FDA’s accelerated approval program is alive and well now, and will remain a viable pathway in the future, despite concerns within the industry and investor communities that recent oncology regulatory actions are hastening the program’s demise.

That was the message delivered by Center for Drug Evaluation and Research Director Janet Woodcock at a June 16 Friends of Cancer Research briefing. The briefing was held to discuss the non-profit group’s study showing that new cancer medicines are approved faster and earlier in the U.S. than in Europe.

However, the setting provided Woodcock an opportunity to offer a timely defense of CDER’s regulatory performance in the oncology setting, which includes a shift toward tighter pre- and post-approval requirements for accelerated approval, less than two weeks before the agency’s June 28-29 hearing on the proposed withdrawal of Avastin’s metastatic breast cancer indication.

Avastin was not mentioned during the briefing. However, both CDER and Genentech have said the integrity and future of the accelerated approval program are inextricably linked to the agency’s ultimate decision on Avastin’s MBC claim (Also see "Accelerated Approval Program’s Future Is On The Line At Avastin Hearing" - Pink Sheet, 23 May, 2011.).

Future Focus On Targeted Therapies

Woodcock made clear that she sees a role for accelerated approval in oncology.

“I think we will continue to consider accelerated approval a very viable pathway,” particularly for targeted therapies, the CDER director said.

Her remarks came in response to comments by Warburg Pincus Managing Director Jonathan Leff, who cited “tremendous concern” within the industry and investment community about the accelerated approval program’s future.

The program’s success, Leff said, can be seen in the results of the Friends of Cancer Research study, published in the July issue of Health Affairs.

Seeking to examine criticisms that FDA is slower and less efficient at reviewing drugs than the European Medicines Agency, the group compared review times for new oncology drugs at FDA and EMA from 2003-2010. The study focused on initial approvals of new molecular entities and novel biologicals for active treatment.

Of 35 new oncology drugs approved by either regulator during the time-frame examined, FDA approved 32 of the products, with a median review time of 182 days from the date of submission to approval. EMA approved 26 products; the median time between application submission and issuance of a positive opinion was 350 days.

Among the 23 drugs approved by both agencies, all were available in the U.S. first.

The results are consistent with an earlier FDA analysis across therapeutic areas (Also see "PDUFA Performance In The FDAAA Era: Over One Third Of Novel 2009 CDER Approvals Took Advantage Of Relaxed User Fee Goal Interregnum" - Pink Sheet, 1 January, 2010.).

Commenting on the differences in the FDA and EMA approval numbers, Leff said: “It strikes me that the most important take-away there is that the accelerated approval pathway has worked and has worked well for oncology.”

More than half of the 32 cancer drugs approved by FDA came through accelerated approval, and more than 10 were approved on the basis of single-arm studies, he said. “Europe has not quite been able to apply that flexibility in looking at data in the oncology area.”

A conditional approval scheme was introduced in Europe in 2006; it only applies for products with unmet medical need among other criteria, and must be renewed based on annual reviews of the risk/benefit equation. Use of the pathway, however, is rare.

Unsettling “Signals” Of Change

Despite the accelerated approval program’s track record of success, industry and investors are questioning the pathway’s reliability going forward.

FDA signals about future regulatory changes are a “major deterrent” to investment in cancer drug development, Leff said.

“There are signals that people have focused on, rightly or wrongly, coming out of the agency suggesting that single-arm studies and some of the endpoints that have been the key to the accelerated approvals, like progression-free survival, might be subject to a different kind of scrutiny and a higher standard in the future than in the past, and that is a major deterrent to making new investment in the area,” Leff said.

Leff’s comments refer to recent moves by the Office of Oncology Drug Products and the Oncologic Drugs Advisory Committee to toughen the pre- and post-approval requirements for accelerated approval drugs.

At a February meeting, ODAC members generally sided with FDA in favoring randomized trials for accelerated approval, although they said single-arm studies are acceptable if the drug has a strong effect and is targeted at a small patient population. The committee also supported more rigorous post-approval requirements (Also see "FDA Will Make Advisory Committee Review Of Accelerated Approvals An Annual Event" - Pink Sheet, 14 February, 2011.).

Leff’s comments also reflect FDA’s growing unease with PFS as a clinical trial endpoint in certain cancer settings. Nowhere is this more evident than with Avastin in MBC. Absent a demonstrated improvement in overall survival or quality of life, the agency has questioned the magnitude of benefit and clinical importance of the VEGF inhibitor’s PFS advantage.

The failure of two trials, AVADO and RIBBON1, to confirm the 5.5-month median PFS benefit seen in the pivotal E2100 study spurred CDER’s proposal to withdraw Avastin’s MBC claim.

“What I’d love to see is for us to focus on what has worked,” Leff said. “Accelerated approval is one of those things in oncology that’s really worked. Let’s try to do more of it. Let’s try and broaden it out and have a conversation about conditional approval or a staged approval process that allows us to make that work even better and even faster in getting important drugs to patients.”

Woodcock said that single-arm studies using historical controls and clinical trials using PFS endpoints remain a viable basis upon which to seek accelerated approval, depending upon the disease setting and the drug effect seen.

“I think we will continue to use historical controls,” she said, with the caveat that such controls are not appropriate “when you’re seeing a very small effect, because you really, honestly, have no idea whether or not a drug works.” The time lapse between the historical data used and the conduct of single-arm studies also can affect reliability of the comparison, she said.

While she left the door open to use of the PFS endpoint, Woodcock noted that it typically does not represent a symptomatic benefit but, rather, a radiological finding. FDA needs to have confidence that a PFS endpoint will actually predict clinical benefit in the form of survival or symptomatic improvement, she said. “That’s our gold standard. We have some confidence in patient benefit, not their x-ray.”

Eying I-SPY As A Protype

Woodcock suggested that changes in the way drugs are developed, rather than a relaxation of FDA approval standards, are needed to restore investor confidence in the sector. Increased used of large screening trials, such as the I-SPY 2 trial in breast cancer, would bring more efficiency into the drug development process, she argued.

I-SPY2 is a five-year, adaptive clinical trial that began in March 2010 under the sponsorship of the Foundation of the National Institutes of Health’s Biomarkers Consortium. The study will test a dozen oncology candidates from several companies in women with high-risk breast cancers, either advancing the compounds or eliminating them after six months.

Graduated candidates will be returned to their sponsors for Phase III study in a targeted population (Also see "Biomarkers Consortium Launches Adaptive Trial To Test Targeted Breast Cancer Drugs" - Pink Sheet, 19 March, 2010.).

While traditional Phase I-III drug development programs take years and include large gaps of time in between phases, screening trials like I-SPY would move the field toward an “industrialization” of clinical trial drug development, making it a more efficient process, Woodcock said.

By Sue Sutter

Accelerated Approval Remains “Viable Pathway,” FDA’s Woodcock Says

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