Patient safety remains at the forefront of the FDA’s intentions to continue and enhance existing drug safety programs and develop new ones under PDUFA VII.
Commitment to Enhanced Communication on Risk Management Activities During Review
Some of the planned enhancements under PDUFA VII, like the switch to standard approaches for the review of NME NDAs and original BLAs, may reveal a shift in focus for the FDA to managing and evaluating risk in the post-market setting.
In addition to indicating that REMS will be included in discussions at pre-submission meetings, FDA has indicated that risk management will be a focus of the mid-cycle communication. FDA notes that these will also be included as discussion topics for the FDA review team at the late-cycle meeting. The mid-cycle communication is an update from the Review Planning and Monitoring (RPM) meeting (generally within two weeks of the midcycle review meetings).
It will continue to summarize significant review issues and provide preliminary thoughts/rationale on the following:
- What additional studies may be required post-marketing, such as Post Market Requirements (PMRS) or Post Marketing Study Commitments (PMCs)
- The ability to provide sufficient risk information using adverse event (AE) reporting and FDA’s Active Risk Identification and Analysis (ARIA) system under the Sentinel Initiative.
- Risk management and REMS
The earlier notification of the potential for additional work on the Sponsor’s part will be very valuable for planning, circulating ideas and strategies, and getting approval before committing to the FDA. For example, knowing a PMR or PMC is likely required allows for more time for the Sponsor to begin planning these studies and having critical discussions about study design and feasibility.
The additional consistency and predictability around when this will be shared will also be helpful for both FDA and Sponsors. In the case of PMRs, depending on the status of an application’s review, FDA is committing to communicating details of anticipated PMRs six (priority review) to eight (standard review) weeks before the PDUFA action date.
FDA has also built time frames and goals for responding to requests for post-approval review for release from existing PMRs.
ARIA and Sentinel
The FDA has also committed to drafting additional processes and procedures for ARIA sufficiency determination.
ARIA was mandated under the FDA Amendments Act (FDAAA) in 2007. It is intended to allow FDA to gain access to data from disparate sources and develop and validate methods to establish a system that links these together and analyzes the resulting safety data.
In 2008, the Sentinel Initiative Pilot was launched to conduct medical product safety surveillance, and the full system was officially released in 2016. The Sentinel structure, data sources, and databases have gained traction over time and are now mentioned extensively in the PDUFA VII goal letter.
Modernization and Improvement of REMS Assessments
In addition to targeted discussions of REMS during the planning stage, as mentioned above, PDUFA VII also indicates many actions the FDA will take to improve assessments of existing REMS.
The first is that assessment planning will be built into REMS by design. FDA plans to issue additional recommendations on this early in 2024. These should include additional identification of key metrics and recommendations for design, assessment, and data quality.
At the same time, the FDA plans to clarify REMS performance evaluation methods and determine if further modifications or revisions to the REMS assessment plan are needed. New guidance on the content and format of the REMS assessment report is also planned for 2026 – 2027.
Optimization of the Sentinel Initiative
As mentioned above, the Sentinel initiative will continue to expand and integrate into FDA drug safety activities under PDUFA VII. This will include communicating with Sponsors and the public, maintaining Sentinels’ source data, transparency of study information via web presence, and maintaining the FDA Sentinel training program.
The FDA also has new initiatives which will be completed in the coming years. By the end of the fiscal year 2025, the FDA will publish an update concerning access to Sentinel’s data via its website. In the same year, it will analyze and report how effectively Sentinel is being utilized for regulatory purposes. Then during the fiscal years of 2023-2027, there will be an update to the PDUFA Financial Report addressing its obligations for updated PDUFA VI commitments on the PDUFA VII Sentinel initiative.
The FDA will take two steps to advance the capabilities of Sentinel:
- Further exploring RWE for study effectiveness and product safety.
- Developing a robust post-marketing approach for assessing drug safety during pregnancy using electronic healthcare data and pregnancy registries.
Pregnancy Safety PMRs and PMCs
FDA adds pregnancy safety PMRs and PMCs at the time of marketing authorization to help inform the Pregnancy and Lactation Labeling Rule (PLLR) on the safety of use in pregnancy and to detect or evaluate safety signals.
Under PDUFA VII, FDA intends to develop a framework to convey the optimal uses of data from different types of post-market pregnancy safety studies. This will incorporate data from different studies used in this context in the past and identify gaps in this data to be filled by “demonstration projects.”
FDA plans to conduct five such demonstration projects to collect data on the performance characteristics of different study designs. The demonstration projects that FDA is currently planning (although they may be modified) are summarized in Figure 1.
The data from these demonstrations will be used to update the framework and create a process for pregnancy post-marketing studies (guidance, MAPP, or SOPP).
Figure 1 Planned Demonstration Projects For Pregnancy Safety Framework
Note for graphic: eHCDB= electronic healthcare database; eHR = electronic health record; MCM =major congenital malformations (MCM)
Note: pregnancy-related outcomes include spontaneous abortion, stillbirth, congenital malformations, etc.
FDA will also review published literature and post-market pregnancy data that have been included in pregnancy labeling. The framework will take into account the following:
- purpose of study
- types of post-market studies
- anticipated exposure in females of reproductive potential (FRP) and pregnant women
- potential toxicity of the drug and proposed risk mitigation
- benefits of the drug
- magnitude and type of risk to be detected.
In addition, this framework will specifically address the use of pregnancy registries as well as Sentinel and other sources of electronic healthcare data.
By late 2023, FDA intends to hold a workshop to help determine the ideal post-market study design(s) for collecting pregnancy safety information. It hopes that the framework will also allow for some decision tree that allows for some predictability in determining the likely necessity and type of pregnancy post-marketing studies to be required.
By: Aaron Pyle, Regulatory Affairs Associate, and Dr. Amanda Beaster, Associate Director of Regulatory Strategy
If you have questions about CMC enhancements or any other PDUFA VII Updates, email firstname.lastname@example.org to speak to a regulatory or CMC expert.
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