• All opinions expressed are those of the presenter and do not represent any organization.

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• FDA: Statistical Software Clarifying Statement

“FDA does not require use of any specific software for statistical analyses, and statistical software is not explicitly discussed in Title 21 of the Code of Federal Regulations [e.g., in 21CFR part 11]. However, the software package(s) used for statistical analyses should be fully documented in the submission, including version and build identification.”

As an organization, we need to ensure compliance and reduce the risk of using R and R packages in regulatory deliverables.

• R is widely used in clinical trial study design.
  • Following Lachin and Foulkes (1986)
  • gsDesign: an R package for group sequential design under proportional hazards.
  • gsDesign2: experimental R packages for group sequential design under non-proportional hazards
  • Bookdown: https://keaven.github.io/gsd-deming/
• R is flexible for handling novel missing data approaches following the estimand framework in ICH E9 (R1)
  • Recurrent event data: Gao et al. (2017) Diao et al. (2020)
  • Robustness: Liu et al. (2021)
• R is used in Bayesian statistics.
  • stan and network meta-analysis for drug reimbursement analysis
• R is widely used in visualization
  • metalite.table1: Interactive demographic table.
  • forestly: Interactive forest plot for DMC safety monitoring in clinical trials

• Clinical study report is a key deliverable for clinical trials to regulatory agencies. (e.g., FDA, CFDA)
  • ICH E3 Structure and Content of Clinical Study Reports.
• We try to fill in gaps to streamline workflow using R for clinical trial development:
  • To develop, validate, and deliver analysis results.
  • To submit analysis results to regulatory agencies in eCTD format.
• Focus on table, listing, figure (TLFs) delivered in RTF/Microsoft Word format.
  • In the pharmaceutical industry, RTF/Microsoft Word play a central role in preparing clinical study reports.
  • Different organizations can have different table standards.

• The R submission working group is a cross-industry pharma working group focusing on improving practices of R-based clinical trial regulatory submission.
  • members and affiliations

• Objective: Create open source example for R-based clinical trial regulatory submissions
• pilot 1 - common analyses
  • 2021.11 Initial submission to FDA.
  • 2022.12 Received FDA response
  • 2022.02 Revised submission to FDA
  • 2022.03 Received final FDA response.
• pilot 2 - shiny app
  • 2022.10 Public review of initial submission to FDA.
• pilot 3 - ADaM data
  • 2022.10 Proposal initiation.

Challenges

• How to submit internally developed (proprietary) R packages?
• How to follow ICH and/or FDA guidances in preparing eCTD package?
• How to enhance reproducibility from FDA reviewer’s perspective?

Assumptions

• Focus on analysis and reporting given available ADaM datasets.

• Open source pilot eCTD submission package to FDA
  • Proprietary R package
  • R scripts for analysis
  • Analysis data reviewer guide (ADRG)
  • etc.
• Development: https://github.com/RConsortium/submissions-pilot1
• eCTD package: https://github.com/RConsortium/submissions-pilot1-to-fda
• R consortium announcement

Initial Submission

• “Using R version 4.1.1, FDA was able to run the submitted code and confirm the applicant’s tables and the submitted figure in report-tlf pdf file.”
• “Using FDA developed code, a statistical analyst was able to independently generate tables using the submitted data.”
• Initial submission FDA response

Revised Submission

• FDA agrees that the initial phase of the R Pilot submission has been completed.
• Revised submission FDA response

• Seek pilot submission opportunities to other regulator agencies.
• Pilot submission with advanced analysis methods (e.g., study design, missing data, Bayesian, etc).