Dear Nele,
The EMA Scientific Advice on MCP-Mod is really worth reading here.
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2014/02/WC500161027.pdf
All materials from the qualification:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp#section3
Some key sentences from the CHMP qualification opinion:
"The MCP-Mod approach is efficient in the sense that it uses the available data
better than the commonly applied pairwise comparisons.
It is fully appreciated that certain benefits that may be derived from an
MCP-Mod approach would also be derived from other model-based approaches and
that modelling approaches are not restricted to those based on dose-response.
MCP-Mod represents one tool in the toolbox of the well-informed drug developer.
In that sense, this opinion does not preclude any other statistical methodology
for model-based design and analysis of exploratory dose finding studies from
being used."
In other words - Many dose-response analyses that are seen by EMA use pairwise
comparisons between doses, despite ICH-E4 saying (>20 years ago) "Study designs
usually should emphasize elucidation of the dose-response function, not
individual pairwise comparisons." So MCP-Mod meets that criteria ("one tool in
the toolbox"), as do the other methods you discuss. Many other approaches could
(and should) be used to properly characterise and learn about
Dose-Exposure-Response.
You can go to town in using a "fit all models" Bayesian model averaging
technique, but in the end "ALL models are wrong" and if you use that technique
then I'd guess that the majority would be "sub-optimal". Question is, how to
best learn what's going on for your drug in this population so that you can
then successfully pick a dose and confirm efficacy? I'm not sure there's a
"best" or one size fits all solution.
Prespecification means that you can easily write a protocol stats section and
SAP, hand off the analysis to a third party and expect a result within 3 days
of the database unblinding. Learning fully about the disease progression,
pharmacology, characterising benefit risk takes a little more work, time and
careful consideration however...
Mike
Mike K. Smith
Pharmacometrics
Pfizer, Sandwich
Tel: +44 (0)1304 643561
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