Accelerated Approval Needs Enforcement Mechanism For Confirmatory Trials

FDA needs to create an enforcement mechanism to ensure that companies with anticancer agents awarded accelerated approval complete confirmatory trials to show actual clinical benefit, the Oncologic Drugs Advisory Committee agreed.

"The very existence of this mechanism of accelerated approval creates a circumstance" that "if I were a company, I am not sure that I would have the same due diligence...for getting some of these studies done than I would if, in fact, I were going for full approval," committee member Silvana Martino, John Wayne Cancer Institute, said.

"There is a recurring theme here that...accelerated approval has been given to drugs, that then allows the drugs to be marketed, and it then allows physicians to not only use it for the indicated purpose, but for other things that may be used there inappropriately," Martino noted.

"Therefore, the sponsor has benefited from the marketplace's use [of the drug] as it gets more and more daylight and more and more time has passed" without having completed the trials to confirm clinical benefit required under the accelerated approval regs. "The inherent problem in all of this" is that no "threat in reality exists" to ensure sponsors complete postmarketing trials, Martino explained.

Voting committee guest Thomas Fleming, PhD, University of Washington, agreed, suggesting that financial considerations vastly diminish a sponsor's sense of urgency to conduct confirmatory trials once a product enters the marketplace.

In the premarket setting there is "no question that the urgency [to perform confirmatory trials] is reinforced significantly by financial considerations." However, "there clearly isn't that same at least financial aspect of consideration" in the postmarketing setting. "That is something that has to be addressed," Fleming said.

FDA convened the committee to review the oncology experience with accelerated approval and solicit means by which to improve upon the process, the ¹ agency's briefing documents explain.

The oncology division is concerned that only four of 15 accelerated anticancer agents have successfully completed confirmatory trials. This experience contrasts with that of HIV, where the vast majority of accelerated therapies have subsequently received full approval (² (Also see "Accelerated Approval Standards Will Be Advisory Committee Topic In March" - Pink Sheet, 16 Dec, 2002.), p. 24).

Committee members were responding to statements made by FDA that it would strongly resist withdrawing a drug from the market if a sponsor failed to perform confirmatory trials in a timely fashion, or if trials failed to show clinical benefit.

"Obviously we have the ability of taking a drug off the market, but you can imagine...that that would be a very difficult decision," Oncology Drug Products Division Director Richard Pazdur, MD, said.

"If you faced an unrecognized toxicity or a severe toxicity, then the agency can clearly then take the drug off the market. But then to say that a drug has been on the market for seven years, and 'by the way, now it doesn't work and we're taking it off the market,' that publicly represents a failure to many people, not only to the company and the FDA, but more importantly to the patients," Pazdur said.

Noting that FDA has yet to withdraw an anticancer agent from the market, the oncology division director added, however, that "past history does not predict future trends."

Committee members suggested that the committee could serve as a sounding board and independent arbiter if FDA wanted to withdraw a drug from the market that ultimately never showed clinical benefit.

"It's hard to yank a drug. There's a lot of political and social" pressure against withdrawing drugs, committee member Bruce Cheson, MD, Georgetown University noted. "This committee would really appreciate the opportunity to be a part of some of the decisions and would serve as an excellent sounding board for some of the very difficult decisions you're going to have to make."

Committee Chair Donna Przepiorka, MD/PhD, University of Tennessee, concurred, saying: "I think what you're hearing from this committee is that we'd be willing to" recommend withdrawal for an oncologic approved under Subpart H that did not demonstrate clinical benefit.

Rather than pulling drugs from the market, FDA is encouraging sponsors to have multiple ongoing studies that could confirm clinical benefit for the drug in anticipation that a postmarketing trial fails.

"There needs to be continuous dialogue during the conduct of these confirmatory trials and strategies in place for alternatives if they fail," Pazdur said. Companies "should be given the opportunity to complete two, three, four trials, or whatever might be needed to demonstrate clinical benefit."

Cancer drugs that fail in confirmatory trials prior to FDA clearance may still receive accelerated approval; "Just because the trials failed does not mean that the drug doesn't work," Pazdur said (³ (Also see "Oncologic Confirmatory Trial Failure Not Fatal To Accelerated Approval – FDA" - Pink Sheet, 17 Mar, 2003.), p. 13).

FDA expects that companies will exert "due diligence" to ensure the completion of postmarketing trials within a reasonable timeframe (see ⁴ (Also see "Cancer Drug Confirmatory Trials Should Be Initiated Early, FDA Says" - Pink Sheet, 24 Mar, 2003.)).

"Both the FDA and the sponsor should have a clear understanding of the regulatory burden, quote 'due diligence,' with periodic review of the timeline" because sponsors' "interpretation of 'due diligence' and my interpretation of 'due diligence'...may be different," Pazdur said.

Although, "we have to allow some degree of flexibility" for certain drugs because "there are some diseases obviously that are going to take a long time for accrual if they're a rare disease....We would not accept years to do a lung cancer trial," he added.

FDA plans to continue to use the forum of the oncology drug committee to place pressure on sponsors to meet their postmarketing commitments in a timely fashion. "I want basically this to be a recurring meeting," Pazdur said. "There is nothing more important than...public opinion to get people motivated to fulfill their commitments."

The oncology division accepts applications for accelerated approval for drugs that meet an "unmet medical need." Single-arm trials are accepted for diseases in which no therapy exists; randomized trials are required to demonstrate superiority over existing therapy, FDA said.

"Accelerated approval is not intended to be an alternative for a product that would not fulfill the criteria that has been established for full approval coming through an alternative mechanism," Oncology Medical Reviewer Steven Hirschfeld, MD/PhD, reminded sponsors.