Recent FDA guidance laying out requirements, processes, and definitions related to the agency’s expedited drug development programs shows that the new breakthrough program should be used alongside other development tools, sources said in response to the FDA Safety and Innovation Act-mandated document. The guidance offers the first regulatory reference to the new breakthrough pathway, reinforcing much of what agency officials have said publicly, but also offering to explain rejected designations to sponsors.
FDA this week unveiled guidance outlining criteria, submission requirements, features and other details regarding fast track, breakthrough, accelerated approval and priority review programs.
“It’s helpful in defining how these four types of tools can support each other,” said Jeff Allen, executive director of Friends of Cancer Research. The group advocated for legislation creating the breakthrough designation intended to get promising treatments for life-threatening diseases more attention from FDA throughout the development process. He said the document illustrates that breakthrough is among other development tools and is not intended to be used in isolation — an idea reinforced by drug center Director Janet Woodcock.
“The breakthrough therapy designation gives us another tool in our ‘toolbox’ to help expedite the development and review of new drugs to treat patients with serious medical conditions and little or no treatment options,” she said in the agency’s blog. “We’ll continue to use the new breakthrough therapy designation and our existing tools to help make our expedited programs even more effective.” Woodcock said 56 percent of novel drugs approved by the drug center in 2012 used some combination of these expedited development tools.
So far, FDA received 62 requests for the breakthrough designation and has granted 20. According to agency statistics from June 14, FDA made decisions on all designations within the statutorily mandated 60-day time frame.
Under FDASIA, Congress mandated FDA release guidance documents on the new pathway and other existing expedited pathways and the document released this week meets those mandates, FDA confirmed.
The document puts into writing many of the breakthrough designation themes FDA officials have been talking about publicly, sources said. However, the guidance is also one component in the agency’s broader trend toward increasing flexibility in drug development, an investor said
“I think it’s a further step along the very positive progression that has been taking place now over the past year or more,” said Jonathan Leff, partner at Deerfield Management, who also serves on the boards for the National Venture Capital Association and Biotechnology Industry Organization. He said FDA, companies, patient advocates and other stakeholders have showed a shared commitment to being flexible and creative, but also rigorous in thinking about clinical development.
He noted that FDA, in denying designation requests, offers to give feedback on the agency’s decision, according to the guidance.
“It’s further than they had to go,” Leff noted. This transparency measure will help product sponsors, but it will be up to companies whether they make any of the information publicly available. While the document gives a common frame of reference for several development programs, FDA also “rightly” says certain aspects of engaging them are a matter of judgment, he noted. For example, the guidance specifies that it would be difficult to detail FDA’s determination of what constitutes a breakthrough drug.
A breakthrough therapy is defined as a drug intended to treat a serious condition and preliminary clinical evidence indicates the drug may demonstrate an improvement on a clinically significant endpoint over available therapies. Drugs receiving the designation receive all the features of a fast track designation, which is also detailed in the guidance, and additional support from the drug center’s senior managers.
Specifically, the document lays out how companies can provide evidence the drug demonstrates a substantial improvement over an available therapy on one or more clinically significant endpoints. This determination is a matter of judgment and will be more challenging when there is an effective therapy already available, the agency says. Approaches include direct comparisons with the available therapy, adding the new drug to the available therapy, showing the drug treats the underlying cause of the disease rather than the symptoms, demonstrating the drug reverses the disease progression while available treatments only provide symptomatic improvement, or showing it provides a safety advantage.
FDA also details circumstances under which a sponsor could lose its breakthrough designation. “For example, a drug’s development program may be granted breakthrough therapy designation using early clinical testing that shows a much higher response rate than available therapies,” the agency explains. “However, subsequent interim data derived from a larger study may show a response that is substantially smaller than the response seen in early clinical testing. Another example is where breakthrough therapy designation is granted to two drugs that are being developed for the same use. If one of the two drugs gains traditional approval, the other would not retain its designation unless its sponsor provided evidence that the drug may demonstrate substantial improvement over the recently approved drug.”