NONMEM Users Network Archive

Hosted by Cognigen

Re: Validation Strategy for NONMEM

From: A.J. Rossini <blindglobe>
Date: Fri, 24 Oct 2008 15:43:58 +0200

Nick -

Unfortunately, correctness of results is outside of "validation".
Validation is basically IT qualification of software/systems, combined
with business processes which should ensure that best practices are
followed (modelers appropriately trained, "best practices" for use of
NONMEM implementeed, appropriate review (VPC/etc) of modeling results)
and related to computational reproducibility (if I do this on a
similarly configured machine with a similiarly configured human, I
should get the same results, "similar" being acceptable in most
cases).

Scientific best practices are attempted to be incorporated, but it's
difficult to proceduralize the art form of data analysis. More
importantly, it would be rather inefficient to have a
cookbook-approach which does provide "best practices" -- such a
cookbook would slow down modeling to a crawl (along with the
requirements for a process to describe how to use it).

So most groups punt on the notion of "validation of data analysis for
correct analysis results", and consider "validation of data analysis
for correct reproduction of the results". The latter is feasible,
the former might be impossible to proceduralize (and besides, if we
could, this list would be far less interesting and controversial :-).

best,
-tony





On Tue, Oct 21, 2008 at 11:11 PM, Nick Holford <n.holford
> Tony,
>
> To expand a bit on your useful validation definition.
>
> Making sure computational results are reproducible does not mean they are
> correct. I believe that most NONMEM analyses cannot be proven to be correct
> therefore the validation efforts only assure reproducibility. Whether this
> makes the validation useful or useless is debatable.
>
> Nick
>
>
>
> A.J. Rossini wrote:
>>
>> There is useless validation, and then there is useful validation. The
>> latter is about making sure your computational results are
>> reproducible, the former is about making sure that your documentation
>> can be photocopied. It's sort of the same thing, if you aren't a
>> modeler.
>>
>> Unfortunately, most on this list tend to be modelers.
>>
>> On Tue, Oct 21, 2008 at 7:37 PM, <Michael.J.Fossler
>>
>>>
>>> After reading this, it is no wonder scientific productivity is at an
>>> all-time low. Imagine if Marie Curie had to qualify her radium-purifying
>>> equipment, or if Alexander Fleming had to validate his petri dishes
>>> before
>>> culturing Penecillium. One day scientists are going to push back against
>>> these IT people, who just make busy work for everyone.
>>>
>>>
>>>
>>> Joachim.Grevel
>>> Sent by: owner-nmusers
>>>
>>> 21-Oct-2008 03:18
>>>
>>>
>>> To
>>> nmusers
>>> cc
>>> Subject
>>> Re: [NMusers] Validation Strategy for NONMEM
>>>
>>>
>>>
>>>
>>>
>>> Dear Mark,
>>>
>>> I am engaged in this question since the beginning of this year (not
>>> finished
>>> yet), and I am happy to share some basics of my experiences:
>>>
>>> 1. It is important to specify where the data for NONMEM analysis
>>> come
>>> from. If they come from a GCP source and are already QA-ed when they
>>> arrive
>>> at the doorstep of NONMEM then your system will only subject to GCP
>>> regulation. Otherwise, you also have to comply with GLP.
>>>
>>> 2. There is no way around what is called here a 'Validation Plan'
>>> and
>>> a 'Risk Analysis'. These documents will trigger a slate of other
>>> documents
>>> (in our case here about 15) which describe Installation, Installation
>>> Validation, Qualification of Users, Modeling Strategy, Review Processes,
>>> System Life Cycle Management etc.
>>>
>>> 3. We found it useful to differentiate between 'Exploratory Work'
>>> and
>>> 'Submission Work'.
>>>
>>> 4. Before you worry about passing inspection by the FDA, you need
>>> to
>>> worry about passing inspection of your own company QA officers.
>>>
>>> 5. Just installing NONMEM with NMQual does not render you new
>>> system
>>> 'validated' or 'qualified'. Here my apologies to the excellent folks at
>>> Metrum, but for various reasons, we ended up not using NMQual.
>>>
>>> 6. You have to know what you are trying to build before you
>>> concern
>>> yourself about QA processes. A number of separate installations on PCs
>>> linked to a file server is a different animal from a server-based
>>> installation with a grid engine.
>>>
>>> 7. It all takes more time than you think: make generous budgets
>>> and
>>> time lines.
>>>
>>> I hope I helped more than I confused,
>>>
>>> Joachim
>>>
>>> __________________________________________
>>> Joachim GREVEL, Ph.D.
>>> MERCK SERONO International S.A.
>>> Exploratory Medicine
>>> 1202 Geneva
>>> Tel: +41.22.414.4751
>>> Fax: +41.22.414.3059
>>> Email: joachim.grevel
>>>
>>>
>>>
>>> "Vilicich, Mark" <Mark.Vilicich
>>> Sent by: owner-nmusers
>>>
>>> 10/17/2008 10:08 PM
>>>
>>> To
>>> <nmusers
>>> cc
>>> Subject
>>> [NMusers] Validation Strategy for NONMEM
>>>
>>>
>>>
>>>
>>>
>>>
>>> Dear All,
>>>
>>> I am interested in perspectives on strategies for "validating" NONMEM.
>>> Also,
>>> experiences from or with the FDA since the FDA is: a key user, customer
>>> of
>>> analysis and auditor of NONMEM use in the industry. Without a large
>>> nonmem
>>> staff here, the challenge I see is in scaling the validation strategy to
>>> provide the most efficient environment for doing analysis that is
>>> defensible
>>> to both internal and external audits based on the associated GxP risk
>>> level.
>>>
>>> Below are the concepts I've cobbled together, though instead of my
>>> reinventing the wheel I appreciate anything you could share. Any and all
>>> gems of insight you can share whether it regard the big picture or some
>>> detailed specifics, IT centric or business process related. You may send
>>> them back to the listserver or me directly as you feel appropriate.
>>>
>>> Details:
>>> ~~~~~~~~~~~~~~~~~~~~~~~~~~~
>>> From searching the archives and other random bits of knowledge on NONMEM,
>>> part of the validation strategy is to recognize that NONMEM is not to be
>>> literally validated. NONMEM may be considered more of a development
>>> environment, optimized for developing specialized forms of complex
>>> analysis
>>> and modeling. As a development platform, an approach could be that NONMEM
>>> itself is qualified and each specific analysis is validated individually.
>>>
>>> To support establishing a defensible NONMEM environment, I've also read
>>> discussions on integrating common software development best practices
>>> such
>>> as version control of the "programming" of nonmem, NMQual and other
>>> commercial and custom tools for capturing all the metadata related to
>>> running a specific NONMEM job. These themes support defining the state of
>>> the NONMEM environment and ability to reproduce the outcomes.
>>>
>>> Also, reading in the archives about the differences in the numeric
>>> outcomes
>>> of NONMEM analyses based on the hardware platform, etc. are helpful to
>>> know
>>> up front and to consider in the validation strategy so it is not destined
>>> to
>>> failure if the target environment is multiplatform or otherwise complex.
>>>
>>> Gaps noticed/topics not discussed:
>>> ~~~~~~~~~~~~~~~~~~~~~~~~~~~
>>> Is there opportunity in looking at the risk based approached sanctioned
>>> by
>>> the FDA a few years ago that would make the total validation deliverable,
>>> including both the application and the model development process, more
>>> lean
>>> and targeted at the primary risk targets?
>>>
>>> Does this scientific software environment lend itself to use of modern
>>> agile
>>> software development methodologies that go far beyond basic iterative
>>> approaches. These methodologies are being used in software development
>>> for
>>> the regulated/GxP industry.
>>>
>>> I've seen the excellent presentation from 2004 that Joga Gobburu from the
>>> FDA gave, seems like there has been some progression of thought or
>>> actions
>>> on the proposals included there. Any references to follow-up information
>>> on
>>> it would be helpful?
>>>
>>> Regards ,
>>>
>>> Mark Vilicich
>>> Early Development
>>> mark.vilicich
>>>
>>> ________________________________
>>>
>>> This message and any attachment are confidential, may be privileged or
>>> otherwise protected from disclosure and are intended only for use by the
>>> addressee(s) named herein. If you are not the intended recipient, you
>>> must
>>> not copy this message or attachment or disclose the contents to any other
>>> person. If you have received this transmission in error, please notify
>>> the
>>> sender immediately and delete the message and any attachment from your
>>> system. Merck Serono does not accept liability for any omissions or
>>> errors
>>> in this message which may arise as a result of E-Mail-transmission or for
>>> damages resulting from any unauthorized changes of the content of this
>>> message and any attachment thereto. If verification is required, please
>>> request a hard-copy version. Merck Serono does not guarantee that this
>>> message is free of viruses and does not accept liability for any damages
>>> caused by any virus transmitted therewith.
>>>
>>
>>
>>
>>
>
> --
> Nick Holford, Dept Pharmacology & Clinical Pharmacology
> University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
> n.holford
> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
>
>



--
best,
-tony

blindglobe
Muttenz, Switzerland.
"Commit early,commit often, and commit in a repository from which we
can easily roll-back your mistakes" (AJR, 4Jan05).

Drink Coffee: Do stupid things faster with more energy!
Received on Fri Oct 24 2008 - 09:43:58 EDT

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to: nmusers-request@iconplc.com.

Once subscribed, you may contribute to the discussion by emailing: nmusers@globomaxnm.com.