Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility.

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk-based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick-start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts.

The European Medicines Agency Experience With Pediatric Dose Selection.

Getting the right dose regimen for children and adolescents is important but poses great scientific, practical, and ethical challenges. At the same time, the availability of data in adults is a huge advantage and needs to be used optimally when designing studies in children and analyzing pediatric data. Furthermore, the processes of maturation and growth are always key when selecting doses for children. All the above make study adaptations and model-informed approaches imperative for dose exposure-response characterization and dose selection in children. This article summarizes the experience gained in the European Medicines Agency on this topic and proposes some general guiding principles for defining objectives, study designs, and methodology tools for pediatric dose selection.

Drug Clearance in Neonates: A Combination of Population Pharmacokinetic Modelling and Machine Learning Approaches to Improve Individual Prediction.

BACKGROUND: Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. OBJECTIVE: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. METHODS: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. RESULTS: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. CONCLUSION: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.

Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics.

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers.

Model-Informed Drug Discovery and Development: Current Industry Good Practice and Regulatory Expectations and Future Perspectives.

Good practices around model-informed drug discovery and development (MID3) aim to improve the implementation, standardization, and acceptance of these approaches within drug development and regulatory review. A survey targeted to clinical pharmacology and pharmacometric colleagues across industry, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) was conducted to understand current and future roles of MID3. The documented standards were generally affirmed as a "good match" to current industry practice and regulatory expectations, with some identified gaps that are discussed. All have seen at least a "modest" step forward in MID3 implementation associated with greater organizational awareness and share the expectation for a future wider use and impact. The priority within organizations was identified as a limitation with respect to the future of MID3. Finally, potential solutions, including a global overarching MID3 regulatory guideline, to facilitate greater acceptance by industry and regulatory decision makers are discussed.

Commentary on the MID3 Good Practices Paper.

During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective.

Hollow Fiber System Model for Tuberculosis: The European Medicines Agency Experience.

The in vitro hollow fiber system model has been qualified by the European Medicines Agency as a methodology for use in support of selection and development of antituberculosis regimens. More data are expected to be generated in the future to further characterize its value.

Changes and determination of dosing recommendations for medicinal products recently authorised in the European Union.

INTRODUCTION: The quantity and quality of data for determining the dose and treatment schedule of medicinal products is directly related to how safe and efficacious these medicines are and how successful they can be used to treat patients. AREAS COVERED: This review provides an analysis of dose-related label modifications of recently approved drugs. It shows which areas could benefit from a better dose-exposure-response understanding, both during initial assessment and after marketing authorisation. This analysis highlights regulators' considerations in dosage evaluations and provides reflections for drug developers on how to ensure best possible dose selection in the interest of the patients. EXPERT OPINION: Using modelling and simulation, pharmacogenomics, population pharmacokinetics, physiologically based pharmacokinetic models and drug-drug interaction studies in conjunction with well-designed clinical trials will improve the understanding of the pharmacology of medicines, of the physiology of the disease and of the dose-exposure-response relationship during drug development. More focus should be given to the investigation of dose and regimens for special populations before applying for marketing authorisation. Consequently, regulators could review dose-exposure-response data with more certainty and better define dose recommendations in the label.

The European Medicines Agency experience with biomarker qualification.

Since the launch of the qualification process in 2009, the CHMP reviewed/is reviewing 48 requests for qualification advice or opinion (as of Sept 2013) related to biomarkers (BM) or other novel drug development tools (e.g. patient reported outcome measures, modeling, and statistical methods). The qualification opinions are available on the EMA website (Qualification of novel methodologies for medicine development, http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp&mid=WC0b01ac0580022bb0#section2 , 2013). Also there is a trend of increasing numbers of qualification requests to CHMP, indicative of the pace that targeted drug development and personalized medicine is gaining and the need to bring the new tools from research to drug development and clinical use. This chapter will focus on the regulatory experience gained so far from the CHMP qualification procedure. Basic qualification principles will be presented. Through qualification examples, we will elaborate on common grounds and divergences between the different stakeholders.

Implementation of proteomic biomarkers: making it work.

While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.

New pathway for qualification of novel methodologies in the European Medicines Agency.

The European Medicines Agency (EMA) qualification process is a new, voluntary, scientific pathway leading to either a Committee for Medicinal Products for Human Use (CHMP) opinion or a Scientific Advice on innovative methods or drug development tools: (i) CHMP Qualification Opinion on the acceptability of a specific use of the proposed method, based on the assessment of submitted data and (ii) CHMP Qualification Advice on future protocols and methods for further method development towards qualification, based on the evaluation of the scientific rationale and on preliminary data submitted. The qualification procedure was established as a response to the drug development bottlenecks and inefficiencies, but also to the availability of new methodologies, not yet integrated in the drug development and clinical management paradigm. The qualification process addresses innovative methods developed by consortia, networks, public/private partnerships, learned societies or pharmaceutical industry. It is expected to facilitate communication between the scientific community and the regulators and to address challenges with the development and use of medicines. In this article, we will present an overview of the process and the up to now scientific advice working party (SAWP) experience.

Role of modeling and simulation in pediatric investigation plans.

Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. Three and a half years since the Paediatric Regulation came into force in 2007, the European Medicines Agency has gained substantial experience in the use of modeling and simulation in pediatric drug development. In this review, we present examples on how the proposed paradigm applies in real case scenarios of planned pharmaceutical developments. We also report the results of a pediatric database search to further 'validate' the paradigm. There were 47 of 210 positive pediatric investigation plan (PIP) opinions that made reference to modeling and simulation (data included all positive opinions issued up to January 2010). This reflects a major shift in regulatory thinking. The ratio of PIPs with modeling and simulation rose to two in five based on the summary reports. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PD) and physiologically based pharmacokinetic models are widely used by industry and endorsed or even imposed by regulators as a way to circumvent some difficulties in developing medicinal products in children. The knowledge of the effects of age and size on PK is improving, and models are widely employed to make optimal use of this knowledge but less is known about the effects of size and maturation on PD, disease progression, and safety. Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm.

Proposals for model-based paediatric medicinal development within the current European Union regulatory framework.

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop.We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model-based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.

Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function.

BACKGROUND: Ribavirin is approved for the treatment of chronic hepatitis C virus (HCV) infection. However, no recommendation exists for dosing patients with impaired renal function. METHODS: The authors performed a pharmacokinetic study in 21 HCV-positive renal or liver transplant patients. The mean creatinine clearance (ClCr) calculated by the Cockcroft-Gault equation was 57 mL/min (0.95 mL/s; range, 17 to 89 mL/min [0.28 to 1.48 mL/s]). Twelve blood samples were obtained during a 96-hour period after the first single administration of 1,000 mg of ribavirin. After the first pharmacokinetics (PK) and the pharmacodynamics (PD) profile was completed, the patients received ribavirin at 1,000 mg/d with or without interferon-alpha. A blood sample was taken monthly just before the oral administration of ribavirin. Plasma ribavirin concentrations were determined by high-performance liquid chromatography. RESULTS: A total of 428 plasma concentrations were analyzed by a population pharmacokinetic method using the NONlinear Mixed Effect Model program. The mean observed ribavirin apparent clearance (CL/F) was 9.1 L/h (with an interindividual variability of 39%). The influences of the age, sex, body weight (BW), serum creatinine (Scr), ClCr, hemoglobin, and graft status on CL/F were examined. CL/F was highly correlated with ClCr (r = 0.63, P < 0.01). The final regression formula was CL/F (L/h) = 32.3 x BW x (1 - 0.0094 x age) x (1 - 0.42 x sex)/Scr, where sex = 0 for men and 1 for women; Scr is in micromoles per liter. Sex had a larger influence on CL/F than that corresponding to the Cockcroft-Gault equation (ie, 15%). CONCLUSION: The authors present the parameters that determine ribavirin clearance in HCV+ transplant patients with normal or impaired renal function. Moreover, we suggest ribavirin daily doses according to various levels of renal function.