FDA Expanding Accelerated Approval Through Guidance, Collaboration

Disease communities will have to be engaged in developing endpoints needed to make accelerated approval happen for more drugs; FDA acknowledges that the pathway is “underutilized in many areas.”

FDA plans to write guidance to clarify for sponsors when accelerated approval is appropriate and to revisit the standards of evidence needed to support that approval pathway as congressional interest grows in expanding the program.

The program for speeding approval of drugs before the full extent of the efficacy and safety is known has been very successful for drugs to treat HIV and cancer and some other diseases, but “we think that it’s underutilized in many areas,” Center for Drug Evaluation and Research Director Janet Woodcock said in a March 7 briefing with reporters.

“There really is not a full understanding of what the pathway is and how to use it,” Commissioner Margaret Hamburg pointed out. Many in industry believe accelerated approval is only for cancer and HIV, and FDA must open channels of communication and do a better job of providing information on the pathway and its full scope, she said.

The agency’s push to expand use of accelerated approval comes as Congress considers legislation aimed at the same goal. For the agency, the legislative action is another opportunity to provide clarity.

FDA needs no new authority with regard to accelerated approval, Woodcock said, but better legislative language might enable the program to be used to its fullest.

A clear statement from Congress that “you can use clinical endpoints as part of accelerated approval … would be helpful,” but no new authorities are needed to expand the program, Woodcock says.

A clear statement that “you can use clinical endpoints as part of accelerated approval, we think, would be helpful, not only for the industry and everyone else involved in drug development, but actually for our own staff to have clarity about what those provisions are,” she said.

Woodcock repeated the concept during a March 8 House Energy and Commerce Subcommittee on Health hearing on possible additions to a Prescription Drug User Fee Act reauthorization measure (Also see "FDA Antibiotic Legislation Should Focus On Criteria, Not Bacteria, Woodcock Says" - Pink Sheet, 8 Mar, 2012.).

Legislators in both the House and Senate appear to be agreeing with the idea. Initial proposals circulated in both chambers have been rewritten to focus on codifying rather than reforming the process (Also see "Accelerated Approval Legislation Picking Up Speed; ULTRA Becoming FAST" - Pink Sheet, 2 Mar, 2012.).

There are potential areas for improvement and innovation, Hamburg conceded at the March 7 briefing, “but we want to do it carefully and cautiously. Dare I say that some of this might be best done not by a congressional committee, but by the scientists and professionals in the area.” FDA is participating in other discussions of alternative licensing (Also see "“Adaptive Licensing” Proposals View REMS As Answer To Limited Evidence" - Pink Sheet, 12 Mar, 2012.).

More Surrogates And Non-Traditional Endpoints

Woodcock expects the review of accelerated approval standards of evidence, which were written in 1999, to result in a clearer explanation of how to show evidence of effectiveness and potentially expand the use of surrogates and clinical endpoints that are not survival or traditional endpoints.

“In many cases, these have to be worked up or developed and we think that people have been kind of a little bit bewildered or confused about this,” Woodcock noted at the briefing. “We not only want to issue these guidances, we’ll have workshops and so forth to try and point people in the right direction.”

One possibility is to use clinical outcomes that are neither surrogates nor the ultimate endpoint to support approval, Woodcock said. Citing an example is difficult “because that’s what needs to be developed.”

But she attempted an example for muscular dystrophy, saying a clinical endpoint could be something like isolated muscle strength. This would involve testing just one muscle. “You might use that as a clinical surrogate, so to speak … and FDA could grant accelerated approval, waiting over time to see if the drug had an effect on function, which is really what you are looking for” in the disease.

Developing clinical endpoints that are not the ultimate measurement of what the therapy is supposed to accomplish will require “work and thought by both the affected community, the docs and patients, as well as the FDA, to come up with these types of constructs, about what would be a reasonable endpoint.”

There has been a lot of effort in this area for cancer and HIV/AIDS and discussion of how to use surrogates, Woodcock noted. “But for other areas, we really need to build more in that way.” She reported to the House panel that FDA soon will issue draft guidance on use of a new surrogate endpoint of pathologic complete response for accelerated approval in primary high-risk breast cancer.

Wanted: Understanding Of Mechanism Of Disease

Progress on endpoints will require “a more robust understanding of both underlying mechanisms of the disease, and from that understanding, what are the likely types of markers or surrogate endpoints that could be utilized,” Hamburg said at the briefing. It also will require input from stakeholders, both patients and providers, who “are most intimately familiar with the natural history of the disease and can help to identify some of these markers.”

An aspect of this collaborative approach is that as potential surrogate endpoints are identified, there needs to be “confidence and agreement beyond the walls of FDA, or one particular review team, that this makes sense and represents a valid approach and is very, very important in our willingness to embrace it going forward,” she said.

FDA is working with the National Institutes of Health and the National Organization for Rare Disorders to encourage disease communities to conduct natural history studies to determine what happens to patients as the disease progresses, (Also see "Rare Diseases Need Ongoing Natural History Studies To Speed Trials, FDA Says" - Pink Sheet, 14 Nov, 2011.). Those in the cystic fibrosis community have produced very good data in this regard, Woodcock said.

There needs to be an upfront discussion about “should we follow cardiac function? Should we follow the renal function? What would be our outcome measure? How would we measure it and so forth.”

Stakeholders need to think about the disease and “do some work and think about what could be used as a measure that would indicate the right direction on therapy,” Woodcock said.

Alzheimer’s is another disease that needs that kind of work, Hamburg added. Right now it’s difficult to diagnose and to track the disease’s progression, she pointed out. “We need to explore bioimaging and other kinds of cognitive measures as well, that could provide those surrogate endpoints for study of Alzheimer’s drugs” (Also see "Alzheimer’s Plan Emphasizes Acceleration, Sets Timeline On Prevention, Cure" - Pink Sheet, 27 Feb, 2012.).

Path For Breakthrough Drugs

Another path to speeding approval of drugs discussed by Woodcock is the identification of “breakthrough” drugs. The agency is working toward a guidance on how to identify and expedite development of such therapies (Also see "FDA Biomedical Innovation Initiative Draws On Familiar Themes" - Pink Sheet, 10 Oct, 2011.).

A breakthrough drug, she explained, is one that in very early clinical trials “shows an effectiveness that’s never really been seen before.”

The question is how to identify such drugs in time to streamline development, rather than after the fact, Woodcock noted.

To address that, the guidance will discuss how FDA would engage intensively with the sponsor and perhaps the scientific community, if possible, “to streamline the studies, including what we could do about manufacturing and so forth. Sometimes we’ve come up with these breakthrough drugs and there’s a shortage on approval and they’re not available for all the people who could take them, so across all the disciplines we would try to make sure that we would make that available.”

Having a specific pathway for breakthrough drugs would reinforce the idea that they are to be addressed in a different way “to get these drugs through, not only rapidly, but in a scientifically valid manner that everyone feels comfortable with the data that’s been generated.”

That was the approach taken with the AIDS crisis, Woodcock pointed out. The entire scientific community was mobilized “to try and get the right endpoints, get the trial design, do what needed to be done to determine which drugs for HIV were going to be effective and then get them out there as soon as possible.”