Lessons From Avastin: Accelerated Approval Needs “Easy On, Easy Off” Mechanism, Pazdur Says

FDA’s oncology office director says the resource-intensive hearing process for withdrawing bevacizumab’s breast cancer claim demonstrates that it is “untenable for a large number of drugs.”

Any reforms aimed at making it easier for drug sponsors to pursue accelerated approval should be accompanied by changes that make it easier for FDA to withdraw drugs when post-approval trials fail to confirm clinical benefit, Office of Hematology and Oncology Products Director Richard Pazdur said at the Conference on Clinical Cancer Research Nov. 14.

Speaking from the audience during a panel discussion on ways to expand the use of accelerated approval, Pazdur said FDA’s experience in withdrawing Avastin’s (bevacizumab) breast cancer claim makes clear that such a cumbersome system needs streamlining if the approval pathway is opened up to more drugs.

In December 2010, the Center for Drug Evaluation and Research determined that accelerated approval of the breast cancer claim for Genentech Inc.’s VEGF-inhibitor should be withdrawn due to a failure to confirm clinical benefit in subsequent studies. However, Genentech opposed CDER’s proposed withdrawal and requested a hearing in front of the commissioner.

Center for Biologics Evaluation and Research Director Karen Midthun served as the presiding officer during the two-day hearing in June 2011, and Commissioner Margaret Hamburg issued her decision in November 2011 ordering the claim withdrawn (Also see "Avastin Loses Its Breast Cancer Claim; FDA’s Hamburg Opts For Withdrawal Over Restrictions" - Pink Sheet, 21 Nov, 2011.).

The Avastin dispute marked the first time that a sponsor had moved forward through the hearing process provided under the accelerated approval mechanism. Midthun has publicly described the proceeding as a resource-draining experience and urged that any new expedited approval pathway include a quicker, easier withdrawal mechanism (Also see "Avastin’s Legacy May Be Quicker Withdrawal Process For New Approval Pathways" - Pink Sheet, 19 Dec, 2011.).

Pazdur echoed those remarks at the Nov. 14 conference. “If we talk about liberalizing accelerated approval, I want to make a plea that we also address the end side of this, how to get drugs off the market in an easy fashion – easy on, easy off that doesn’t really require a tremendous amount of resources,” he said.

The agency has been able to negotiate with most sponsors to remove accelerated approval drugs from the market when confirmatory trials are negative, Pazdur said. However, the Avastin dispute demonstrated that the hearing process for withdrawing accelerated approval “is untenable for a large number of drugs. It just consumes too much time of the agency to really adhere to that type of process. So we need an easy-off type of thing, and that has to be accomplished by some legislative changes.”

Pazdur said the oncology review division has occasionally asked sponsors to “to put in writing that they will waive their right to a hearing” when evaluating whether accelerated approval would be appropriate on the basis of data that is “relatively tenuous.”

After his remarks at the conference, Pazdur told “The Pink Sheet” this practice began before the Avastin proceeding and the request has been made of only two or three sponsors, all of whom have agreed. “It’s not a routine thing,” Pazdur said, adding that it’s a way of letting sponsors know the agency has concerns about the sufficiency of the data. The drugs that have been the subject of such agreements remain under development, he said.

“Carrots” Needed To Encourage On-Time Studies

Pazdur also cited the need for new incentives that encourage sponsors to conduct confirmatory trials in a timely fashion.

“What is the company’s reason for a timely completion of a study if they know we’re not going to take the drug off the market? None,” Pazdur said. “And in fact if they have a marginal drug it’s even more important for them to drag this out as long as possible until their patent life expires, potentially.”

He suggested that legislative changes on marketing exclusivity or drug pricing could provide a “carrot” for speedier completion of confirmatory trials. “A carrot has to occur,” he said. “It’s not just the stick. … The companies will figure a way to get around the stick. It’s always better to have a carrot that makes them want to do the trial.”

Richard Schilsky, University of Chicago, said the answer may rest in changes to reimbursement policies for off-label use.

“If somehow we got to a point where the reimbursement was time-limited until the confirmatory trials were completed, that would probably push the completion of those trials much more quickly,” Schilsky said. “When the drug use can be reimbursed across any line of therapy and any indication once it’s out there in the marketplace, there’s really no incentive for a sponsor to get these trials done.”