Regulatory Focus™ > News Articles > FDA, Industry Outline Impact of PDUFA V at 2012 RAPS

FDA, Industry Outline Impact of PDUFA V at 2012 RAPS

Posted 30 October 2012 | By Alexander Gaffney, RAC

Renewed every five years, the Prescription Drug User Fee Act (PDUFA) is one of the single most important and successful pieces of legislation affecting both the US Food and Drug Administration (FDA) and the pharmaceutical and biopharmaceutical industries.

The legislation, originally conceived and passed in 1992, operates on a relatively simple principle: in return for industry-paid user fees, FDA is responsible for hiring additional staff with which to review drug applications and meeting certain performance metrics.

After the success of the first PDUFA, dubbed PDUFA I, legislators worked with FDA and industry to pass four more iterations of the legislation:

  • PDUFA II, also known as the FDA Modernization Act, addedfaster review times for FDA to adhere to and more specific goals in return for additional user fees from industry;
  • PDUFA III, also known as the Bioterrorism Preparedness & Response Act, significantly increased funding to FDA in return for more interaction with regulators during the first review cycle;
  • PDUFA IV, also known as the FDA Amendments Act, increased funding yet again, this time in return for additional pre-market review by FDA and the institution of a more modernized post-market safety system.

The fifth iteration of the law, explained Beth Duvall, associate director for regulatory affairs at FDA's Office of New Drugs, raises the bar for both FDA and industry once more.

Speaking at the 2012 RAPS conference in Seattle, WA, Duvall said PDUFA V-passed as part of a larger package of legislation known as the FDA Safety and Innovation Act (FDASIA)-seeks to build upon the successes of the past while finding new ways to improve safety, regulatory science  and submission standards.

Industry to Enjoy Host of New Benefits-for a Price

Industry was consulted early on in the reauthorization process, and it expressed a number of concerns, including non-standardized Risk Evaluation and Mitigation Strategies (REMS) plans, a lack of communication with FDA, a lack of consistency and inefficient processes. FDA agreed with many of both patients' and industry's concerns, but expressed a now-familiar concern: a lack of funding and resources to devote to new approaches to assist industry and patients.

PDUFA V addresses both concerns, bringing in new funding for FDA in return for standardized REMS plans, increased use of FDA's Sentinel system to monitor adverse events, an enhanced and clarified risk-benefit framework, standardized electronic submission data, more communication with FDA staff, and more.

The biggest change for industry out of the list may in theory be the simplest: allowing industry to talk more frequently during the earlier stages of the review process for New Drug Applications and Biologics License Applications. Under PDUFA V, sponsors will be able to meet with FDA at what Duvall said were "key milestones," including pre-submission, mid-cycle and late-cycle. Staff will also be trained in best practices for communicating with industry, and FDA will eventually generate guidance for its staff on how to interact with sponsors.

Eventually, sponsors will also benefit from FDA defining a structured benefit-risk framework, though Duvall cautioned it would unfold over five years and involve a thorough consultative process. Other long-term goals, including new methods for conducting meta-analyses and developing new guidance for the development of therapies for rare diseases, are also included in the legislation.

Duvall said new standards for the submission of electronic drug submission data could be highly beneficial to sponsors and FDA alike. She highlighted electronic submissions from several different sponsors showing different ways of naming variables and files-variances that take time to sort out and understand. A standardized process could stand to benefit sponsors, she said, highlighting data showing electronic common technical document (eCTD) submissions are 12% more likely to receive approval than paper-based submissions. Correlation, it goes without saying, does not necessarily equate to causation for this observation, though Duvall said the data was controlled for various factors.

Review Times: More is Less

One of the most significant and wide-ranging changes under PDUFA V pertains to the review of applications. Duvall said the agency will be working under new timelines structured to provide sponsors with more opportunity to interact with FDA in return for an additional two months of review time.

"The program is structured to see if more review time and greater transparency in the review process can lead to greater review efficiency and decrease the number of review cycles necessary for approval …without changing FDA's approval standard," said Duvall. The goal, she explained, is to increase the number of first cycle approvals by improving the quality of regulatory submissions.

Under the new system, FDA's review clock will start 60 days after the filing of a submission, and sponsors will be able to access early-, mid- and late-cycle meetings with FDA to determine potential deficiencies or optimal strategies.

Sponsors will also be able to file 30-day late submissions for what Duvall called, "minor components," such as updated stability data or an audited, final version of a report presented in the submission in draft form. Submissions, noted Duvall, must not materially impact the review of the application. Duvall compared the submissions to cooking. Major components are similar to the core ingredients used to bake bread; without those ingredients, you cannot bake something. Minor components are like the bread's flavoring or toppings in that they help to further characterize the type and quality of the bread, but don't define it as such.

REMS: New and Improved

REMS plans are also set for an overhaul, explained Duvall.

Since the passage of the FDA Amendments Act of 2007 first allowed FDA to mandate the use of REMS, their use has been steadily increasing in frequency and complexity. FDASIA changes this by making the use of REMS more standardized, particularly within product and therapeutic classes. Duvall explained that FDA's goal under the new legislation is to reduce the burden that REMS present to industry, practitioners, patients and the healthcare system itself. Some practitioners complain, for instance, that the number of warnings and the way in which they are passed on to patients takes too much time.

In the future, said Duvall, the most restrictive REMS plans might include education and certification for prescribers, patient education and monitoring and the use of patient registries. More importantly, under PDUFA V, industry may engage in preliminary discussion of REMS during a pre-submission meeting with FDA. Those discussions will continue throughout the review cycle in mid-cycle and late-cycle meetings, explained Duvall.

Patients Come into the Fold

One of the newest changes under PDUFA V will be the more systematic and institutional inclusion of patients' perspectives in the drug review process, said Duvall. "Patients who live with a disease have a direct stake in the drug review process and are in a unique position to inform the analysis of severity of condition and current state of the treatment armamentarium," she said. "The review process could benefit from systematic approach to obtaining patient perspective on disease severity or unmet medical need."

These perspectives will be built into what Duvall identified as "patient-reported outcomes," or PROs.

This patient participation started with the negotiations over the language to be used for FDASIA, and is slated to increase in scope as FDA enacts the legislation. The agency recently launched consultations on more than 20 different disease areas, with plans to launch additional consultations in the near future. The goal, it said, is to understand the views of patients and their unique needs and understanding of the risk-benefit balance for their particular condition.

"The human drug and biologic review process could benefit from a more systematic and expansive approach to obtaining input from patients who experience a particular disease or condition," FDA noted in its Federal Register posting announcing the program.

Data Overload

But one of the most striking challenges for FDA regulators going forward may simply be dealing with the massive amounts of data and submissions it receives on a constant basis.

Between June 2011 and June 2012, observed Duvall, FDA received 557,917 electronic adverse event reports, more than 7,000 investigational new drug applications, and thousands more reports, supplements, and meeting requests. Just tracking this work is tremendously complicated, particularly when so many of them are attached to specific PDUFA V goals, explained Duvall.

Devoting resources to FDA's essential activities while avoiding superfluous ones was an important consideration to both industry and FDA, explained Duvall. In 2008, right after the passage of the FDA Amendments Act, FDA's new mandates actually caused its goal-achievement rate to drop compared to previous quarters. Whereas FDA had been able to approve approximately 91% of drug submissions on time in the first quarter of 2008, that number dropped to around 77% by the second quarter of 2009 before rebounding sharply.

Still, the cumulative results of the PDUFA iterations are undeniable. Duvall pointed to data showing  that since 1993, when PDUFA I went into effect, the median time to approval for new drug applications (NDAs) for new molecular entities (NMEs) and new biologic entities (NBEs) have plunged, going from 19 months to just 10. First-in-the-world drug approvals for the US, once languishing at around 10%, has increased to 60%, giving US patients first access to more than 1,500 new drugs and biologics.

Other Changes

Speeding up the development of new regulatory science tools is another top priority under FDASIA, panelists explained. New capacities to take in pharmacology, clinical and biomarker data are all a part of the new law, and FDA hopes especially to spur the use of biomarkers and pharmacogenomic markers to allow for cheaper, more effective trials. As it stands now, said Duvall, FDA just doesn't have the capacity to use much of the data. "Clinical trial designs employing biomarkers have increased over 280% over the last three years.  Current capacity permits reviewers to support only 50% of the workload from therapeutic review divisions," she explained. New funding should increase this capacity and allow regulators to use the data in more cases.

74-Day letters sent by FDA, used to describe deficiencies in a submission, will also now include a notice regarding whether sponsors can expect an advisory committee to review their respective application, as well as a planned review timeline and projected dates for mid-cycle meetings and advisory committee meetings.

These changes are going to take time, confirmed Duvall. "We're going to be convening a lot of meetings for things coming out of PDUFA V," she said.


Duvall also confirmed what many sponsors may already know anecdotally: Sponsors are increasingly focusing on the development of new drug products for rare diseases. Since 2000, when rare disease submissions numbered around 60 per year, submissions have nearly tripled in number to around 160 in 2009. More recent data was unavailable. The number of rare drug submissions approved, however, has remained relatively constant, averaging slightly below 20 per year since around 1998.

"While orphan product development has usually occurred at smaller companies, there is now increasing interest among large pharmaceutical companies," she explained. One example is Pfizer, whose newly formed Rare Disease Research Unit represents a clear-and large-investment in the rare disease area.


Duvall concluded by saying that while FDA and industry's ambitions under PDUFA V are ambitious, the contingencies and common-sense flexibilities built into the law should allow both sides to meet their obligations.

Congress, too, has a keen interest in both parties meeting their obligations under the law. Duvall explained that nearly any metric called for under the law will be tracked and reported to Congress. An outside auditing organization will also be charged with conducting several reviews of the program-both from an FDA- and industry-centric perspective-and reporting on it periodically.

In the meantime, said Duvall, much remains to be done.

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