Role of modelling and simulation: a European regulatory perspective.

Modelling and simulation (M&S) of clinical data, e.g. pharmacokinetic, pharmacodynamic and clinical endpoints, is a useful approach for more efficient interpretation of collected data and for extrapolation of knowledge to the entire target population. This type of documentation is included in the majority of marketing authorization applications for new medicinal products. This article summarizes the current status of regulatory review with respect to the role of M&S in Europe from the perspective of the Swedish Medical Products Agency. At present, regulatory bodies in Europe encourage the application of the M&S approach during drug development. However, there is a lack of consensus and transparent guidance documents. The main regulatory usage is in the evaluation of dose choices in sub-populations and as support for the dosing regimen in general. The regulatory review of conestat alfa illustrates how the dose recommendation was revised during the approval procedure based on M&S information. A survey of marketing authorization applications for new medicinal products approved in 2010 revealed that the use of the information gained from M&S documentation varies with respect to both regulatory review and the applicants' presentation of the data in the submitted dossier. Increased utilization and broadened application of M&S is anticipated in pharmaceutical development, where one area of focus is medicines for paediatric patients. Accordingly, the regulatory agencies will need to increase their capability to assess and utilize this type of information, and an interactive process among regulatory agencies is warranted to provide more unified regulatory assessment and guidance. Moreover, applicants are encouraged to expand on the usage of exposure-response models to map the systemic exposure range that yields safe and efficacious treatment and to improve the presentation of the gained knowledge in summary documents of the marketing authorization applications.

Regulatory aspects of pharmacokinetic profiling in special populations: a European perspective.

The clinical efficacy and safety profile of a new medicinal product is established in phase III studies, which are usually restricted to a well defined patient population. This population may not fully represent the population in which the product will be used once it is on the market. Pharmacokinetic studies in special populations are performed to estimate drug exposure in subpopulations of patients with characteristics that may affect drug exposure. The clinical consequences of altered exposure are then assessed, taking pharmacokinetic/pharmacodynamic relationships into consideration. If needed, specific treatment recommendations should be developed.Recommendations regarding pharmacokinetic characterization in special populations are given in a number of European guidelines. The pharmacokinetic characteristics, therapeutic window and intended use of the medicinal product influence the need for pharmacokinetic studies of a new medicinal product. There are a number of methodological issues to be considered when designing pharmacokinetic studies in special populations: the study design, study population and control group, the dosing regimen to be used, the analytes to be measured, and the distribution and range of the factor to be studied. The data should be presented in sufficient detail to enable assessment by regulatory authorities of the conducted analysis and conclusions drawn. Assessment of the data should include an evaluation of how and to what extent the pharmacokinetics in specific subpopulations deviate from the exposure at the therapeutic dose in the clinical efficacy and safety studies, and if there is a need for specific treatment recommendations. Based on the available information on the pharmacokinetic/pharmacodynamic relationships for efficacy and safety and/or the exposure at the therapeutic dose in the phase III population where efficacy and safety have been demonstrated, target criteria (a target exposure range) should be defined. Within the target exposure range, there should be no clinically relevant difference in efficacy and safety. Should the exposure in a specific group fall outside the defined target criteria, appropriate treatment recommendations need to be developed. The aim should be to develop dosing recommendations that will allow the majority of the patients to obtain exposure within the defined target range. If it is not possible to develop suitable dosing recommendations in a subgroup of patients, there may be a need for specific warnings or wordings regarding monitoring of the patients. It may also be an option to exclude that patient group from the indication. The resulting treatment recommendations should ensure safe and effective use of the drug in the entire population for which it has been approved.

A guide for reporting the results of population pharmacokinetic analyses: a Swedish perspective.

Population pharmacokinetic analyses are frequently part of regulatory submissions and are mainly used to provide information on special populations (effects of age, renal impairment, etc) and drug-drug interactions. A varying standard of population analysis reports has been received at the Medical Products Agency in Sweden, some very good and some unassessable. In the latter case, it may be that it is a report of an inadequate analysis or may be a report of a perfectly acceptable analysis, but too little detail has been provided in the report for the conclusions reached to be properly assessed. A sufficient level of detail must be present in these reports in order for them to be assessable and to allow the conclusions reached to be incorporated into the summary of product characteristics. The report should specify the goal(s) of the analysis, describe in detail the origin and nature of the data, clearly describe the model-building process, include a range of goodness of fit (GOF) plots to support decisions made during the model-building process, and demonstrate that the final model is a good description of the data. The use of color in GOF plots is encouraged so that key features are easily visible. Covariate effects in the final model should be clearly presented and their clinical relevance discussed. In the case of many covariates in the final model, it may be useful to perform some simulations to illustrate the effect of various covariate combinations for a series of different "typical" subjects.