PDUFA V Changes To Speed Drug Development and Approvals

With the FDA Safety and Innovation Act (FDASIA) of 2012 now a year old, Food and Drug Administration officials are busy implementing its provisions that offer new approaches to clinical trial design and application review. A change in review timelines adopted in the latest Prescription Drug User Fee Act (PDUFA V) reauthorized by FDASIA, promises to save time and money for all parties. The squeeze on federal government budgets may slow development of some important programs, but regulators and sponsors are working hard to establish new models that streamline regulatory procedures.

Right the first time

A main thrust of PDUFA V is to approve more applications in only one review cycle, instead of rejecting a filing until the sponsor answers questions raised during the review process. Initial reviews by the Center for Drug Evaluation and Research (CDER) may take longer—60 days were added to the first-cycle review clock—but there should be fewer "complete response" letters with requests for data that can take months, if not years to fulfill.

This policy overrides the initial PDUFA program, which set tight deadlines for application reviews to overcome "drug lag" with a then-speedier European review process. Now the agency believes that achieving more first-cycle approvals, even if some come a little late, is a more productive approach, explained Theresa Mullin, Director of CDER's Office of Planning and Informatics, at the DIA/FDA Statistics Forum in May.

The program offers incentives for sponsors to file more complete applications to begin with, and for FDA to articulate clearly its requirements and expectations. That extra 60 days gives agency reviewers time to ensure that an application meets all basic requirements when it comes in and that major amendments should not be necessary.

An analysis of 862 applications reviewed by CDER from fiscal years 2003 to 2009 shows that the agency increased first cycle reviews by allowing some applications to miss the PDUFA review goal and thus be labeled "late." Applications that received a first-cycle but late approval, Mullin explained, are more likely to be priority applications that require a Risk Evaluation and Mitigation plan, advisory committee review and/or postmarketing studies.

Tight review timetables bear some responsibility for the decline in first-cycle reviews by making it more difficult to resolve issues upfront, agreed Jay Siegel, Chief Biotechnology Officer and Head of Global Regulatory Affairs at Janssen. He is optimistic that FDA-sponsor meetings during the review process will address application shortcomings and avoid complete response letters. The new program, Siegel noted, reflects "increased trust" by sponsors that FDA will "act in good faith to expedite issue resolution and approval."

Industry and FDA are watching this experiment closely. An independent assessment by the Eastern Research Group will evaluate application completeness and amendments submitted by sponsors; timing and adequacy of FDA communications; and the percentage of applications approved in the first cycle, including those with review clock extensions. However, it may be tricky to assess the success of the new review model, Siegel acknowledged, because first-cycle reviews already began to move up under PDUFA IV. An interim assessment due March 31, 2015 will be discussed at a public meeting, as will the final assessment set for the end of 2016.

Setting standards

Expeditious review is more likely for applications filed according to a standardized electronic format, such as the electronic Common Technical Document (eCTD). Mullin noted that eCTD applications had a 12% higher probability of approval in the first review cycle, compared to filings in other formats. Although many applications now adopt the CTD standard, she pointed out that there still is great variability and unpredictability in application structure and content, which creates "a major obstacle to timely, consistent, and efficient review within the PDUFA timeframes." Standard e-submissions should help FDA reviewers locate needed data in the document—just as it's easier to shop in a familiar supermarket, Mullin commented.

To move towards the e-submission process for all applications authorized by FDASIA, FDA issued a draft guidance in January on standards and format of e-submission applications, setting the stage for a final document by year-end. The aim is to achieve all-electronic submission of NDAs, BLAs, and supplements two years later, and for all original INDs in another year.

To support this process, FDA is collaborating with several organizations developing data standards for clinical terminology for a number of distinct therapeutic indications. Data standards are critical for eliminating the "regulatory Tower of Babel," where each applicant speaks its own scientific "dialect," observed Steven Wilson, Director of the Division of Biometrics III in CDER's Office of Biostatistics. He and other FDA statisticians are seeking consensus on the use of meta-analyses, biomarker validation, and pre-qualification of patient reported outcomes to improve the clinical trial process.