PMID- 22407972
OWN - NLM
STAT- MEDLINE
DCOM- 20121108
LR  - 20120710
IS  - 1539-1612 (Electronic)
IS  - 1539-1604 (Linking)
VI  - 11
IP  - 4
DP  - 2012 Jul-Aug
TI  - Analysis of dose-response in flexible dose titration clinical studies.
PG  - 280-6
LID - 10.1002/pst.1498 [doi]
AB  - Assessing dose-response from flexible-dose clinical trials (e.g., titration or 
      dose escalation studies) is challenging and often problematic due to the 
      selection bias caused by 'titration-to-response'. We investigate the performance 
      of a dynamic linear mixed-effects (DLME) model and marginal structural model 
      (MSM) in evaluating dose-response from flexible-dose titration clinical trials 
      via simulations. The simulation results demonstrated that DLME models with 
      previous exposure as a time-varying covariate may provide an unbiased and 
      efficient estimator to recover exposure-response relationship from flexible-dose 
      clinical trials. Although the MSM models with independent and exchangeable 
      working correlations appeared to be able to recover the right direction of the 
      dose-response relationship, it tended to over-correct selection bias and 
      overestimated the underlying true dose-response. The MSM estimators were also 
      associated with large variability in the parameter estimates. Therefore, DLME may 
      be an appropriate modeling option in identifying dose-response when data from 
      fixed-dose studies are absent or a fixed-dose design is unethical to be 
      implemented.
CI  - Copyright (c) 2012 John Wiley & Sons, Ltd.
FAU - Xu, Xu Steven
AU  - Xu XS
AD  - Advanced PK-PD Modeling and Simulation, Clinical Pharmacology, Janssen Research & 
      Development, Titusville, NJ, USA. sxu26@its.jnj.com
FAU - Yuan, Min
AU  - Yuan M
FAU - Nandy, Partha
AU  - Nandy P
LA  - eng
PT  - Journal Article
DEP - 20120311
PL  - England
TA  - Pharm Stat
JT  - Pharmaceutical statistics
JID - 101201192
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - Computer Simulation
MH  - Controlled Clinical Trials as Topic/*methods
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Linear Models
MH  - *Models, Statistical
MH  - Pharmaceutical Preparations/*administration & dosage
MH  - Selection Bias
MH  - Time Factors
EDAT- 2012/03/13 06:00
MHDA- 2012/11/09 06:00
CRDT- 2012/03/13 06:00
PHST- 2012/03/13 06:00 [entrez]
PHST- 2012/03/13 06:00 [pubmed]
PHST- 2012/11/09 06:00 [medline]
AID - 10.1002/pst.1498 [doi]
PST - ppublish
SO  - Pharm Stat. 2012 Jul-Aug;11(4):280-6. doi: 10.1002/pst.1498. Epub 2012 Mar 11.