some issues about NONMEM

From: Xiaofeng Wang - xiaofeng.wang@bms.com Subject: [NMusers] some issues about NONMEM Date: 2/10/2004 10:23 AM Dear everyone: Recently I was advised about some tricky issues existing in NONMEM. I would like to know more about these issues from you. 1 About NONMEN patches to correct the bugs in NONMEM I was informed that NONMEN has several bugs and there are patches to correct these bugs. Also, I was advised that FDA will not accept the results got from NONMEN without being corrected by these patches. But these patches are not available to the public except a few people in this community. Therefore, my questions are: a) If FDA will not accept the results, is there any guideline issued by FDA which patches that a user has to have? b) Has Globomax advised NONMEM users on these patches? c) Could those people who aware these bugs and have patches make their knowledge public, so the community can be benifited? 2 About FO and FOCE method I was also advised to use the results from FOCE, since the results from FO are not countable (type I error, etc)... From FO and FOCE algorithm, it can see that FO is applicable to the situation where interindividual variability is small, while FOCE handles the case when inter-individual variability is large. Therefore, results from both FO and FOCE should be close if the interindividual variability is small. Thus, I would like to know more why results from FO should not be accepted even when interindividual variability is small. I have a few publications discussing about the type I error. However, when should we consider the Type I error? I will read these publications but wish someone could clarify a little bit more before I start to read. In addition, if results from FO are different from FOCE, permutation (?) has to be done to check the problem. I have zero knowledge about it. What is this permutaion method? How to conduct it? Thank you, xiaofeng

From: "Rombout, Dr. Ferdinand" - Ferdinand.Rombout@grunenthal.de Subject: [NMusers] some issues about NONMEM Date: 2/10/2004 10:51 AM Dear all, I can do nothing else than fully agree with the remarks about patches. Recently I lost an email from the discussion group about one patch. Luckely I remembered seeing this email and could get some information from Globomax. However my own search in the stored messages did not lead to any finding!! If I had not read the email, I would not have been aware. In light of 21CFRpart11 requirements from the FDA this is not acceptable. Globomax should have the obligation to notify each person having a valid NONMEM licens about any need for changes and they should do so in writing to each individual separate (I think we users have that right by having the yearly license fee). They should also advice users whether revalidation of systems/previous results are needed. Regards, Ferdie Rombout

From: Nick Holford - n.holford@auckland.ac.nz Subject Re: [NMusers] some issues about NONMEM Date: 2/11/2004 2:30 PM Xiaofeng, NONMEM patches -- the silence from Maryland is deafening. You can find some information about methods for determining the null distribution of objective function differences here http://wfn.sourceforge.net/wfnrt.htm. Note that these methods can only guide you in making model building decisions based on P value criteria. They cannot diagnose nor fix problems with bias or imprecision in parameter estimates that might arise from any NOMMEM estimation method such as FO or FOCE. You can use simulation (parametric bootstrap) to explore the possible bias in estimation. Confidence intervals in parameter estimates can be obtained using the non-parametric bootstrap ( http://wfn.sourceforge.net/wfnbs.htm). All these methods are time consuming (and often impractical) because they typically involve hundreds if not thousands of runs for each model you want to test. Before assuming (based only on advice from your colleagues) that FDA will not accept results I suggest you try talking to FDA. If you can talk to a pharmacometrician at FDA you should get practical and helpful advice tailored to your particular problem. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

From: Diane R Mould - drmould@attglobal.net Subject: Re: [NMusers] some issues about NONMEM Date: 2/11/2004 4:59 PM Dear All I agree that it would be very good to have a repository where all the relevant patches and fixes were readily available for users. The fixes have all been posted to NMUSERS and should be available in the NMUSER archives, but because they are not stored together, they are not easily retrievable. A set of test kits to help the user make certain that the patch was correctly installed and works would also be nice to have as well. As to the quality of work done on a system that has not been upgraded and maintained, I think that it is important to make sure that software is running as well as it can when doing work for regulatory purposes. Some of the patches reported by GLOBOMAX have dealt with errors that could result in substantial differences if runs were done on unpatched systems versus patched systems (e.g. the nested if-then-else bug). I would hope that all the regulatory authorities (not just the FDA) would be making a similar effort to maintain NONMEM to the best standards recommended by the vendor. Therefore, it is important that both sides maintain any system to the best standards possible to minimize potential discrepancies. But perhaps more importantly, this issue has more to do with the analysis and the science then the acceptability of the work by the regulatory authorities. It seems to me that ignoring recommended fixes is just not good science, particularly because many of the patches have dealt with aspects of modeling that many users could encounter during the course of regular work. Diane

From: "Gastonguay, Marc" - marc.gastonguay@snet.net Subject: Re: [NMusers] some issues about NONMEM Date: 2/11/2004 8:21 PM Dear nmusers, As Diane points out, it would be nice to have an official central repository of recommended NONMEM updates/patches and, unfortunately, posts to nmusers describing NONMEM patches are not easily retrievable. I don't think that any end-users would intentionally ignore recommended fixes; the problem seems to be a lack of awareness and a less than optimal method of communicating these recommendations. In an effort to help the user community identify the necessary patches, I am sharing an UNOFFICIAL list of recommended NONMEM code patches (for supported NONMEM routines) that I have accumulated since NONMEM V level 1.1 was released. I think that all of these have been announced by the NONMEM Project Group over nmusers, and I would suggest that this list should be used as a checkpoint for keywords to search the nmusers archive for the original posting. Please do not use my list as the source for your code patches. I cannot verify that this list is complete, but in the absence of an official list, this should provide some practical guidance. Please keep in mind that some of these fixes will have little or no impact on some problems. Details are usually provided with each patch announcement. If you are concerned that you have missed any of these, you should probably test the impact of these code changes on any prior analyses that you think might have been affected. I hope that this is useful and that it does not cause any additional confusion. I would, of course, be grateful for any corrections or additions to this list. In my opinion, the best solution would be an official, vendor-supported patch repository on the web. Marc ================================ Marc R. Gastonguay, Ph.D. Gastonguay Consulting LLC 3 Winterset Lane Simsbury, CT 06070 Tel: 860.651.5318 Email: marc.gastonguay@snet.net

From: Nick Holford - n.holford@auckland.ac.nz Subject Re: [NMusers] some issues about NONMEM Date: 2/11/2004 10:50 PM Marc, Thanks for your patch list. I would like to add this set of 3 patches to tr\GENCOM.for which fixes code generating FSUBS with large NM-TRAN LIBRARY models (Suggested by Stu Beal 11 July 2002). GENCOM Fixes bug for emitting BBBBBB() code CHARACTER*12 WORK C Insert after previous declaration for WORK CHARACTER*13 WORKX Replace following commented code: C WRITE (WORK,'(A,I4.4,A)') 'BBBBBB(',I,')' C IF (LL.EQ.14) THEN C LINE(LL+1:)=WORK C LL=LL+12 C ELSE C LINE(LL+1:)=','//WORK C LL=LL+13 with this WRITE (WORKX,'(A,I5.5,A)') 'BBBBBB(',I,')' IF (LL.EQ.14) THEN LINE(LL+1:)=WORKX LL=LL+13 ELSE LINE(LL+1:)=','//WORKX LL=LL+14 C Fixes bug for emitting DIMENSION COM code Replace following commented code: C WRITE(LINE,'(A,I4.4,A)') 'DIMENSION COM(',COMMAX,')' C LL=19 with this WRITE(LINE,'(A,I6.6,A)') 'DIMENSION COM(',COMMAX,')' LL=21 -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

From: "Piotrovskij, Vladimir [PRDBE]" - VPIOTROV@PRDBE.jnj.com Subject: Re: [NMusers] some issues about NONMEM Date: 2/12/2004 4:19 AM Marc, I presume NONMEM VI will include those bug fixes. Could you confirm please? Best regards, Vladimir

From: "Gastonguay, Marc" - marc.gastonguay@snet.net Subject: Re: [NMusers] some issues about NONMEM Date: 2/12/2004 6:31 AM Vladimir, I would think so, but I'll leave it up to GloboMax/NONMEM Project Group to comment on what will be included in NONMEM VI. Marc

From: "Gastonguay, Marc" - marc.gastonguay@snet.net Subject: Re: [NMusers] some issues about NONMEM Date: 2/12/2004 6:58 AM Thanks for the addition, Nick. I was unable to find a related post on the nmusers archive. Could you please provide some guidance about the model/data conditions requiring the GENCOM fixes? Thank you. Marc

From: Xiaofeng Wang - xiaofeng.wang@bms.com Subject: Re: [NMusers] some issues about NONMEM Date: 2/12/2004 9:35 AM Thanks both Nick and Marc for providing valuable information and suggestions to the community. I would like to thank Nick specially for his advise in his other email to me, also to Diane. I am not sure if NMusers would agree with me: maybe Globomax can raise either liscense fee or maintainace fee to a certain level that the extra revenue can cover the cost for Globomax to fix the bugs, and to conduct the testing and validation of NONMEN? xiaofeng

From: Nick Holford - n.holford@auckland.ac.nz Subject Re: [NMusers] some issues about NONMEM Date: 2/12/2004 1:12 PM Marc, This fix was provided to me directly by Stuart after I had reported a problem to nmconsult. If you need this fix then it will be obvious because NM-TRAN produces illegal Fortran code and your compiler will complain. The fix is needed when using very large models which require larger array dimensions than were originally anticipated in FSUBS. The patches to GENCOM allow these larger arrays to be emitted by NM-TRAN. In my case it was triggered by using the $SUBROUTINE LIBRARY option with ADVAN6 with 50 THETA, 56 ETA and 3 EPS parameters. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ _______________________________________________________