When the Model Does Not Fit the Data, the Model Is Wrong
Khuenl-Brady, Karin S. M.D., D.E.A.A.*; Eikermann, Matthias M.D., Ph.D.
We appreciate Drs. Fisher's and Shafer's interest in our work.1
We agree with their view that our model did not optimally fit all data points. There is a large variation in the placebo and 2.0 mg/kg group, and it was difficult to define a model that optimally fits these data points. For higher doses of sugammadex, the model fits the data very well.
We have conducted a Phase 2 clinical trial. Those studies attempt to learn what is a good (if not optimal) drug regimen to achieve useful clinical value (acceptable benefit/risk). In contrast to the confirming phases of drug development, the learning phases entail so-called explanatory analyses; i.e.
, analyses that estimate the quantitative relationship between inputs and outcomes according to some mechanistic view of the relationship.2
In a Phase 2 study, a nominal design, including all ostensibly controllable factors affecting the conduct of the trial, is an abstract ideal. In fact, in any real study, deviations from nominal design are inevitable.2
We decided to apply the model to our data which has been defined a priori
, and has been used for several data sets on sugammadex which already have been published.3–5
We did not want to retrospectively change the predefined approach of our statistical efficacy analysis. In future confirmatory studies on sugammadex it will be possible to develop and apply a more sophisticated model. The suggestions of Drs. Fisher and Shafer will be very useful in that context.
Karin S. Khuenl-Brady, M.D., D.E.A.A.,*
Matthias Eikermann, M.D., Ph.D.
*Medical University Innsbruck, Innsbruck, Austria. email@example.com
1. Pühringer FK, Rex C, Sielenkämper AW, Claudius C, Larsen PB, Prins ME, Eikermann M, Khuenl-Brady KS: Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: An international, multicenter, randomized, dose finding, safety assessor-blinded, phase II trial. Anesthesiology 2008; 109:188–97
2. Sheiner LB, Steimer JL: Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 2000; 40:67–95
3. Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM: Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: Efficacy, safety, and pharmacokinetics. Anesthesiology 2007; 106:935–43
4. de Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M: Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: A multicenter, dose-finding and safety study. Anesthesiology 2007; 107:239–44
5. Sorgenfrei IF, Norrild K, Larsen PB, Stensballe J, Ostergaard D, Prins ME, Viby-Mogensen J: Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: A dose-finding and safety study. Anesthesiology 2006; 104:667–74
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