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Pink Sheet – Think You Have A “Breakthrough” Drug? Think Again, FDA’s Woodcock Says

Pink Sheet – Think You Have A “Breakthrough” Drug? Think Again, FDA’s Woodcock Says

CDER director says breakthrough designation requests are frequently denied because evidence suggests only an incremental advance over standard therapy; other reasons for denial include showing no clinical advantage and a development program being placed on clinical hold.

A pharmaceutical sponsor requesting “breakthrough therapy” designation must demonstrate that its product provides more than just an incremental advance over standard of care, Center for Drug Evaluation and Research Director Janet Woodcock said.

At a May 6 Friends of Cancer Research briefing on the breakthrough therapy program, Woodcock described what CDER staff look for when deciding whether a drug warrants special regulatory attention under the expedited pathway.

“What we’re really talking about here is could your therapy, based on your preliminary data if it’s replicated … be a game-changer for that disease,” she said. “Could that be something, if you had that disease, you’d say, ‘I want to get that before anything else that’s out there. I want to be on this drug because it’s going to do the best for me.’”

At the briefing and in an article in the May issue of Clinical Pharmacology and Therapeutics, Woodcock discussed some of the more common reasons why breakthrough designation requests are denied. These include showing only an incremental advance over existing standard of care or no clinical advantage at all, or when the underlying development program is the subject of an FDA clinical hold.

Woodcock’s observations and informal advice should hold considerable sway with drug developers, who may face a long wait for formal FDA guidance on how companies can determine if their current data for a given product merits the highly coveted breakthrough designation.

Searching For Clarity

Created by the FDA Safety and Innovation Act of 2012, the breakthrough program is aimed at shortening the development and review time of new treatments for serious conditions when preliminary clinical evidence suggests they may offer substantial improvement over existing therapies on one or more clinically significant endpoints.

Breakthrough requests submitted to CDER are reviewed by the Medical Policy Council, which comprises senior officials from across the center (“CDER Medical Policy Council Balances “Breakthrough” Requests With Broader Issues” —”The Pink Sheet,”Apr. 15, 2013).

As would be expected with implementation of a new regulatory pathway, there has been confusion and uncertainty within industry about how FDA determines whether a product is worthy of the “all hands on deck” level of attention it has committed to bring to breakthrough-designated products (“Stakeholders Still Confused About Breakthrough Standards, Difference From Fast Track” —”The Pink Sheet,”Aug. 12, 2013).

The agency’s first formal advice on the program came by way of a June 2013 draft guidance on all four expedited drug development and review programs for drugs and biologics (“FDA Expedited Programs Guidance: “Available Therapies” Depends On U.S. Standard Of Care” —”The Pink Sheet,”Jul. 1, 2013).

However, the guidance left industry and other stakeholders clamoring for more detail and clarity on a host of issues, including the timing of breakthrough request submissions, the types of data needed to support such requests and the process for withdrawing the designation (“FDA “Available Therapy” Determination Is A Moving Target, Industry Groups Say” —”The Pink Sheet,”Sep. 2, 2013).

Woodcock said the agency’s forthcoming final guidance on expedited programs “will have more advice about what is sort of the line between a breakthrough and something that’s more of an incremental improvement to help guide people in whether they want to apply or not, but it won’t have a tremendous number of work examples because we just aren’t there yet in working on that policy.”

The agency plans to issue separate guidance that will assist sponsors in determining if their data merit a breakthrough application, but industry should not look for that document any time soon, Woodcock suggested.

“I think that will probably be awhile,” she said. “We want to get our final guidance on the different expedited programs out first and then we’ll work on this other one.”

While industry will be looking for more guidance, companies that have already gained product approval under the breakthrough process suggested some tweaks in the current program that potentially could improve its effectiveness(see related story,““Breakthrough” Review: FDA And Sponsors Discuss Ways To Improve Efficiency” —”The Pink Sheet,”May 12, 2014).

Breakthrough Vs. Ordinary Drug Development

While they await an FDA guidance, sponsors would be wise to take note of the reasons why CDER is denying close to half of all requests for designation.

Through May 5, the drugs center had received a total of 156 requests for designation; it has granted 44 and denied 73, with action pending on the rest.

In the journal article, Woodcock said the percentage of denials is not surprising because breakthrough “is a new program and no further elucidation of the statutory criteria has been made public.”

In almost all cases, FDA has agreed with the sponsor that the condition at issue meets the criteria for a serious disease lacking adequate treatment, Woodcock said. “However, failure of the preliminary clinical data to suggest a ‘substantial’ benefit over existing therapy has been a major reason for denial; in situations where some standard-of-care therapy exists, a distinction between small, ‘incremental’ improvements and game-changing effects must be made.”

Expanding on this thought at the FOCR briefing, Woodcock said, “I think the most common thing we’re seeing is incremental improvements that are slightly better than what is out there but nothing to write home about, you might say. And that’s ordinary drug development in our mind; that is not a breakthrough therapy.”

The value of various efficacy endpoints has been a significant area of discussion in weighing the requests, according to Woodcock. In addition, the CDER director suggested some sponsors are far more optimistic about their drugs’ breakthrough potential than the evidence from their clinical programs would suggest.

“A non-trivial percentage of the denied applications appear to represent the triumph of hope over evidence – for example, cases in which no clinical advantage over existing therapy had been shown or the sponsor was not being permitted by the FDA to proceed with further clinical testing because of safety concerns,” Woodcock said in the journal article.

While she recognized the need for further FDA guidance, Woodcock nevertheless said such a document would not necessarily keep sponsors from requesting the designation for products not worthy of the program. “Probably no matter what guidance you put out some people will test the waters and send in what they’ve got.”

Like other CDER officials who have spoken publicly on the subject, Woodcock said there has generally been uniform agreement among the Medical Policy Council members as to what constitutes a breakthrough.

“In general, it’s been pretty clear to us,” she said. “We’ve only had a few knock-down fights over whether or not a designation should be granted. Generally we’re in agreement. We can do it on email after presentation of the case.”

Woodcock made clear that she expects breakthrough will not be the last of the novel regulatory pathways created to speed new drugs to market.

“A final question might be: does the [breakthrough] designation program complete the suite of development and regulatory options needed for people suffering from serious, currently untreatable diseases? The answer is probably no,” Woodcock said in the journal article.

“For example, the FDA has been involved in discussions of additional pathways for antibiotics intended to treat infections with drug-resistant organisms, where the benefit/risk assessment is very different from that for the same infections with susceptible organisms. Mechanisms for evaluating treatments for very rare, slowly progressive diseases are lacking, yet there is no doubt that treatment options for these patients are urgently needed. Nevertheless, the [breakthrough] designation program probably represents another milestone in the process of differentiating development programs based on patient need and the resultant benefit/risk trade-offs.”…