Accelerated Approval Requests Based On Low Efficacy Frustrate FDA

FDA appears to be increasingly frustrated with sponsors who seek accelerated approval based upon the lowest possible efficacy standard.

"When we have a meeting like this, we have a litany of sponsors come in and pose this question to us: What is the lowest response that you will take? What is the fewest number of patients you will take?" Division of Oncology Drug Products Director Richard Pazdur said during an Oncology Drugs Advisory Committee meeting Dec. 1. "It's called how low can you go?"

Pazdur's comments came during ODAC's review of Inex/Enzon's Marqibo (vincristine sulfate liposomes). The committee recommended against accelerated approval for relapsed aggressive non-Hodgkin's lymphoma in part because off-label treatments were considered "available therapy" (¹ , p. 20).

The Marqibo application appeared to underscore concerns with the accelerated approval process itself.

"This really is a problem I have with this entire accelerated approval process," committee member Silvana Martino, University of Southern California, said. Martino chaired the Marqibo review.

"We're looking for what is the least amount of data to be convincing, and I think that is the wrong approach," she said. "But, what I see that we do, especially with accelerated approval, is what is the least amount that you can show me in which I will then give you a reward for that?"

"As a medical community we have to rethink what our objectives are and what our purposes are. They should be much greater than that," Martino said.

Pazdur agreed. "This is one of the reasons we have been discussing this, emphasizing the accelerated approval commitments."

"The purpose of accelerated approval was not accelerated drug company profit," Pazdur said. "It was accelerated access to people that had desperate illnesses that needed the therapies, and we were allowing basically a surrogate to be used to get these therapies out early to patients that needed it."

Standards for accelerated approval also became an issue during the committee's same-day review of Ilex' pediatric leukemia agent Clolar (clofarabine).

The committee recommended accelerated approval of Clolar for refractory or relapsed pediatric acute lymphoblastic leukemia, but not for pediatric refractory or relapsed acute myelogenous leukemia (² (Also see "Ilex Clolar Advisory Committee Splits On Pediatric Leukemia Approvals" - Pink Sheet, 6 Dec, 2004.), p. 22).

Pazdur urged the committee to consider that Ilex had not yet initiated its confirmatory trials for accelerated approval.

With a Dec. 30 user fee deadline, it seems unlikely that Ilex could initiate the trials by the time FDA reaches a review decision.

"It is quite bothersome that we're at this point of talking about approval of the drug and not having met with the sponsor" about confirmatory trials, he said. "This is something that you will have to take into consideration regarding this drug."

"Usually the sponsor would come in and discuss these trials with this drug," Pazdur said. "There should be a comprehensive development program for drugs, and this would include perhaps an exploratory study. However, we encourage early initiation of randomized studies, not 'let's get the drug approved and then let's talk about randomized studies.'"

FDA's oncology drugs division "is very concerned about the lack of ongoing studies at this time," Pazdur said. "These studies are to be done with due diligence. One has to question if they haven't been done to date, has the sponsor demonstrated due diligence?"

Although a lack of confirmatory trials might not prevent approval, the agency may be particularly frustrated because ODAC has previously emphasized the need for timely accelerated approval follow-up studies.

In March 2003, the committee urged FDA to create an enforcement mechanism to ensure that sponsors who received accelerated approval complete confirmatory trials to show actual clinical benefit (³ (Also see "Accelerated Approval Needs Enforcement Mechanism For Confirmatory Trials" - Pink Sheet, 24 Mar, 2003.), p. 30).

ODAC also recommended that sponsors initiate confirmatory trials early (⁴ (Also see "Cancer Drug Confirmatory Trials Should Be Initiated Early, FDA Says" - Pink Sheet, 24 Mar, 2003.), p. 31).