This tool kit is a resource intended to support stakeholders in their decision-making regarding dosage optimization, i.e., identifying the dosage(s) that maximize the benefit/risk profile of a drug. Collection and interpretation of relevant data (see table below) can provide support for the dosage(s) chosen for evaluation in a clinical trial and/or help identify gaps in the dosage optimization strategy. The tool kit can be used iteratively to support decision-making throughout clinical development and to ultimately select the dosage(s) to be evaluated in the registration trial. In this tool kit, “registrational trial(s)” refer to the trial(s) designed to evaluate safety and effectiveness in support of a marketing application.
Which dosages will be evaluated during dose escalation?
Which dosages will be chosen for further investigation; e.g., in a randomized dosage evaluation*?
What dosages will be selected for the registration trial(s)?
Information to Support Dosage Optimization
Rationale for clinical starting dosage and dose-escalation range, including available nonclinical modeling (i.e., biomarkers, tumor size).
Additional information such as: pharmacological evidence in relevant nonclinical species; dose- and exposure-response relationships from cellular systemics and animal models; and potential on- and off-target relationships.
Single-dose and multiple-dose pharmacokinetics, proportionality and time-dependence.
Effect of intrinsic and extrinsic factors (e.g., body size, immunogenicity, race, ethnicity, age, food intake, organ impairment, concomitant medications) on the parent drug and active metabolites.
Major active metabolites and their relative contribution to activity and safety compared to that of the parent drug.
MAD and MTD, if identified
Safety information for each dosage evaluated
Duration of exposure
Incidence of TEAEs including all grade, grade 3 to 4, serious, and fatal events.
Dosage modifications for TEAEs, including time course and incidence of interruptions, reductions, and discontinuations, and most common TEAEs leading to dosage modifications.
Incidence of key TEAEs of interest, including grade 1-2 TEAEs which may affect tolerability.
Relative dose intensity
Additional measures of safety and tolerability if applicable (e.g., laboratory data), including rationale to support utility of the measure to estimate safety or tolerability.
Patient-reported outcome data regarding symptomatic TEAEs.
Alternative dosages (e.g., step-up dosing, intermittent dosing) to mitigate acute or transient toxicities.