[NMusers] Test2

[Pascal Girard]

Test2



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[NMusers] Test

[Pascal Girard]

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[NMusers] Two Positions at Merck Pharmacometric Department in Darmstadt and Lausanne

[Pascal Girard]

Dear NMUSER,

Merck is seeking two creative, motivated scientists to join our Pharmacometric 
department as Senior Scientists, one  in Darmstadt, Germany 
(https://career012.successfactors.eu/career?company=merckgroup   Req Id 147355) 
and one in Lausanne, Switzerland (Req Id 151627).

As the biopharma business of Merck, we have an enduring commitment to transform 
lives through innovative medicines and high-value solutions. We focus on areas 
of high unmet medical needs and are a leader in providing differentiated 
medicines to help improve patient outcomes in key areas such as cancer, 
multiple sclerosis, infertility, endocrine and metabolic disorders. With 
headquarter in Darmstadt, Germany,  we're active on all continents and offer 
leading brands in 150 countries. In the United States and Canada we operate 
under the name EMD Serono through separately incorporated affiliates.

YOUR ROLE
Pharmacometric Department, part of GED/QPD/QP, contributes to clinical 
development efficiency by providing core expertise modeling in the 
quantification of the relationship between dose, exposure and response, and 
factors affecting its variability. As senior pharmacometrician, you will have 
to elaborate, design, execute/supervise and report 
pharmacokinetic/pharmacodynamic (PK/PD) and modeling and simulation analysis in 
order to support model informed drug development discovery, in collaboration 
with pharmacology, clinical and biostatistics teams. As an experienced 
scientist, you will also keep up-to-date with scientific development in PK/PD 
and share your own expertise with pharmacometric colleagues

WHO YOU ARE
- PhD, MD, PharmD or Master with 4+ years of experience in PK/PD Modeling, of 
which 2+ in (Bio)Pharmaceutical Industry
- NONMEM and R experience is a requisite;
- experience with XPose, PsN, MONOLIX, SIMULX, SIMCYP, etc would be a good asset
- Communicate technical results and details effectively with scientists and 
clinicians
-At ease in working in a dynamic matrix organization; is a team-player
- Fluent in speaking and writing English; fluency in other European languages, 
particularly German or French, is an asset

To apply to the Darmstadt position, please  visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup   and enter the 
Requisition ID: 147355.

To apply to the Darmstadt position, please  visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup   and enter the 
Requisition ID: 151627.

With best regards,

Pascal Girard
Director, Head of Pharmacometry

Merck

Merck Institute for Pharmacometrics,
EPFL Innovation Park - Building I, CH-1015 Lausanne, Switzerland
Email: pascal.gir...@merckgroup.com<mailto:pascal.gir...@merckgroup.com> | 
www.merckgroup.com<http://www.merckgroup.com>
Mandatory information can be found at: http://www.merckgroup.com/mandatories



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Re: [NMusers] ASCO and pharmacometrics

[Pascal Girard]

Dear Dennis, Joga, Naoto-san and All

Dennis, I fully agree with your two comments .

Concerning my mail, I should have written: the abstract "corrected by 
clinicians challenging **up to** the last comma and p-value." Which means they 
did much more than looking at commas, which by the end greatly improved the 
abstract. They valued the work, care about science, wanted to understand and by 
the end improved the abstract to give it all chances.

I fully concur also with Joga and believe this is the path to follow.

Kind regards

Pascal
Envoy? de mon iPhone

Le 7 avr. 2016 ? 19:11, Dennis Fisher 
<fis...@plessthan.com<mailto:fis...@plessthan.com>> a ?crit :

I agree with Phil.  I have presented recently at two large endocrine meetings, 
one in the US, one in Europe.  In both cases, I took complicated PK/PD models 
and kept it simple, emphasizing how the models could / would be used in 
clinical development and clinical practice.  The response at both meetings was 
excellent - lots of people expressing interest in the models (and, 
interestingly, two of the competitors to the company for which I was consulting 
tried to enlist my consulting help).

And, I disagree with Nick's comment yesterday.  Perhaps oncology clinicians are 
concerned about commas (I cannot speak to that issue) but I truly doubt Nick's 
claim that they don't care about science - the advances in oncology in recent 
years have been remarkable.


Dennis Fisher MD
P < (The "P Less Than" Company)
Phone: 1-866-PLessThan (1-866-753-7784)
Fax: 1-866-PLessThan (1-866-753-7784)
www.PLessThan.com<http://www.plessthan.com/>



On Apr 7, 2016, at 7:49 AM, Lowe, Phil 
<phil.l...@novartis.com<mailto:phil.l...@novartis.com>> wrote:

I would echo Pascal's point. Getting pharmacometric work into large clinical 
conferences is not straightforward. It can be done (see 
link)http://erj.ersjournals.com/content/46/suppl_59/PA5091.abstract but note 
where I was in the author list as the sole modeller. It helps to work closely 
with the clinicians on the messaging. That said, it was fun at the meeting, 
explaining the data and model curves to clinicians with them asking how such 
knowledge could impact their patients. An eye-opener. Keep trying Naoto!

All the best, Phil

Philip J Lowe PhD
Executive Director Pharmacometrics Scientist
Novartis Pharma AG, WSJ-027.6.25 or WSJ-386.12.48.46
4056 Basel, Switzerland
Phone: +41 61 324 4676
phil.l...@novartis.com<mailto:phil.l...@novartis.com>

From: owner-nmus...@globomaxnm.com<mailto:owner-nmus...@globomaxnm.com> 
[mailto:owner-nmus...@globomaxnm.com] On Behalf Of Pascal Girard
Sent: 06 April 2016 10:39
To: Naoto Hayashi; jgre...@btconnect.com<mailto:jgre...@btconnect.com>
Cc: nmusers
Subject: RE: [NMusers] ASCO and pharmacometrics

Dear Naoto,

In the past, Rene Bruno got one poster accepted with discussion at ASCO. He is 
our "champion" !

I got one accepted on model for Exp-Tumor Size - OS at European Cancer Congress 
2013 . But I can tell you that a medical writer rewrote it entirely and it took 
1 month to get it reviewed and corrected by clinicians challenging every comma 
and p-value.

To give you an idea of the respective size of the meetings: ACOP N=500, PAGE 
N>600, ECC N> 10,000, ASCO N>20,000.

So the advice I would give, is just improve the quality and readability of our 
abstract and it will make it. By readability, I mean show it to an oncologist 
clinician. If he does not understand, rewrite it with the help of a medical 
writer ...

With best regards / Mit freundlichen Gr??en /  Cordialement

Pascal




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RE: [NMusers] ASCO and pharmacometrics

[Pascal Girard]

Dear Naoto,

In the past, Rene Bruno got one poster accepted with discussion at ASCO. He is 
our ”champion” !

I got one accepted on model for Exp-Tumor Size – OS at European Cancer Congress 
2013 . But I can tell you that a medical writer rewrote it entirely and it took 
1 month to get it reviewed and corrected by clinicians challenging every comma 
and p-value.

To give you an idea of the respective size of the meetings: ACOP N=500, PAGE 
N>600, ECC N> 10,000, ASCO N>20,000.

So the advice I would give, is just improve the quality and readability of our 
abstract and it will meke it. By readability, I mean show it to an oncologist 
clinician. If he does not understand, rewrite it with the help of a medical 
writer …

With best regards / Mit freundlichen Grüßen /  Cordialement

Pascal

Vacation
7 April


From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On 
Behalf Of Naoto Hayashi
Sent: 06 April 2016 09:46
To: jgre...@btconnect.com
Cc: nmusers 
Subject: Re: [NMusers] ASCO and pharmacometrics

Dear Joachim,

Thank you so much for your reply.

Their abstract instruction allows very small number of characters, and no 
enough room to express what we had established in this work.

Although we described the unique results in the table, they probably could not 
understand its meaning, or the model's outcome that I was so excited has no 
meaning to oncologist.

It seemed so nice work for me and I hope that US pharmacometrician society 
would communicate with ASCO people for our future.

Thanks!

Best regards,
Naoto Hayashi, PhD


2016-04-06 15:58 GMT+09:00 Joachim Grevel 
>:
Dear Naoto,
Your experience is also mine. For a combined TTE safety and efficacy analysis I 
earned the online publication. The organisers do not believe in modelling, 
unless it describes what is already visible in graphs and tables of raw data.
This is just my personal impression. I have not been to ASCO either.

Good luck,
Joachim


Joachim Grevel, PhD
Scientific Director
BAST Inc Limited
Science & Enterprise Park
Loughborough University
Loughborough, LE11 3AQ
United Kingdom

Tel: +44 (0)1509 222908
www.bastinc.eu



From: owner-nmus...@globomaxnm.com 
[mailto:owner-nmus...@globomaxnm.com] On 
Behalf Of Naoto Hayashi
Sent: 06 April 2016 02:38
To: nmusers@globomaxnm.com
Subject: [NMusers] ASCO and pharmacometrics


Dear all,

I have a question and appreciate it if somebody can answer to me.

We had submitted an abstract to ASCO annual meeting presentation 2016, and its 
contents included a pharmacometrics work of quantitative safety profile 
analysis of an anticancer drug.  The behave of the safety index time courses is 
very unique and its results showed a very high usefulness of this drug.  The 
abstract also included the table of population PK/PD parameters that expressed 
its nature, and it was compared with the similar older drug safety profile and 
demonstrated very high safer profile quantitatively.

I have some experiences to publish some articles of population PK/PD work in 
several clinical pharmacology journals in the past, and I was so confident for 
just a poster presentation in ASCO.  However, the judgment was “publication 
only”, i.e. just presentation in online but no poster presentation and no 
official record of publication officially.

So, my question is whether pharmacometrics work is difficult to be picked up in 
ASCO presentation.  Or, was my work evaluated to have no worth to be presented 
even in poster session because the pharmacometrics works presented in ASCO are 
having very high level?

I have never visited ASCO before, and I just want to hear opinions about how 
much of importance is considered for pharmacometrics work in ASCO.

Thanks a lot in advance for your comments/thoughts.

Best regards,
Naoto Hayashi




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[NMusers] forest plots in Xpose?

[Pascal Girard]

Dear NONMEM users, Dear Uppsala Folks, Dear Christopher

I was looking for some Xpose function that would automatically create a forest 
plot from NONMEM output in order to present the results of covariate analysis, 
assuming that all covariate models have been implemented the same way with same 
NULL  value. The only thing I found was the Covariates function in the popPK 
package, which makes use of Xpose, developed by Christoffer Tornoe while he was 
at FDA. http://www2.uaem.mx/r-mirror/web/packages/popPK/popPK.pdf

But this package looks like to be no longer supported and has been removed from 
the CRAN.

Has anyone developed such a package?

With best regards / Mit freundlichen Grüßen /  Cordialement / 祝好 / よろしくお願いします

Pascal

Pascal Girard
Director, Pharmacometry
Merck Serono | Global Early Development

"Merck – Living Innovation"

Merck Institute for Pharmacometrics - Merck Serono S.A.
EPFL Innovation Park - Building I, CH-1015 Lausanne, Switzerland
Phone: +41 21 900 3702 | Mobile:  +41 79 508 7898
Email: pascal.gir...@merckgroup.com | www.merckserono.com
Mandatory information can be found at: http://www.merckgroup.com/mandatories
Please consider your environmental responsibility before printing this e-mail




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[NMusers] Quantitative Pharmacology Positions @ Merck Serono

[pascal . girard]

Merck is a global leader in specialized pharma and chemicals, and for almost 
350 years we have improved people's quality of life. This is due to the 
creativity and team spirit of our 40,000 employees around the world, so we're 
committed to help them develop and to reward their excellence.

PHARMACOMETRICIAN POSITIONS @ Merck Serono
The Quantitative Pharmacology department at Merck Serono gathers under the same 
roof modelers with broad expertise from translational PKPD to PBPK, and up to 
pharmacometrics. We work on projects covering small molecules, large molecules 
modalities and more recently ADCs, all the way in the drug development value 
chain from early Discovery up to Life Cycle Management, with exciting programs 
in (Immuno-) Oncology and (Auto-) Immune Diseases. Our group is expanding and 
we have several open opportunities in   in Frankfurt area/Germany and in 
Lausanne/Switzerland.

WHO YOU ARE:
You are an enthusiastic, strong team player, reliable, dedicated, competent 
professional seeking opportunities to develop and grow in a dynamic environment 
and recognized group? Go to 
https://career012.successfactors.eu/career?company=merckgroup  and enter the 
Req ID that interests you:
* Team Leader, Pharmacometry, Frankfurt area, Germany (Req ID: 
41221)
* Senior Scientist, Pharmacometry, Frankfurt area, Germany (Req ID: 
88561)
* Senior Scientist, Pharmacometry, Lausanne, Switzerland (Req ID: 
59283)
* Postdoc Pharmacometry (1.5 Y contract), Lausanne, Switzerland 
(Req ID: 86766)

PROFESSIONAL SKILLS  EXPERIENCE SPECIFIC FOR THE TEAM LEADER POSITION
* Being an established senior scientist
* 5 to 7+ years experience in PKPD Modeling, of which 3+ in 
BioPharmaceutical Industry.
* Having successfully run pharmacometric project in drug 
development and/or having some experience of management over a small team of 
pharmacometry.
* Experience with PKPD MS input into drug development.

PROFESSIONAL SKILLS  EXPERIENCE FOR ALL POSITIONS
* Good command of NONMEM is an absolute prerequisite, experience 
with MONOLIX is an asset.
* Good command of R is an absolute prerequisite, experience with 
SAS is  an asset.
* Experience with PsN and Xpose is another asset.
* Experience with Clinical Trial Simulation tools is another asset, 
alike for other analytical/modeling/ optimization/presentation software or 
language, e.g. ADAPT, SAAM II, BERKELEY MADONA, SIMCYP
* Experience in writing and using PKPD models, particularly 
mechanistic-models and in developing disease progression models is an asset.
* Overall good knowledge of common PC software.

PERSONAL SKILLS  COMPETENCIES
* Strong problem solving skills and ability to analyze complex 
problems
* Has interest in, and knowledge of, both mathematical and 
(patho-)physiological aspects of MS in drug development
* Is enthusiastic, self-motivated and has good communication 
skills, and at ease in working in a dynamic matrix organization; is a 
team-player. Communicate technical details effectively with scientists and 
clinicians colleagues


With best regards ,

Pascal Girard
Director, Pharmacometry
Merck Serono | Global Early Development

Merck - Living Innovation

Merck Institute for Pharmacometrics - Merck Serono S.A.
EPFL Innovation Park - Building I, CH-1015 Lausanne, Switzerland
Phone: +41 21 900 3702 | Mobile:  +41 79 508 7898
Email: pascal.gir...@merckgroup.com | www.merckserono.com
Mandatory information can be found at: http://www.merckgroup.com/mandatories
Please consider your environmental responsibility before printing this e-mail

This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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 
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[NMusers] Merck Serono: Manager in Pharmacometrics position

[pascal . girard]

MERCK SERONO IS THE BIOPHARMACEUTICAL DIVISION OF MERCK
At Merck Serono, we discover, develop, manufacture and market innovative small 
molecules and biopharmaceuticals in our focus therapeutic areas:
* Oncology
* Neurodegenerative diseases
* Fertility
* Endocrinology
* CardioMetabolic Care
With headquarter in Darmstadt, Germany, and over 16,000 people worldwide, we're 
active on all continents and offer leading brands in 150 countries. In the 
United States and Canada, EMD Serono operates through separately incorporated 
affiliates.

Merck Serono is seeking a creative, motivated scientists to join our 
Pharmacometric department as local Manager. The position will be based  in 
Darmstadt (Germany).

To apply please visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup   and enter the 
Requisition ID: 41221.

PURPOSE OF THE ROLE
The manager will report to the head of pharmacometry. He will have her/his own 
pharmacometric project and will also have to lead  and provide input  and 
guidance to a local team of senior pharmacometricians who develop MS 
methodologies and expertise in drug development and make them available to 
facilitate more efficient and informative clinical trials, inform decision 
making, and globally support Clinical Pharmacology, Exploratory Medicine, 
Clinical Development, Clinical Teams and Projects.

PROFESSIONAL SKILLS  EXPERIENCE SPECIFIC FOR THE MANAGER
* Being an established senior scientist
* 5 to 7+ years experience in PKPD Modeling, of which 3+ in 
BioPharmaceutical Industry.
* Having successfully run pharmacometric project in drug 
development and/or having some experience of management over a small team of 
pharmacometry.
* Experience with PKPD MS input into drug development.

KEY TASKS  RESPONSIBILITIES
* Globally support the Quantitative Pharmacology department within 
Global Early Development
* Provide MS input into Clinical Development Plans
* Participate to sound translational science, from animal to 
healthy subjects, to patients, to special populations
* Plan, perform, interpret, present, track and record MS-related 
activities within allocated projects and studies
* Keep up-to-date with scientific development in MS, and 
regulatory guidance and trends
* Develop internal expertise in advanced population PKPD modeling, 
with emphasis on physiological and mechanistic approaches
* Explore, evaluate and implement appropriate pharmacometric tools 
and methodologies; participate to the improvement of the MS processes and 
technological platform
* Representation of the whole of Quantitative Pharmacology in 
transactions with internal and external stakeholders

EDUCATION/LANGUAGES
* Master or higher degree in Clinical Sciences related disciplines 
(Medicine, Physiology, Pharmaceutical Sciences, etc) and strong expertise in 
Pharmacometrics/biostatistics. Alternatively, degree in Mathematics/Statistics 
and strong experience in clinical development.
* Fluent in written and oral English
* Fluency in other European languages, particularly German, is an 
asset

PROFESSIONAL SKILLS  EXPERIENCE
* Good command of NONMEM is an absolute prerequisite, experience 
with MONOLIX is an asset.
* Good command of R is an absolute prerequisite, experience with 
SAS is  an asset.
* Experience with PsN and Xpose is another asset.
* Experience with Clinical Trial Simulation tools is another asset, 
alike for other analytical/modeling/ optimization/presentation software or 
language, e.g. ADAPT, SAAM II, BERKELEY MADONA, SIMCYP
* Experience in writing and using PKPD models, particularly 
mechanistic-models and in developing disease progression models is an asset.
* Overall good knowledge of common PC software.

PERSONAL SKILLS  COMPETENCIES
* Strong problem solving skills and ability to analyze complex 
problems
* Has interest in, and knowledge of, both mathematical and 
(patho-)physiological aspects of MS in drug development
* Is enthusiastic, self-motivated and has good communication 
skills, and at ease in working in a dynamic matrix organization; is a 
team-player. Communicate technical details effectively with scientists and 
clinicians colleagues

To apply please visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup   and enter the 
following Requisition ID 41221  for the manager position in Darmstadt.

With best regards,

Pascal Girard
Director, Head of Pharmacometry
Merck Serono | Global Early Development

Merck - Living Innovation

Merck Institute for Pharmacometrics - Merck Serono S.A.
EPFL Innovation Park - Building I, CH-1015 Lausanne, Switzerland
Phone: +41 21

[NMusers] RE: Standard errors of estimates for strictly positive parameters

[pascal . girard]

Dear Aziz,

NM does not return the asymptotic SE of THETA(1) in model 1 on the log-scale. 
So I would use model 2.

With best regards / Mit freundlichen Grüßen /  Cordialement

Pascal

From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On 
Behalf Of Chaouch Aziz
Sent: 11 February 2015 17:22
To: nmusers@globomaxnm.com
Subject: [NMusers] Standard errors of estimates for strictly positive parameters


Hi,



I'm interested in generating samples from the asymptotic sampling distribution 
of population parameter estimates from a published PKPOP model fitted with 
NONMEM. By definition, parameter estimates are asymptotically (multivariate) 
normally distributed (unconstrained optimization) with mean M and covariance C, 
where M is the vector of parameter estimates and C is the covariance matrix of 
estimates (returned by $COV and available in the lst file).



Consider the 2 models below:



Model 1:

TVCL = THETA(1)

CL = TVCL*EXP(ETA(1))



Model 2:

TVCL = EXP(THETA(1))

CL = TVCL*EXP(ETA(1))



It is clear that model 1 and model 2 will provide exactly the same fit. 
However, although in both cases the standard error of estimates (SE) will refer 
to THETA(1), the asymptotic sampling distribution of TVCL will be normal in 
model 1 while it will be lognormal in model 2. Therefore if one is interested 
in generating random samples from the asymptotic distribution of TVCL, some of 
these samples might be negative in model 1 while they'll remain nicely positive 
in model 2. The same would happen with bounds of (asymptotic) confidence 
intervals: in model 1 the lower bound of a 95% confidence interval for TVCL 
might be negative (unrealistic) while it would remain positive in model 2.



This has obviously no impact for point estimates or even confidence intervals 
constructed via non-parametric bootstrap since boundary constraints can be 
placed on parameters in NONMEM. But what if one is interested in the asymptotic 
covariance matrix of estimates returned by $COV? The asymptotic sampling 
distribution of parameter estimates is (multivariate) normal only if the 
optimization is unconstrained! Doesn't this then speak in favour of model 2 
over model 1? Or does NONMEM take care of it and returns the asymptotic SE of 
THETA(1) in model 1 on the log-scale (when boundary constraints are placed on 
the parameter)?



Thanks,



Aziz Chaouch
This message and any attachment are confidential and may be privileged or 
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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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, 
Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

Click http://www.merckgroup.com/disclaimer to access the German, French, 
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[NMusers] Merck Serono: Manager and Senior Scientist in Pharmacometrics job posting

[pascal . girard]

 of common PC software.

PERSONAL SKILLS  COMPETENCIES
* Strong problem solving skills and ability to analyze complex 
problems
* Has interest in, and knowledge of, both mathematical and 
(patho-)physiological aspects of MS in drug development
* Is enthusiastic, self-motivated and has good communication 
skills, and at ease in working in a dynamic matrix organization; is a 
team-player. Communicate technical details effectively with scientists and 
clinicians colleagues

To apply please visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup   and enter the 
following Requisition ID 41221  for the manager position in Darmstadt  or 
Requisition ID 59283  for the Senior Scientist in Lausanne or Darmstadt.

With best regards,

Pascal Girard
Director, Pharmacometry
Merck Serono | Global Early Development

Merck - Living Innovation

Merck Institute for Pharmacometrics - Merck Serono S.A.
EPFL Innovation Park - Building I, CH-1015 Lausanne, Switzerland
Phone: +41 21 900 3702 | Mobile:  +41 79 508 7898
Email: pascal.gir...@merckgroup.com | www.merckserono.com
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[NMusers] Test

[pascal . girard]

Test

Pascal Girard
This message and any attachment are confidential and may be privileged or 
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person. If you have received this transmission in error, please notify the 
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Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

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Spanish and Portuguese versions of this disclaimer.

[NMusers] Senior Scientist MS Position at Merck Serono

[pascal . girard]

Merck Serono is the biopharmaceutical division of Merck
At Merck Serono, we discover, develop, manufacture and market innovative small 
molecules and biopharmaceuticals in our focus therapeutic areas:

* Oncology

* Neurodegenerative diseases

* Fertility

* Endocrinology

* CardioMetabolic Care
With headquarter in Darmstadt, Germany, and over 16,000 people worldwide, we're 
active on all continents and offer leading brands in 150 countries. In the 
United States and Canada, EMD Serono operates through separately incorporated 
affiliates.

Merck Serono is seeking a creative, motivated scientist to join our 
Pharmacometric department  in Darmstadt (Germany).

Position Title Senior Scientist, Modeling  Simulation
To apply please visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup  and enter the 
Requisition ID: 41221.

PURPOSE OF THE ROLE
To develop MS methodologies and expertise in drug development and make them 
available to facilitate more efficient and informative clinical trials, inform 
decision making, and globally support Enabling Clinical Science, TIPs, Clinical 
Development, Clinical Teams and Projects.

KEY TASKS  RESPONSIBILITIES

* Globally support the Quantitative Pharmacology department within 
Global Early Development

* Provide MS input into Clinical Development Plans

* Participate to sound translational science, from animal to healthy 
subjects, to patients, to special populations

* Plan, perform, interpret, present, track and record MS-related 
activities within allocated projects and studies

* Keep up-to-date with scientific development in MS, and regulatory 
guidance and trends

* Develop internal expertise in advanced population PKPD modeling, with 
emphasis on physiological and mechanistic approaches

* Explore, evaluate and implement appropriate pharmacometric tools and 
methodologies; participate to the improvement of the MS processes and 
technological platform

* Representation of the whole of Quantitative Pharmacology in 
transactions with internal and external stakeholders


EDUCATION/LANGUAGES

* Master or higher degree in Clinical Sciences related disciplines 
(Medicine, Physiology, Pharmaceutical Sciences, etc) and strong expertise in 
Pharmacometrics/biostatistics. Alternatively, degree in Mathematics/Statistics 
and strong experience in clinical development.

* Fluent in written and oral English

* Fluency in other European languages, particularly German, is an asset

*
PROFESSIONAL SKILLS  EXPERIENCE

* 3+ years experience in PKPD Modeling, of which 1+ in 
BioPharmaceutical Industry.

* PKPD MS input into drug development.

* Good command of NONMEM is an absolute prerequisite, experience with 
MONOLIX is an asset.

* Good command of R is an absolute prerequisite, experience with SAS is 
 an asset.

* Experience with PsN and Xpose is another asset.

* Experience with Clinical Trial Simulation tools is another asset, 
alike for other analytical/modeling/ optimization/presentation software or 
language, e.g. ADAPT, SAAM II, BERKELEY MADONA, SIMCYP

* Experience in writing and using PKPD models, particularly 
mechanistic-models and in developing disease progression models is an asset.

* Overall good knowledge of common PC software.

PERSONAL SKILLS  COMPETENCIES

* Strong problem solving skills and ability to analyze complex problems

* Has interest in, and knowledge of, both mathematical and 
(patho-)physiological aspects of MS in drug development

* Is enthusiastic, self-motivated and has good communication skills, 
and at ease in working in a dynamic matrix organization; is a team-player. 
Communicate technical details effectively with scientists and clinicians 
colleagues

To apply please visit the careers pages on  
https://career012.successfactors.eu/career?company=merckgroup  and enter the 
following Requisition ID 41221.

With best regards,

Pascal Girard
Director, Modeling  Simulation
Merck Serono | Global Early Development

Merck - Living Innovation

http://www.merckserono.com/en/careers/about_merck_serono/about_merck_serono.html

This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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

RE: [NMusers] Bootstrap, re-using inital model run results

[pascal . girard]

Dear Anuhbia,

Since bootstrap is performed to replace the estimation of precision that 
is performed in the $COV step, you definitively do not need the $COV 
option when you do a bootstrap. 

Then CI are obtained based on the quantiles of the bootstrap estimates.

Kind regards, 

Pascal Girard, PhD
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898




From:   anubha_gu...@eisai.net
To: Mats Karlsson mats.karls...@farmbio.uu.se
Cc: jos.lomme...@merck.com, nmusers@globomaxnm.com
Date:   14/02/2013 10:33
Subject:RE: [NMusers] Bootstrap, re-using inital model run results
Sent by:owner-nmus...@globomaxnm.com



Dear Mats

My question is more related to boot strapping itself.

if data set and model I am working with takes long time to run, then 
during bootstrap run I only run $EST and skip $COV step. We will get 
confidence interval for parameter from bootstrap results. 

What is your opinion on that?

Best regards

Anubha

...
Anubha Gupta, PhD
Associate Director,
Modeling and Simulation 
Clinical Pharmacology
Scientific and Clinical Support CFU
European Knowledge Centre
Mosquito Way, Hatfield, Herts.
AL10 9SN
United Kingdom


Mats Karlsson ---14/02/2013 08:50:29---Dear Jos,


From:

Mats Karlsson mats.karls...@farmbio.uu.se

To:

'Lommerse, JPM \(Jos\)' jos.lomme...@merck.com, 
nmusers@globomaxnm.com

Date:

14/02/2013 08:50

Subject:

RE: [NMusers] Bootstrap, re-using inital model run results

Sent by:

owner-nmus...@globomaxnm.com


Eisai Limited
Registered in England No. 2242511
Registered Address: European Knowledge Centre, Mosquito Way, Hatfield, 
Hertfordshire, AL10 9SN
Please note our new telephone no. is +44 (0) 845 676 1400 and the fax is 
+44 (0) 845 676 1401 


Dear Jos,
 
If you haven’t run the original model (indicated by absence of lst-file 
with the same prefix) psn will run it before the bootstrap. If you have 
run it, PsN will not rerun it. It will use the results in the 
corresponding lst file. If you have run it and called it something else, 
you could use the “-out=xxx.yyy” to point to the correct file if that does 
not follow naming conventions. If you have  not run it and really don’t 
want to run it, you could substitute xxx.yyy for some other output file 
with similar structure.
 
Best regards,
Mats
 
Mats Karlsson, PhD
Professor of Pharmacometrics
 
Dept of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
75124 Uppsala
 
Phone: +46 18 4714105
Fax + 46 18 4714003
 
From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] 
On Behalf Of Lommerse, JPM (Jos)
Sent: 14 February 2013 08:29
To: nmusers@globomaxnm.com
Subject: [NMusers] Bootstrap, re-using inital model run results
 
Hi
 
I would like to ask to NONMEM community whether it is possible to re-use 
the results of a nonmem model run when starting bootstrapping.
As I understand, a bootstrap run using PsN starts with a single 
calculation of the model of interest and data set as is. Once this initial 
model run
has completed, the actual bootstrapping starts by sampling from the 
initial data set to the requested number of samples.
However, the initial run often has been carried out already, and the 
bootstrap method this seems to be repeated.
 
I am dealing with a rather time consuming model / data set. Therefore I 
was wondering whether it is possible the re-use the results of a nonmem
model run and start the bootstrapping directly without repeating this 
initial nonmem model run. I was not able to find any option to do so. 
Perhaps there 
is way around?
 
Thanks,
 
Jos
 
Jos Lommerse 
Assoc. Prin. Scientist, Quant. Sciences
Clinical PK-PD
T: +31 412 661456
F: +31 412 662555
jos.lomme...@merck.com 

MSD
Molenstraat 110, 5342 CC Oss
PO Box 20, 5340 BH Oss
The Netherlands 
  
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Re: [NMusers] Different EBE estimation between original and enriched dataset with MDV=1

[pascal . girard]

 data records were, perhaps, as an
 example:

 Time  covariate  MDV
 1.01.0   0
 1.52.0   0

 With the filled in data set, perhaps you filled in the covariates as
 follows:

 Time  covariate  MDV
 1.01.0   0
 1.25   1.0   1
 1.52.0   0

 Or perhaps you made an interpolation for the covariate at the inserted
 time of 1.25, to be 1.5.  But NONMEM made the following equivalent
 interpretation during your original estimation:

 Time  covariate  MDV
 1.01.0   0
 1.25   2.0   1
 1.52.0   0

 That is, when the time record 1.25 was not there, it supplied the
 numerical integrater with the covariate value of 2.0 for all times from
  1.0 to =1.5, as stated earlier.

 Even though MDV=1 on the inserted records, NONEMM simply does not
 include the DV of that record in the objective function evaluation, but
 will still use the other information for simulation, by simulation I
 mean, for the numerical integration during estimation.

 In short, your model has changed regarding the covariate pattern based
 on the expanded data set.


 By the way, there is a utility program called finedeata, that actually
 facilitates data record filling, with options on how to fill in
 covariates, in nonmem7.3 beta.  I will send the e-mail to this shortly.

 If you are not using covariates in the manner I described above, then
 please ignore my lengthy explanation.



 Robert J. Bauer, Ph.D.
 Vice President, Pharmacometrics, RD
 ICON Development Solutions
 7740 Milestone Parkway
 Suite 150
 Hanover, MD 21076
 Tel: (215) 616-6428
 Mob: (925) 286-0769
 Email: robert.ba...@iconplc.com
 Web: www.iconplc.com

 -Original Message-
 From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com]
 On Behalf Of Leonid Gibiansky
 Sent: Friday, November 23, 2012 12:15 PM
 To: pascal.gir...@merckgroup.com
 Cc: nmusers@globomaxnm.com
 Subject: Re: [NMusers] Different EBE estimation between original and
 enriched dataset with MDV=1

 Hi Pascal,
 I think the problem is in the precision of the integration routine. With
 extra points, you change the ODE integration process and the results. I
 would use TOL=10 or higher in the original estimation. I have seen cases
 when changing TOL from 6 to 0 or 10 changed the outcome quite 
significantly.
 Leonid

 --
 Leonid Gibiansky, Ph.D.
 President, QuantPharm LLC
 web: www.quantpharm.com
 e-mail: LGibiansky at quantpharm.com
 tel:(301) 767 5566



 On 11/23/2012 11:08 AM, pascal.gir...@merckgroup.com wrote:
   Dear NM-User community,
  
   I have a model with 2 differential equations and I use ADVAN6 TOL=5.
   In $DES, I am using T the continuous time variable. The run 
converges,
   $COV is OK, and the model gives a reasonable fit. In order to compute
   some statistics which cannot be obtained analytically, I need to
   compute individual predictions based on individual POSTHOC parameters
   and an extended grid of time for interpolating the observed times.
  
   So I have
   1) added to my original dataset extra points regularly spaced with
   MDV=1. To give you an idea, my average observation time is 25, with a
   range going from 5 to 160. So my grid was set so that I have a dummy
   observation every 1 unit of time.
   2) rerun my model using $MSFI to initialize the pop parameters, with
   MAXEVAL=0 and POSTHOC options so that individual empirical Bayes
   estimates (EBE) parameters for each patient would be first
   re-estimated, then the prediction would be computed.
  
   Then I
   3)  checked that my new predictions computed from the extended 
dataset
   match the predictions of the original dataset at observed time 
points.
   I had the surprise to see that for some individuals those predictions
   match, for some others they slightly diverge, and for few others they
   are dramatically different. I checked the EBEs and they were clearly
   different between the original dataset and the one with the dummy 
points.
   4) I decided to redo the grid with only one dummy point every 1/4 of
   time unit. The result was less dramatic, but still for most of my
   individuals the EBEs predictions were diverging from the original 
ones
   computed without the dummy times.
  
   Of course the solution for me is to estimate the EBEs from the
   original dataset, export them in a table and reread them to 
initialize
   the parameter of my individuals using only dummy time points and no
   observations.
  
   This problem reminds me something that was discussed previously on
   nm-user, but I could not recover the source in the archive.
  
   Anyway is this something known and predictable that when adding dummy
   points with MDV=1 to your original dataset you sometimes get very
   different EBEs ? Are there cases/models/ADVAN  where the problem is
   likely to happen? Is their a way to fix it it in NONMEM other than 
the
   trick I used?
  
   Thanks for your replies!
  
   Kind regards,
  
   Pascal Girard

RE: [NMusers] Different EBE estimation between original and enriched dataset with MDV=1

[pascal . girard]

 finedeata, that actually 
facilitates data record filling, with options on how to fill in 
covariates, in nonmem7.3 beta.  I will send the e-mail to this shortly.

If you are not using covariates in the manner I described above, then 
please ignore my lengthy explanation.



Robert J. Bauer, Ph.D.
Vice President, Pharmacometrics, RD
ICON Development Solutions
7740 Milestone Parkway
Suite 150
Hanover, MD 21076
Tel: (215) 616-6428
Mob: (925) 286-0769
Email: robert.ba...@iconplc.com
Web: www.iconplc.com

-Original Message-
From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] 
On Behalf Of Leonid Gibiansky
Sent: Friday, November 23, 2012 12:15 PM
To: pascal.gir...@merckgroup.com
Cc: nmusers@globomaxnm.com
Subject: Re: [NMusers] Different EBE estimation between original and 
enriched dataset with MDV=1

Hi Pascal,
I think the problem is in the precision of the integration routine. With 
extra points, you change the ODE integration process and the results. I 
would use TOL=10 or higher in the original estimation. I have seen cases 
when changing TOL from 6 to 0 or 10 changed the outcome quite 
significantly.
Leonid

--
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web:www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel:(301) 767 5566



On 11/23/2012 11:08 AM, pascal.gir...@merckgroup.com wrote:
 Dear NM-User community,

 I have a model with 2 differential equations and I use ADVAN6 TOL=5. 
 In $DES, I am using T the continuous time variable. The run converges, 
 $COV is OK, and the model gives a reasonable fit. In order to compute 
 some statistics which cannot be obtained analytically, I need to 
 compute individual predictions based on individual POSTHOC parameters 
 and an extended grid of time for interpolating the observed times.

 So I have
 1) added to my original dataset extra points regularly spaced with 
 MDV=1. To give you an idea, my average observation time is 25, with a 
 range going from 5 to 160. So my grid was set so that I have a dummy 
 observation every 1 unit of time.
 2) rerun my model using $MSFI to initialize the pop parameters, with
 MAXEVAL=0 and POSTHOC options so that individual empirical Bayes 
 estimates (EBE) parameters for each patient would be first 
 re-estimated, then the prediction would be computed.

 Then I
 3)  checked that my new predictions computed from the extended dataset 
 match the predictions of the original dataset at observed time points. 
 I had the surprise to see that for some individuals those predictions 
 match, for some others they slightly diverge, and for few others they 
 are dramatically different. I checked the EBEs and they were clearly 
 different between the original dataset and the one with the dummy 
points.
 4) I decided to redo the grid with only one dummy point every 1/4 of 
 time unit. The result was less dramatic, but still for most of my 
 individuals the EBEs predictions were diverging from the original ones 
 computed without the dummy times.

 Of course the solution for me is to estimate the EBEs from the 
 original dataset, export them in a table and reread them to initialize 
 the parameter of my individuals using only dummy time points and no 
 observations.

 This problem reminds me something that was discussed previously on 
 nm-user, but I could not recover the source in the archive.

 Anyway is this something known and predictable that when adding dummy 
 points with MDV=1 to your original dataset you sometimes get very 
 different EBEs ? Are there cases/models/ADVAN  where the problem is 
 likely to happen? Is their a way to fix it it in NONMEM other than the 
 trick I used?

 Thanks for your replies!

 Kind regards,

 Pascal Girard, PhD
 pascal.gir...@merckgroup.com
 Head of Modeling  Simulation - Oncology Global Exploratory Medicine 
 Merck Serono S.A. * Geneva
 Tel:  +41.22.414.3549
 Cell: +41.79.508.7898

 This message and any attachment are confidential and may be privileged 
 or otherwise protected from disclosure. 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 KGaA, 
 Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, Darmstadt, Germany and any of its subsidiaries do 
 not guarantee that this message is free of viruses and does not accept 
 liability for any damages caused by any virus transmitted therewith.

 Click _http://www.merckgroup.com/disclaimer_to access the German, 
 French, Spanish and Portuguese versions of this disclaimer.
ICON plc made the following

[NMusers] Different EBE estimation between original and enriched dataset with MDV=1

[pascal . girard]

Dear NM-User community,

I have a model with 2 differential equations and I use ADVAN6 TOL=5. In 
$DES, I am using T the continuous time variable. The run converges, $COV 
is OK, and the model gives a reasonable fit. In order to compute some 
statistics which cannot be obtained analytically, I need to compute 
individual predictions based on individual POSTHOC parameters and an 
extended grid of time for interpolating the observed times. 

So I have 
1) added to my original dataset extra points regularly spaced with MDV=1. 
To give you an idea, my average observation time is 25, with a range going 
from 5 to 160. So my grid was set so that I have a dummy observation every 
1 unit of time.
2) rerun my model using $MSFI to initialize the pop parameters, with 
MAXEVAL=0 and POSTHOC options so that individual empirical Bayes estimates 
(EBE) parameters for each patient would be first re-estimated, then the 
prediction would be computed.

Then I
3)  checked that my new predictions computed from the extended dataset 
match the predictions of the original dataset at observed time points. I 
had the surprise to see that for some individuals those predictions match, 
for some others they slightly diverge, and for few others they are 
dramatically different. I checked the EBEs and they were clearly different 
between the original dataset and the one with the dummy points.
4) I decided to redo the grid with only one dummy point every 1/4 of time 
unit. The result was less dramatic, but still for most of my individuals 
the EBEs predictions were diverging from the original ones computed 
without the dummy times.

Of course the solution for me is to estimate the EBEs from the original 
dataset, export them in a table and reread them to initialize the 
parameter of my individuals using only dummy time points and no 
observations. 

This problem reminds me something that was discussed previously on 
nm-user, but I could not recover the source in the archive. 

Anyway is this something known and predictable that when adding dummy 
points with MDV=1 to your original dataset you sometimes get very 
different EBEs ? Are there cases/models/ADVAN  where the problem is likely 
to happen? Is their a way to fix it it in NONMEM other than the trick I 
used?
 
Thanks for your replies!

Kind regards,

Pascal Girard, PhD
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898



This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, 
Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

Click http://www.merckgroup.com/disclaimer to access the German, French, 
Spanish and Portuguese versions of this disclaimer.

RE: [NMusers] Error files when using multicore runs and psn == Fatal Error: Record SIZES is not valid

[pascal . girard]

Hi Robert,

Thanks for your quick reply. Unfortunately, I could not make it work. 

I have 17,000 records. So just after $PROB. I inserted your suggestion: 
$SIZES LIM1 = 2 
and I got the following error : 
 Fatal Error: Record SIZES is not valid

So I tried also the default value for LIM1:
$SIZES LIM1=1 
and also the example given on page 166 of Help guide viii
$SIZES LIM1=3 MAXFCN=200 NO=500
and always got the Fatal Error: Record SIZES is not valid message.

I looked into Help guide viii (pp 166-167 and 463-464) but did not find 
any relevant information how to set $SIZES. What would be your suggestion?

Thanks again for your help, because it's highly frustrating not being able 
to use the multi-cores when you have such long runs. 

Kind regards

Pascal Girard, PhD
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898




From:   Bauer, Robert robert.ba...@iconplc.com
To: pascal.gir...@merckgroup.com pascal.gir...@merckgroup.com, 
nmusers@globomaxnm.com nmusers@globomaxnm.com
Cc: orestis.papasoulio...@merckgroup.com 
orestis.papasoulio...@merckgroup.com, 
olaf.lichtenber...@merckgroup.com olaf.lichtenber...@merckgroup.com
Date:   11/07/2012 18:55
Subject:RE: [NMusers] Error files when using multicore runs and 
psn
Sent by:owner-nmus...@globomaxnm.com



Pascal:
I cannot help regarding having all console messages sent to the proper 
files in the PSN environment, but I can assist in avoiding your present 
NONMEM error.  If you insert at the beginning of the control stream file
$SIZES LIM1=??
and insert a large enough value for ??, then file buffer 10 will not be 
used, and the error is avoided.  The value should be at least as large as 
the number of data records (lines) in your data file (see section I.6 of 
..\guides\nm720.pdf).
 
Although nmfe72 in parallel mode has been tested successfully in our hands 
to use the file buffers for large data sets, it may not work in all grid 
environments.  Setting the LIM values large enough avoids using buffer 
files, and utilizes only memory. The problem also runs faster when buffer 
files are not used.
 
Robert J. Bauer, Ph.D. 
Vice President, Pharmacometrics, RD
ICON Development Solutions
7740 Milestone Parkway
Suite 150
Hanover, MD 21076
Tel: (215) 616-6428
Mob: (925) 286-0769
Email: robert.ba...@iconplc.com
Web: www.iconplc.com
 

From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] 
On Behalf Of pascal.gir...@merckgroup.com
Sent: Wednesday, July 11, 2012 11:19 AM
To: nmusers@globomaxnm.com
Cc: orestis.papasoulio...@merckgroup.com; 
olaf.lichtenber...@merckgroup.com
Subject: [NMusers] Error files when using multicore runs and psn

Dear All, 

We are using psn version: 3.4.2 together with NONMEM 7.2.0  on a Linux Sun 
Grid Engine (SGE). When using multi-cores run on SGE, it happens sometimes 
that NONMEM returns a log file where the MONITORING OF SEARCH starts and 
nothing is reported. 

Looking into the psn directory, I found files which have the name of my 
script file + an extension made of letters and numbers that contains an 
error message that is not shown on the log file. For example my nm-tran 
script file is run003.mod and my log file run003.lst ends with: 

 MONITORING OF SEARCH: 

Stop Time: 
Wed Jul  10 21:05:18 CEST 2012 

Then I recover a file named run003.mod.o9501 in run003/NM_run1 directory 
created by psn. Sometimes this file contains an explicit  error message, 
sometimes more cabalistic information as: 
WARNINGS AND ERRORS (IF ANY) FOR PROBLEM1 
  
 (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION. 
 CREATING MUMODEL ROUTINE... 
Recompiling certain components 

 USING PARALLEL PROFILE mpi_12cores.pnm 
 MPI TRANSFER TYPE SELECTED 
Exit status = 1 
IN MPI 
Starting MPI version of nonmem execution ... 
License Registered to: Merck KGaA 
Expiration Date:14 SEP 2013 
Current Date:   11 JUL 2012 
Days until program expires : 428 


 Iterative Two Stage (No Prior) 
 MONITORING OF SEARCH: 

At line 240 of file  (unit = 10, file = 'WK1_FILE10') 
Fortran runtime error: End of file 
Fatal error in MPI_Send: Other MPI error, error stack: 
MPI_Send(174).: MPI_Send(buf=0xde71a0, count=80030, 
MPI_INTEGER, dest=1, tag=1, MPI_COMM_WORLD) failed 
MPIDI_CH3I_Progress(150)..: 
MPID_nem_mpich2_blocking_recv(948): 
MPID_nem_tcp_connpoll(1720)...: 
state_commrdy_handler(1556)...: 
MPID_nem_tcp_recv_handler(1446)...: socket closed 
rank 1 in job 1  deda1x0481_36189   caused collective abort of all ranks 
  exit status of rank 1: return code 2 

Questions: 
1) Is there a way to force psn and/or NONMEM to collect the error message 
in the log file when using multi-cores run ? 
2) What about cabalistic error messages as the one above? 

Thank you for your help, 

Kind regards

Pascal Girard, PhD

RE: [NMusers] Error files when using multicore runs and psn == Fatal Error: Record SIZES is not valid

[pascal . girard]

Hi Nastia,

I tried your trick which would have broken the first table law rule The 
first NM-TRAN control record must be a $PROBLEM record  and put $SIZES as 
very first record and got following error:

_read_problems: First non-comment line in modelfile run.mod is not a 
$PROB record. NONMEM syntax violation.

So the first table law rule still resists or you may have a different 
NONMEM version.  :-)

I also checked the bug list 
ftp://nonmem.iconplc.com/Public/nonmem720/nm720_bug_list.pdf , but nothing 
is mentioned.

Anyway, thanks for the suggestion!

Kind regards

Pascal 




From:   Kassir Nastya nastya.kas...@umontreal.ca
To: pascal.gir...@merckgroup.com, Bauer, Robert 
robert.ba...@iconplc.com
Date:   12/07/2012 16:13
Subject:RE: [NMusers] Error files when using multicore runs and 
psn == Fatal Error: Record SIZES is not valid



Hi Pascal,
 
$SIZES goes at the begginning of your control stream, before $PROB.
 
I hope it helps.
 
Best regards,
 
Nastya
 

Nastya Kassir, Pharm.D.

Senior Scientist 

Pharsight Consulting Services(tm)
A division of Certara(tm)
Email: nkas...@pharsight.com mailto:nkas...@pharsight.com 

Phone: 1 (514) 789-2180 # 2157 
Mobile: 1 (438) 862-0935   
Fax: (514) 789-2192 

www.pharsight.com http://www.pharsight.com/ 




From: owner-nmus...@globomaxnm.com on behalf of 
pascal.gir...@merckgroup.com
Sent: Thu 7/12/2012 09:21
To: Bauer, Robert
Cc: nmusers@globomaxnm.com; olaf.lichtenber...@merckgroup.com@merck.de; 
orestis.papasoulio...@merckgroup.com@merck.de; 
owner-nmus...@globomaxnm.com
Subject: RE: [NMusers] Error files when using multicore runs and psn == 
Fatal Error: Record SIZES is not valid


Hi Robert, 

Thanks for your quick reply. Unfortunately, I could not make it work. 

I have 17,000 records. So just after $PROB. I inserted your suggestion: 
$SIZES LIM1 = 2 
and I got the following error : 
 Fatal Error: Record SIZES is not valid 

So I tried also the default value for LIM1: 
$SIZES LIM1=1 
and also the example given on page 166 of Help guide viii 
$SIZES LIM1=3 MAXFCN=200 NO=500 
and always got the Fatal Error: Record SIZES is not valid message. 

I looked into Help guide viii (pp 166-167 and 463-464) but did not find 
any relevant information how to set $SIZES. What would be your suggestion? 


Thanks again for your help, because it's highly frustrating not being able 
to use the multi-cores when you have such long runs. 

Kind regards 

Pascal Girard, PhD 
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898




From:Bauer, Robert robert.ba...@iconplc.com 
To:pascal.gir...@merckgroup.com pascal.gir...@merckgroup.com, 
nmusers@globomaxnm.com nmusers@globomaxnm.com 
Cc:orestis.papasoulio...@merckgroup.com 
orestis.papasoulio...@merckgroup.com, 
olaf.lichtenber...@merckgroup.com olaf.lichtenber...@merckgroup.com 
Date:11/07/2012 18:55 
Subject:RE: [NMusers] Error files when using multicore runs and 
psn 
Sent by:owner-nmus...@globomaxnm.com 






Pascal: 
I cannot help regarding having all console messages sent to the proper 
files in the PSN environment, but I can assist in avoiding your present 
NONMEM error.  If you insert at the beginning of the control stream file 
$SIZES LIM1=?? 
and insert a large enough value for ??, then file buffer 10 will not be 
used, and the error is avoided.  The value should be at least as large as 
the number of data records (lines) in your data file (see section I.6 of 
..\guides\nm720.pdf). 
 
Although nmfe72 in parallel mode has been tested successfully in our hands 
to use the file buffers for large data sets, it may not work in all grid 
environments.  Setting the LIM values large enough avoids using buffer 
files, and utilizes only memory. The problem also runs faster when buffer 
files are not used. 
 

Robert J. Bauer, Ph.D. 

Vice President, Pharmacometrics, RD 

ICON Development Solutions 

7740 Milestone Parkway 

Suite 150 

Hanover, MD 21076 

Tel: (215) 616-6428 

Mob: (925) 286-0769 

Email: robert.ba...@iconplc.com 

Web: www.iconplc.com http://www.iconplc.com/ 






From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com 
mailto:owner-nmus...@globomaxnm.com ] On Behalf Of 
pascal.gir...@merckgroup.com
Sent: Wednesday, July 11, 2012 11:19 AM
To: nmusers@globomaxnm.com
Cc: orestis.papasoulio...@merckgroup.com; 
olaf.lichtenber...@merckgroup.com
Subject: [NMusers] Error files when using multicore runs and psn

Dear All, 

We are using psn version: 3.4.2 together with NONMEM 7.2.0  on a Linux Sun 
Grid Engine (SGE). When using multi-cores run on SGE, it happens sometimes 
that NONMEM returns a log file where the MONITORING OF SEARCH starts and 
nothing is reported. 

Looking

RE: [NMusers] Error files when using multicore runs and psn == Fatal Error: Record SIZES is not valid

[pascal . girard]

Hi Nastya,

You were right : it is my psn installation that refuses to see something 
else than $PROB as first line as I just checked by running it directly 
from nmfe72 

You cannot stop the progress!

Thanks again and Kind regards 

Pascal 



From:   Kassir Nastya nastya.kas...@umontreal.ca
To: pascal.gir...@merckgroup.com, Bauer, Robert 
robert.ba...@iconplc.com, nmusers@globomaxnm.com
Date:   12/07/2012 17:25
Subject:RE: [NMusers] Error files when using multicore runs and 
psn == Fatal Error: Record SIZES is not valid



Hi Pascal,
 
I have already used it with NONMEM 72 and it works, but not in psn.
 
$SIZES LIM6=1000
$PROBLEM XX
 
Best regards,
 
Nastya
 



From: pascal.gir...@merckgroup.com [mailto:pascal.gir...@merckgroup.com]
Sent: Thu 7/12/2012 11:09
To: Kassir Nastya; Bauer, Robert; nmusers@globomaxnm.com
Subject: RE: [NMusers] Error files when using multicore runs and psn == 
Fatal Error: Record SIZES is not valid


Hi Nastia, 

I tried your trick which would have broken the first table law rule The 
first NM-TRAN control record must be a $PROBLEM record  and put $SIZES as 
very first record and got following error: 

_read_problems: First non-comment line in modelfile run.mod is not a 
$PROB record. NONMEM syntax violation. 

So the first table law rule still resists or you may have a different 
NONMEM version.  :-) 

I also checked the bug list 
ftp://nonmem.iconplc.com/Public/nonmem720/nm720_bug_list.pdf 
ftp://nonmem.iconplc.com/Public/nonmem720/nm720_bug_list.pdf  , but 
nothing is mentioned. 

Anyway, thanks for the suggestion! 

Kind regards

Pascal 




From:Kassir Nastya nastya.kas...@umontreal.ca 
To:pascal.gir...@merckgroup.com, Bauer, Robert 
robert.ba...@iconplc.com 
Date:12/07/2012 16:13 
Subject:RE: [NMusers] Error files when using multicore runs and 
psn == Fatal Error: Record SIZES is not valid 






Hi Pascal,

$SIZES goes at the begginning of your control stream, before $PROB.

I hope it helps.

Best regards,

Nastya


Nastya Kassir, Pharm.D.

Senior Scientist 

Pharsight Consulting Services(tm)
A division of Certara(tm)
Email: nkas...@pharsight.com mailto:nkas...@pharsight.com 
mailto:nkas...@pharsight.com  

Phone: 1 (514) 789-2180 # 2157 
Mobile: 1 (438) 862-0935   
Fax: (514) 789-2192 

www.pharsight.com http://www.pharsight.com/ http://www.pharsight.com/  
 




From: owner-nmus...@globomaxnm.com on behalf of 
pascal.gir...@merckgroup.com
Sent: Thu 7/12/2012 09:21
To: Bauer, Robert
Cc: nmusers@globomaxnm.com; olaf.lichtenber...@merckgroup.com@merck.de; 
orestis.papasoulio...@merckgroup.com@merck.de; 
owner-nmus...@globomaxnm.com
Subject: RE: [NMusers] Error files when using multicore runs and psn == 
Fatal Error: Record SIZES is not valid


Hi Robert, 

Thanks for your quick reply. Unfortunately, I could not make it work. 

I have 17,000 records. So just after $PROB. I inserted your suggestion: 
   $SIZES LIM1 = 2 
and I got the following error : 
Fatal Error: Record SIZES is not valid 

So I tried also the default value for LIM1: 
   $SIZES LIM1=1 
and also the example given on page 166 of Help guide viii 
   $SIZES LIM1=3 MAXFCN=200 NO=500 
and always got the Fatal Error: Record SIZES is not valid message. 

I looked into Help guide viii (pp 166-167 and 463-464) but did not find 
any relevant information how to set $SIZES. What would be your suggestion? 


Thanks again for your help, because it's highly frustrating not being able 
to use the multi-cores when you have such long runs. 

Kind regards 

Pascal Girard, PhD 
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898




From:Bauer, Robert robert.ba...@iconplc.com 
To:pascal.gir...@merckgroup.com pascal.gir...@merckgroup.com, 
nmusers@globomaxnm.com nmusers@globomaxnm.com 
Cc:orestis.papasoulio...@merckgroup.com 
orestis.papasoulio...@merckgroup.com, 
olaf.lichtenber...@merckgroup.com olaf.lichtenber...@merckgroup.com 
Date:11/07/2012 18:55 
Subject:RE: [NMusers] Error files when using multicore runs and 
psn 
Sent by:owner-nmus...@globomaxnm.com 






Pascal: 
I cannot help regarding having all console messages sent to the proper 
files in the PSN environment, but I can assist in avoiding your present 
NONMEM error.  If you insert at the beginning of the control stream file 
$SIZES LIM1=?? 
and insert a large enough value for ??, then file buffer 10 will not be 
used, and the error is avoided.  The value should be at least as large as 
the number of data records (lines) in your data file (see section I.6 of 
..\guides\nm720.pdf). 
 
Although nmfe72 in parallel mode has been tested successfully in our hands 
to use the file buffers

[NMusers] Error files when using multicore runs and psn

[pascal . girard]

Dear All,

We are using psn version: 3.4.2 together with NONMEM 7.2.0  on a Linux Sun 
Grid Engine (SGE). When using multi-cores run on SGE, it happens sometimes 
that NONMEM returns a log file where the MONITORING OF SEARCH starts and 
nothing is reported. 

Looking into the psn directory, I found files which have the name of my 
script file + an extension made of letters and numbers that contains an 
error message that is not shown on the log file. For example my nm-tran 
script file is run003.mod and my log file run003.lst ends with: 

 MONITORING OF SEARCH:

Stop Time:
Wed Jul  10 21:05:18 CEST 2012

Then I recover a file named run003.mod.o9501 in run003/NM_run1 directory 
created by psn. Sometimes this file contains an explicit  error message, 
sometimes more cabalistic information as:
WARNINGS AND ERRORS (IF ANY) FOR PROBLEM1
 
 (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.
 CREATING MUMODEL ROUTINE...
Recompiling certain components

 USING PARALLEL PROFILE mpi_12cores.pnm
 MPI TRANSFER TYPE SELECTED
Exit status = 1
IN MPI
Starting MPI version of nonmem execution ...
License Registered to: Merck KGaA
Expiration Date:14 SEP 2013
Current Date:   11 JUL 2012
Days until program expires : 428


 Iterative Two Stage (No Prior)
 MONITORING OF SEARCH:

At line 240 of file  (unit = 10, file = 'WK1_FILE10')
Fortran runtime error: End of file
Fatal error in MPI_Send: Other MPI error, error stack:
MPI_Send(174).: MPI_Send(buf=0xde71a0, count=80030, 
MPI_INTEGER, dest=1, tag=1, MPI_COMM_WORLD) failed
MPIDI_CH3I_Progress(150)..: 
MPID_nem_mpich2_blocking_recv(948): 
MPID_nem_tcp_connpoll(1720)...: 
state_commrdy_handler(1556)...: 
MPID_nem_tcp_recv_handler(1446)...: socket closed
rank 1 in job 1  deda1x0481_36189   caused collective abort of all ranks
  exit status of rank 1: return code 2 

Questions:
1) Is there a way to force psn and/or NONMEM to collect the error message 
in the log file when using multi-cores run ?
2) What about cabalistic error messages as the one above?

Thank you for your help, 

Kind regards

Pascal Girard, PhD
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898



This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, 
Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

Click http://www.merckgroup.com/disclaimer to access the German, French, 
Spanish and Portuguese versions of this disclaimer.

Re: [NMusers] How to model delayed count data due to time needed to form an event

[pascal . girard]

Dear Yaming,

My 2 cents ... 

You may need a joint model for time to first AE with left and right 
censoring (see tutorial on TTE from Holford and Lavieille last year at 
PAGE) and a model for your count data.
 
This paper may help, although it does not fully cover your case:
Ito K, Hutmacher M, Liu J, Qiu R, Frame B, Miller R. Exposure-response
analysis for spontaneously reported dizziness in pregabalin-treated 
patient with generalized anxiety disorder. Clin Pharmacol Ther. 2008 
Jul;84(1):127-35.

Kind regards / Mit freundlichen Grüßen / Bien cordialement

Pascal Girard, PhD
pascal.gir...@merckgroup.com
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.508.7898




From:   Yaming Hang yaming.h...@biogenidec.com
To: nmusers@globomaxnm.com nmusers@globomaxnm.com
Date:   18/06/2012 17:42
Subject:[NMusers] How to model delayed count data due to time 
needed to form an event
Sent by:owner-nmus...@globomaxnm.com



Dear NONMEM Users,
 
I’m dealing with some longitudinal count data (number of AEs observed in 
fixed time interval over certain time period). One feature with the data 
is the delay in PK/PD relationship because it takes time to develop the AE 
(i.e. there is lag time between the start of the AE formation process and 
the time you can observe the AE). The onset of the process of developing 
an AE is clearly PK dependent, but the exact time (or PK level) it onsets 
can never be observed.  In addition, the exact time that the AE first 
appears is also not available, we only know the interval during which it 
first appears. What is a good approach to handle this kind of delay? Is 
there any published paper for similar data type?
 
Many thanks in advance for you suggestions!
 
Yaming Hang, Ph.D.
Pharmacometrics
Biogen Idec
14 Cambridge Center
Cambridge, MA 02142
Office: 781-464-1741
Fax: 617-679-2804
Email: yaming.h...@biogenidec.com
 
 



This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, 
Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

Click http://www.merckgroup.com/disclaimer to access the German, French, 
Spanish and Portuguese versions of this disclaimer.

[NMusers] EOP2A experience?

[pascal . girard]

Dear All,

I am interested on the FDA guidance about End of Phase 2 A (EOP2A) 
meetings. Some of you certainly have participated 
into the preparation or have attended such meeting (during the pilot phase 
or after) and have real life experience. If so, it would be much 
apreciated if you could share some of this experience. Thank you in 
advance for your replies.

Kind regards,

Pascal Girard


This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, 
Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

Click http://disclaimer.merck.de to access the German, French, Spanish and 
Portuguese versions of this disclaimer.

[NMusers] MS position in oncology at Merck Serono

[pascal . girard]

Job description
Merck Serono is the division for innovative small molecules and 
biopharmaceuticals of Merck KGaA. We are searching for a Modeling  
Simulation (MS) scientist to strengthen our group dedicated to oncology. 
Merck Serono offers a pleasant, challenging and motivating working 
environment, with a sustained oncology pipeline and is committed to foster 
MS in drug development..

Your main tasks and responsibilities are:
To contribute to clinical development by providing, developing and sharing 
MS methodologies and expertise;
To analyse, report and present population pharmacokinetic-pharmacodynamic 
(PK/PD) results;
To develop drug disease models;
To interface with CROs and external experts in Population PK/PD modelling;
To support functions, Clinical Teams and Projects in oncology.

Qualifications 
For this position, you would have acquired a PhD and at least 2 years 
experience in pharmacometry (academic post-doc and/or pharma industry). 
Expertise in population PK/PD and drug disease models is mandatory.

You should have a high personal integrity, be a team player and possess a 
high level of trustworthiness. Good communication skills in oral and 
written English and interest in mathematical and pathophysiological 
aspects of MS are taken for granted. The ability to discuss with external 
experts and CROs round off your profile. 

Working knowledge of NONMEM software is a requirement; good command of 
complementary method(s) and software (MONOLIX, Bayesian software, TS2, 
optimal pop PK/PD designs ?) would be an asset, together with knowledge of 
R/Splus, SAS or Matlab programming languages. 

Interested candidates should send their application to Martin Baltes, 
Human Resources - Merck KGaA - Darmstadt (martin.bal...@merck.de).


Pascal Girard, PhD
Head of Modeling  Simulation - Oncology
Global Exploratory Medicine
Merck Serono S.A. · Geneva
Tel:  +41.22.414.3549
Cell: +41.79.445.5045 



This message and any attachment are confidential and may be privileged or 
otherwise protected from disclosure. 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 KGaA, Darmstadt, Germany and any of its subsidiaries do 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. Merck KGaA, 
Darmstadt, Germany and any of its subsidiaries do not guarantee that this 
message is free of viruses and does not accept liability for any damages caused 
by any virus transmitted therewith.

Click http://disclaimer.merck.de to access the German, French, Spanish and 
Portuguese versions of this disclaimer.