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D-E-R at the centre of drug development and regulatory approval - a viewpoint

From: Alan Maloney <al_in_sweden>
Date: Fri, 27 Mar 2015 10:26:40 +0100

Dear All,

I have been meaning to send this out for a while now, and Nele's mail =
about MCP-MOD was a good trigger (since I believe D-E-R should extend =
far beyond being a Phase 2 activity).

I am keen to see drug development, and the regulatory requirements for =
approval, change.

This short text summarises my viewpoint, and I hope in the coming years =
I will see it a reality!

A new paradigm; Dose response for efficacy and safety at the centre of =
drug development and regulatory approval

The Problem: Drug development needs to change. Despite huge expenditure, =
pharmaceutical companies and regulators are frequently faced with trying =
to interpret weak and contradictory data from poorly designed studies. =

The Solution: The goal of drug development should be to generate data =
and results which facilitate a clear assessment of the benefits and =
risks of the investigational drug. Thus the clinical development program =
should seek to accurately and precisely determine the Dose Response (DR) =
for multiple efficacy and safety endpoints in the target patient =
population. This should be achieved through integrated DR and Exposure =
Response (ER) analyses using all data from late stage studies, allowing =
regulators and pharmaceutical companies to agree on both the best =
starting dose and maximum dose for potential approval.

The Roadmap: When DR/ER analyses are correctly placed at the centre of =
the approval process, it highlights the significant inadequacies in the =
historic Phase 2/3 paradigm. Fundamentally, all late stage studies =
should be designed to achieve (for a given total sample size), the =
maximum accuracy and precision across multiple endpoints in the pivotal =
integrated DR/ER analyses. The technical methodology to achieve this is =

That is, forget about p-values from single doses and single studies, and =
instead focus on the precision of the treatment effects across the dose =
range using all late stage study data simultaneously (and design your =
studies accordingly). These results should be the central foundations to =
identifying potential dose regimens for approval, for the drug company =
and regulators alike.

Along those lines, I have begun making some YouTube presentations on =
various topics that relate is some way to the above (some more general, =
some more technical). Here is the list, and the YouTube link.

L1 - The Goal of Clinical Drug Development
L2 - Phase 2 Study Design - General Principles
L3 - Why the Sigmoidal Emax Model is Special
L4 - Phase 2 Study Design - Technical Details
L5 - Individual and Population Dose Response
L6 - Statistical Modelling - Uncertainty and Sensitivity Analysis

Since the videos can be painfully slow to watch, I wanted to share the =
raw presentations as well, as you can more quickly flick through any =
that might be of some interest. This link should send you to the =
PowerPoint and PDF versions of the above (you do not need to sign up to =
Dropbox to view the files). In case it doesn't work, just email me and I =
will send them to you. Please share with anyone you think might be =


If you do review them and have any comments or questions, I would be =
very happy to hear from you.

Kind regards,


p.s. I am not expecting this audience to be strongly in disagreement =
with the above from a scientific viewpoint, since I expect we all see an =
integrated POP PK analysis across studies as superior to a "by study" =
type analysis, and hence doing the same for efficacy and safety =
endpoints seems equally sound. Hence even though I have been involved in =
conducting the above type of analyses, the Phase 2 and 3 studies were =
never designed (/optimised) with these integrated analyses in mind, and =
the results were not used as the primary analysis. Thus I feel we need =
the regulators to say "this is the analyses we want to see and will base =
our assessment on" before we will move forward. This will profoundly =
help companies see that larger (and longer) Phase 2 studies are not =
"wasted" investments, but will indeed contribute to the final results =
(as they should).

Al Maloney
Consultant Pharmacometrician

Phone: +46 35 10 39 78

Received on Fri Mar 27 2015 - 05:26:40 EDT

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