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December 20, 2012 10:36 pm

FDA, industry push to tweak accelerated approval pathway likely to have underwhelming results for mid-to-large pharma

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This article is provided to readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market.


A US Food and Drug Administration (FDA) plan to hasten approvals and improve FDA-industry coordination will likely have minor impact on mid-to-large pharma, four drug industry consultants told BioPharm Insight.

FDA is in the process of developing draft guidance on expedited drug development pathways including accelerated approval, said an FDA spokesperson. The guidance is expected by July 2013.

Agency staff involved in drafting the document attended the recent Friends of Cancer Research’s Conference on Clinical Cancer Research Conference in Washington, DC. The agency staff is aware of the ideas suggested by various speakers at the meeting, the spokesperson said, noting these and other ideas are being considered.

A panel at the conference proposed three changes, noted Dr Richard Schilsky, deputy director, Comprehensive Cancer Center, University of Chicago, who moderated the panel: use of new surrogate markers of clinical benefit as endpoints; a structured process to assess the use of adaptive clinical trial designs; and redefining unmet medical need to include any cancer for which available therapy is not curative, regardless of the line of treatment.

Mid-to-large pharma already comfortable

Consultants this news service spoke to said, for the most part, the accelerated approval paradigm is adequate. It is possible smaller companies could benefit but most mid-to-large pharma understand the process well, they added.

The proposed changes are “relatively pie in the sky,” said Gregory Dombal, chief operating officer, Halloran Consulting Group, Massachusetts. He disagreed with the underlying premise that FDA-industry discussion options are in need of repair.

Rather, Dombal noted, the lack of discussion transparency and industry’s generally inadequate clinical rigor are problematic.

The conventional requirements for accelerated approval are reasonably well understood across the industry, said an ex-FDA member and current drug industry consultant. Firms such as Roche (VTX:ROG), Merck (NYSE:MRK), GlaxoSmithKline (LON:GSK), Seattle Genetics (NASDAQ: SGEN), Onyx Pharmaceuticals (NASDAQ: ONXX) and Pharmacyclics (NASDAQ: PCYC) seem to have a good handle of regulations in the oncology space already.

Novartis (VTX:NOVN), ArQule (NASDAQ:ARQL), Curis (NASDAQ: CRIS) and other companies in the histone deacetylase space also seem to do well with the current process, Dombal added.

For smaller players, the consultant said, aspects that trip up applications include: decisions on which surrogate markers make for appropriate clinical trial endpoints and why; the most suitable settings for use of a surrogate to reflect clinical benefit; and the magnitude of effect size required for a surrogate to show clinical benefit.

A second consultant, also an ex-FDA member, noted changes could help small companies that do not have the resources to conduct randomized Phase III trials.

Surrogate endpoint scenarios

The idea behind asking for guidance on surrogate endpoints, Schilsky said, is to facilitate more rapid drug assessment.

All the consultants interviewed, however, noted guidance on new surrogate endpoints may be problematic. Without a somewhat definitive boundary for surrogate endpoints, the agency will be reluctant to use industry suggestions, noted David Lim, a Virginia-based regulatory consultant. Current regulations allow endpoint flexibility and enable the FDA to judge whether a drug is acceptable for accelerated review, said the second consultant.

The pharma industry has failed in a myriad of attempts to demonstrate that surrogate endpoints correlate with clinical benefit, Dombal said. Industry would like clinical benefit to mean response rates or progression-free survival (PFS), while the FDA strongly prefers overall survival as a measure of clinical benefit.

“Time and again, studies have failed to validate clinical benefit is achieved with early suggestions of success from surrogate endpoints,” he added, noting the example of Roche/Genentech’s Avastin (bevacizumab).

Guidance on surrogate endpoints is a good step in theory, but the Avastin experience makes the FDA shy of any surrogates, so it will be difficult to get firm agency commitments, agreed Linda Pullan, founder of her California-based eponymous drug consulting firm.

Avastin was approved for breast cancer based on PFS data. FDA-mandated post-approval studies, however, showed only a small effect on tumor growth without evidence that patients lived longer or had a better quality of life, leading to the breast cancer indication being revoked.

Adaptive development debate

The panel also called for a prospective, structured process for FDA and sponsors to reach agreement early in clinical development as to whether accelerated approval is a goal and what the most appropriate endpoints and study design would be, Schilsky noted.

Prospective agreement on accelerated approval already exists, Dombal said, noting the Fast Track process is designed to ensure that a product is targeted early on for accelerated approval.

Agreement on endpoints and study design for approval is granted at any point via Special Protocol Assessment (SPA).

“However, industry has too often not delivered data of adequate quality and then expected FDA to approve the product, weakening the utility and effectiveness of the existing SPA process,” Dombal added.

While laying out specific meetings may be helpful, the second consultant noted, the FDA will be reluctant to tie down, as industry would like, upfront, ironclad agreements on trial designs and sponsor expectations. The comparator standard of care may change over several years, so the agency likes to retain flexibility, he added.

The FDA does not encourage an adaptive clinical development plan, as early data often is not convincing that the drug will actually work, Dombal said. Adaptive clinical trials would be a big change in FDA-industry relations but probably very complex to implement, Pullan noted.

Unmet medical need

With regard to broadening the definition of “unmet medical need,” Schilsky said, “doing so would facilitate studies of new agents in less heavily pretreated patients and still hold open the possibility that accelerated approval could be granted.” Many cancers are curable when diagnosed at an early stage, he noted. Among metastatic cancers, certainly advanced testicular cancer is curable with chemotherapy, he added.

The whole point of expanding the definition is that most advanced cancers are not curable with currently available therapies, Schilsky said. “Anyone who thinks these are minor changes either doesn’t understand the current process or doesn’t understand our proposal,” he added.

The term “not curative,” Dombal noted, would by definition mean all oncology treatments perhaps with the exception of some specific surgeries. The nature of cancer, specifically when cellular or genetic aberrations affect the pathways that drive cell anchoring, adhesion and migration, means that “sleeper” tumors could exist whenever even a single tumor cell has broken off and lodged elsewhere, he explained.

Unmet need redefined as including any line of therapy might accelerate approval in crowded areas such as non-Hodgkin’s lymphoma (NHL) or colorectal cancer, said Pullan.

The change could also mean that sponsors do not have to expend resources to attain a truly refractory relapsed patient population, which can be a tiny number of very sick patients, she added.


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