Randomized exposure-controlled trials : Impact of randomization and analysis strategies

• 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 Emax; (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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

Clinical trial simulation

Model-based analysis

Pharmacometrics

Randomized concentration-controlled trial

Randomized dose-controlled trial

Study design

PHARMACY

FARMACI

Publikations- och innehållstyp

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