October 1, 2013 (Vol. 33, No. 17)

Breakthrough Therapy Designation Is Changing How the Agency Operates

The Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law on July 9, 2012. FDASIA section 902 provided for a development path, the breakthrough therapy designation, for new drugs. Since last July, the agency has received a total of 82 applications for the designation, and has published a draft guidance titled “Guidance for Industry: Expedited Programs for Serious Conditions––Drugs and Biologics” on June 25, 2013.

The FDA’s new development path is specifically designed for experimental agents that produce large and unprecedented treatment effects in early clinical trials. If a drug is designated a breakthrough therapy, the FDA says it will expedite the development and review of the drug, reviewing all such requests within 60 days of receipt, and either grant or deny the request.

As of August 13 of this year, 25 designations have been granted and 32 denied.

Pharma industry execs, who generally have few happy words to utter about the agency, have thus far praised the new program that most say will get new drugs to patients who need them faster. Patient advocacy groups are also on board, and the FDA has made significant efforts to ensure that all stakeholders understand what the new designation means.

New Designees

The FDA handed the latest designation, announced by the company on August 27, to Catalyst Pharmaceutical Partners’ Firdapse™ to treat Lambert-Eaton myasthenic syndrome (LEMS), being evaluated in a Phase III trial for the treatment of symptoms associated with LEMS. Topline results from the double-blind portion of the study are expected in the second quarter of 2014.

Other breakthrough designees this year include Merck’s cancer drug lambrolizumab (MK-3475) in recognition of the dramatic clinical benefits observed in an open-label, Phase I trial involving people with advanced melanoma.

According to trial investigator Omid Hamid, M.D., chief, translational research and immunotherapy and director, Melanoma Therapeutics at the Angeles Clinic and Research Institute, “It’s never a good time to be a patient. But at this point, if you are, it’s the dawning of a new day where we have the return of hope of having a significant therapy.

“One of the best things about getting this breakthrough designation is that it drives patients to clinical trials, and it drives patients to the understanding that there is continued work being done.”

Bristol-Myers Squibb, Genentech, Amplimmune, and CureTech all similarly have drugs directed at either PD-1 or its ligand. But, according to Dr. Hamid, the lambrolizumab antibody is the only drug to have been shown publicly to work in people for whom Yervoy has failed. In the trial data presented last year, 11 of 27 participants who had previously tried Yervoy showed an objective antitumor response to the new experimental Merck antibody.

Other experimental cancer drugs designated as breakthrough drugs include Pfizer’s palbociclib (PD-0332991) for metastatic breast cancer; Novartis’ LDK378 for ALK-positive lung cancer; and Johnson & Johnson’s/Pharmacylics’ ibrutinib (PCI-32765) for various types of leukemia and lymphoma. “We are getting meetings very quickly with the FDA,” said Peter Lebowitz, global oncology therapeutic area head with J&J’s Janssen division. “FDA is working with us to solve issues.” He expects the designation will have a “big impact” on how quickly the company can advance ibrutinib.

All Hands on Deck

J&J and Vertex, both represented at a congressional briefing on having both received early breakthrough therapy designations, agreed that the designation’s greatest value was that it prompted an “all-hands-on-deck” mentality at CDER. This approach brings together the needed review disciplines, including chemistry and manufacturing, and involves senior leadership early on. The designation also provides more direct and collaborative engagement with the agency.

According to the FDA, there are “differences in what needs to be demonstrated to qualify for the program.” A breakthrough therapy program is for a drug that treats a serious or life-threatening condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.

In contrast, the agency says, a fast-track program is for a drug that treats a serious or life-threatening condition, and nonclinical or clinical data demonstrate the potential to address unmet medical need.

The FDA has also designated a separate senior management team focused solely on the approval of these therapies. The agency, commentators say, has stressed the importance of efficient drug development programs that show these medicines demonstrate at least one significant improvement in clinical endpoints for conditions in which therapies already exist.

And the agency says that, while breakthrough therapy and fast-track designations sound similar, a clear distinction between the two is that the breakthrough designation can rely on preliminary clinical evidence demonstrating substantial improvement on a significant clinical endpoint, while the fast-track could be based on nonclinical data such as the drug’s mechanism of action.

Janet Woodcock, M.D., director of the FDA’s drugs division, said during the discussion that the breakthrough pathway was designed to accommodate new science, particularly targeted therapies that may work in people with certain genetic mutations. She further noted that just because the review process is speeded up there is no guarantee of approval and that the designation can be withdrawn should a better therapy come to market while the breakthrough drug is still undergoing review.

In the 1990s, she said, the agency was not seeing drugs whose promise could be detected in early clinical trials. But Dr. Woodcock reports that companies that earn breakthrough status will have the ear of the agency. “We expect many of these would come available very quickly with Phase I data,” she said.

Richard Pazdur, M.D., head of the FDA’s office of hematology and oncology products, says the new designation catalyzes communication between a company and the agency and that a breakthrough designation means that there are more times a company can expect to be able to pick up a phone and get an answer.

“The designation can lead to cleared calendars,” Dr. Pazdur said, “and it also means that the senior management of the FDA division becomes involved, not just the reviewers who serve on the FDA’s front lines.” And, he noted, a breakthrough cancer drug should be “transformative.”

“The true measure of success is going to be how active we are in working with the companies,” Dr. Pazdur says. “If someone gets a breakthrough therapy and it’s business as usual, than the breakthrough therapy is meaningless.”

And Jeffrey Leiden, M.D., Ph.D., CEO of Vertex Pharmaceuticals, who also spoke at the briefing and whose cystic fibrosis drug Kalydeco was approved under the designation, said his company’s experience working with the FDA was dramatically different from the normal drug approval process.

Under breakthrough designation, he said, “everything is on the table” for discussion in order to move the process along as quickly as possible. Communications that might typically take weeks and months take minutes under the breakthrough pathway.

“We pick up the phone and talk in real time,” Dr. Leiden said. “It makes the process immeasurably smoother.”

And patient advocacy organizations are on board with the novel designation. “It’s great to see that the FDA has embraced this,” says Jeff Allen, executive director of Friends of Cancer Research, a Washington, DC–based think tank and advocacy organization that first proposed the breakthrough designation. “I think what’s most promising is that there are drugs that are having this magnitude of effects in disease settings where there are so few options.”

Impact on Other Programs

Dr. Woodcock says the FDA will manage breakthrough applications along with its entire portfolio of submissions, but some stakeholders express concern about whether the demands of the exceedingly popular program will affect the agency’s handling of other applications.

The agency is now facing questions about whether the growing number of breakthrough designations has pulled resources away from other applications, an indication there may be concerns about the demands the program is placing on the agency.

“We have a body of work we have to do,” Dr. Woodcock said. “We just do the best we can. It’s a portfolio we have to manage.”

All parties hope that the new drug designation will speed more effective drugs to patients with dire diseases more quickly.

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