Sponsors interested in seeking “breakthrough therapy” status should first consult their FDA review division to assess whether existing data potentially support designation under the expedited regulatory pathway.

Early consultation with agency reviewers would help reduce the number of requests that are ultimately rejected, saving the agency and sponsors countless hours in the process, FDA officials said during an April 24 meeting convened by the Brookings Institution’s Center for Health Policy under a cooperative agreement with FDA.

While early consultation was one of the key recommendations offered by agency staff and sponsors to head off frivolous breakthrough requests, the possibility of a user fee to dissuade such submissions also was floated (see sidebar).

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Informal Consultation …

The breakthrough program has proven hugely popular with industry since it was introduced more than two-and-a-half years ago with enactment of the FDA Safety and Innovation Act.

The Center for Drug Evaluation and Research had received 248 requests for designation as of April 17, while the Center for Biologics Evaluation and Research had received 49 requests through March 31 ([A#00150406016]).

However, only one-third of all designation requests submitted are granted. Data from an internal agency analysis suggest that trial design/analysis issues are the most common reason why requests are denied, followed by lack of “substantial improvement” over available therapies as is required by the statute (see related story, Also see "Totality Of ‘Breakthrough’ Evidence Guides FDA Designation Decisions" - Pink Sheet, 4 May, 2015.).

That analysis also showed that large sponsors have a higher rate of granted requests than small or private sponsors (see related story,[A#00150504006]).

FDA officials say the process of evaluating requests that are not even close to qualifying for the designation can be time-consuming and a drain on the agency’s already-stretched resources Also see "Lifting the ‘Breakthrough’ Veil: FDA Increases Transparency To Reduce Futile Requests" - Pink Sheet, 5 January, 2015..

The Brookings meeting was aimed at enhancing clarity and public understanding of the qualifying criteria for designation and reducing the number of frivolous requests in the process.

FDA reviewers presented several case studies of actual products that have received breakthrough status and the data upon which they were designated. Since the agency is precluded from disclosing any information about breakthrough requests for specific products absent the sponsors’ permission, FDA staff presented two hypothetical cases of breakthrough requests that were denied.

A common theme that came out of various presentations from FDA and industry speakers was that informally consulting with the agency before submitting a breakthrough request can be productive for all parties, especially small companies or those with less regulatory experience.

Division of Neurology Products staff “are available for consultation” before a breakthrough request is submitted, clinical team leader Ronald Farkas said.

“If there’s significant doubt in the applicant’s mind that the application would support breakthrough designation and they want interaction with the division, probably the way to do that is to call us or contact us through other methods” and get feedback, he said. “That would be the most effective way to help the program along.”

Representatives from the oncology review division advocated a similar approach.

“There’s always sort of a mechanism to indirectly or informally … get in touch with the FDA prior to submitting so that the FDA can kind of give the sponsor an idea of whether this is the kind of data that we are looking for in order to grant breakthrough,” said Dickran Kazandjian, a medical officer in the Division of Oncology Products II. “That’s kind of a way to minimize the waste” and to save resources for both FDA and companies.

… Aids Ariad’s Second Bid

Ariad Pharmaceuticals Inc. followed this early consultation approach in its second bid for a breakthrough designation for brigatinib, an anaplastic lymphoma kinase inhibitor in development for patients with ALK+ non-small cell lung cancer that is resistant to Pfizer Inc.’s Xalkori (crizotinib).

The company first submitted a designation request in May 2013 on the basis of Phase I data comprising 16 evaluable ALK+ NSCLC patients who had received prior treatment with crizotinib but no other ALK inhibitors. Twelve of the 16 patients (75%) experienced a partial response, but only five of the responses were confirmed.

The company submitted the request without first running the supporting data by FDA. The agency denied the request in July 2013, determining that an insufficient number of patients had been studied and follow-up was too short to evaluate duration of response Also see "Ariad Unfazed By FDA Breakthrough Denial" - Pink Sheet, 8 August, 2013..

Ariad contacted FDA in May 2014 about a resubmission, this time with data from more than 50 patients.

David Kerstein, Ariad’s medical director for clinical research and development, said the company “described the quality of the data that we would be submitting and really asked for feedback as to whether this would be supportive based on the original feedback we received in terms of increased patients and increased follow-up.”

Ariad resubmitted the request in August 2014 with “three times more patients experience and a significant amount of follow-up particularly with duration of response” and progression-free survival data, he said.

Of the 51 evaluable ALK+ NSCLC patients who had received prior treatment with crizotinib and no other ALK inhibitors, the objective response rate was 69%, with duration of response ranging from 1.6 months to 14.7 months.

FDA granted the designation request in October 2014.

Kerstein said the feedback Ariad received from FDA with its rejection of the initial request helped guide the company’s decision around when to submit the second time.

Talking to FDA about “those kinds of questions before even initial submission would potentially change how we might have” operated, he said.

Non-binding Advice

For drugs or biologics with active INDs, this type of informal communication is typically initiated through a phone call or other communication with the FDA regulatory project manager who is managing that IND, Division of Oncology Products II clinical team lead Marc Theoret said.

However, Theoret stressed the preliminary and informal nature of such conversations.

“In these discussions, it’s clear that this is not a binding advice. It’s just an informal discussion regarding the data that would be submitted,” he said. “Sponsors are free to submit a breakthrough request irrespective of that informal discussion.”

Even with the caveats around the advice being non-binding, such early interaction with FDA ahead of a breakthrough request submission “is a great idea,” said Biotechnology Industry Organization Senior VP-Science Policy Kay Holcombe. “I think that companies that don’t regularly interact with regulators don’t understand that you can actually do that.”

Unsure About ‘Breakthrough’-Worthiness? Talk To FDA First

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