A breakthrough therapy designation should not include a relaxed statistical standard for the product, an industry statistician recommended.

As the program for products showing early potential of a dramatic therapeutic advance gains in popularity and FDA considers extending its elements to other products, agency statisticians said they have limited experience with those applications so far in part because many have not reached Phase III.

Some may be working to better describe the bar to become a breakthrough product numerically.

Still, Barry Schwab, clinical biostatistics head for neuroscience at Janssen Pharmaceutical Cos., asked that the agency work to maintain the rigor of its statistical requirements and principles as more breakthrough products navigate the review and approval processes.

“Expectations within the sponsor should not be all carte-blanche,” he said April 9 during the Drug Information Association-FDA Statistics Forum. “I’m not saying that it is, but I think there’s a potential for it to be, thinking that suddenly there could be a relaxation of some of the many things that we’ve been talking about.”

The breakthrough therapy designation, created in the 2012 FDA Safety and Innovation Act, allows earlier and greater agency involvement with products showing the potential to be a significant advance over existing therapies.

It has become incredibly popular in the nearly two years since its inception. The agency has received more than 150 designation requests and granted about 40 (see chart). A few breakthrough products also have gained marketing approval ([A#06140301005]).

Fiscal Year 2014 Breakthrough Therapy Designations
Center	Requests	Granted	Denied
CDER*	50	8	17
CBER^ǂ	17	1	10
Through April 4; ^ǂThrough March 31 Source: FDA*

And now there may be plans to extend the program to more products in the coming years. Commissioner Margaret Hamburg said she wants FDA to use the program’s increased and early sponsor-agency interaction to its advantage in other products (see related story,[A#00140414013]).

Researchers also are concerned that the agency could not stem patient demand for breakthrough products even if clinical trials do not confirm the early activity Also see "“Breakthrough Therapies” Deserve Skepticism, Researchers Say" - Pink Sheet, 26 March, 2014..

“The basic rigorous principles still would need to apply and that’s our job to make sure that that’s true, especially when we’re only looking at small amounts of data quickly to get this approval under this designation and then might follow on with something else after,” Schwab said.

Janssen is among the most experienced sponsors with the designation to date. It and Pharmacyclics Inc. have received three designations, all for its Bruton’s kinase inhibitor Imbruvica (ibrutinib). The product was approved in relapsed or refractory mantle cell lymphoma in November 2013 ([A#14131113009]).

Novartis AG recently announced one of the first designations for a vaccine, Bexsero, in meningococcal group B. Eiger BioPharmaceuticals Inc. also gained a designation for its gene therapy Mydicar in testing as a chronic heart failure treatment ([A#14140410002]).

Expectations Beyond The Upper Confidence Limit

FDA does not appear to have looked at enough applications to ascertain whether the potential statistical issues Schwab mentioned are in fact present.

Clinical data is required to gain the designation and most have been based on Phase I and II trials. Because of that, many FDA statisticians have not had much interaction with the applications.

More communications and sponsor interactions are expected once products advance to the Phase III trial planning and review stages.

Rajeshwari Sridhara, director of the Division of Biometric V in the Center for Drug Evaluation and Research’s Office of Translational Science, said FDA is only looking for activity, not efficacy, when deciding on a breakthrough designation.

“Nobody is saying that the efficacy has been established,” said Sridhara, who is heavily involved with the agency’s oncology product review divisions Also see "Avastin Hearing: The Interrogators" - Pink Sheet, 27 June, 2011..

“If that’s the case, we should be approving the drug at the time,” she added. “It’s only recognizing that there’s some extraordinary activity here.”

Sridhara said her idea of a breakthrough product is one that is better than the upper confidence limit that could be expected with existing therapy.

“In my mind, when it is presented even in a single-arm study, if the response rate in all of the history or whatever standard therapy that’s there, if in some way we can say that it’s greater than the upper confidence limit that you would think of, if it’s at that point, then it deserves a breakthrough designation,” she said.

“What we have seen is where you have 10% as your response rate with your standard … therapy and then you see a 50% response rate, it’s a no-brainer to say this is a breakthrough designation,” Sridhara said.

Lisa LaVange, director of the Office of Biostatistics in CDER’s Office of Translational Science, said nobody has set the ideal trial for a breakthrough product and the agency may never determine it.

“There’s nothing about it yet to say … here’s the design you need for a breakthrough,” she said. “It’s very different to me than an accelerated pathway with this surrogate marker and this endpoint.”

Industry has asked FDA to release a scientific guidance describing its bar to gain the designation, but the agency said it wants to gain some experience with the program before writing it Also see "Breakthrough Therapies: FDA Not Writing A Scientific Guidance – Yet" - Pink Sheet, 29 April, 2013..

Draft guidance on the agency’s expedited approval programs, which included a description of breakthrough, raised more questions, including how it differs from the fast-track status ([A#00130909002]).

Statisticians Largely Out Of The Designation Decision?

Review divisions write designation recommendations to senior CDER officials, who make the designation recommendation. But LaVange said statisticians may not be heavily involved.

“The medical policy council meets to review these applications and a statistician may or may not be in the room when the designation is decided on because it’s not seen as a statistical concept like an approval decision,” she said.

FDA said in an April 11 email that the council only makes “an advisory recommendation” to the review division. The agency also said statisticians are included “as needed” when review divisions look at designation requests.

The council, which tackles big-picture, non-product-specific issues for the center, reviews breakthrough designations to ensure consistency with the decisions. It consists of CDER Director Janet Woodcock, Office of New Drugs Director John Jenkins and others, but a statistician is not specifically required ([A#00130415012]).

Success, But At A Price

Breakthrough’s popularity already has generated concerns about an FDA resource drain. Agency officials have said they would manage the product portfolio, but some items may slip around the edges Also see "FDA Strains Under New NDA Review Model; Will Industry Want To Retain It?" - Pink Sheet, 16 December, 2013..

So far, designee sponsors have been pleased with the agency attention. Start-up Scioderm Inc. said it has received better agency access and an increased focus on how its epidermolysis bullosa treatment can move through development faster ([A#14140210001]).

Pharmacyclics officials also said FDA acted like a development partner once ibrutinib gained the designation, including discussing issues much earlier in the process, instead of waiting for the pre-NDA meeting ([A#00130610014]).

Patients also are attempting to drive the process, writing members of Congress asking for input into FDA’s designation process ([A#14140313004]).

Breakthrough Therapies: Maintain The Statistical Rigor, Industry Says

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