Breakthrough Therapies: FDA Not Writing A Scientific Guidance – Yet

The agency needs more experience making the decisions before it lays out the evidence threshold for a breakthrough designation, CDER Director Janet Woodcock says.

Aspiring breakthrough therapy sponsors likely will have to infer the necessary bar to gain a designation for the time being, until FDA gains its own handle on it.

Center for Drug Evaluation and Research Director Janet Woodcock said FDA is not writing a scientific guidance on the threshold for breakthrough therapy designation now, but may be in a position to do so after more designation decisions are made and breakthrough products begin to be approved.

The guidance likely would help sponsors understand the amount and magnitude of evidence necessary to prove a product has an unprecedented effect that is worthy of the designation.

At least for now, sponsors thinking about requesting a designation likely will have to study those that were granted and, eventually, the approvals of breakthrough products.

Woodcock said the agency does not have a detailed standard for a breakthrough therapy and it probably needs to spend more time with the new tool before articulating it.

“Right now it’s ‘you know it when you see it,’” she said April 23 during a panel discussion at the Food and Drug Law Institute Annual Conference. “Of course that isn’t very sustainable over the long term, but I think we have to get a number of experiences under our belt before we would go out and say what we think breakthrough really looks like.”

Products that show a dramatic improvement over existing therapies early in development can receive the designation, which could allow abbreviated clinical trials and early involvement from senior FDA staff to help gain approval faster.

The agency has set some preliminary requirements to facilitate requests, including the type of data and other items that must be included in the package (Also see "Industry Wants A Breakthrough Therapy, Even Without All The Standards" - Pink Sheet, 29 Oct, 2012.).

Guidance Would Promote Predictability

A scientific guidance on FDA thinking likely would increase the predictability of the program, as well as potentially reduce some of the unnecessary work reviewing applications that are not real breakthroughs.

Industry has complained repeatedly that FDA risk-benefit determinations and clinical trial design decisions should be more predictable (Also see "Regulatory Freelancing: Rare Disease Group Hopes To Shape FDA Guidance" - Pink Sheet, 22 Apr, 2013.).

Virginia Beakes-Read, Eisai Inc. executive director for global regulatory policy and intelligence, said during the conference that she was not surprised the agency is not ready to outline the data requirements for breakthrough products because it needs to see how the program works in practice.

But she also said that some sponsors believe they have a breakthrough product, even though she is not convinced. A guidance likely would help them decide whether to seek a designation.

Beakes-Read said she wants “to be able to work with sponsors and drug development partners and say ‘this is kind of realistic,’ rather than trying to put together a package when there’s not much hope for it going anywhere.”

Woodcock did acknowledge that it appears industry may need some help understanding the breakthrough designation, which was created in 2012 as part of the FDA Safety and Innovation Act. She liked the idea of perhaps talking in a few months about what the agency has seen.

“We’re turning down about half of them,” Woodcock said. “So obviously more information is needed out there about what this would look like. Hopefully some of these products will rapidly go through development and get approved and then we can have some discussions about what their early clinical data looked like that made us think that was remarkable.”

The lack of detail about the program has not stopped industry from requesting designations. In early April, FDA had received 41 designation requests, granted 11, and denied 12 (Also see "FDA “Breakthrough Therapy” Designations" - Pink Sheet, 15 Apr, 2013.).

FDA remains in an awkward position in terms of offering guidance about the designation because it is not able to talk about products under development.

Sponsors must disclose a breakthrough designation and in some cases choose to not release the information (Also see "As “Breakthrough Therapy” Designations Rise, So Do Disclosure Questions" - Pink Sheet, 15 Apr, 2013.).

What Happens When FDA’s Comfortable With Breakthrough?

There also are questions about how FDA will administer the program once it takes shape.

The CDER Medical Policy Council, with input from the application reviewers, now makes breakthrough determinations. Beakes-Read wondered how long the council will continue as the primary decision-maker.

“With the procedural guidance, what are the medical policy council’s procedures? How are they working with the review divisions?” she asked. “How do they communicate their thoughts about drug development because I would imagine that at one point this would move into the review divisions and not need that same kind of oversight [as] when the program’s first being developed.”

So far there has been no gray area in the decision-making process. The council and reviewers have agreed on which designation requests should be granted, FDA officials have said (Also see "CDER Medical Policy Council Balances “Breakthrough” Requests With Broader Issues" - Pink Sheet, 15 Apr, 2013.).

Another issue Beakes-Read raised was a breakthrough program’s effect on other regulators’ approval decisions.

Sponsors likely would not be interested in or likely could not afford to run a conventional development program to gain approval in Europe or another jurisdiction after completing an abbreviated breakthrough program in the U.S.

The issue already has come up with biosimilars. Some companies have asked for harmonization of requirements in the U.S. and Europe to keep development costs down.

FDA and the European Medicines Agency have said they are working to adopt similar standards so sponsors only need one data package for a biosimilar application going to both agencies (Also see "FDA, EMA Seek Biosimilar Pathway Convergence" - Pink Sheet, 26 Sep, 2011.).

Desktop Reference Will Include Breakthrough Info

More information about the breakthrough designation is expected to be part of the agency’s desktop reference guide for expedited approval pathways, which is expected in the coming months.

The guidance is intended to distinguish and clarify all the various pathways, such as accelerated approval and fast track.

“I told people I want a table. I want them all [in a] side-by-side comparison,” Woodcock said. “Everybody can have that table and then they won’t ask us that question anymore.”

The comprehensive guidance also should meet FDASIA requirements to issue guidance on breakthrough and accelerated approval (Also see "FDA To Provide Expedited Approval Desktop Reference" - Pink Sheet, 29 Oct, 2012.).