[R] SAS or R software

A.J. Rossini blindglobe at gmail.com
Mon Dec 20 08:22:35 CET 2004

All good points; in my current organization there seem to be 3 hurdles
that need to be crossed.  Most are internal issues, but all related to
conservative interpretation of Part 11.

1. Qualifications:  installation, operational, and performance.  R
clearly satisfies the first and third, the second perhaps needs
someone in R core or similar (i.e. consultant, etc)  needs to provide
the OQ.

2. Statistical results as derived variables (i.e. data).  If so, then
Part 11 can apply, if not it might not.

3.  Removing the "Open Source" moniker (which gets legal people really
upset) and treating R as quality vendor-supplied code under a novel
licensing scheme which has source available and for which a business
case can be made.  Back in the old days (i.e. when I was in high
school in the 80s), our school mini computers had source for the OSs
available, and for most critical vendor or contractor suppiled
software, we had source.  In fact, it was standard!

Anyway, I'm slowly working on these issues internally.  At somepoint,
there will be a breakthrough at one pharma, making it easier for the
rest.  Right now my issue is how to deal with Clinical QA, the
equivalent group is a nightmare bureaucracy to work through, I'm sure,
at most large pharmas.


On Sat, 18 Dec 2004 14:10:40 +0100, Henric Nilsson
<henric.nilsson at statisticon.se> wrote:
> Marc Schwartz said the following on 2004-12-18 01:19:
> > As you are likely aware, other statistically relevant issues are
> > contained in various ICH guidance documents regarding GCP considerations
> > and principles for clinical trials:
> >
> > http://www.ich.org/UrlGrpServer.jser?@_ID=475&@_TEMPLATE=272
> ICH E9 states that (p. 27):
> "The computer software used for data management and statistical analysis
> should be reliable, and documentation of appropriate software testing
> procedures should be available."
> Some commercial software vendors (SAS, Insightful, and StatSoft) offer
> white papers stating that their software can work within an 21 CFR Part
> 11 compliant system.
> http://www.sas.com/industry/pharma/develop/papers.html
> http://www.insightful.com/industry/pharm/21cfr_part11_Final.pdf
> http://www.statsoft.com/support/whitepapers/pdf/STATISTICA_CFR.pdf
> Some commercial vendors (SAS and Insightful) also offers tools for
> validation of the installation and operation of the software. SAS has
> http://support.sas.com/documentation/installcenter/common/91/ts1m3/qualification_tools_guide.pdf
> and S-PLUS has validate().
> As a statistical consultant working within the pharamceutical industry,
> I think that our clients find the white papers being some kind of
> quality seal. It signals that someone has actually thought about the
> issues involved, written a document about it, and even stated that it
> can be done. Of course, there's a lot of FUD going on here. But if our
> lives can be made simpler by producing similar white papers and QA
> tools, why not?
> (But for some people, only SAS will do:
> Last week we were audited on behalf of a client. One of the specific
> issues discussed were validation and the Part 11 compliance of S-PLUS.
> In this specific trial, data are to be transferred from Oracle Clinical
> -> SAS -> SPLUS, and they auditors were really worried about the first
> and last link of that chain. Finally, they suggested using only SAS...
> And in this particular case, Part 11 is really a non-issue since
> physical records exists (i.e. case report forms) and all final S-PLUS
> output and code will also be stored physically (i.e. print-outs) -- no
> need for electronic signatures here!)
> > There is also a general guidance document for computer systems used in
> > clinical trials here:
> >
> > http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm
> >
> > Though it is to be superseded by a draft document here:
> >
> > http://www.fda.gov/cder/guidance/6032dft.htm
> From the introduction (p. 2):
> "This document provides guidance about computerized systems that are
> used to create, modify, maintain, archive, retrieve, or transmit
> clinical data required to be maintained and/or submitted to the Food and
> Drug Administration (FDA)"
> The `retrieve' part is certainly applicable. If we regard R as
> off-the-shelf software, the guidance says (p. 11):
> "For most off-the-shelf software, the design level validation will have
> already been done by the company that wrote the software. Given the
> importance of ensuring valid clinical trial data, FDA suggests that the
> sponsor or contract research organization (CRO) have documentation
> (either original validation documents or on-site vendor audit documents)
> of this design level validation by the vendor and would itself have
> performed functional testing (e.g., by use of test data sets) and
> researched known software limitations, problems, and defect corrections.
> Detailed documentation of any additional validation efforts performed by
> the sponsor or CRO will preserve the findings of these efforts.
> In the special case of database and spreadsheet software that is: (1)
> purchased off-the-shelf, (2) designed for and widely used for general
> purposes, (3) unmodified, and (4) not being used for direct entry of
> data, the sponsor or contract research organization may not have
> documentation of design level validation. FDA suggests that the sponsor
> or contract research organization perform functional testing (e.g., by
> use of test data sets) and research known software limitations,
> problems, and defect corrections.
> In the case of off-the-shelf software, we recommend that the following
> be available to the Agency on request:
> * A written design specification that describes what the software is
> intended to do and how it is intended to do it;
> * A written test plan based on the design specification, including both
> structural and functional analysis; and
> * Test results and an evaluation of how these results demonstrate that
> the predetermined design specification has been met."
> I think the guidance is quite clear here. We must prove to the FDA, at
> their wish, that the software used is working properly. In order to do
> this, we seem to need documents describing the development process and
> the QA tools used by R Core. An idea of what we'll need may be found in
> the `Computer Systems Validation in Clinical Research - A Practical
> Guide (Edition 1)' at
> http://www.acdm.org.uk/public/publications/publications.htm
> Especially section 2.4, 5 + subsections, 8 + subsections, and 9.7 +
> subsections seem relevant. (I've ordered the 2nd edition, but it hasn't
> arrived yet.)
> Henric
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A.J. Rossini
blindglobe at gmail.com

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