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 known.
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
https://www.youtube.com/channel/UCxHZo1i0Hqo4dBDHrcKPtaQ
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 interested.
https://www.dropbox.com/sh/ylsjnqdv8d5586c/AACZWFNyLuNUChosSkXEeiDia?dl=0#
If you do review them and have any comments or questions, I would be very happy
to hear from you.
Kind regards,
Al
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
E-mail:[email protected]
E-mail:[email protected]