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Oncology Times:
doi: 10.1097/01.COT.0000451720.90722.cf
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FDA's Breakthrough Therapy Designation: Update from Janet Woodcock

Eastman, Peggy

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WASHINGTON—It's only two years old, but the U.S. Food and Drug Administration's Breakthrough Therapy designation has proven to be far more popular than anticipated with drug sponsors—potentially good news for cancer patients. Therapies granted this designation must show very early clinical evidence suggesting a substantial improvement over existing treatments for serious or life-threatening diseases.

At a Capitol Hill congressional briefing here hosted by the advocacy organization Friends of Cancer Research (FOCR), speakers hailed the novel regulatory pathway's ability to bring effective new therapies to cancer patients rapidly. The bill authorizing the breakthrough therapy designation was signed into law on July 9, 2012.

To date, sponsors have submitted 178 requests for this designation, the FDA has granted 44 such designations, and six drugs have been approved—four of which are for cancer treatment.

Case in point: ceritinib (Zykadia) for ALK-positive non-small cell lung cancer (NSCLC), approved on April 29 of this year for patients whose disease has relapsed on initial treatment with crizotinib, the only other approved ALK tyrosine kinase inhibitor (TKI).

“We have been inundated” with requests for the breakthrough therapy designation, said Janet Woodcock, MD, Director of FDA's Center for Drug Evaluation and Research. She said the new designation is working well, with “pretty much unanimity” within FDA on which investigational products should receive the designation. The agency intends to issue a guidance document that will contain advice on use of FDA's regulatory designations for new drug approvals.

“It's very inspiring to work on something that's really going to make a difference to lives,” Woodcock said. “The pace of this designation is much faster than we had expected.”

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The most common reason the agency would deny the breakthrough designation is when investigational therapies show only incremental improvements in treatment, she noted. “That is not a breakthrough.” Rather, the breakthrough designation is for a therapy that shows “spectacular early results” and could be a “game changer.” She added that the FDA is well aware, though, that even if a given new therapy does show spectacular early results, they may not be borne out.

“We had no idea how successful this would be,” said Ellen Sigal, PhD, FOCR Chair and Founder. “It wasn't an obvious leap of faith,” added Sigal, whose organization was a prime mover in advocating for the designation and working on its regulatory framework with the FDA. FOCR helped take the new designation from a concept to a white paper to legislation to a new FDA tool.

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Comments from Sandra Horning

The FDA breakthrough designation “really reduces a lot of the ambiguity about what constitutes a breakthrough,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Genentech and an emeritus professor of medicine at Stanford University. She said that reduced to a word, designation can be called “mindset,” giving drug sponsors a can-do mindset about bringing new therapies to cancer patients as rapidly as possible.

At the briefing, Horning described her company's experience with the breakthrough designation for Gazyva (obinutuzumab), approved on November 1, 2013 for chronic lymphocytic leukemia (CLL); it was approved within about nine months. She noted that because CLL is incurable and many patients are older (over age 70) and have co-morbid conditions, an effective new therapy is a welcome option for oncologists treating this patient population. Horning said Genentech and the FDA had many meetings and that the drug was approved six weeks ahead of its scheduled FDA deadline.

“For us, honestly speaking, this program came at the perfect time,” said Urta Gayko, PhD, Senior Vice President of Global Regulatory Affairs at Pharmacyclics, which developed ibrutinib (Imbruvica) for mantle cell lymphoma (MCL)—approved in about four and a half months under the breakthrough designation, also ahead of its FDA deadline. Gayko noted that when her company sent in its application, the data included only a few hundred patients, “but now we have a few thousand patients benefiting from this.”

If there is a downside to the new designation, it is the burst of high-pressure work required for shortened review under this new regulatory pathway. “It is a lot of work,” Woodcock said, noting that the compressed review process is very demanding for both the FDA and the drug sponsor. But the good news, she said, is that the new process does not require multiple reviews.

“This is the highest workload that you can imagine... you have to put in this effort,” Gayko said, describing hearing from the FDA on a Friday afternoon and needing to produce data on Monday, which required a weekend of intense, concentrated work.

JANET WOODCOCK, MD
JANET WOODCOCK, MD
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‘Resource Intensive’

“It is very resource intensive,” Sigal said of the breakthrough designation. “There's a huge amount of work” at FDA, an agency already considered under-staffed to handle its workload, she noted.

Speakers discussed other challenges with breakthrough-designated therapies, including: technical, manufacturing issues relating to having the new therapy available to patients when it is approved; aligning a breakthrough therapy with its companion diagnostic, if there is one; and ensuring that a breakthrough-designated therapy—which is usually very costly—is reimbursed by insurers.

Gayko noted that from the standpoint of a sponsor, there are many “practical things that need to happen” to bring a new therapy to patients. She said it would be helpful for the FDA to give a drug sponsor an informal target date for completing the breakthrough therapy review so the company could gear up for distribution.

As for companion diagnostics, Horning said, “I think there are technical issues about companion diagnostics that are in front of us all. This is still a very challenging area for all of us—everything from development to reimbursement.”

In terms of the cost of breakthrough drugs, Sigal said, “We all know they're very expensive, but on the other hand, many of them are curative.” Thus if they are curative, they are well worth reimbursement, she pointed out.

Also speaking at the briefing was Bayard W. “Chip” Kennett, a 33-year-old former Senate staffer who has ALK-positive stage IV NSCLC. Diagnosed at age 31, Kennett—who has a wife and two preschoolers—had a relapse on crizotinib. Given four different types of treatment, he entered a clinical trial with ceritinib—“It literally has kept me alive,” said Kennett, who said he feels well and that the drug has minimal side effects.

Kennett, who now works for Raytheon Company, told OT he knows he is young for this diagnosis, and wants to learn more about its genetics—especially since he has two small children. He said he is grateful that he and his wife have excellent insurance.

Wolters Kluwer Health | Lippincott Williams & Wilkins

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