RE: Using MCP-MOD in dose finding for Phase 3

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 LEGAL NOTICE Unless expressly stated otherwise, this message is confidential and may be privileged. It is intended for the addressee(s) only. Access to this e-mail by anyone else is unauthorised. If you are not an addressee, any disclosure or copying of the contents of this e-mail or any action taken (or not taken) in reliance on it is unauthorised and may be unlawful. If you are not an addressee, please inform the sender immediately. Pfizer Limited is registered in England under No. 526209 with its registered office at Ramsgate Road, Sandwich, Kent CT13 9NJ