The Next PDUFA: New Performance and Procedural Goals

Regulatory NewsRegulatory News | 15 July 2016 |  By 

Exactly one year after the first round of negotiations over the sixth iteration of the Prescription Drug User Fee Act (PDUFA), the US Food and Drug Administration (FDA) on Friday released the full details of the performance and procedural goals for fiscal years 2018 through 2022.

The 46-page document, which outlines how the agency will use the user fees provided to it from industry, breaks down not only the planned deadlines for new guidance documents and pilot projects, but also highlights recurring themes of recent importance, including on patient input to the regulatory process, use of real-world evidence, biomarker qualification and increased pharmacovigilance.

The new review times for new drug applications (NDA) and biologics license applications (BLA), as well as goals on original efficacy supplements, resubmitted efficacy supplements, original manufacturing supplements and review performance goal extensions, are summarized in the following chart:


In addition, the document offers details on FDA’s program for better review transparency and communications between FDA and industry, as well as information on clinical holds, the major dispute resolution process, information on special protocol question assessment and agreements and goals for the review of proprietary names to reduce medication errors.

Outlined below is a breakdown of further topics that the letter delves into specifically, with particulars on FDA’s deadlines.

Communication Between FDA and Sponsors During Drug Development

Timely interactions between FDA and sponsors during drug development is a core agency activity, and with this in mind, FDA is pledging to maintain dedicated drug development communication and training staffs in its Center for Drug Development (CDER) and Center for Biologics Evaluation and Research (CBER).

“One function of the staff is to serve as a liaison that will facilitate general and, in some cases, specific interactions between sponsors and each Center. The liaison will serve as a point of contact for sponsors who have general questions about drug development or who need clarification on which review division to contact with their questions…The second function of the staff is to provide ongoing training to the review organizations on best practices in communication with sponsors,” the text says.

Early Consultation on the Use of New Surrogate Endpoints

Early consultation in the drug development program allows the review team to consult with FDA senior management to evaluate the sponsor’s proposal before providing advice on the proposed biomarker as a new surrogate endpoint to support accelerated or traditional approval.

Requests to engage with FDA on new surrogate endpoints will be considered a Type C meeting request, meaning discussions will center on the feasibility of the surrogate as a primary endpoint, and identify any gaps in knowledge and how they might be addressed. To qualify for this consultation, these Type C meeting requests must be accompanied by the complete meeting background package at the time the request is made that includes preliminary human data indicating impact of the drug on the biomarker at a dose that appears to be generally tolerable.

Information on other meeting types includes:


Advancing Development of Drug-Device and Biologic-Device Combo Products

FDA will also develop staff capacity and capability across the medical product centers and the Office of Combination Products (OCP) to more efficiently, effectively and consistently review and respond to submissions that include combination products. The additional capacity will include staff who will focus on the review of cGMP, engineering aspects, human factors and bridging study protocols and study reports, as well as labeling, to include instructions-for-use materials.

By no later than 31 December 2017, FDA will begin tracking workload and timelines for cross-center consultations to enable appropriate allocation of resources and regularly assess the progress of combination product review.

And by no later than 30 September 2018, FDA will outline in appropriate internal documents the agency’s process for resolving internally any scientific or regulatory issues that arise, as well as a commitment for the medical product centers and OCP to coordinate and complete reviews and related activities. The topic areas and expected completion dates of these documents are:

  • Human Factors Assessments (31 March 2019)
  • Quality assessment of combination products, including coordination of facility inspections (30 September 2019)
  • Patient-oriented labeling, including instructions-for-use materials for those drug-device and biologic-device combination products regulated by CBER and CDER (30 September 2019)

By no later than 31 December 2018, FDA will make available on its website key points of contact in OCP and the medical product centers for combination product review, and the agency will maintain and update this information periodically. FDA will also establish submission procedures for Human Factors protocols no later than 30 September 2018, and beginning in FY 2019, FDA will establish timelines to review and provide comment on the protocols for Human Factors studies of combination drug-device and biologic-device products within 60 days.

Performance goals for FDA will be phased in as follows: By FY 2019, review 50% of human factors protocol submissions within 60 days and provide sponsor with written comments. By FY 2020, review 70% of human factors protocol submissions within 60 days and provide sponsor with written comments. By FY 2021, review 90% of human factors protocol submissions within 60 days and provide sponsor with written comments.

Rare Diseases

The Rare Disease Program staff in CDER will be integrated into review teams for rare disease development programs and application review to provide their unique expertise on flexible and feasible approaches to studying and reviewing such drugs to include, for example, innovative use of biomarkers, consideration of non-traditional clinical development programs, use of adaptive study designs, evaluation of novel endpoints, application of new approaches to statistical analysis and appropriate use of FDA’s expedited development and review programs (i.e., Fast Track, Breakthrough, Priority Review, and Accelerated Approval).

By the end of FY 2019, FDA will publish draft guidance or update previously published guidance issued by the medical product centers and OCP for review staff and industry describing considerations related to drug-device and biologic-device combination product on the topics noted below. The draft guidance(s) will be finalized by the end of FY 2022.

  • Bridging studies, including the bridging of data from combination products that employ different device components for the same drug or biologic and the same device component across different drugs and biologics
  • Patient-oriented labeling (e.g., instructions-for-use)

Enhancing Use of Real World Evidence for Use in Regulatory Decision-Making

By no later than the end of FY 2018, FDA will complete one or more public workshop(s) with patients, biopharmaceutical companies and academia to gather input into issues related to Real World Evidence (RWE) use in regulatory decision-making.

By no later than the end of FY 2019, FDA will initiate (or fund by contract), appropriate activities (e.g., pilot studies or methodology development projects) aimed at addressing key outstanding concerns and considerations in the use of RWE for regulatory decision making.

And by no later than the end of FY 2021, FDA will publish draft guidance on how RWE can contribute to the assessment of safety and effectiveness in regulatory submissions, for example in the approval of new supplemental indications and for the fulfillment of postmarketing commitments and requirements.

FDA says it will work toward the goal of publishing a revised draft or final guidance within 18 months after the close of the public comment period.

Incorporating the Patient’s Voice in Drug Development and Decision-Making

As part of efforts to collect and utilize patient and caregiver input that can more consistently inform drug development and regulatory decision making, FDA will:

  • Strengthen staff capacity to develop and use patient-focused methods to inform drug development and regulatory decisions, composed primarily of clinical, statistical, psychometric, and health outcomes research expertise, which will be integrated into review teams during drug development and application review where the sponsor intends to use patient input or clinical outcome assessment (COAs) such as patient-reported outcomes (PROs).
  • Develop a series of guidance documents to focus on approaches and methods to bridge from initial patient-focused drug development meetings, like those piloted under PDUFA V, to fit-for-purpose tools to collect meaningful patient and caregiver input for use in regulatory decision making.
  • By the end of FY 2018, FDA will publish a draft guidance addressing: standardized nomenclature and terminologies, methods to collect meaningful patient input throughout the drug development process and methodological considerations for data collection, reporting, management and analysis.
  • By the end of FY 2019, FDA will publish a draft guidance describing processes and methodological approaches to the development of holistic sets of impacts on topics including: methods for sponsors, patient organizations, academic researchers, and expert practitioners to develop and identify what are most important to patients in terms of burden of disease, burden of treatment and other critical aspects.
  • By the end of FY 2020, FDA will publish a draft guidance describing approaches to identifying and developing measures for an identified set of impacts (e.g., burden of disease and treatment), which may facilitate collection of meaningful patient input in clinical trials. The guidance will address methods to measure impacts in a meaningful way and identify an appropriate set of measure(s) that matter most to patients.
  • By the end of FY 2021, FDA will publish a draft guidance on clinical outcome assessments, which, when final, will, as appropriate, revise or supplement the 2009 Guidance to Industry on Patient-Reported Outcome Measures.

“For each of the above, FDA will work toward the goal of publishing a revised draft or final guidance within 18 months after the close of the public comment period on the draft guidance,” the agency says.

FDA will also create and maintain a repository of publicly available tools on its website, which will include FDA’s clinical outcome assessment compendium, patient-focused drug development meeting resources and ongoing efforts on patient-focused drug development.

Enhancing Benefit-Risk Assessment in Regulatory Decision-Making

As part of PDUFA VI, FDA pledges that by 31 March 2018, the agency will publish an update to the implementation plan titled “Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making,” which will include a report on the progress made during PDUFA V and a plan for continued implementation during FYs 2018- 2022.

By the end of FY 2019, FDA will convene and/or participate in, at least one meeting, conducted through a qualified third party, to gather industry, patient, researcher and other stakeholder input on key topics.

By the end of FY 2020, FDA will publish a draft guidance on benefit-risk assessments for new drugs and biologics to articulate FDA’s decision-making context and framework for benefit-risk assessment, illustrating the application of the benefit-risk framework throughout the human drug lifecycle, using a case study approach, if appropriate.

Beginning in FY 2021, FDA will conduct an evaluation of the implementation of the benefit-risk framework in the human drug review program. This evaluation will assess how reviewers across the organization apply the benefit-risk framework and identify best practices in use of the benefit-risk framework.

Advancing Model-Informed Drug Development

To aid the development and application of exposure-based, biological and statistical models derived from preclinical and clinical data sources, FDA will

  • develop its regulatory science and review expertise and capacity to support the highly-specialized evaluation of model-based strategies and development efforts
  • convene a series of workshops to identify best practices on (1) physiologically-based pharmacokinetic modeling; (2) design analysis and inferences from dose-exposure-response studies; (3) disease progression model development, including natural history and trial simulation; and (4) immunogenicity and correlates of protection for evaluating biological products, including vaccines and blood products.

Starting in FY 2018, FDA will conduct a pilot program for such modelling approaches and will grant a pair of meetings designed for the pilot, consisting of an initial and a follow-up meeting on the same drug development issues to occur within a span of approximately 120 days.

By the end of FY 2019, FDA will publish draft guidance, or revise relevant existing guidance, on model-informed drug development.

Enhancing Capacity to Review Complex Innovative Designs

Starting in FY 2018, FDA will conduct a pilot program for highly innovative trial designs for which analytically derived properties (e.g., Type I error) may not be feasible, and simulations are necessary to determine trial operating characteristics.

By the end of Q2 of FY 2018, FDA will convene a public workshop to discuss various complex adaptive, Bayesian, and other novel clinical trial designs, with a particular focus on clinical trial designs for which simulations are necessary to evaluate the operating characteristics, and the acceptability of those designs in regulatory decision-making.

By end of FY 2018, FDA will publish draft guidance on complex adaptive (including Bayesian adaptive) trial designs.

Enhancing Capacity to Support Analysis Data Standards for Product Development and Review

To support the enhancement of analysis data standards for product development and review in the human drug review program, FDA will develop the staff capacity to support the pre- and postsubmission discussion of standardized datasets and programs, and maintain the knowledge of and engage in collaborations about standards models used in the design, analysis and review of clinical and non-clinical studies. Examples of these standards models could include the Standard for Exchange of Nonclinical Data (SEND), Clinical Data Acquisition Standards Harmonization (CDASH), Study Data Tabulation Model (SDTM), and Analysis Data Model (ADaM).

In parallel, FDA will improve staff capacity to assist with FDA development and updating of therapeutic area user guides (TAUGs) to include the appropriate content for the analysis data standards used in submission and review.
By end of FY 2019, FDA will convene a public workshop to advance the development and application of the analysis of data standards.

By end of FY 2020, FDA will develop or revise, as appropriate, relevant guidance, MAPPs, SOPPs and training associated with submission and utilization of standardized analysis datasets and programs used in review, and on the processes, procedures, and responsibilities related to the receipt, handling, and documentation of submitted analysis data and programs.

Qualification Pathway for Biomarkers

FDA will develop the staff capacity to enhance biomarker qualification review by increasing base capacity and will pilot processes to engage external experts to support review of biomarker qualification submissions.

By the end of FY 2018, FDA will convene a public meeting to discuss 1) taxonomy for biomarkers used in drug development, and 2) a framework with appropriate standards and scientific approaches to support biomarkers under the taxonomy, including scientific criteria to determine acceptance of a biomarker qualification submission and essential elements of a formal biomarker qualification plan.

By the end of FY 2018, FDA will also publish draft guidance on proposed taxonomy of biomarker usage and related contexts of use.

By the end of FY 2020, FDA will publish draft guidance on general evidentiary standards for biomarker qualification to be supplemented with focused guidance on specific biomarker uses and contexts.

FDA also says it will list biomarker qualification submissions that are in the qualification process on a public website, to be updated quarterly.

Following qualification of a biomarker FDA will post reviews and summary documents that outline the qualification program and data supporting a qualification decision, though sponsors who do not use this qualification pathway will have an opportunity to interact with the Agency through traditional channels.

Postmarket Safety Evaluation by Expanding Sentinel and Integration Into Pharmacovigilance Activities

FDA will use user fee funds to conduct a series of activities to systematically implement and integrate Sentinel in FDA pharmacovigilance practices. These activities will involve augmenting the quality and quantity of data available through the Sentinel System, improving methods for determining when and how that data is utilized, and comprehensive training of review staff on the use of Sentinel.

FDA will also enhance its communication with sponsors and the public regarding general methodologies for Sentinel queries, including what the Agency has learned regarding the most appropriate ways to query and use Sentinel data. This can be done through enhancement of existing mechanisms and/or greater frequency of such mechanisms.

By the end of FY 2019, FDA will hold or support a public meeting engaging stakeholders to discuss current and emerging Sentinel projects and seek stakeholder feedback and input regarding gaps in the current system to facilitate the further development of Sentinel and its system of Active Risk Identification and Analysis (ARIA).

By the end of FY 2020, FDA will establish policies and procedures (MAPPs and SOPPs) to facilitate informing sponsors about the planned use of Sentinel to evaluate a safety signal involving their respective products.

By the end of FY 2020, FDA will facilitate integration of Sentinel into the human drug review program in a systematic, efficient, and consistent way through staff development and by updating existing SOPPs and MAPPs, as needed.

By the end of FY 2020, FDA will develop a comprehensive training program for review staff (e.g., epidemiologists, statisticians, medical officers, clinical analysts, project managers, and other review team members) to ensure that staff have a working knowledge of Sentinel, can identify when Sentinel can inform important regulatory questions, and are able to consistently participate in use of Sentinel to evaluate safety issues.

By the end of FY 2022, FDA will analyze, and report on the impact of the Sentinel expansion and integration of FDA’s use of Sentinel for regulatory purposes, e.g., in the contexts of labeling changes, poatmarket requirements or postmarket commitments.

Timely and Effective Evaluation and Communication of Postmarketing Safety Findings

FDA will use user fee funds to continue to support the review, oversight, tracking and communication of postmarket drug safety issues. More specifically, by the end of FY 2019, FDA will update existing policies and procedures (MAPPs and SOPPs) concerning tracking postmarketing safety signals to include consistent and timely notification to a sponsor (1) when a serious safety signal involving a product is identified and (2) to the extent practicable, not less than 72 hours before public posting of a safety notice.

By the end of FY 2022, FDA will conduct, or fund by contract, an assessment of how its data systems and processes, as described in MAPPs and SOPPs, support review, oversight, and communication of postmarketing drug safety issues.

New FDA Hires

As far as the number of hires FDA is intending to make through 2022, the agency offers this chart:


FDA will also publish a PDUFA 5-year financial plan no later than the Q2 of FY 2018, and in each subsequent fiscal year.


Prescription Drug User Fee Act; Public Meeting; Request for Comments


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