[R] 21 CFR Part 11 Compliance and R

Berton Gunter gunter.berton at gene.com
Mon May 23 22:38:25 CEST 2005

To further add to and perhaps clarify Frank's remark: 21 CFR Part 11 defines
certain requirements for electronics records. A general requirement relevant
for statistical software used in submissions is, I presume (quoted):

  " Persons who use closed systems to create, modify, maintain, or 
transmit electronic records shall employ procedures and controls 
designed to ensure the authenticity, integrity, and, when appropriate, 
the confidentiality of electronic records, and to ensure that the signer 
cannot readily repudiate the signed record as not genuine. Such 
procedures and controls shall include the following:
    (a) Validation of systems to ensure accuracy, reliability, 
consistent intended performance, and the ability to discern invalid or 
altered records. "

Note that there is no requirement for ANY specific software -- only that a
process for software validation has been followed. Presumably, ANY
reasonable validation process can be used and, as R already has extensive
built-in validation suites, these certainly should go a long way toward
fulfilling the bulk of this validation requirement. 

The widespread use of SAS within the pharmaceutical industry is simply a
historical legacy (many would say an archaic one, but we won't go there).
Because of a huge existing infrastructure and code base, many companies
don't/can't even consider changing it. This is a common paradigm for
technological change: RCA was working mightily on improving vaccuum tubes
for their TV sets even as Sony was using transistors to blow them away. My
understanding is that it will take decades at least for fiber optics to
replace the gazillions of miles of copper in the phone network even though
that copper is a major obstacle to wider bandwidth and new services.

Older technologies are frequently difficult to displace merely because they
are there. This is certainly heightened in a regulatory environment where
anything that slows approval of a submission -- for example, use of software
that FDA reviewers may not be as familiar with -- is avoided. But that
neither mandates nor argues for avoidance. If R produces better submissions
more efficiently, then why not use it?

-- Bert Gunter
Genentech Non-Clinical Statistics
South San Francisco, CA
"The business of the statistician is to catalyze the scientific learning
process."  - George E. P. Box

> -----Original Message-----
> From: r-help-bounces at stat.math.ethz.ch 
> [mailto:r-help-bounces at stat.math.ethz.ch] On Behalf Of Frank 
> E Harrell Jr
> Sent: Monday, May 23, 2005 12:37 PM
> To: Richard Haney
> Cc: r-help at stat.math.ethz.ch
> Subject: Re: [R] 21 CFR Part 11 Compliance and R
> Richard Haney wrote:
> > I have used S-PLUS, R, MATLAB and SAS for many years, and I 
> am actually 
> > quite happy to use any  of these four languages.  The 
> reason may in part 
> > involve my using the various languages for the purposes to 
> which they seem 
> > most suited.  Hence there are many things for which I would 
> not use SAS or 
> > MATLAB, but for which I would greatly prefer to use R instead.
> > 
> > On the other hand ( to take one of a couple of examples), 
> in the past I 
> > have not even been permitted to use "R" whatsoever in 
> clinical trials 
> > applications, which also typically involve a need for CFR Part 11 
> > compliance.   In this context, though, may I ask if there 
> are people who 
> > have recently been able to use R for clinical trials work 
> that is done 
> > within an FDA-approved 21 CFR Part 11-compliant framework?
> Rich,
> Whoever told you that is not well-informed.  CFR Part 11 has 
> to do with 
> critical software that runs medical devices and about certain primary 
> data management software.  It does not apply to statistical analysis 
> software.  We use R all the time in industry-sponsored and 
> NIH sponsored 
> clinical trials.  You do not need to seek FDA's approval.  
> FDA accepts 
> all comers and does not dictate software policy for analysis. 
>  They even 
> accept Excel and Minitab for NDAs.  There are many messages 
> related to 
> this in the r-help archive; please look at them.
> Frank
> > 
> > Thanks very much.
> > 
> > Rich Haney
> > Richard.Haney at duke.edu
> > Duke Comprehensive Cancer Center
> -- 
> Frank E Harrell Jr   Professor and Chair           School of Medicine
>                       Department of Biostatistics   
> Vanderbilt University
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