Starting to implement a law before it is signed sounds dangerous. Just suggesting the possibility has an insidious undertone; but, in the case of some recent actions by the FDA in advance of the Prescription Drug User Fee Act reauthorization, it looks more like a sign of the wise use of the full PDUFA process to manage the agency efficiently.

In several areas, FDA has begun processes that are well within its current authority so that it will be ahead of the game when PDUFA V is signed. The agency is moving on some areas flagged by industry during the pre-legislative negotiations in 2010-2011.

The early changes highlight that the PDUFA process works on several schedules: the one that is most closely observed – and even charted for performance goals – is the one determined by the eventual legislative action; but there is also the impact of the negotiating process from which FDA learns from sponsors what processes or policies are causing delays and/or confusion. Preparing for PDUFA and listening to the outside, industry stakeholders becomes almost as important as the Capitol Hill process.([A#2010500119])

Four key areas of FDA’s pre-PDUFA reforms are in REMS evaluations; patient involvement in the pre-approval process; targeted enhancements for rare disease research; and changes to the NDA review deadlines.

FDA is getting underway on the first threeissues by holding open public meetings: a workshop on the social science methodology for REMS evaluations on June 7; the inaugural Patient Network meeting on May 18; and a workshop on the natural history studies for rare diseases on May 16-17.

All three initiatives are specifically described in the core of the PDUFA proposal, FDA’s agreement letter from the negotiations with the drug industry. (See chart for a list of policy deadlines set by the goal letter.)

For example, to clarify the goals and objectives of REMS evaluations, FDA committed in the agreement to have “one or more” workshops on the topic by September 30, 2013, to be followed by a guidance by September 30, 2014.

The June 7 workshop gets the agency off to a prompt start. The REMS assessment issue is a complex new field for FD,A essentially asking the agency to set up a methodology for determining the effectiveness of education and communication programs analogous to its process (developed over 50 years) for determining the adequacy of premarket efficacy determinations. Also see "FDAAA Impact Analysis (Year 4): The REMS Retreat Continues - For Now" - Pink Sheet, 29 May, 2012.

Patient Engagement a Priority in PDUFA V

Similarly, on the rules of engagement for bringing patients into the drug review process, FDA has started fast. The May 18 network meeting initiates a process of defining how and when to seek out patient perspectives on drug development objectives and drug approval criteria. This is an important part of FDA’s attempt to refine and update the benefit-risk assessment for new product approvals. Also see "Patient Advocacy 3.0: Outreach Stretches to First Stages of Regulatory Development" - Pink Sheet, 16 April, 2012.

Center for Drug Evaluation & Research Director Janet Woodcock suggested at the meeting a preference for devising a system for electronic access for patient groups (as opposed to face-to-face meetings with FDA staff) to provide a different perspective on background information on a condition (symptoms and clinical manifestations) and a patient-view context of existing treatments.

The agency plans a second meeting on the logistics for bringing patient input into the FDA review process for October. In the commitment letter for PDUFA, the agency said that it would hold at least 20 meetings (17 sponsored by CDER and three sponsored by the Center for Biologics Evaluation & Research) during the five years following passage of PDUFA V.

At the May 18 meeting, the agency explained a process already well underway to select the 20 conditions for these meetings. The agency plans to publish the list in September. Also see "FDA's Patient-Centered Drug Center" - Pink Sheet, 15 December, 2011.

On a separate, but parallel track, FDA is also pursuing more patient input into the development requirements for rare disease drugs. Bringing patient groups into this special area of drug development is a related part of FDA’s overall objective of getting more perspective from the patient.

The agency’s two-day workshop on the natural history of rare diseases was the first step toward a PDUFA commitment to have a public meeting by the beginning of calendar 2013 on “the complex issues in clinical trials for studying drugs for rare diseases.”

These fast starts on the meeting schedules for PDUFA V objectives do not, of course, assure final success on resolving the regulatory challenges around the topics. But it is an important start; and the meetings that have already been held demonstrate a level of seriousness and endeavor on FDA’s part.

Getting Ready for Longer Reviews

Another part of PDUFA V that is already in place may make sponsors less happy: the agency appears informally to have moved to the lengthened NDA/BLA review periods set out in the reauthorization agreement.

By adding pre-filing review periods of 60 days to both priority and standard applications, the PDUFA agreement will effectively lengthen review times to eight months (from six months) for priority drugs and 12 months (from 10 months) for standard reviews. FDA has argued that those times reflect the realities of prompt and through reviews; the review period may last longer, the agency says, but should end with an approval rather than a “complete response” more often.

The recent uptick in three-month extensions on pending reviews reflects the realities of the extended timeframes that FDA is seeking in PDUFA V. Through early May, FDA extended the reviews of at least nine drugs beyond their initial PDUFA dates. Two of those nine extensions were for priority applications: Pfizer Inc. /Bristol-Myers Squibb Co.’s Eliquis (apixaban) and Salix Pharmaceuticals Ltd.’s crofelemer.

During the first week in June, two more sponsors reported three-month extensions: Gilead Sciences Inc. for the priority prevention supplement for Truvada (tenofovir/emtricitabine) from June 15 to September 14 and Novo Nordisk AS for the ultra-long-acting insulin Tresiba (degludec) from July 29 to October 29.

While the current delays are for problems specific to each application (Truvada, for example, relates to a revisit of the design of the REMS education program for the new use), they reflect the reality of a slightly longer review period in the future for most NDAs and BLAs.

Enhancing Benefit Risk Assessment

FDA will publish draft five-year plan to develop and implement a structured risk/benefit assessment by Dec. 31, 2012
FDA will conduct two public workshops on benefit-risk consideration from the regulators perspective during 2013
FDA will hold 4 disease-specific meetings per year involving FDA review teams, patient groups and other stakeholders to better refine the benefit-risk assessment in the class. (CDER will convene 17 of the meetings, and CBER the other three over PDUFA V).
FDA will hold a public meeting on patient report outcomes before Sept. 30, 2014. PROs are a separate item in the PDUFA V agreement, but clearly link into this broader initiative.

Advancing Development of Drugs for Rare Diseases

Create “Rare Disease Program” staff within CDER and CBER by Sept. 30, 2013
Hold a public meeting on complex issues for clinical trials in rare diseases before April 2014.
Implement staff training for all CDER and CBER review staff on rare disease issues by Sept. 30, 2015.
Develop a tool to evaluate the success of the Rare Disease Program by Sept. 30, 2016.

Post-Marketing Safety Enhancements

REMS Process improvements

Issue REMS guidance by Sept. 30, 2013
Hold public meetings on (a) strategies to standardize REMS (b) methodologies to assess REMS by Sept. 30, 2013
Issue report on integration of REMS into the healthcare delivery system by December 31, 2013
Issue guidance on REMS assessment methodologies by Sept. 30, 2014

Sentinel

Hold stakeholder meetings to discuss current and emerging Sentinel projects by Sept. 30, 2013
Over PDUFA V, FDA will fund 4-6 activities based on feedback, with examples being expanding the H1N1 surveillance or evaluating class-wide adverse effects (such as CV events or suicidality)
Conduct (or contract out for) an assessment of Sentinel for informing regulatory action by Sept. 30, 2015 and again by Sept. 30, 2017

Other milestones

Enhanced Communication in Drug Development

FDA will develop a dedicated drug development staff in CDER and CBER by Sept. 30, 2013
The staff will provide training to all review employees by Sept. 30, 2014
Draft guidance on drug development communication will be published by March 30, 2015

Meta-analysis

Hold public meeting on meta-analysis methods by Sept. 30, 2013
Publish a draft guidance on the topic by Sept. 30, 2015
Finalize guidance within 18-months of close of comments on draft

Biomarkers/Pharmacogenomics

Hold public meeting on strategies to facilitate biomarker development by Sept. 30, 2013

Electronic Submissions

Issue draft guidance on standards and formats of electronic application submissions by Dec. 31, 2012
Finalize guidance 12 months after close of comment period
Phase in requirements: 24-months after final guidance for NDAs/BLAs
36-months for INDS
Develop standardized clinical data terminology by Sept. 30, 2017

Getting a Jump on PDUFA V: Fast Start on REMS, Patient Input – And Longer Reviews

More from Post-Marketing Regulation & Studies

More from Product Reviews