FDA officials are floating a proposal for a review process informally dubbed “reverse accelerated approval.”
This mechanism would come into play in situations where the data that have already been provided to the agency may justify approval of supplemental indications.
This way, sponsors would not be required to conduct new confirmatory trials when they seek approval of supplemental new drug applications.
As it reconsiders its methodology, FDA is suggesting that additional trials are not always necessary for some supplemental indications if high-quality data already exist.
The framework is designed to expedite regular approvals for supplemental applications for drugs that may work across multiple indications. For example, historical data may be used for approving supplemental indications based on intermediate endpoints.
This approach would be especially useful in cases where there is an urgent unmet need and randomized clinical trials are not feasible. Its informal nickname notwithstanding, the process would examine all available evidence, independent of the order in which it was developed, and facilitate approval of a drug for additional uses based on an intermediate endpoint.
The agency’s review and assessment of sNDAs, is similar to the original NDA framework. The development process can take years, and approval relies on conventional clinical endpoints and robust data.
Richard Pazdur, director of FDA’s Oncology Center of Excellence, speaking at the Friend of Cancer Research’s annual meeting in November, described the developing framework as a form of “reverse accelerated approval”—a tongue-in-cheek spin on the agency’s accelerated approval process.
“People didn’t like that term, because it sounded like we were moving away from accelerated approval, but at the end of the day you have the same information,” Pazdur said at the meeting Nov. 14.
It’s just a matter of sequence, Pazdur said.
“You’ve already shown the clinical benefit in another setting,” Pazdur said. “And what we’ve done in most of the accelerated approvals is we have always asked for a trial to be done in a related disease setting. So we’re really not lowering the standard here. It’s just sequential difference of how we go about really showing clinical benefit has been demonstrated for a particular drug.”
Per the existing accelerated approval process, industry sponsors have the option of conducting safety and efficacy trials after a drug has been approved, instead of completing all studies prior to bringing the agent to FDA. To qualify, the investigational drug must address a serious or life-threatening condition and demonstrate effect on an intermediate clinical endpoint or surrogate endpoint.
Subsequent regular approval for drugs that qualify for accelerated approval is contingent on demonstration of clinical benefit using conventional clinical endpoints, which may require several years of clinical trials.
But, what if additional RCTs are not possible or ethical? What if clinical benefit in these cases needs to be measured outside conventional overall survival and progression-free survival endpoints?
For some sNDAs, it may be possible for sponsors to obtain regular FDA approval based on other criteria.
For instance, data for the drug’s original NDA may be taken into consideration, since conventional clinical endpoints have already been evaluated for the first indication. The regular approval could also rely on intermediate endpoints: objective response rate—a direct measure of tumor shrinkage using standard criteria—or duration of response.
“The goal here is to maximize efficiency,” Jeff Allen, president and CEO of Friends of Cancer Research, said to The Cancer Letter. “The working proposed criteria, that if met, would encourage development of data to support additional uses and alleviate the requirement for extra studies if the benefit has been previously shown. This approach isn’t intended to change the evidence needed for approval, just flexibility to the order in which it’s developed.”
In a white paper put together by Friends of Cancer Research and published Nov. 30, a panel of academic oncologists, FDA officials, industry representatives, and patient advocates wrote:
“In these rare cases, especially when new therapies are needed for patient populations with large unmet clinical needs and who face no other treatment options, an intermediate endpoint such as ORR, or DoR is considered the most appropriate way, or sufficient to assess clinical benefit.
“Currently, the FDA grants full [regular] approval to sNDAs based on an intermediate endpoint on a case-by-case scenario, but there are no available or standardized guidelines that could help:
- Weigh the urgency in a scenario of unmet clinical need, and
- Assess the type and quality of evidence necessary to provide sufficient confidence in the decision to grant full approval to drugs used for a supplemental indication.”
FDA said it would continue to examine available evidence for approved drugs to determine whether there are sufficient data to support full approval in new supplemental indications based on intermediate endpoints.
According to the white paper, previous regular approval of drugs using an intermediate endpoint in a new indication have been based on the following characteristics:
- Unmet clinical need
- Optimal understanding of natural history of disease
- Well-understood mechanism of action and performance of drugs in different disease settings
- Robust and well-established safety database
- Reliable study endpoint that has consistently demonstrated clinical benefit
- Accurate and well-instituted companion diagnostics
A streamlined approach that relies on the use of historical data and expedites the approval of drug combinations may be useful for regulating future supplemental indications for the following drugs, the authors wrote:
- Entrectinib and larotrectinib, tyrosine kinase inhibitors that are being tested in tissue-agnostic open-label, multicenter, global phase II basket studies for the treatment of patients with solid tumors that harbor a fusion affecting tropomyosin receptor kinase fusions (NTRK1/2/3), ROS1, or ALK. These drugs may potentially work across multiple indications.
- Keytruda (pembrolizumab), a PD-1 inhibitor first approved in 2014 under accelerated approval for the treatment of patients with unresectable or metastatic melanoma. Since the initial approval, Merck has submitted applications for 10 other indications, some of which were approved under accelerated approval. A number of other indications were fully approved after clinical benefit based on overall survival was demonstrated.
- Imbruvica (ibrutinib), a kinase inhibitor initially granted accelerated approval for the treatment of patients with mantle cell lymphoma who had received at least one prior therapy in an open-label, multi-center, single-arm trial based on ORR as the efficacy outcome.