Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion

• Published in: Pharmaceutical statistics : the journal of the pharmaceutical industry Vol. 8; no. 1; pp. 38 - 49
• Main Authors: Hummel, Jürgen, McKendrick, Sue, Brindley, Charlie, French, Raymond
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2009
• Subjects: Clinical Trials, Phase I as Topic - methods; Confidence Intervals; Data Interpretation, Statistical; Dose-Response Relationship, Drug; equivalence criterion; exploratory dose proportionality; Humans; Models, Statistical; pharmacokinetics; power calculations; power model; Therapeutic Equivalency
• ISSN: 1539-1604; 1539-1612
• DOI: 10.1002/pst.326

This article reviews currently used approaches for establishing dose proportionality in Phase I dose escalation studies. A review of relevant literature between 2002 and 2006 found that the power model was the preferred choice for assessing dose proportionality in about one‐third of the articles. This article promotes the use of the power model and a conceptually appealing extension, i.e. a criterion based on comparing the 90% confidence interval for the ratio of predicted mean values from the extremes of the dose range (Rdnm) to pre‐defined equivalence criterion (ϑL,ϑU). The choice of bioequivalence default values of ϑL=0.8 and ϑU=1.25 seems reasonable for dose levels only a doubling apart but are impractically strict when applied over the complete dose range. Power calculations are used to show that this prescribed criterion lacks power to conclude dose proportionality in typical Phase I dose‐escalation studies. A more lenient criterion with values ϑL=0.5 and ϑU=2 is proposed for exploratory dose proportionality assessments across the complete dose range. Copyright © 2008 John Wiley & Sons, Ltd.