life.sciences.regulatory.trends.2016.jpgSara Bobbit is a Senior Regulatory Consultant for the Paragon's Life Sciences practice.

With the current PDUFA authorization ending on September 30, 2017, the FDA held a public meeting to discuss the PDUFA VI reauthorization packageThe meeting was part of the finalization process prior to sending the package to Congress for consideration and passage at the start of 2017.

As the PDUFA construct allows the agency to collect user fees in order to better serve fee payers, here are the main ways PDUFA VI will benefit sponsors:

  • Streamlined and clarified expectations for communication during drug development.
  • Increased agency capacity for review of breakthrough therapies, new molecular entities, orphan drugs for rare disease, and trials with biomarkers as surrogate endpoints.
  • Timely notification of post-marketing safety events and expansion of the Sentinel Program.
  • Improved agency ability to accommodate complex innovative trial designs, Real World Evidence, and Model-Informed Drug Development in regulatory decision making.
life.sciences.regulatory.update.2016.jpgNow, let us take a closer look at the many goals put forward in PDUFA VI and how they may impact industry stakeholders.

Pre-market Review

Many of the enhancements related to pre-market review are centered on meetings and communication between sponsors and the FDA. Sponsors will now be able to request Written-Response-Only (WRO) for any meeting type. The agency aims to take some of the guesswork out of communication during drug development by conducting a third-party assessment of current practices followed by a public meeting to review results. This will lead to an updated guidance on how best to communicate with the agency throughout the process.

Sponsors will need to stay apprised as the agency plans to update expectations for the timing of actions like agency responses to meeting requests, submission of meeting packages, and issuance of preliminary responses for Type B and C meetings. They will also need to be more cautious when it comes to submitting manufacturing facility information, as manufacturing supplements where previously excluded facilities are identified may now trigger a goal date extension.

Program Specific Enhancements

PDUFA VI will allow the agency to bolster the already popular Rare Disease Program and Breakthrough Therapy Program by allowing for increased staffing, training on best practices for review and regulation, and outreach to sponsors and patient-groups. The New Molecular Entity (NME) Review Program will see the implementation of a formal communication plan and codification of current practices for program flexibility and expedited reviews.  NME applications that are “filed over protest” will be subject to program performance goals, but will not benefit from program elements, while any subsequent resubmissions will not have performance goals. NME sponsors will gain increased flexibility for scheduling advisory committee meetings and will have the ability to hold follow-up informal teleconferences to discuss feedback from such meetings.

The FDA will offer sponsors early consultation when considering the use of biomarkers as surrogate endpoints for product approval. Such consultations will be considered Type C meetings with briefing packages, including preliminary human data indicating impact of the drug on said biomarker, due at the time of meeting request.

With the anticipated increase in combination drug and device product submissions, the agency plans to boost staff capacity and streamline the process for reviews of such submissions. Third-party reviews of their process will be conducted and Manuals of Policies and Procedures (MAPPs) will be established. FDA will also establish procedures and performance goals for reviewing protocols for human factors studies and will update guidance on bridging studies and patient-oriented labeling.

Post-Marketing Safety

The agency is planning to support the management, oversight, and communication of post-marketing drug safety issues by improving the processes and IT systems that capture and track this information. They will also update policies and procedures to include consistent and timely sponsor notification when a serious safety signal is identified and at least 72 hours before the public posting of a quarterly FDAAA 921 safety notice.

After the successful completion of the Mini-Sentinel pilot program, the agency recently transitioned to the full Sentinel System. The goal of the system is to provide the agency rapid and secure access to vast amounts of electronic healthcare data to monitor the safety of regulated products while safeguarding patient privacy. PDUFA VI will allow for the continued expansion of the program by growing data sources and core capabilities, integrating the system into post-marketing review activities, and developing a comprehensive training program for review staff.

Improving Regulatory Decision Tools

In an effort to keep pace with sponsor innovation, the agency plans to strengthen its capabilities to review complex innovative clinical trial designs, to use Real World Evidence (RWE) in regulatory decision-making, and to accommodate Model-Informed Drug Development (MIDD). Approaches to achieve these ends will include running pilot programs, increasing staff capacity, holding public workshops, and creating or updating guidance documents, MAPPs, and SOPs. FDA will also keep up with sponsors submitting NDAs and BLAs in fully-standardized electronic format by enhancing staff capacity to efficiently review analysis data sets and programs with training, updated therapeutic area user guides, a public workshop, and new or revised MAPPs and SOPs.

Clarification will be provided to industry around the agency’s current benefit-risk assessment approach through an updated implementation plan and guidance document. Evidentiary standards for biomarkers will be elucidated through the development of guidance documents, MAPPs, and SOPs. A public meeting will be held to discuss drug development tool (DDT) qualification for biomarkers and a public website will be maintained for the communication of a list of biomarker qualification submissions currently in process.

Continuing their efforts to better incorporate the patient’s voice into regulatory decision making, the agency intends to conduct public workshops, update guidance documents with patient-community input, identify the impacts that are most important to patients, and find better ways to incorporate clinical outcome assessments into trial endpoints. They will revise MAPPs and SOPs to incorporate this focus, develop a repository of information on publicly available tools and ongoing efforts, and train staff on the development and use of patient-focused methods for drug development and regulatory decisions.

life.sciences.regulatory.2016.jpgIncreased Transparency for Electronic Submissions and Data Standards

The predictability and transparency of the electronic submission process will be bolstered by the agency publishing descriptions of the overall process, milestones, notifications, process for rejections, and validation criteria. They will publish performance targets for the Electronic Submission Gateway (ESG) such as expected upload duration, timeframe between milestones and notifications, and measurements of overall availability during business hours. Communication will be improved when it comes to submission milestone notifications and advanced notice for system downtimes.

Quarterly meetings will be held to share performance updates with industry. Annual public meetings will be held to seek stakeholder input on ESG performance, future targets, emerging needs and technology initiatives to inform the FDA’s IT strategic plan. Metrics on ESG performance against published targets, volume and types of submissions, standards adoption, and conformance will be posted at least annually. Long term sustainability of data standards will be ensured through collaborations with Standards Development Organizations (SDOs).

Enhanced PDUFA Resource Management

In order to boost agency accountability in resource management, they plan to modernize their time reporting to aid in capacity planning and conduct a third-party assessment of financial administration of the PDUFA program. A 5-year financial plan will be published in FY2018 with updates published each consecutive year, and public meetings held each year starting in FY2019 to review progress against these goals.

Sponsors will see modifications to the user fee structure and target revenue allocations as the agency aims to enhance financial predictability, stability, and efficiency. This will include changes like the discontinuation of establishment and supplement fees, shifting a greater portion of the target revenue allocation to predictable fee-paying types, modifying the program fee billing date to avoid multiple billing cycles, keeping product program fees under 5 for each distinct approved application, and discontinuing the fees-exceed-costs waiver.

Increased Hiring Capacity

To ensure the agency is able to meet its goals and successfully provide the above mentioned benefits to sponsors, they intend to increase their ability to hire and retain qualified staff through a modernized hiring system, dedicated expert HR contractors, and a dedicated function for the recruitment and retention of scientific staffing. FDA will set clear goals for hiring and conduct a comprehensive assessment of hiring and retention practices to meet these ends.

life.sciences.regulatory.chart.2016.pngChart by Paragon's Tom Beatty