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Randomized exposure‐controlled trials; impact of randomization and analysis strategies
Author(s) -
Karlsson Kristin E.,
Grahnén Anders,
Karlsson Mats O.,
Jonsson E. Niclas
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02887.x
Subject(s) - randomization , statistical power , randomized controlled trial , medicine , statistics , clinical study design , biomarker , clinical trial , clinical endpoint , computer science , pharmacology , mathematics , chemistry , biochemistry
What is already known about this subject • When characterizing an exposure–response relationship it has been suggested that the randomized concentration‐controlled trial (RCCT) is potentially a more informative design than a randomized dose‐controlled trial design (RDCT). • Traditionally, these trials have been analysed by group‐wise comparison or similar statistics. • The aim of this study was to compare different randomization schemes when a model‐based analysis has been performed. What this study adds • Alternative randomization schemes may not have the proposed advantages if a model‐based analysis is employed. Aims In the literature, five potential benefits of randomizing clinical trials on concentration levels, rather than dose, have been proposed: (i) statistical study power will increase; (ii) study power will be less sensitive to high variability in the pharmacokinetics (PK); (iii) the power of establishing an exposure–response relationship will be robust to correlations between PK and pharmacodynamics (PD); (iv) estimates of the exposure–response relationship are likely to be less biased; and (v) studies will provide a better control of exposure in situations with toxicity issues. The main aim of this study was to investigate if these five statements are valid when the trial results are evaluated using a model‐based analysis. Methods Quantitative relationships between drug dose, concentration, biomarker and clinical end‐point were defined using pharmacometric models. Three randomization schemes for exposure‐controlled trials, dose‐controlled (RDCT), concentration‐controlled (RCCT) and biomarker‐controlled (RBCT), were simulated and analysed according to the models. Results (i) The RCCT and RBCT had lower statistical power than RDCT in a model‐based analysis; (ii) with a model‐based analysis the power for an RDCT increased with increasing PK variability; (iii) the statistical power in a model‐based analysis was robust to correlations between CL and EC 50 or E max ; (iv) under all conditions the bias was negligible (<3%); and (v) for studies with equal power RCCT could produce either more or fewer adverse events compared with an RDCT. Conclusion Alternative randomization schemes may not have the proposed advantages if a model‐based analysis is employed.