Sponsors seeking insight into when a single-arm trial will be deemed acceptable support for accelerated approval by FDA and its Oncologic Drugs Advisory Committee can look to the recent review of Seattle Genetics’ Adcetris (brentuximab) for clues.

The biologic is the “poster child for a single-arm accelerated approval,” ODAC Chairman Wyndham Wilson, National Cancer Institute, declared during a July 14 session that garnered unanimous support for approval of the drug to treat two rare lymphomas (Also see "Seattle Genetics Hoping Adcetris Label Expansion Trials Can Be Confirmatory" - Pink Sheet, 18 July, 2011.).

At a February meeting, ODAC agreed with FDA’s push to have sponsors conduct randomized trials to demonstrate efficacy for accelerated approval (Also see "FDA Will Make Advisory Committee Review Of Accelerated Approvals An Annual Event" - Pink Sheet, 14 February, 2011.

The exception, committee members suggested, would be in the case of diseases with few patients and drugs with high activity. They did not define what level of activity is high enough.

While the panelists still have not provided numbers for this calculus, they have indicated they know success when they see it.

“This drug meets the criteria that we discussed back in February for a single-arm trial that could mean accelerated approval. It’s a rare disease, [has] a high level of activity and the toxicity profile is acceptable,” Mikkael Sekeres, Cleveland Clinic, said.

In the Adcetris trials, 73% of 102 patients with relapsed or refractory Hodgkin’s lymphoma following an autologous stem cell transplant achieved the primary endpoint of objective response; 86% of 58 patients with relapsed or refractory systemic anaplastic large-cell lymphoma met that same endpoint.

“The signal is extremely high. The results, I can tell you from my own viewpoint, are very, very good, and the high complete remission rate is extremely good,” Wilson concluded during the discussion of brentuximab for relapsed and refractory Hodgkin’s lymphoma.

PFS Could Be Appropriate Confirmation

The panel discussion also indicated ODAC members believe progression-free survival can be an appropriate endpoint in cancer trials.

PFS would be reasonable in confirmatory trials for Hodgkin’s lymphoma if the data were “very good,” Wilson said, while Julie Vose of the University of Nebraska found it only “adequate” in that patient population.

Sekeres, a supporter of overall survival as the appropriate endpoint in oncology trials, said he could be comfortable with “some sort of solid patient-reported outcome data that goes hand-in-hand with progression-free survival.”

Without a PRO measure, “progression-free survival alone is a pyrrhic victory,” he contended.

The importance of quality of life data to bolster the case for PFS data is one of the take-away messages from FDA's attempt to withdraw the breast cancer accelerated approval for Genentech’s Avastin. The agency made clear that having evidence of QoL or symptom relief would have helped support that the PFS benefit was clinically meaningful (Also see "Quality-Of-Life Data Take On Added Significance With Avastin Debate" - Pink Sheet, 18 July, 2011.).

Industry and venture capitalists have voiced concerns that applying a higher standard for use of single-arm trials and PFS is inhibiting investment (Also see "Accelerated Approval Remains “Viable Pathway,” FDA’s Woodcock Says" - Pink Sheet, 27 June, 2011.).

Schedule For Confirmatory Trials

Office of Oncologic Drug Products Director Richard Pazdur took the opportunity of the Adcetris review to drive home the agency’s commitment to ensuring that sponsors conduct a robust and timely set of trials to confirm the benefit of drugs approved under the accelerated pathway.

At the February ODAC meeting, he said FDA wanted to see a commitment to a multi-trial post-approval program and that the program should be enunciated prior to approval.

While directing his comments to Seattle Genetics about what is expected for brentuximab if it is to be approved by its Aug. 30 PDUFA date, Pazdur outlined what sponsors should bring to the negotiating table with regard to trial commitments.

FDA “really wants to see a comprehensive program, a portfolio of trials that the company may want to do, and have frank discussion on which trials make the most sense,” he said. “You should have timely well-thought out completion dates for these studies” even if it’s a set of trials, such as Phase I and then Phase II or Phase III, he noted. “These dates need to be confirmed, well thought out and be realistic.”

Citing authorities granted in the FDA Amendments Act, Pazdur pointed out, “there are penalties which you would be subject to if [deadlines] are not met.”

At the end of the day, he said, “we have to have a portfolio of trials that we feel fairly comfortable with, and one of these trials is going to answer the question. Here again, I don’t want to be back here in four years saying what’s going on with this drug?”

By Cathy Dombrowski

Adcetris Review Adds Some Clarity To Principles For Accelerated Approval

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