8, 2013).

CDRH requested that a Friends of Cancer Research working group propose ways of streamlining the development of companion diagnostics for breakthrough drugs. The group’s draft proposals (PDF)were presented at the Sept. 6 conference, which was co-sponsored by FOCR and the Alexandria Center for Life Science.

The white paper identified five areas in which the process for development and FDA clearance or approval of a companion diagnostic could be expedited (see box).

Five Proposals For Expediting Development And Review Of Breakthrough Therapy Companion Diagnostics

Automatic designation of IVD companion diagnostic devices for use as part of a breakthrough drug approval as eligible for priority review

Use of highly coordinated administrative processes and management commitments for review of IVD companion diagnostics that are commensurate with those processes offered for breakthrough therapies

Use of risk-based processes to determine required companion diagnostic analytical studies for each assay type at time of PMA or 510(k) filing

Use of risk-based approaches to determine requirements for data and testing related to quality systems, manufacturing processes and software testing and documentation

Use of a “Continued Access” supplement IDE to enable a broader set of labs to be ready for testing immediately upon contemporaneous approval of the companion diagnostic and therapeutic product

Source: “A Risk-based Approach for In Vitro Companion Diagnostics Device FDA Approval Process Associated with Therapies that have Breakthrough Designation” (Conference Draft)

The recommendations suggest risk-based approaches to determining the amounts and types of data needed prior to approval and data that can wait until after approval.

The paper lays out ideas for streamlining data requirements with regard to the types of samples required for analytical studies, and the types and designs of analytical studies. It proposes that the inspection and paperwork burden be reduced for manufacturers that have other PMA-approved products or have recently successfully completed a quality systems inspection. Risk-based approaches also are urged for determining the level of manufacturing process validation and software validation required at time of PMA submission and for approval.

CDRH’s Elizabeth Mansfield, director of the personalized medicine staff in the Office of In Vitro Diagnostics and Radiological Health (OIR), said the recommendations echo some of the efficiencies the center either has implemented internally or is working to formalize.

The breakthrough program created by FDASIA “was not accompanied by anything on the device side that would give us equivalent powers to assign a breakthrough designation to a device,” Mansfield said.

“However, you’ll be glad to know that, in fact, we actually already have ways in CDRH of handling this and we do prioritize companion diagnostic reviews and we automatically grant them priority review. I believe what we need to do is to make that a well-known policy and memorialized, and I hope that that will be done through a guidance document that we hope to publish in draft shortly.”

Mansfield said CDRH staff understands the value of companion diagnostics and breakthrough therapies. “We are working very hard to identify as many ways as we can to make the diagnostic side catch up with the drug side. In fact … so far our timelines are actually the drug timelines. We don’t take the whole diagnostic review timeline.”

CDRH Director Jeff Shuren noted the center has been pilot-testing a regulatory pathway for novel medical devices that are viewed as groundbreaking. The center rolled out its Innovation Pathway program in February 2011, tested a device, made changes, and just had three more devices go through the program, he said ("CDRH's Innovation Pathway: A Quicker Route For Breakthrough Devices?" — "The Gray Sheet," Feb. 14, 2011 and "CDRH Launches ‘Innovation Pathway 2.0’ With End-Stage Renal Devices" — "The Gray Sheet," Apr. 16, 2012).

“Essentially, it involves early extensive collaboration between CDRH and the innovator, and we actually develop a regulatory roadmap,” Shuren said. “It’s a development plan of what it kind of takes to get to market. And we engage actually before there’s even clinical data on the device. There is senior management involvement and we have a case manager, kind of a liaison between the sponsor and the FDA team.”

Shuren said the pilot program has been a success for companies that have participated, helping them to reduce development time and costs. “What we haven’t done is we haven’t established that as a formal program, and that is one of our next steps.”

Furthermore, although accelerated approval is not a formal regulatory mechanism on the device side, CDRH has taken an “accelerated approval-like approach on an ad hoc basis in the past” in deciding when to accept a greater degree of uncertainty about a device’s benefit/risk profile or, in the case of a companion diagnostic, its analytical validity, Shuren said.

“The way we do that is considerations of shifting data pre-market to post-market,” the CDRH director said. “We have made that an explicit consideration in our benefit/risk framework we put out in the spring 2012, which says we will accept greater uncertainty in some instances, such as [if] you’re treating a life- threatening condition, and/or you’re addressing an unmet medical need.”

That framework, issued in the form of a March 2012 final guidance, describes how the risks and benefits of devices are considered during pre-market reviews ("FDA’s Final Risk-Benefit Guidance Excludes 510(k)s, Adds De Novo Petitions" — "The Gray Sheet," Apr. 2, 2012).

The center also is working on guidances that address the appropriate balance between pre- and post-market data collection and explore other clinical trial efficiencies ("CDRH’s Shuren Signals More Guidance, Enhanced Pre-Market Payer Role" — "The Pink Sheet" DAILY, Aug. 26, 2013). “We are currently working on that policy and you can anticipate that will also include opportunities and features of” an accelerated approval-like framework and breakthrough therapy components, Shuren said, adding that the white paper’s recommendations potentially could be folded in.

Quality Systems Are “Biggest Challenge”

Despite the efforts CDRH has made to keep up with the breakthrough drugs program, the center is striving to figure out where more efficiencies can be gained, Mansfield said.

“I was very happy to see in proposals three and four some risk-based things put forward where we could actually consider where we need the most information and what types of information we might be able to set aside until later,” she said. “We do risk-based review all the time. … However I believe we may be able to take that further. Our standard is actually a reasonable assurance of safety and effectiveness, it’s not a guarantee. Therefore, if a manufacturer can bring forward what we both agree is reasonable, then I think that’s quite possible.”

She said there may be room for using product development protocols for companion diagnostics to breakthrough products. A product development protocol “is an essentially binding agreement between FDA and the manufacturer about what will be in the submission and that must be in the submission, and if it’s all there, then FDA essentially must agree to it.”

Although such plans have been used infrequently, if at all, for in vitro diagnostics, “it may be something to consider here where we have timelines and critically ill people waiting for drugs.”

However, despite efforts to streamline development requirements and reviews from the analytical and clinical side, “probably the biggest challenge for us … will be from the quality systems side,” Mansfield said.

“One of our issues in handling that is that … we, OIR, don’t do the inspections, don’t go out into the field. That’s done by an entirely different group of people who would have to be attuned to what they should be looking for that might be different than what they’re typically looking for. That’s not to say it can’t be done. It will just take probably considerably more conversations because there’s simply more people in the room who have to agree.”

Looking To Congress?

Mansfield said many of the draft proposals could be implemented under FDA’s existing statutory authority, although they might require development of new regulations or policies.

However, seeking further legislative authority also is not out of the question.

“Certainly, a push from Congress for doing things sometimes can be helpful,” Shuren said, “but we’re also looking at how far can we really take it under our current authority and whether we may be able to take it further if there were changes in the law. That’s something we are currently exploring.”

If CDRH believes it needs additional legislative authority, the next reauthorization cycle for the Medical Device User Fee Act would be a natural vehicle for that request and an opportunity to try to wrangle more resources for activities related to breakthrough drugs.

The breakthrough program was incorporated in FDASIA separate from the Prescription Drug User Fee Act reauthorization, meaning that the law did not give CDER or CBER any additional funding for breakthrough-related activities beyond the user fees that already had been negotiated with the pharmaceutical industry under PDUFA. For this reason, stakeholders have questioned how CDER will be able to manage the increased demands created by the breakthrough program with its limited resources, and whether non-breakthrough drug reviews will suffer as a result ("FDA’s Breakthrough Designations Face Question Of Review Resources" — "The Pink Sheet" DAILY, Jul. 25, 2013).

Similarly, there was no provision in MDUFA, which also was reauthorized as part of FDASIA, for additional CDRH funding in connection with the breakthrough program.

“When we went through this reauthorization on both sides, I don’t think any of us were really thinking about implications for companion diagnostics,” Shuren said. “So we didn’t have the drug folks sitting at the table [for MDUFA], and we weren’t really at the table for PDUFA to say, ‘Well, if we’re going to have an increased volume of companion diagnostics, are we sure there’s enough funding to make sure we handle it.’” He added that the across-the-board government cuts known as sequestration have “thrown a terrible monkey wrench into our resources and what we’re able to do.”

“Our resources are challenged, that’s the bottom line,” Shuren said. “Right now, for companion diagnostics we’ve been able to handle the workload that’s been coming in the door. Of course, if we’re seeing a major uptick in that, that creates challenges for us.”

Another potential challenge could be in assuring the public, including payers, about the quality and level of data underpinning approval of breakthrough therapies and companion diagnostics.