Ralf Herold

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.

A European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)

Conducting clinical trials in the paediatric population is difficult for a host of reasons that include logistical, methodological, financial and ethical problems. Indeed for many paediatric conditions, their low prevalence means that multicentre studies performed on an international scale often represent the only possibility to gather a sufficient number of patients (ie, to obtain clinically and statistically valid results) over a reasonable period of time, especially for drug trials. However, such studies are difficult to conduct for several reasons including ethical issues such as assignment to placebo, lack of adequate paediatric methods to assess response to therapy, lack of adequate paediatric formulations, the need for specific study designs, inadequate funding as the consequence of the small potential market and limited funding for investigator led academic studies. In addition, there are several bureaucratic constraints related to ethics approval and clinical trial authorisation that often hinder investigator led academic sponsored clinical trials, which do not have the extensive logistical support normally provided by pharmaceutical companies.1 The overall result is that, until recently, evidence regarding the safety and effectiveness of available treatment regimens tended to be from small, open, uncontrolled trials or from anecdotal reports and non-randomised case series. From a logical and scientific point of view, one of the key issues to overcome these problems is to work with established clinical trials networks that have a wide international representation and a good scientific reputation. In this regard, the adoption of legislations to encourage paediatric clinical trials both in Europe and in the USA has opened a new era in the …

Pharmacometrics for Regulatory Decision Making

As a methodology to rationalize and inform drug development, pharmacometrics (modelling and simulation) is widely appreciated by industry, academia and regulators in general. However, the integration of pharmacometric analyses into regulatory decision making is not formally established and has been the subject of discussion in many scientific and regulatory fora. The article by Lee et al. published in this issue of the journal provides instructive case studies of how pharmacometrics can be used by regulators to help decision making, interaction with companies, reviewing and labelling. Their case studies indicate that pharmacometrics is not a tool reserved only for companies for internal decision making, but also is a powerful platform that regulators may use to compile and analyse data in order to support approval and labelling. This is considered to have beneficial effects for both industry, in terms of resource optimization, and for prescribers and patients, who obtain more precise labelling instructions and optimal therapeutic interventions, respectively. The increasing impact of pharmacometrics on US FDA approval and labelling (see table I in the article by Lee et al.) indicates the success of the methodology and the need to make best use of all available data during regulatory decisionmaking, especially in controversial cases or when data are scarce (e.g. in orphan diseases or paediatrics). In Europe, modelling and simulation was identified by the European Medicines Agency (EMA) Think-Tank Group on Innovative Drug Development and Committee for Medicinal Products for Human Use (CHMP) as one of the key methodologies to overcome bottlenecks in drug development. There is no EMA guideline that generally defines how pharmacometrics should be used in regulatory decision making. Indeed, it is difficult to discuss this methodology outside a specific context (e.g. the clinical condition, feasibility of trials, availability of good biomarkers for safety and efficacy, availability of clinical efficacy and safety data from other groups, and stage of development). In general, the hurdle for regulatory acceptance ofmodelling and simulation seems lower in the exploratory phases than in the confirmatory phases of medicine development. On the basis of information compiled from various clinical efficacy/safety and methodological EMA guidelines, and discussions by the EMA Scientific Advice Working Party (SAWP) and Paediatric Committee (PDCO), we have identified the following cases to exemplify the spectrum of current thinking in the European regulatory setting. Examples where the use of modelling and simulation is well appreciated are: hypothesis generation and learning throughout drug development; use of models to minimize the burden of pharmacokinetic/ pharmacodynamic evaluations in current studies and to optimize future experiments; use of models for selection of doses to be further tested in clinical trials. Examples where the use of modelling and simulation could be accepted if properly justified are: use of models for final recommendation of intermediate doses that were not specifically tested in phase II/III trials; population pharmacokinetic analysis in phase II/III to support regulatory claims (e.g. the absence of suspected drugdrug interactions and the effect of pharmacogenetics on exposure); modelling and simulation to bridge efficacy data. Examples where the use of modelling and simulation is generally seen as controversial are: model-based inference as the ‘sole’ evidence of efficacy/ safety, notwithstanding exceptional scenarios; approval based on simulated data for efficacy and safety. An important criterion that regulators check when assessing the weight of modelling and simulation in a given submission is the quality of the exercise. The principles of transparency, traceability, parsimony, external validity and internal validity, COMMENTARY Clin Pharmacokinet 2011; 50 (10): 625-626 0312-5963/11/0010-0625/

Medicines for pediatric oncology: can we overcome the failure to deliver?

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The European Medicines Agency: An Overview of Its Mission, Responsibilities, and Recent Initiatives in Cancer Drug Regulation

To date, children do not have access to the medicines necessary to treat pediatric cancers. Pediatric tumors have different names and specificities from adult tumors that go far beyond the naming issue. In most other therapeutic areas, with the main exception in pediatric rheumatology, the diseases affecting children are close to those affecting adults with respect to type of diseases and pathophysiology. Owing to specific gene mutation and expression profiles and fast tumor growth, cancers affecting children are different. An aggravating factor for the lack of authorized medicines is the rarity of the diseases, representing a small market overall, although they are frequent among serious pediatric diseases. Cancer represents the second main cause of death in children and treatments place a heavy burden on the child and his or her family. The uncertainties on long-term prognosis owing to potential late relapses, as well as complications of chemotherapy and radiotherapy add to this burden. However, pediatric oncology is also the area where treatments have achieved outstanding results through rigorous protocols (using medicines off-label), resulting in long-term survival and cures [1]. Another paradox is that most of the treatments used today were established by academics and hospital pediatric oncologists over the last decades, generally with little help or interest from large pharmaceutical companies. This meant in practice that access to anticancer medicines was always significantly delayed for children [2] in contradiction with ethical principles and existing guidelines such as the International Conference on Harmonization guideline on the development of pediatric medicines (E11), which requires simultaneous submission for adults and children when the disease is serious or life threatening, when there are limited or no therapeutic alternatives [101]. In fact, behind the success lies another reality. If most of the success comes from effective treatments of acute pediatric leukemia and lymphoma, many other tumors – especially advanced stages and those of the CNS such as high-grade glioma – remain without effective therapeutic options, with short survival and devastating effects on the child and the family [3]. Regulatory initiatives in the USA, then in Europe, aim to ensure that medicines intended for adults are developed for children where there are unmet pediatric needs [102,103]. Unfortunately, to date in pediatric oncology these have not been so successful for several reasons. As part of the US Best Pharmaceutical for Children Act (BPCA), the US FDA can issue Written Requests based on public health needs describing how a company can develop a medicine for children, with the prospect of getting additional Medicines for pediatric oncology: can we overcome the failure to deliver?

Bridging the gap: a review of dose investigations in paediatric investigation plans

The European Medicines Agency (EMA) is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union (EU). Since 2005, the agency has become responsible for the approval of all new oncology drugs in the EU. In this article we describe the mission, role, and responsibilities of the EMA, and provide a brief summary of recent initiatives related to cancer drug regulation. The EMA recently published its Road Map to 2015. Over the next 5 years, the agency aims to continue to stimulate drug development in areas of unmet medical needs. Concerning drug safety, one of the priorities over the next few years will be to establish a more proactive approach in ensuring patient safety. This is the result of new EU legislation coming into force in 2012 that will strengthen the way the safety of medicines for human use is monitored in the EU. In terms of its general operation, the agency is committed to increased openness and transparency, and to build on its interactions with stakeholders, including members of academia, health care professionals, patients, and health technology assessment bodies. The agency recently created an oncology working party to expand the current guideline for the development and evaluation of cancer drugs. The guideline focuses on both exploratory and confirmatory studies for different types of agents. The current revision will address a number of topics, including the use of biomarkers as an integrated part of drug development and the use of progression-free survival as a primary endpoint in registration trials. Clin Cancer Res; 17(16); 5220–5. ©2011 AACR.

Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project

Aims In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. Methods We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Results Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Conclusions Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure−response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies.

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

ABSTRACT Introduction: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

European Union Clinical Trials Register: on the way to more transparency of clinical trial data.

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.

Scaling Dose-Exposure-Response from Adults to Children

European Medicines Agency, London, UK It is of public interest to access trial information complementary to that published in journal articles. Public desire for such a provision has grown due to concerns that scientists, pharmaceutical companies and journal editors would tend to publish positive outcomes whereas negative data would often remain unpublished [1]. Making available information about clinical trial protocols in a publicly accessible registry and unique identification of all trials is one way of addressing this issue [2,3]. Legal requirements have been put in place to this effect in several regions of the world, including in the EU (in 2004) and in the USA. (in 1997) [4]. The International Committee of Medical Journal Editors (ICMJE) adopted a policy in 2004 which requires, as a condition for consideration for publication in member journals, that trials be registered in a public registry [5,101]. Public registration of trials before recruitment of the first subject and publication of the trial results have been included as principles of the Declaration of Helsinki [102]. An exhaustive public registry allows patients and health professionals to know which trials are being conducted and are open for enrollment. This facilitates participation in research for studying medical advances and potentially life-saving therapies. Public registries ensure that researchers can find out what has already been done, or is underway, helping to avoid redundant research. They provide a tool to cross check publications in medical journals and to scrutinize research methodology [6]. The registered information needs to be comprehensive and accurate [7,8]. Only one third of reviewers of clinical research articles routinely use the information recorded in registries [9]. Therefore, the value of such tools needs to be emphasized in the scientific community. The launch of the European Union Clinical Trials Register (EU-CTR) in 2011 was a significant advance in the availability of public information on clinical trials. The EU-CTR makes public a broad set of information on clinical trials held in the EU regulators clinical trials database (EudraCT). This article intends to present the main features of EudraCT and its public face, EU-CTR.