R in regulated environments [R for BE/BA]

posted by Helmut Homepage – Vienna, Austria, 2019-08-28 14:58  – Posting: # 20527
Views: 3,595

Dear all,

[image]since occasionally the question is asked whether R is accepted in regulatory environments, here the answers:
  1. Yes, if the installation and code is validated.
  2. If you are an expert and understand what #1 means with all its pitfalls,
    • stop reading the post here;
    • otherwise, get a cup of coffee and continue.

Any (!) system has to pass three levels (definitions given in ISO 9000 and by the FDA in 1999 and 2002):
  1. Installation Qualification (IQ)
       The system is compliant with appropriate codes and approved design intentions, and that vendor’s recommendations are suitably considered.
  2. Operational Qualification (OQ)
       The system is capable of consistently operating within stated limits and tolerances.
  3. Performance Qualification (PQ)
       The system is meeting all release requirements for functionality and safety and that procedures are effective and reproducible.
Whereas #1 generally is the job of the vendor, #2 can be shared between the vendor and user, the responsibility for #3 lies entirely in the hands of the user.
   Since the source code of commercial software is not accessible to the user, only a black box validation can be performed (i.e., compare results of reference data sets with published ones). Open source software (e.g., R, GNU Octave, …) allows – by definition – a white box validation but this can be tough (requires an experienced coder). Hence, in practice most users opt for a black box validation as well. See also reference data sets for various designs in BE.1,2,3

Quotes from relevant documents:
When it comes to R, a lot is going on – especially with support of regulators, the academia, and innovators.9,10,11,12 Sebastian Wolf of Roche Diagnostics presented11 a 500,000+ lines Shiny application.14 ;-)
   One reason for the increasing popularity of R in the industry is that the statistical curriculum gradually shifted from SAS to R and nowadays graduates are at least “bilingual” (nerds are even proficient in FORTRAN and/or C). Young statisticians are no more willing to accept a “SAS only” working environment.


  1. Schütz H, Labes D, Fuglsang A. Reference Datasets for 2-Treatment, 2-Sequence, 2-Period Bioequivalence Studies. AAPS J. 2014; 16(6): 1292–7. doi:10.1208/s12248-014-9661-0. [image] free resource.
  2. Fuglsang A, Schütz H, Labes D. Reference Datasets for Bioequivalence Trials in a Two-Group Parallel Design. AAPS J. 2015; 17(2): 400–4. doi:10.1208/s12248-014-9704-6. [image] free resource.
  3. Schütz H, Tomashevskiy M, Labes D, Shitova A, González-de la Parra M, Fuglsang A.Reference Data­sets for Studies in a Replicate Design intended for Average Bioequivalence with Expanding Limits. AAPS J. 2020; 22(2): Online First 7 February 2020. doi:10.1208/s12248-020-0427-6.
  4. International Council for Harmonisation. Statistical Principles for Clinical Trials E9. 5 February 1998.
  5. European Medicines Agency, GCP Inspectors Working Group. Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials. London, 9 June 2010.
  6. US FDA. Statistical Software Clarifying Statement. May 6, 2015. Study Data Standards.
  7. World Health Organization. Technical Report Series No. 996, Annex 9. Guidance for organizations performing in vivo bioequivalence studies. Geneva, May 2016.
  8. International Council for Harmonisation. Integrated Addendum to ICH E6(R1): Guideline For Good Clinical Practice E6(R2). 9 November 2016.
  9. The R Foundation for Statistical Computing. R: Regulatory Compliance and Validation Issues. A Guidance Document for the Use of R in Regulated Clinical Trial Environments. Vienna, March 25, 2018. [image] free resource.
  10. Smith D. How R is used by the FDA for regulatory compliance. June 29, 2017.
  11. R/Pharma 2018. Harvard University, 15/16th August, 2018. Program.
  12. Rickert J. Conference Report: R / Pharma 2018. R J. 2018;10(2):579–80.
  13. pharmaR. Validation Overview.
  14. Wolf S. How to Build A Shiny “Truck”! 2018-08-14.

Cheers,
Helmut Schütz
[image]

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