Oct. 2022


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

  • Some slides need to be scrolled down to see the full content.

Clarification from FDA

“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.
  • 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


  • Clinical study report is a key deliverable for clinical trials to regulatory agencies. (e.g., FDA, CFDA)
  • 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.

R Consortium Pilot Submission

The R Consortium R Submission Working Group

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

Objective and Timeline

  • 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.

Pilot 1 Challenges and Assumptions


  • 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?


  • Focus on analysis and reporting given available ADaM datasets.


FDA Response

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

Future Work

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


Reproducibility Spectrum