FDA is changing its accelerated approval guidelines to allow for approval of several different oncologic agents for the same indication under Subpart H procedures, Commissioner McClellan said during the American Society of Clinical Oncology annual meeting in Chicago May 31.

The reinterpretation will allow sponsors to claim that an agent treats an "unmet medical need" even if other drugs have been approved for the same population under accelerated approval.

Only when an agent confirms clinical benefit in Phase IV trials will the indication no longer qualify for Subpart H.

FDA has adopted "a change in our accelerated approval guidelines so that for cancer drugs that have met accelerated approval, other products will also be able to get accelerated approval status for that indication until one of these therapies actually demonstrates in its Phase IV study commitments a confirmatory clinical benefit in patients," McClellan said.

The reinterpretation ensures that accelerated approval is not a de facto award of market exclusivity that could result in discouraging research (¹ Also see "FDA Accelerated Approval Review Asks If Reg Gives De Facto Exclusivity" - Pink Sheet, 20 January, 2003., p. 21).

The more immediate impact will be to simplify the potential approval pathway for several late-stage oncology agents, including Bristol/ImClone's Erbitux (see ² Also see "Erbitux BLA Resubmission Plan Set; Will Test Accelerated Approval Rules" - Pink Sheet, 9 June, 2003.).

In addition to making it easier for some therapies to enter the market, the new approach to oncology approvals should help encourage sponsors to complete postmarketing studies in a timely fashion, McClellan told ASCO.

With this change, FDA will have "Phase IV studies completed on indications where new treatments don't exist," he said.

The commissioner has repeatedly emphasized the importance of a reliable postmarketing program to allow sponsors and FDA to work on reducing the pre-market drug development timeframe.

McClellan told the Pharmaceutical Research & Manufacturers of America annual meeting, for example, that the time has come for industry to take Phase IV "seriously" (³ Also see "Rx Industry Must Take Phase IV “Seriously,” Commissioner Tells PhRMA" - Pink Sheet, 31 March, 2003., p. 11). FDA also recently launched a long-planned website to publicly track the progress on Phase IV commitments (⁴ Also see "FDA Launches Phase IV Tracking System; Baseline Is 20% Completion Rate" - Pink Sheet, 26 May, 2003., p. 3).

The concerns about postmarketing confirmatory trials are particularly acute in oncology, where only four of the 15 anticancer agents approved under Subpart H have completed Phase IV studies confirming clinical benefit.

A March meeting of the Oncologic Drugs Advisory Committee highlighted the need for an incentive or enforcement mechanism to ensure that sponsors complete Phase IV commitments for anticancer agents (⁵ Also see "Accelerated Approval Needs Enforcement Mechanism For Confirmatory Trials" - Pink Sheet, 24 March, 2003., p. 30).

McClellan also used the ASCO podium to announce an inter-agency collaborative agreement between FDA and the National Cancer Institute intended to accelerate development of cancer therapies (⁶ 'The Pink Sheet' June 2, 2003, In Brief).

One aspect of the agreement will be the involvement of NCI in funding Phase IV trials, McClellan noted.

In addition, the two agencies will work together to develop new biomarkers in oncology that could further expand the use of the accelerated approval process.

"We think the NCI's support for developing methods that can improve our understanding about the relationship between potential biomarkers that can be observed relatively early in the clinical development process and clinically important endpoints - both important outcome benefits as well as risks in the clinical setting - can help our regulatory activities a lot," McClellan said.

Pharmacogenomics "is still really in its infancy and there's a ton of information out there and we don't really have any clear idea of what it means for regulatory decision implications....So our hope is that by pooling our efforts in collaboration we can eventually, sooner rather than later, permit better-targeted, less costly, more efficient clinical testing."

"We're working on this now thanks to some ASCO co-sponsored workshops to assess the evidence that exists today on potential surrogate endpoints with the goal of developing clear guidance about efficient pathways of regulatory approval for the major solid cancers," McClellan noted (⁷ Also see "“Underpowered” Cancer Trials Are Becoming “Major Problem” – FDA’s Pazdur" - Pink Sheet, 21 April, 2003., p. 25).

FDA Oncology Drug Products Division Director Richard Pazdur, MD, speaking during an ASCO session later the same day, stressed that the effort to develop new biomarkers should not be viewed as a move away from gold-standard clinical endpoints.

"Although we should be willing to accept new targets, new surrogate endpoints, new mechanisms of action...ultimately the success of any therapy will eventually be measured by clinical outcomes. Do our patients live longer or do they have a better life?" Pazdur said.

"Although our therapies may be aimed at a target, we are not treating the target. We are treating the patient whose goals and aspirations are for cure, prolongation of life or a better life. If we cannot identify a population via a target who will preferentially respond to a given therapy, then we truly do not have a clinically relevant target," Pazdur said.

Developing validated biomarkers is in concert with the broader goal of the collaboration outlined by McClellan and NCI Director Andrew von Eschenbach to expedite the entry of new anticancer drugs into the market.

"I'm concerned that we are not seeing as many drugs approved in recent years as we have in the past," McClellan said. "The joint task force that we are announcing today is going to improve how our agencies work together to achieve this goal of getting safe and effective treatments to patients as quickly as possible."

FDA cited its collaboration with NCI as aiding in the approval of Millennium's multiple myeloma agent Velcade (bortezomib) as a recent example (⁸ [A#00650200001], p. 3).

The collaboration is "going to build on each agency's strength in fulfilling their mission and it's going to help improve the knowledge base for our approval standards and especially help support the translational research and post-approval studies that we need to improve our ability...to make regulatory decisions about safe and effective treatments," McClellan said.

"Our regulatory standards are an important influence on the entire technology development process." FDA can move "the process of technology development along by making sure that our regulatory methods keep up with changing technologies," McClellan said.

In addition to developing validated biomarkers, the FDA/NCI collaboration is seeking to create a broader bioinformatics database that will provide FDA with a "much stronger science base" when making regulatory decisions, the commissioner said.

The goal is "to create an overarching and more inclusive bioinformatics platform that can capture and integrate data in clinical research across all of the sectors of the development process," McClellan said.

The database would have information "from the initial preclinical testing of micro-array models to actual clinical testing in the studies that lead up to product approval decisions [and] to postmarket evaluation of actual use of treatments in patients in real world settings," McClellan said. "That will create a much stronger science base, a much stronger knowledge base for regulatory activities."

"NCI has made a tremendous investment already in developing electronic information systems that help FDA get information in the kinds of ways to understand information appropriately on adverse events that occur in clinical trials in Phase II and Phase III," McClellan noted.

"Recording medical information in a standardized way helps us do our job and we can expand that effort to include other parts of the clinical development process, giving us a more extensive knowledge base to use both for approval decisions and for effective postmarket monitoring of patient care."

FDA and NCI also are exploring "representation upon each other's advisory boards and we are also exploring joint training and joint appointment programs."

Cancer drug development appears to be of great interest to the commissioner. When McClellan "was finally confirmed by the Senate at 10 o'clock on Thursday night...at 9 a.m. the next morning he welcomed me into his office" to talk about the issue, von Eschenbach, MD, said during the ASCO plenary session.

FDA Revising Accelerated Approval Standard In Oncology; Biomarkers Sought

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