NONMEM Users Network Archive

Hosted by Cognigen

FDA Exposure-Response Guidance - can pharmacometricians work towards a common position?

From: Alan Maloney <al_in_sweden>
Date: Mon, 7 May 2018 12:14:41 +0000

Dear All,

You may have seen Yaning Wang's post to NMUSERS, requesting comments on the FDA Exposure-Response guidance document.

The deadline for comments in 5 July 18 (about 8 weeks).

I think Dose-Exposure-Response should be at the centre of drug development and regulatory approval. As Lewis Sheiner wrote "...the intellectual focus for clinical drug development should be on understanding (i.e., science and learning)”, and I see this best addressed through D-E-R analyses (for all efficacy and safety endpoints). As such, we should design our studies to be most informative for these integrated analyses (i.e. wide dose (exposure) ranges throughout drug development). A key additional point is the omnipresence of IIV in PD, meaning that we should, in general, look to approve (wide) dose ranges, enabling individual patient titration. Personalised dosing is a key component of personalised/precision medicine, and the ‘one size fits all’ approach to drug dosing is just wrong #. I recently wrote a paper and gave a brief presentation on this topic, and you can find a link to a dropbox folder with the paper and presentation at the bottom of this email if you would like to check them out.##

I think it would be great if the pharmacometrics community could discuss and agree a common position statement on where we think Dose-Exposure-Response fits into the drug development and regulatory review process. Perhaps ISoP would be the best vehicle to move this forward, and I briefly chatted about this recently with Siv Jonsson from Uppsala (ISoP board member), and I hope it is something they decide to work on. However with just 8 weeks left to provide comments on the FDA guidance document, it is not realistic to think this could happen so fast!

Thus I had planned to provide comments before the deadline, but wondered if there was anyone else out there who planned to do the same, and would be interested in sharing ideas beforehand. If you do, please mail me, and perhaps we could have an informal mailing list to share ideas and ways forward. At best, we might be able to submit a joint document outlining our views (say with 6 signatures), or simply agree to disagree, and submit 6 different opinions. I think we would not have a lot to lose by communicating beforehand, and it may be quite useful.

If you are interested, let me know as soon as possible. I will be attending PAGE, so perhaps if anyone is interested in this topic and also attending, we could find some time to chat then.

Let me know if anything in unclear,



# I know there are many of you doing important and valuable work on dose individualisation, but this is often at the ‘post approval’ stage. For me, the combination of population dose-exposure-response with innovative designs that quantify and optimise titration algorithms should become the foundation for modern drug development and regulatory assessments, and thus generate drug labels that are fit for purpose (…could be as simple as a basic titration algorithm such as “start at 1mg, and double dose every 4 weeks if tolerated but insufficient response, up to a maximum dose of 8mg”, to a full (web) application facilitating optimal TDM).

## This link should work. If not, just email me and I will send you the files.

p.s. Thank you GloboMax/ICON for allowing me to use your mailing list to engage other pharmacometricians

Alan Maloney PhD
Consultant Pharmacometrician

Phone: +46 35 10 39 78

Received on Mon May 07 2018 - 08:14:41 EDT

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to:

Once subscribed, you may contribute to the discussion by emailing: