Challenges in Clinical Data Analysis with RIan CookRaleigh-Durham-Chapel Hill R Users Group

January 24, 2013

Background

• R is a full-featured and mature environment for clinical data analysis

• Significant use of R by industry in non-regulated environments, but R has been slower to penetrate regulated environments, e.g. clinical trials, financial services

• Common misperception exists that R cannot support the various regulatory requirements for validation/qualification

FDA Regulatory Guidance

• 21 CFR Part 11 - Electronic Records; Electronic Signatures

• Validation of systems to ensure accuracy, reliability and consistent intended performance

• Paper equivalence in deployed environment

• 21 CFR Part 58 - Good Laboratory Practice (GLP)

• 21 CFR Part 312 - Good Clinical Practice (GCP)

• 21 CFR Part 210 - Current Good Manufacturing Practice (cGMP)

• Guidance for Industry - Computerized Systems Used in Clinical Investigations (2007)

• General Principles of Software Validation; Final Guidance for Industry and FDA Staff (2002)

JSM : Use of R in Regulated Environment

• FDA talk with Sue Bell at JSM 2006:“Times ‘R’ A Changing: FDA Perspectives on Use of ‘Open Source’”

• No regulation prohibiting open source

• FDA narrowly interprets and enforces 21 CFR 11• Software installation, operation and performance must be

“qualified” to be reproducibly installed and tested to ensure accuracy, reliability and consistent intended performance in regulated company’s environment (IQ/OQ/PQ)

• FDA expects to be able to reconstruct a clinical study submitted to the agency

• FDA may ask to see the regulated company’s documentation that demonstrates software qualification

useR! : Use of R in Regulated Environment

• useR! 2007 session hosted by Marc Schwartz• Perception of SAS as the gold standard, but reasons to

be optimistic about future of R in regulated environments

• useR! 2007 Frank Harrell talk• Validation should encompass practices to prevent user

error• R includes tools to eliminate tedious low-level commands

and manual actions, resulting in fewer sources of error

• useR! 2007 Anthony Rossini and David A. James (Novartis) talk• R presents risks in regulated environments, but

manageable given proper validation and qualification procedures

useR! : Use of R in Regulated Environment (continued)

• useR! 2007 Mat Soukup (FDA) talk• FDA Reviewer Expectations/Requests for

submissions generated with R• What R functions are used and where do they reside (base

vs. user-contributed packages)?• Have the R functions been properly validated in user

environment?• Can the validation tests be reproduced?• Is there any certification of the validation test?• Are there any known data structures which can potentially

alter results?

useR! : Use of R in Regulated Environment (continued)

• Announcement of document from the R Foundation at useR! 2007:

“R: Regulatory Compliance and Validation Issues: A Guidance Document for the Use of R in Regulated Clinical Trial Environments”

• Document addresses significant hurdles, but burden of implementation on users

http://www.r-project.org/doc/R-FDA.pdf

useR! : Use of R in Regulated Environment (continued)

• useR! 2011 Ian Cook and Michael O’Connell (TIBCO) talk• Framework for successfully complying with regulatory

software validation requirements when using R• useR! 2012 Jae Brodsky (FDA) talk

• Drug developers may use R in their FDA submissions.• "R use at the FDA is completely acceptable and has

not caused any problems."

Learning More

“Clinical Trial Data Analysis Using R” (2010)• Presents methods for

analysis of clinical trial data

• Shows step by step how to implement the statistical methods using R

http://www.crcpress.com/product/isbn/9781439840207