Industry Wants A Breakthrough Therapy, Even Without All The Standards

A few requests have gone to FDA for candidates to be named breakthrough therapies and gain access to shorter development programs, but the agency has not established all the program requirements yet.

FDA is already receiving requests for the new breakthrough therapy designation, even though the agency has not made some decisions about how the program will function.

Less than a handful of requests have been made, according to John Jenkins, director of the Center for Drug Evaluation and Research’s Office of New Drugs. He was unsure of the exact number, but said Oct. 22 at a rare diseases conference sponsored by the National Organization for Rare Disorders and Drug Information Association that he has seen at least one request, but there may be three or four.

Those likely will be watched closely as the agency determines how much improvement a treatment must show and how much data will be required to make the case for a designation. They will also set the early tone for how well industry embraces the designation.

The breakthrough designation was created in the FDA Safety and Innovation Act enacted earlier this year. It reauthorized the prescription drug and medical device user fees, created generic drug and biosimilar programs and made other policy changes (Also see "FDASIA Is Signed, Not That White House Wanted Anyone To Notice" - Pink Sheet, 16 Jul, 2012.).

Breakthrough status was part of a congressional mandate in the statute to speed the development of drugs and decrease the cost of clinical trials. Candidates with the designation must show a dramatic improvement over existing therapies in early testing to potentially receive its benefits, which include abbreviated clinical trials and early involvement by senior FDA officials (Also see "FDA “Breakthrough” Designation Bill Revives Debate About Legislating Flexibility" - Pink Sheet, 27 Mar, 2012.).

Though the agency has not finalized the program, it has set up some basic requirements for submitting a breakthrough request. It states that until formal guidance is released, breakthrough requests should be filed with an IND or as an IND amendment.

In addition to basic information about the product, sponsors should also briefly justify why the product deserves the designation, including the evidence that it is intended to treat a serious or life-threatening condition and preliminary clinical data indicating a substantial improvement over existing treatments.

The agency said in most cases the information could be contained in a 10- to 20-page document.

The Preliminary Breakthrough Request

Until formal guidance is issued, FDA requires the request to be filed either with an IND or as an IND amendment, with a cover letter and the following information:

• Identification in the submission cover letter as a request for breakthrough therapy designation in bold, capital letters
• The IND application number, if applicable
• The proprietary and/or generic name and established name if the candidate is a drug or the proper name and trade name if it is a biologic
• The division or office where the IND is being submitted or is active
• The proposed indication

A brief summary of information explaining why the product qualifies as a breakthrough therapy also is necessary, including:

• Evidence that the drug is intended, alone or in combination, to treat a serious or life-threatening disease or condition
• Preliminary clinical evidence indicating the drug may demonstrate substantial improvement over existing therapies in one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development
• If applicable, a list of relevant documents previously submitted to the IND with references to submission dates so they can be located. Copies of the documents can be resubmitted as appendices to the designation request if not too voluminous.

All of the requests that have been received remain under review, Jenkins said. The agency has 60 days from the date of receipt to make its decision. Since the program launched Oct. 1, the earliest deadline for decisions should be about Dec. 1.

One of the requests may involve Eli Lilly & Co.’s Alzheimer’s drug solanezumab. The company said recently that even though the drug did not meet cognitive and functional primary endpoints in two trials, an analysis of pooled data revealed statistically significant results in some patients. A company official indicated Lilly was exploring regulatory tools that could provide options other than restarting Phase III (Also see "Efficacy Signal For Lilly’s Solanezumab Stirs The Alzheimer’s Pot" - Pink Sheet, 15 Oct, 2012.).

Breakthrough Withdrawal Process Undecided

Jenkins implied the agency will be careful in making breakthrough designations because they will carry weight with investors, who may view the status as an indicator of approval.

He also cautioned, “We’re likely to see some who think they are breakthrough and we don’t.”

FDA already works with sponsors with applications that show particularly encouraging results, Jenkins pointed out. However, FDA has not clearly identified the standards it will use to award the designation, which may limit the number of early requests.

Jenkins said he thinks a breakthrough designation is a “high bar.” It is “not something that would normally meet our definition for priority review,” he said.

“This is a result that’s so impressive, so unexpected, and has such a dramatic impact on the treatment of patients with that disease, that both FDA and the sponsor, everyone should put all the resources into discussing how to expedite that drug, if … that promise holds up through the further drug development program,” Jenkins said.

There are no requirements in the law about how much data is required to gain the designation and Jenkins said FDA has to determine how it will track breakthrough therapies over time.

“We also have to deal with whether you can lose a breakthrough designation if it doesn’t hold up,” he said after the presentation.

More details about the program standards should be included in a comprehensive expedited approval guidance that the agency is compiling to describe newly-created pathways like breakthrough status. It also should clarify changes to accelerated approval and differentiate it from other systems like priority review and fast track, since some terms are used to describe many of them (Also see "FDA To Provide Expedited Approval Desktop Reference" - Pink Sheet, 29 Oct, 2012.).

Could It Be A Bad Decision For A Sponsor?

Gaining a breakthrough designation would seem to be a major win, but FDA already has warned that it may not be ideal for all sponsors.

The endorsement will mean the agency will consider early in the development process how the candidate can progress through the development process with minimal effort and cost, assuming it continues to show the same promise.

Sponsors may be allowed to conduct shorter and smaller clinical trials with fewer patients.

Jenkins noted that breakthrough sponsors will have to think about manufacturing and other plans earlier than they typically may. He said the expedited pathway may require a factory to be ready much sooner than under a normal development program.

It may mean a small company would have to raise more capital earlier in order to take full advantage of the designation.

The program will require more early communication with FDA, which the agency has been encouraging for many of its development initiatives.

Increasing communication between sponsors and the agency was a major theme of the recent prescription drug user fee reauthorization.

Industry and FDA agreed to extend the review time for new molecular entity NDAs and novel BLAs by two months, in part to allow for mid- and late-cycle communications during the review to discuss problems and questions that arise. Ideally, sponsors can make corrections while the review is ongoing and allow for more first-cycle approvals (Also see "Buying Time: Industry Sacrifices Early To Gain Later With PDUFA V Review Model" - Pink Sheet, 1 Oct, 2012.).

The new biosimilar approval pathway, and associated user fee program, will also promote early communication. The agency created several formal meetings so sponsors can meet with FDA reviewers during the IND stage and in some cases receive an in-depth data review (Also see "Biosimilar User Fee Meeting Schedule Allows FDA Data “Pre-Review”" - Pink Sheet, 17 Sep, 2012.).

Industry Showing Early Interest In Other FDASIA Mechanisms

Some of the other new pathways created in FDASIA are gaining interest quickly as well.

The agency already has designated an antibiotic as a qualified infectious disease product, which would allow fast track and priority review status and an additional five years of exclusivity upon approval.

The product, Melinta Therapeutics Inc.’s new fluroquinolone delafloxacin, is in Phase II for several indications (Also see "Antibiotic Legislation Offers Big GAIN For Small Firm: Rib-X Extends Delafloxacin Exclusivity" - Pink Sheet, 18 Sep, 2012.).

FDASIA’s Generating Antibiotic Incentives Now (GAIN) section created the additional incentive to encourage more antibacterial development, especially for resistant pathogens (Also see "With GAIN In Place, Antibiotic Improvements Depend On FDA Implementation" - Pink Sheet, 13 Aug, 2012.).