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Tufts study: Data suggest breakthrough therapy designation meets goals


By Marie Powers
Staff Writer

Nearly 18 months after its launch by the FDA, the breakthrough therapy designation (BTD) is showing the potential to meet the agency’s stated goal of speeding the development and review of drugs that show early evidence of offering substantial improvement over existing therapies on a clinically significant endpoint. By approving only 30 percent of the first 113 BTD requests submitted, the FDA demonstrated the program offers meaningful differentiation from other review processes, including priority review, fast track and accelerated approval, according to the Tufts Center for the Study of Drug Development (CSDD), which conducted an assessment of the BTD program.

“You could anticipate that there was going to be a fairly rigorous threshold” for accepting BTD requests, Christopher-Paul Milne, director of research at Tufts CSDD, told BioWorld Today. An acceptance rate of 30 percent – which subsequently has dropped further, he said – “indicates that it’s meaningful to get the designation.”

The Tufts study was based on Tufts CSDD proprietary databases, FDA publications, Thompson Reuters Cortellis data and professional literature for BTD determinations made between July 9, 2012, and Dec. 17, 2013. (Editor’s note: Thomson Reuters is the parent company of BioWorld Today.)

Legislation requiring the FDA to mentor sponsors developing breakthrough therapies was introduced in the U.S. Congress in April 2012. The goal was to allow sponsors to work closely with the FDA to develop trial designs that would shorten or combine traditional phases of drug development and to hold regular discussions and timely meetings through the development of a breakthrough product. (See BioWorld Today, March 9, 2012, and April 2, 2012.)

When the FDA weighed in on proposals, the agency’s guidance defined a “clinically significant endpoint” as one “that measures an effect on irreversible morbidity or mortality or on symptoms that represent serious consequences of the disease.” Sponsors also could request the BTD if a drug offered a significantly improved safety profile compared with available therapy or demonstrated findings that suggest an effect on:

• an established surrogate endpoint;

• a surrogate endpoint or intermediate clinical endpoint that’s reasonably likely to predict a clinical benefit; or

• a pharmacodynamic biomarker that doesn’t meet the criteria for an acceptable surrogate endpoint but strongly suggests the potential for a clinically meaningful effect on the underlying disease. (See BioWorld Today, June 26, 2013.)

During the first year, principal reasons reported by the FDA for denying BTD included inclusion of data that were preliminary or nonclinical, reliance on a subset of data identified in post-hoc analyses of failed studies, dependence on biomarkers or surrogate endpoints without sufficient supporting evidence and failure to demonstrate substantial improvement over available therapy. Having this type of feedback early in the clinical development process may help sponsors not only to accelerate promising therapies but also to halt development quickly on compounds that fail to show requisite clinical evidence.

So far, the FDA appears to be meeting the objectives of the BTD guidance document, Milne said, including the use of early intensive guidance to sponsors and organizational commitment up to and including senior officials at the agency.

“I won’t say that’s surprising, but it’s a good indication they are on board with their goals for this program,” he said.


The BTD assessment, reported in the January/February Tufts CSDD Impact Report, revealed that orphan and oncology drugs dominated the first class of BTDs awarded by the FDA but that central nervous systems (CNS) drugs and diagnostics – which currently represent only 3 percent and 5 percent, respectively, of BTD approvals – will likely benefit from the program going forward.

In terms of numbers, neurology compounds currently are fourth behind oncology, antiviral and hematology candidates in seeking the BTD pathway, according to Milne.

“FDA recognizes that this is a challenging area and is beginning to broaden the flexibility with which they will look at that quantum of evidence, particularly for an indication like Alzheimer’s,” he said. For example, the agency is increasingly willing to look at markers for preventing progression of disease, Milne pointed out.

He cautioned sponsors about using the first three drugs approved through the BTD pathway as role models in terms of indication, mechanism of action or unmet medical need. Imbruvica (ibrutinib, Pharmacyclics Inc./Janssen Biotech Inc.), Gazyva (obinutuzumab, Genentech Inc./Biogen Idec Inc.) and Sovaldi (sofosbuvir, Gilead Sciences Inc.) all “were late in terms of how much help they actually got from the BTD” since they were already into advanced trials when the program was established, he said. (See BioWorld Today, Nov. 4, 2013, Nov. 14, 2013, and Dec. 9, 2013.)

Still, three approvals in the first year of the program – and approved BTD requests for pharmas as well as medium-sized and larger biotechs – “gives sponsors an indication of the direction that FDA is taking the program,” Milne added. “These are pretty complex drugs, and these are the kinds of drugs that are going to need this help.”

Other candidates that received BTD range from Syndax Pharmaceuticals Inc.’s lead product entinostat to treat locally recurrent or metastatic estrogen receptor-positive breast cancer to Boehringer Ingelheim Pharmaceuticals Inc.’s volasertib to treat patients 65 or older with previously untreated acute myeloid leukemia. (See BioWorld Insight, Sept. 23, 2013.)

A major challenge for the BTD program is whether the FDA can sustain the early momentum. The BTD application “is not terribly onerous” to submit, so it behooves sponsors to take a shot with drug candidates that might meet the criteria, Milne said. Consequently, he added, “the FDA is a little overwhelmed with the degree to which sponsors have responded to this. We may want to look at how well FDA is able to keep up the pace and whether they’re going to put some additional resources into the program.”

Increasingly, BTD drug candidates will attract interest not only from patients and physicians but also from investors and payers, Milne predicted, noting that investors are looking “beyond incremental innovation” in deciding where to place their bets.

Payers, too, are looking for independent validation of a drug’s efficacy and justification for the spiraling prices of new molecular entities and biologics. “As we get into this new era of targeted medicines, the BTD will become a benchmark for how well any particular product is regarded as it enters the marketplace,” Milne said.