Is Breakthrough Therapy Designation a Sponsor’s Golden Ticket?

Is the Food and Drug Administration’s (FDA) Breakthrough Therapy Designation a golden ticket to instant success or a mirage leading us down a road to nowhere (with a nod to the Talking Heads)?

Many of us remember fondly the classic movie, Willy Wonka & the Chocolate Factory, where children buy chocolate bars to win a golden ticket and tour the chocolatier’s factory. Once inside the factory, the children and their guardians tour the amazing manufacturing site, meet the Oompa Loompas, and taste many new candies. However, not all is rosy as, one by one, the kids misstep and are miniaturized by Wonka Vision, turned into a blueberry, fall into a chocolate river and get sucked through an extraction pipe system, or rejected as a “bad egg.” Ever our hero, Charlie, makes a mistake and almost loses it all. Bottom line: what looks like Paradise is fraught with challenges, obstacles, and easy missteps.

The Food and Drug Administration Safety and Innovation Act (FDASIA), enacted on July 9, 2012, amended section 506 of the Federal Food, Drug, and Cosmetic Act and established a new way to expedite the review of drugs and biologics manufactured for serious or life-threatening conditions. Breakthrough Therapy (BT) designation requires preliminary clinical evidence indicating that the drug or biologic may demonstrate substantial improvement over existing therapies on at least one clinically significant endpoint.

While FDA has other expedited review programs, such as fast track designation, priority review, and accelerated approval, the intent behind BT designation is to encourage outside-the-box product development where the FDA, in certain cases, might speed up a product review by, for example, allowing sponsors to rely upon non-clinical information, rather than clinical evidence. It is important to recognize that BT products are not guaranteed approval, although there are some in the business world that might think so.

FDA issued guidance in June 2013 describing its expectations for BT designation, although every case will be different.

Qualifying Criteria

In order for a drug or biologic to be designated as a BT, it must fulfill certain criteria:

Intended to Treat a Serious or Life-Threatening Disease or Condition

The product must be “intended . . . to treat a serious or life-threatening disease or condition.” The agency defines “serious disease or condition” as:

Disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

Examples of BT-designated therapies, to date, include several diseases related to muscle degeneration and to numerous types of cancer. According to the agency, the product must be “intended to have an effect on a serious aspect of a condition,” e.g., a product intended to improve diagnosis of a serious condition, which would lead to improved outcomes.

Preliminary Clinical Evidence

The sponsor must submit a designation request for each product indication, accompanied by “preliminary clinical evidence [that] indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints.” FDA encourages a sponsor to obtain preliminary data early in the drug’s development demonstrating that the therapy is superior to an existing therapy, or to a placebo if no existing therapy is available, or to develop data comparing the new treatment plus the current U.S. Standard of Care (SOC) to the SOC alone. In practice, FDA has frequently relied on Phase II studies and, at least partly, on Phase III studies in at least two BT-related cases to designate a drug as a “breakthrough therapy.” The agency also recommends that a sponsor include a “sufficient number of patients in such studies,” but does not further clarify on what constitutes “sufficient.”

i.     Substantial Improvement Over Existing Therapies

The evidence must provide for the possibility that the therapy provides “substantial improvement over existing therapies.” Whether improvement over existing therapy is substantial or as the agency also calls it, has a “clear advantage,” depends on the duration of the effect and the importance of the clinical outcome. According to FDA, substantial “improvement will be clear” when there is no existing therapy, or the existing therapy demonstrates “a modest response and the new therapy shows an effect on an important outcome.” “Substantial improvement” can also be shown if the sponsor demonstrates that the new drug has an “important safety advantage” as shown by the occurrence of serious adverse events when compared to existing therapies and yet has a similar efficacy profile.

Some studies that FDA has relied upon to grant BT designation have demonstrated:

  • that the drug extended progression-free and overall survival, and that it had “a very acceptable tolerability profile;”  

  • an 80% response rate in patients who had experienced disease progression after a treatment with another drug; patients who received the drug had a 37% reduction in mortality at six months after an acute heart failure compared to those who received conventional treatment, that the drug helped patients breathe better both during and after acute heart failure, that the drug reduced the rate of heart failure worsening, that its side effects are comparable to conventional therapy, and that the drug is well tolerated; and

  • a drug’s regimen provided high sustained viral response rates with 12 weeks of therapy in patients who had not beenpreviously treated and in those who had failed prior therapy.

The agency considers “existing” or “available therapy” to mean those therapies that are approved or licensed in the U.S. for the same indication for which the new product is being developed and which are relevant to the current SOC for the indication at the time FDA is deciding whether to grant designation. To determine the current SOC, the agency considers recommendations from scientific institutions, such as the National Comprehensive Cancer Network. In at least four recent cases, FDA has designated therapies to treat a disease or the disease’s symptoms for which there was no alternative therapy and, in at least two cases, has granted designation for therapies in which there were limited alternative therapies.

ii.     Clinically Significant Endpoint

The required evidence of substantial improvement must relate to one or more clinically significant endpoints. FDA defines this type of endpoint as one that “measures an effect on irreversible morbidity or mortality or on symptoms that represent serious consequences of the disease.” Examples of findings that would satisfy this requirement include a “significantly improved safety profile” over existing therapy with evidence of similar efficacy, plus findings necessary for Accelerated Approval (i.e., an effect on a surrogate endpoint or intermediate clinical endpoint reasonably likely to predict a clinical benefit).

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