Agnès Saint Raymond

Three years of paediatric regulation in the European Union.

PurposeTo investigate whether the Paediatric Regulation has already succeeded in addressing the needs of the paediatric population both quantitatively with respect to paediatric development plans and trials, and qualitatively with respect to the content of the plans. The Paediatric Regulation No 1901/2006 entered into force in Europe on 26 January 2007, with the aim to improve the development of medicinal products, to address the lack of age-appropriate formulations and to provide information on efficacy, safety and dosing for the paediatric population. The Regulation requires applications for marketing authorisations to be accompanied by either a product-specific waiver or a paediatric investigation plan, to be agreed by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA).MethodsA retrospective analysis of the applications for Paediatric Investigation Plans (PIPs) and Waivers submitted to the EMA, from 2007 until end of 2009, was performed. The content of scientific opinions adopted by the Paediatric Committee was compared to the proposals submitted by industry, and the paediatric clinical trials registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database were examined.ResultsAn increasing paediatric medicine development can be expected following the adoption of this legal framework. The highest number of PIPs was in the fields of endocrinology (13.4%), oncology (11%) and infectious (10.8%) and cardiovascular diseases (7.1%), but most therapeutic areas now benefit from paediatric development. A large number of PIPs include measures for the development of age-appropriate formulations (23%), and most include studies on dosing, efficacy and safety to cover the respective paediatric subsets, including the mostly neglected neonates (26%). In many proposals (38%), however, the PDCO had to request major modifications to the proposed PIPs to ensure that the results will meet the needs, in particular by requesting better methodology. The proportion of paediatric trials as a percentage of all clinical trials has moderately increased (from 8.2 to 9.4% of all trials), and this may reflect the fact that paediatric trials are generally deferred (82%) until after adult development.ConclusionsThis is the first analysis of the general impact of the Paediatric Regulation on the development of medicinal products in Europe. Three years after the implementation of the Paediatric Regulation, we were able to identify that the PIPs address the main gaps in knowledge on paediatric medicines. The key objective of the Paediatric Regulation, namely, the availability of medicines with age-appropriate information, is going to be achieved. It is clear also that modifications of the initial proposals as requested by the PDCO are necessary to ensure the quality of paediatric developments. The impact on the number of clinical trials performed remains modest at this point in time, and it will be of high interest to monitor this performance indicator, which will also inform us whether paediatric medicine research takes place in Europe or elsewhere.

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 …

Paediatric investigation plans for pain: painfully slow!

PurposeTo examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA).MethodsPaediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis.ResultsOf the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products.ConclusionsThe small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis.

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

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.

Preamble may not improve consent and assent process.

To the Editor: Drs Masera and D’Angio [1] propose a preamble to informed consent (IC) documents. The preamble intends to reduce the complexity of IC information, but in our view, as proposed, the preamble would violate a major ethical principle, that of patient autonomy. We agree that specific written information may meet the needs of a family confronted with a serious diagnosis, e.g., by explaining the disease and providing reassurance. However, the preamble would compromise the patient–physician relationship by undermining the trust that underpins it. It misleads the patient into believing that entering a trial is the only treatment option, and reveals to some extent a conflict of interests of investigators. Alternatively to entering the trial, best standard of care should always be offered as equivalent option. We do believe that research has benefits for children, but their protection is essential. Respect for the autonomy of the patient in deciding on trial participation is required. There has been a number of examples of well-meaning research applied unethically [2]. As aptly put by Kristin A. Long in the same issue [3], ‘‘Pediatric cancer treatment lies at the juxtaposition of research and clinical care’’. If the preamble blurs the distinction between care and research, then there is no more juxtaposition and the patients have no choice. Although the preamble recommends to read the full IC document carefully, it presents the main topics in a simplified way, leading to perceive the IC document content as redundant or unnecessary. Thus, providing a preamble without improving ‘‘lengthy, complex, and largely incomprehensible’’ IC documents may create a negative bias toward the IC and further diminish its informative value. We suggest that it would be more valuable to emphasize the choices of patients, at diagnosis and throughout treatment. IC and assent are indeed continuous processes [4]. In this respect it is striking, as discussed by Long [2], that some pediatric oncologists are not seeking adolescent’s assent. Restricting patients’ choices might damage seriously the patient–physician relationship, in particular should the trial treatment fail, or the trial burden be unbearable. Conversely, we suggest to increase transparency of the IC and assent process in paediatric trials as recently recommended [5,6]; this is even in the interest of those running the trial. The academic community does its utmost to take account of the patients’ best interests and to safeguard patients from low quality research. However, individual investigators are also driven by the professional need to accumulate funding, data, and publications. Conflicts of interest, including of a non-financial nature, are a recognized cause of bias. We suggest including a balanced presentation of expected outcomes [5,6] of each option within the IC document. It would also be useful to share elements of IC documents that were effective and well accepted by families in a multilingual repository. Increasing public awareness of the choices in healthcare would help make IC become true patient empowerment. Trust between the patients and the physicians, whether they are the treating clinicians or conducting clinical research, cannot be established without full transparency.

Role of modeling and simulation in pediatric investigation plans: 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.