PDUFA V nears final act

PDUFA reauthorisation is through the Congress and headed to the White House soon. After two years of wrangling over its shape, the legislation to re-authorise the user fees that finance the US drug review process has passed with relatively little debate, passing both chambers on overwhelmingly positive votes and containing both a carrot and a stick for drugmakers.

On the positive side, the legislation designates a new category of candidates called “breakthrough therapies” that would enable greater interaction between regulators and companies when promising treatments emerge for serious and life-threatening diseases. However, the bills also clarify the FDA’s ability to withdraw drugs granted licenses under accelerated approval if their safety and efficacy is not confirmed.

Clean document

In the big picture, the industry should be breathing a sigh of relief over the fact that relatively clean legislation has materialised. The last reauthorisation in 2007 codified the use of sometimes-burdensome risk evaluation and mitigation strategies (REMS) and other post-marketing safety scrutiny, driven by the 2004 withdrawal of the pain reliever Vioxx over increased cardiovascular risk.

This time, the fifth such renewal of the Prescription Drug User Fee Act, or PDUFA V, a specific catalysing event has not emerged. Thus, much of the focus in this renewal – the law expires every five years - has been improving interaction between the FDA and drug companies to avert first-cycle drug rejections and multiple application cycles.

The new law does not specify the new procedures for FDA to follow, but they were contained in accompanying performance goals the regulator agreed with the industry and published in advance of congressional action. The new procedures include a specific timeline of meetings to discuss outstanding issues, including a presubmission meeting to review a draft application followed by a 60-day review period before a drug is submitted (FDA sets out new PDUFA framework, January 16, 2012).

With a skilfully negotiated agreement, it is not surprising that Congress did not meddle too much in the performance goals as it drafted the legislation that mandates the drug submission fees – though oversight will undoubtedly follow. However, issues such as the worries about post-marketing studies of cancer drugs approved under accelerated appeals required new authority to address.


The withdrawal of Avastin in metastatic breast cancer, to which Roche objected and triggered a two-day hearing, no doubt drove the inclusion of provisions clarifying the FDA’s authority (Roche and FDA take logical next steps with Avastin, November 21, 2011).

No company had ever challenged an FDA request to withdraw a product before, so the two-day hearing of the oncology advisory committee demonstrated the need for clearer authority (Roche reaches end of Avastin appeal road, June 30, 2011). The House and Senate bills both would give the FDA administrator authority to withdraw with an opportunity for an “informal” hearing, but the shape of the hearing process will be left to regulation.

In the case of Avastin in breast cancer, the lack of evidence supporting a survival benefit and the life-threatening side effects were clear, prompting the agency’s action. The legislation goes even further, however; it also would give the administrator authority to withdraw accelerated approval drugs for which companies fail to complete confirmatory trials – a clear gauntlet thrown down after a review of missing clinical data last year (After Avastin FDA takes tough look at accelerated approvals, February 9, 2011).

Breaking through

Whilst tightening up perceived failings in the accelerated approval process, the bills also clarify the ability of the FDA to authorise a drug for accelerated approval based on effectiveness on endpoints that can be measured before and are reasonably likely to have an effect on disease progression or death.

They also seek to speed approval for some drugs by designating them “breakthrough therapies” for serious and life-threatening conditions. Drugs so declared would need to demonstrate in early clinical development substantial improvement over currently used therapies.

Designation as a breakthrough therapy would then allow for enhanced and expedited interaction with and advice from regulators on development of a clinical programme, including design consultation to minimise the number of patients exposed to compounds that may be less effective. As with the clarifications on withdrawal authority, specific procedures will be left to regulation that could take at least two and half years to develop; no doubt the specifics of this programme will be closely watched.

It is looking more like PDUFA renewal will be a relatively quiet affair, accomplished well before the September 30 deadline, the end of the federal fiscal year at which point the authority to levy fees on drug makers expires. With some more collaborative approaches proposed with the agency and new opportunities to accelerate candidates for unmet medical needs – counterbalanced by greater authority to withdraw approvals – drugmakers have gotten a pretty good result.

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