FDA is developing a policy by which the agency can approve subsequent indications of cancer drugs with less rigorous follow-up trials, FDA Commissioner Scott Gottlieb announced Thursday (Nov. 30). The agency will also provide more guidance on how FDA believes it can approve treatments based on intermediate clinical endpoints, which one expert explained may be significant when exploratory or so-called go-no-go trials show a significant improvement and time is of the essence to get the drugs approved.
Both moves by FDA appear to align with recommendations by Friends of Cancer Research (FOCR), and the group’s president told Inside Health Policy that the group is “very supportive” of the steps Gottlieb outlined.
Gottlieb’s announcements came during an Energy & Commerce check-in on implementation of the 21st Century Cures Act, where the commissioner held up FDA’s progress in a number of fields, including: oncology, regenerative medicine, digital health, least burdensome device reviews and combination products, among others.
“To fully leverage these opportunities, and in keeping with the spirit of Cures, we’re working on a similar proposal for cancer drugs already approved for one indication — approval for a supplemental application, where the approval concerns a second indication, can sometimes appropriately rely on a more targeted data set, like a single-arm study. We intend to issue guidance further clarifying the circumstances in which this is appropriate,” Gottlieb said Thursday.
A recent Friends of Cancer Research whitepaper, “Capitalizing on the Totality of Evidence to Streamline Approvals for Supplemental Indications,” outlined the potential benefit of a streamlined approach toward secondary indications.
“The review and assessment of [subsequent new drug applications (sNDAs)] is very similar to that of the original NDA, which consume considerable time and resources and may not always add much value to the regulatory determination of safety and efficacy of a drug for which previous submissions have established a well-characterized profile. Indeed, approved drugs are backed up by a wealth of high-quality data collected from previous submissions, along with post-marketing experience and published literature, which should also be considered when seeking approval for a new indication. These robust data could provide an additional level of confidence on the drug’s efficacy and safety, and expedite its regulatory approval process for a new indication,” the paper states.
FDA has applied these principles before, but to our knowledge the agency never outlined this approach as matter of policy or in any formal way before Gottlieb’s comments, a FOCR spokesperson explained.
But FOCR cautioned that such an approach should consider the extent of the unmet clinical need of the proposed secondary indication and whether a randomized controlled trial is feasible.
The paper also outlines a slew of factors it says FDA should weigh when considering a secondary endpoint based on less than a full sNDA, including: the natural history of the disease; relatedness; drug mechanism & pharmacology; dose & regimen; the drug’s safety profile; efficacy; benefit-risk ratio; and the availability of companion diagnostics.
FDA is also working on better explaining how the agency can use authority granted in the Food and Drug Administration Safety and Innovation Act (FDASIA) to approve drugs based on intermediate endpoints.
“Even though the observed benefit, in this case, is on a clinical endpoint — an early look at survival — and not a surrogate measure of benefit, we believe using an accelerated approval approach often could be valuable. Congress clarified our authority under FDASIA to grant accelerated approval based on intermediate clinical endpoints. We want to better define what’s meant by intermediate endpoints to ensure that product developers with promising drugs take full advantage of this provision and can consider it in a broader range of such settings,” Gottlieb said.
FOCR President Jeff Allen explained that this clarity may be helpful for companies that conducted mid-sized exploratory trials that weren’t necessarily powered to show complete effect on long-term survival but effectiveness was so apparent in the small trial that the company and regulators want to get the product available as soon as possible.
These product approvals would likely be coupled with post-marketing studies, as is typical with FDA’s accelerated approval program, according to Gottlieb.
Lack of follow through on postmarketing studies for oncology drugs, as well as what some say are lackluster performance on overall survivability (OS) or quality of life (QoL) measures, led to an editorial in the Journal of the American Medical Association (JAMA) urging changes to FDA’s postmarketing requirements for cancer drugs.
“We suggest 3 improvements to the accelerated pathway for cancer drug approvals. First, confirmatory postmarketing studies for accelerated drug approvals should include both OS and QoL outcomes because these are the 2 facets of clinical benefit currently being used by the FDA. Second, preapproved QoL measures should be published for specific drug classes. Third, anticipated or clinically significant changes in OS and in QoL measures should be defined a priori to facilitate the identification of drugs whose ‘postmarketing clinical study fails to verify clinical benefit,’” University of California San Francisco physicians Scott Bauer and Rita Redberg wrote in the February 2017 editorial.