Have Population PK analyses been conducted and have all important covariates been explored to explain interindividual or intra-individual variability in PK? Do exposure-response or PK/PD analyses together with clinical data suggest that unexplained or explained variability in PK may change the benefit-risk profile of the medicine in certain clinical scenarios and thus specific risk minimisation measures should be included in the RMP such as restrictions/precautions/dose adjustments in special populations or therapeutic drug monitoring or a safety or efficacy study. Interactions Critical presentation of study results. Comments on drug-drug interactions should be provided if data are available (the presentation of data should be similar to preceding sections and should preferably be included in a summary table). • In vitro Data from CTD module 5.3.2 in-vitro studies using human biomaterials. Assessor’s comment • In Silico Populate with data from various eCTD modules depending on the question being answered. Discuss the role of PBPK models. How do simulated data compare to the in vivo data. Discuss confidence in in–silico predictions based on submitted or literature data and the impact on dosing recommendations. Is the in house or commercial PBPK platform qualified for the intended purpose? Assessor’s comment • In vivo Data from CTD module 5.3.3.4 Extrinsic factor PK study reports. post-
Duration of main phase: Duration of Run-in phase: Duration of Extension phase: <time> <time> <not applicable> <time> <not applicable> Hypothesis <Superiority> < Equivalence> <Non-inferiority> <Exploratory: specify> Treatments groups {add as many rows as needed to describe the treatment groups} <group descriptor> {provide abbreviation for use later in the table of the results section} <treatment>. <duration>, <number randomized> <group descriptor> <treatment>. <duration>, <number randomized> <group descriptor> <treatment>. <duration>, <number randomized> Endpoints and definitions {add as many rows as needed to describe the endpoints; for the secondary endpoints select the ones considered most relevant and reported in the results section} <Co- >Primary endpoint <label> {generate abbreviation for use later in the table of the results section} <free text> {provide brief description} <Secondary> <other: specify> endpoint <label> <free text> {provide brief description} <Secondary> <other: specify> endpoint <label> <free text> {provide brief description} Database lock <date> Results and Analysis {present the result separate for each analysis that is considered relevant for the conclusion on the trial; in any case the pre-specified primary analysis should be presented} Analysis description Primary Analysis Analysis population and time point description <Intent to treat> <Per protocol> <other: specify> {consider adding a brief description of the definition of the population} <time point> Descriptive statistics and estimate variability Treatment group <group descriptor> {as per above terminology} <group descriptor> {as per above terminology} <group descriptor> {as per above terminology} Number of subject <n> <n> <n> <endpoint> {label as above} (<statistic>) {e.g. mean, median, etc} <point estimate> <point estimate> <point estimate> <variability statistic> {e.g. standard deviation, confidence interval, etc} <variability> <variability> <variability> <endpoint> (<statistic>) <point estimate> <point estimate> <point estimate> <variability statistic> <variability> <variability> <variability>
<endpoint> (<statistic>) <variability statistic> <point estimate> <variability> <point estimate> <variability> <point estimate> <variability> Effect estimate per comparison {add as many rows as needed to describe the relevant statistical testing performed} <Co->Primary endpoint Comparison groups <group descriptors> {as per above terminology} <test statistic> {e.g. difference between groups} <point estimate> <variability statistic> {e.g. confidence interval, etc} <variability> P-value {indicate statistical test used, e.g. ANOVA} <P-value> <<Co->Primary > <Secondary><ot her: specify> endpoint {indicate endpoint using terminology as per section “Endpoint and definitions} Comparison groups <group descriptors> <test statistic> <point estimate> <variability statistic> <variability> P-value <P-value> <<Co->Primary > <Secondary><ot her: specify> endpoint Comparison groups <group descriptors> <test statistic> <point estimate> <variability statistic> <variability> P-value <P-value> Notes <free text> {consider amongst others the following information: reasons for drop-outs critical findings with regard to the analysis} Analysis description <Secondary analysis> <Co-primary Analysis> <Other, specify: > {also indicate if the conduct of the analysis was pre-specified} {repeat all the above sections for analysis that is each considered relevant} Clinical studies in special populations Special studies e.g. in children, in the elderly and in patients with renal or hepatic impairment. Describe these studies as suggested for the main studies including considerations on dose adjustments. Age 65-74 (Older subjects number /total number) Age 75-84 (Older subjects number /total number) Age 85+ (Older subjects number /total number) Controlled Trials