7-29-2013 - Pink Sheet - FDA Breakthrough Troubles Emerge In Effort To Speed Development | Friends of Cancer Research

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7-29-2013 - Pink Sheet - FDA Breakthrough Troubles Emerge In Effort To Speed Development

7-29-2013 - Pink Sheet - FDA Breakthrough Troubles Emerge in Effort to Speed Development

July 29, 2013

by Derrick Gingery

Inspection schedules, diagnostic review and other issues have emerged as some of FDA’s breakthrough therapy designees wend their way closer to the review and approval stages, and FDA says more guidance will be needed.

Despite the excitement surrounding FDA’s breakthrough designation, some problems have developed, indicating more work will be necessary to ensure the program runs smoothly.

Some of the issues seem to have emerged as the agency began dealing with products that have obtained the designation, intended for therapies showing a dramatic improvement over existing treatments.

Jay Siegel, Johnson & Johnson head of global regulatory affairs, said facility inspection logistics have emerged as a problem, in part because they involve international travel.

J&J’s Janssen Pharmaceuticals Inc. is working with Pharmacyclics Inc. to develop ibrutinib, which has received multiple breakthrough designations.

Siegel said FDA wanted to know what facilities would require inspections so it could be ready when the application was submitted, but has run into travel problems.

“The agency came to us proactively and said, ‘Well let’s make sure we get these inspections scheduled,’” Siegel said July 24 during a Friends of Cancer Research briefing on the breakthrough therapy program. “But apparently scheduling foreign inspections … is not an easy thing to do, even if you are the FDA. And so that’s an issue that we’re still looking at working on.”

But Siegel also said a number of issues should arise as more breakthrough products move through the FDA review process.

“I’m sure there’ll be other issues too that we just need to figure out how to deal with because every time you accelerate one thing something else becomes the rate-limiting step that’s keeping the drug from the patients,” he said.

The breakthrough therapy designation is intended to help speed the development of products with early clinical evidence showing a dramatic improvement over existing therapy. Sponsors can gain streamlined development as well as early and more frequent involvement from FDA officials throughout development.

The program has far exceeded the expectations that accompanied its creation in the 2012 FDA Safety and Innovation Act. At that time, it was predicted that the agency would designate two to four breakthrough products per year.

Since breakthrough’s enactment, FDA has designated 25 products, all within the Center for Drug Evaluation and Research. A total of 77 requests have been received, and 24 have been denied ("FDA “Breakthrough Therapy” Designations" — Pharmaceutical Approvals Monthly, July 2013).

The program’s popularity already is prompting questions about whether the agency has the resources to balance the demands of breakthrough products without creating problems for the other submissions it must review ("FDA’s Breakthrough Designations Face Question Of Review Resources" — "The Pink Sheet" DAILY, Jul. 25, 2013).

Payers, Diagnostics Also An Issue

Other pending issues, some of which are not new, appear to be exacerbated by the breakthrough designation.

Siegel said many breakthrough therapies are targeted treatments, which means they may need a companion diagnostic.

FDA’s Center for Devices and Radiological Health must approve the diagnostic portion of the application and the simultaneous review by the drug and device centers can complicate the process. Siegel said this has not been optimized by developers or FDA.

Industry has asked FDA for more written guidance and policy related to combination products and companion diagnostics, saying increased oral communication between FDA and sponsors is not enough ("For Combination Product Development, Industry Says Talk Is Cheap" — "The Pink Sheet," Jan. 28, 2013).

The breakthrough program’s uniqueness also could create problems for sponsors looking to market designees outside the U.S.

While FDA may accept an alternative data package for a breakthrough product, other regulators might not. Siegel said EU regulations already conflict with U.S. guidance in terms of whether a control group is required in some trials.

“I am optimistic and hopeful … that foreign regulatory authorities will want to catch up with this program when they see what it brings to American citizens,” he said. “We have some preliminary reports from our teams … meeting with regulatory authorities in Japan and China. When they talk about the breakthrough, when they talk about the timelines, there’s interest [among] regulators there: ‘Well, how can we accelerate this?’”

Likely the most important upcoming issue for breakthrough therapies may be obtaining payer support upon approval.

Siegel raised questions about whether payers will create hurdles for breakthrough therapies because their expedited development plan likely will include less evidence based on accepted endpoints and in smaller patient populations than conventional drugs would obtain to gain approval.

“That could mean restriction of market access, restriction of reimbursement … [which] will be a tremendous disincentive for development of innovative therapy,” Siegel said. “That really is going to require some attention.”

The issue may be especially relevant to targeted therapies, which are aimed at small patient populations by definition.

Ellen Sigal, chair and founder of the Friends of Cancer Research, said advocates and sponsors will have to find better economic data to illustrate the benefit of a targeted therapy to payers.

“We’re not helping patients, we’re not helping payers or anyone if we’re giving ineffective treatments,” she said. “Patients who have a disease are being treated, but often with the wrong treatment and there is a huge, besides the economic cost, a huge cost to the patients.”

Ibrutinib and Genentech Inc.’s obinutuzumab became the first two breakthrough products to submit applications for FDA review ("Ibrutinib, Obinutuzumab Are Early Tests Of How Fast Breakthrough Reviews Will Be" — "The Pink Sheet" DAILY, Jul. 10, 2013).

Additional Guidance Will Feed Pathway

FDA appears to be planning much more guidance and policy to further smooth the breakthrough therapy pathway and deal with the questions that already have arisen.

CDER Director Janet Woodcock said much of the work to build the review pathway for breakthrough is still under way.

She said questions about diagnostics and dealing with patient subsets still need to be addressed in agency guidance.

“This pathway, although we’ve been designating drugs, still requires a lot of care and feeding to make it become robust,” Woodcock said during the briefing.

Industry already has asked FDA to write a scientific guidance outlining the magnitude of evidence necessary to be named a breakthrough therapy, but the agency does not have the experience to articulate it yet, Woodcock has said.

The standard now is “you know it when you see it” ("Breakthrough Therapies: FDA Not Writing A Scientific Guidance – Yet" — "The Pink Sheet," Apr. 29, 2013).

FDA said in its expedited approvals guidance released earlier this year that a potential breakthrough’s dramatic improvement should be shown against the current standard of care ("FDA Expedited Programs Guidance: “Available Therapies” Depends On U.S. Standard Of Care" — "The Pink Sheet" DAILY, Jun. 25, 2013).