The resource-draining experience of revoking Avastin’s breast cancer claim means that any new expedited or “progressive approval” pathway should include a quicker, easier withdrawal mechanism, according to Center for Biologics Evaluation and Research Director Karen Midthun.

Speaking at Elsevier Business Intelligence’s FDA/CMS Summit on Dec. 8, Midthun suggested that the agency’s resources should be taken into consideration when it comes to creating a mechanism to quickly revoke approval of drugs licensed under new regulatory pathways, which are being considered under reauthorization of the Prescription Drug User Fee Act.

The Avastin hearing process “required tremendous resources and time,” CBER’s Midthun said.

Midthun served as presiding officer at the two-day hearing in June on the Center for Drug Evaluation and Research’s proposed withdrawal of Avastin’s (bevacizumab) accelerated approval for metastatic breast cancer. Midthun said she believes the hearing process was fair, open and functioned as intended, Nevertheless, “it clearly was a process that required tremendous resources and time,” she said of the formal regulatory dispute that lasted almost a year.

This burden should be taken into consideration amid growing calls for creation of a new progressive or expedited drug approval pathway, Midthun said, suggesting the need for a more abbreviated withdrawal process than played out in the Avastin matter.

A First-Of-Its-Kind Proceeding

The 11-month saga over Avastin’s MBC claim began in December 2010, when CDER proposed to revoke the indication due to the failure of two post-marketing trials to confirm the 5.5-month improvement in median progression-free survival seen in the study upon which accelerated approval was granted in 2008. Avastin’s sponsor, Genentech Inc., opposed CDER’s proposal. Under the accelerated approval mechanism, the company requested a hearing in front of the commissioner.

FDA Commissioner Margaret Hamburg granted Genentech’s hearing request and tapped Midthun to serve as her designee for the process ([A#14110224007 ]).

In that role, Midthun ruled on disputes between CDER and Genentech over hearing procedures and the types of evidence that could be introduced at the proceeding. She presided over the June hearing that was at times raucous and interrupted by outbursts from patient advocates who supported keeping the claim on-label. At the conclusion of the hearing, the agency’s Oncologic Drugs Advisory Committee voted 6-0 in favor of revoking the indication. Hamburg followed with a decision to withdraw Nov. 18 Also see "Avastin Loses Its Breast Cancer Claim; FDA’s Hamburg Opts For Withdrawal Over Restrictions" - Pink Sheet, 21 November, 2011..

Avastin marked the first time a sponsor had moved forward through the hearing process with a challenge to CDER’s proposal to withdraw accelerated approval of an indication or drug.

Shire PLC requested a hearing on CDER’s proposed withdrawal of accelerated approval for the hypotension drug ProAmatine (midodrine) in September 2010, three months before Genentech filed its hearing request. Although Shire’s request is still pending, the company and CDER recently agreed upon a plan for new confirmatory trials of midodrine. If Hamburg accepts the joint proposal, it would negate the need for a hearing Also see "Not The Next Avastin? Plan For New ProAmatine Studies Would Negate Shire’s Withdrawal Hearing Request" - Pink Sheet, 19 December, 2011..

Resources, Resources, Resources

At the FDA/CMS Summit, Midthun was asked how she thought the Avastin hearing process played out and whether there would be any lasting impact on the accelerated approval mechanism.

“I think that the process played out the way it was intended,” Midthun responded. “It’s the first time we actually went through that process. I think we learned a lot from it.”

Although her remarks about Avastin were fairly brief, what is striking are Midthun’s repeated references to the intensive workload created by the hearing process. Three times during her remarks she sought to describe the resource strain created by the withdrawal process.

“I think that we would all agree it’s important to be able to have input, but it also is very, very resource intensive, and I think it’s something to think about if we contemplate perhaps a path where we would anticipate having more products approved under accelerated approval or perhaps more products through some other potential pathway.”

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Midthun’s latter reference stemmed from an earlier panel discussion involving Office of New Drugs Director John Jenkins about progressive approval, a concept embodied in legislation drafted by Sen. Kay Hagan, D-N.C. Hagan’s measure is aimed at speeding approval of drugs that provide a meaningful advancement in the treatment of serious or life-threatening diseases through the creation of new regulatory pathways for progressive and exceptional approval Also see "FDA “Progressive Approval” And “Exceptional Approval” Pathways Possible Under Senate Bill" - Pink Sheet, 14 November, 2011..

The Hagan measure is reflective of growing momentum, both outside and within the agency, for new approval systems to speed novel drugs to market. FDA’s Innovation Initiative calls for development of an expedited approval pathway for drugs that show exceptional promise in early studies, and agency staff have been involved in the development of various proposals for shortening drug development time Also see "Expedited Approval Pathway Concept Draws Strong Support But Different Proposals" - Pink Sheet, 5 December, 2011..

Under Hagan’s proposal, a sponsor still would have the opportunity to request a hearing on proposed withdrawal of a drug licensed under the progressive or exceptional approval mechanisms. If the request is granted, the sponsor would have the option of deciding whether the hearing should include a standing advisory committee.

The legislation appears to require that a final decision on withdrawal be issued within 180 days of the sponsor’s initial challenge. Had this timeline been applied in the Avastin case, this would have meant a ruling on the MBC claim by late June, cutting five months off the process.

The expedited withdrawal process envisioned under the Hagan measure still may not do enough to lessen the resource drain on FDA.

Current FDA regulations governing accelerated approval withdrawal procedures do not impose a deadline for a final decision. Although the process envisioned under the Hagan measure would move faster than was the case with Avastin, the proposal still may not do enough to lessen the agency’s resource burden.

“I think that we need to think about, if you have an accelerated approval, then you should also be able to have a mechanism for accelerated withdrawal,” Midthun said. “It does take a lot of resources and I think that’s also something that we need to think about.”

The resource burden involved in conducting evidentiary hearings appears to be a growing concern for the agency.

In a recent submission to Hamburg, CDER argued that postponing a decision on Ista Pharmaceuticals Inc.’s request for a hearing on its rejected Bromday application until after a February advisory committee meeting would be “most consistent with the efficient use of limited agency resources” ([A#14111205002 ]).

Genentech To Midthun: “Thank You”

Midthun’s role in the first-ever accelerated approval withdrawal proceeding won plaudits from the party on the losing end.

At the conclusion of Midthun’s remarks at the FDA/CMS Summit, Genentech VP-Regulatory Affairs Michelle Rohrer introduced herself from the audience, explaining that she led the Avastin hearing team.

“Certainly Genentech didn’t take the decision to go to a hearing lightly,” Rohrer said. “I wanted to personally thank you on behalf of the company for the integrity that you brought to the entire process. We very much are in your debt.”

“Thank you very much,” Midthun responded. “I really thought that everyone really brought tremendous thoughtfulness to the process, and I’m very grateful that was also how you also perceived it because I think we really tried very hard to make sure that it was a fair and open process.”

Elsevier Business Intelligence, the conference sponsor, is also publisher of The RPM Report and "The Pink Sheet."

Avastin’s Legacy May Be Quicker Withdrawal Process For New Approval Pathways

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