Janet Woodcok rolls out a new category for “breakthrough” drugs at FDA. Credit: Brendan McDermid/Reuters/Newscom Two cystic fibrosis drugs have gained the first breakthrough therapy designation from the US Food and Drug Administration (FDA). In January, the agency announced that Vertex's Kalydeco (ivacaftor) alone and in combination with the experimental compound VX-809 would be the first to benefit from an expedited review process designed for potentially lifesaving drugs. In March, FDA added two oncology drugs to this pathway: the experimental lymphoma drug ibrutinib from Pharmacyclics of Sunnyvale, California, and the Novartis candidate drug LDK378 for treating lung cancer. All three companies appear delighted but cautious about what the FDA breakthrough designation will mean for their products. Whereas Vertex states the implications “cannot be determined,” Pharmacyclics has remained resolutely silent during its recent public stock offering. FDA is considering another initiative, the Generating Antibiotic Incentives Now (GAIN) pathway, as an alternative approval pathway for unmet medical needs, which, at first blush, appears to be intended mainly for antimicrobial drugs.

Breakthrough status is reserved for new drugs and biological products intended for “rare” and “serious or life-threatening” diseases, with preference for products that are “genetically targeted.” The concept stems from informal discussions several years ago between stakeholders and agency officials about how to deal with “a new drug or drug combination for a severe illness that shows remarkable activity very early in clinical development,” says Jeff Allen, executive director of Washington, DC–based Friends of Cancer Research. These ideas were shared with influential members of the US Congress, who incorporated them into the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), known as the Prescription Drug User Fee Act V (PDUFA V; Nat. Biotechnol. 30, 733–734, 2012).

The criteria for granting breakthrough status are not entirely evident, and the FDA does not grant such designation unless companies request it. Companies welcome the opportunity to collaborate more closely with the FDA. Alessandro Riva, global head of oncology development and medical affairs at Novartis in Basel, referring to LDK378, points out that breakthrough status “includes all of the fast-track program features, as well as more intensive FDA guidance.”

Meanwhile, the new FDA alternative approval pathway being developed takes some of its momentum from the Generating Antibiotic Incentives Now (GAIN) provisions that are part of PDUFA V. GAIN explicitly provides incentives for developers of antimicrobial products, such as extended market exclusivity and fast-track reviews.

Despite some doubts over whether the GAIN provisions in PDUFA V provide adequate authority to implement this new pathway, “the development is already happening, even without written guidance,” says David Shlaes, a consultant based in Stonington, Connecticut, who specializes in antibiotic development. “FDA does this for cancer drugs all the time, but for antibiotics it's really new.” In practical terms, an alternative pathway appears to mean accepting clinical trial results at a much earlier stage and overhauling trial design features that he and many others considered impediments to testing and approving such products.

Although the language and processes differ, much about this pathway echoes what the new FDA breakthrough designation seeks to accomplish, albeit for different treatments for different diseases. FDA is likely to restrict the clinical uses of any antimicrobials that travel this new regulatory pathway through product labeling, Shlaes says. Such restrictions will add upward pressures to the pricing of such products to recoup investment costs. But one potential general advantage from such higher prices, he points out, is that clinicians will be more inclined to use such products sparingly, which might postpone pathogens developing resistance to them.

Author information Affiliations Washington, DC Jeffrey L Fox Authors Jeffrey L Fox View author publications You can also search for this author in PubMed Google Scholar

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