Introduction

This blog provides an update on PHUSE activities related to the recently released premarket safety documents by the FDA. Additional volunteers are welcome to participate in any of the planned next steps, and we are happy to gather other ideas to consider as PHUSE projects, as follow-up to the FDA safety documents.

Background Information on the FDA Documents

The FDA posted two premarket safety documents on 5 September 2022: one on standard safety tables and figures (1), and another on FDA Medical Queries (2). They hosted an associated Duke-Margolis workshop on 14 September 2022 (3) and presented at the PHUSE Computational Science Symposium (CSS) on 22 September 2022 (4). The FDA accepted comments on the two documents and workshop through to 5 December 2022. As noted by the FDA presenters, the intent of posting the two documents was to be transparent on what tables, figures and listings are being recommended from an FDA OND/CDER/BIRRS group to FDA clinical reviewers, and they are interested in receiving feedback on their recommendations.

PHUSE Involvement

The PHUSE Safety Analytics Working Group Co-Leads (Greg Ball and Mary Nilsson) were invited to participate as panellists for the Duke-Margolis workshop. This provided an opportunity to share PHUSE activities related to safety analyses and adverse event groupings. The workshop was well attended (>1000 attendees), indicating a high level of interest in safety analytics.

At the PHUSE CSS 2022, in addition to the plenary session, there was a 90-minute breakout session facilitated by the Safety Analytics Working Group Co-Leads. A lot of additional context and insight was obtained, with multiple opportunities for increased collaboration identified.

A PHUSE project team was formed to gather comments on the two FDA documents from the PHUSE Community. The project team submitted comments (5), which were primarily based on positions/recommendations stated in one of the many PHUSE deliverables (6) pertaining to standard safety tables and figures (posted 2013–2022). The comments also identified opportunities for referencing PHUSE deliverables to provide a more robust discussion on pros/cons of various analytical choices and to link to relevant educational information.

Next Steps

The PHUSE Safety Analytics Working Group Co-Leads will continue to work with PHUSE FDA representatives on how best to collaborate on safety-related deliverables with overlapping or complementary content. Currently, project teams have FDA representatives, and the Co-Leads will discuss whether additional representation might be warranted.

The PHUSE AE Groupings in Safety (AEGiS) project team will likely create a deliverable(s) related to the implementation of the FDA Medical Queries. This forum also provides an opportunity for discussion and shared learning around the topic of adverse event groupings in general (creating/maintaining groupings; when to use groupings, use cases for specific groupings, etc).

The PHUSE Analyses & Displays for Laboratory Data project team, who finalised a white paper in August 2022 prior to the release of the two FDA documents, will discuss whether to update the white paper to incorporate some/all of the FDA recommended tables and figures and/or move to different deliverables (e.g. recommendations for labs of special interest, recommendations to developers of interactive displays).

The PHUSE Analyses & Displays for Hepatotoxicity project team, who is working on a deliverable with recommended tables, figures and listings for liver-related data, will discuss the draft displays already created based on shared learning amongst project team members versus those provided in the FDA document. The white paper is planned to be released for public review in Q1 2023.

The PHUSE Adverse Event Collection Recommendations project team plans to collaborate with the FDA on the idea to discontinue the practice of collecting the investigator relatedness assessment for non-serious events, as noted in a December 2020 PHUSE Blog titled ‘Investigator Assessment of Causality – Opportunity for Simplification’ (7). This was highlighted as a topic for discussion during the PHUSE CSS 2022 breakout session, given the inclusion of an optional table in the FDA’s document involving the investigator relatedness assessment.

The PHUSE Treatment Emergent Definitions Recommendations project team plans to collaborate with the FDA on treatment emergent definitions as follow-up to the FDA’s proposals included as part of the Duke-Margolis workshop.

The PHUSE Safety Analytics Working Group Co-Leads will discuss whether to create a project to consider updating the 2017 PHUSE Adverse Events white paper. The project team could compare the recommendations in the white paper to the FDA document and discuss other evolving topics related to the analysis of adverse events (e.g. using a time-to-event analytical approach more broadly; using the estimand framework for safety).

The PHUSE Safety Analytics Working Group Co-Leads will discuss with PHUSE FDA representatives whether to create a project team to serve as an industry consulting group on any topics related to their two documents and the feedback they received.

Additional volunteers are welcome to join any of our project teams, and we welcome ideas for future projects. To get involved, please contact workinggroups@phuse.global.

References

(1) Center for Drug Evaluation and Research (CDER) and Biomedical Informatics and Regulatory Review Science (BIRRS) Team. (2022). Advancing Premarket Safety Analytics Workshop Meeting Material Standard Safety Tables and Figures Integrated Guide. Retrieved 2 January 2022 from https://www.regulations.gov/document/FDA-2022-N-1961-0002

(2) Center for Drug Evaluation and Research (CDER) and Biomedical Informatics and Regulatory Review Science (BIRRS) Team. (2022). Advancing Premarket Safety Analytics Workshop Meet Material FDA-DM FMQs. Retrieved 2 January 2022 from https://www.regulations.gov/document/FDA-2022-N-1961-0001

(3) Duke-Margolis Center for Health Policy. (2022). Advancing Premarket Safety Analytics. Retrieved 2 January 2022 from https://healthpolicy.duke.edu/events/advancing-premarket-safety-analytics

(4) PHUSE Computational Science Symposium. (2022). Wednesday Plenary Session. Retrieved 2 January 2022 from https://phuse.s3.eu-central-1.amazonaws.com/Archive/2022/CSS/US/Silver%20Spring/PRE_05.pdf

(5) PHUSE Safety Analytics Working Group. (2022). Comments on FDA Premarket Safety Analytics documents. Retrieved 2 January 2022 from https://www.regulations.gov/comment/FDA-2022-N-1961-0021, https://www.regulations.gov/comment/FDA-2022-N-1961-0023, https://www.regulations.gov/comment/FDA-2022-N-1961-0017

(6) PHUSE Standard Analyses and Code Sharing Working Group and PHUSE Safety Analytics Working Group. (2013–2022). Retrieved 2 January 2022 from https://phuse.global/Deliverables/1

(7) PHUSE Adverse Event Collection Recommendations Project Team. (2020). Investigator Assessment of Causality – Opportunity for Simplification? Retrieved 2 January 2022 from https://phuse.global/Communications/PHUSE_Blog/investigator-assessment-of-causality-opportunity-for-simplification