Agnes Saint-Raymond

Juvenile animal studies for the development of paediatric medicines: a description and conclusions from a European medicines agency workshop on juvenile animal testing for nonclinical assessors

A workshop organised by the European Medicines Agency involved assessors and experts present in a Nonclinical Working Group evaluating juvenile animal studies for Paediatric Investigation Plans in collaboration with the Paediatric Committee and the Safety Working Party of the Committee for Human Medicinal Products. The objective of the workshop was to analyse which juvenile animal studies proposals were received and agreed by the Paediatric Committee, to check consistency and how to apply the existing European guideline on juvenile animal studies. A comparison of main organ system development in man vs. animal species was presented to guide the review and to support species selection and protocol design. An analysis of juvenile animal studies included in finalised PIPs was also presented. Out of 109 paediatric investigation plans finalised between November 2008 and March 2009, 43 included one or more juvenile animal studies. In most cases the preferred species was the rat; one species only was requested to be studied (20/22), but in a minority two species were required (2/22). When deciding on the characteristics of the juvenile animal studies, such as age of animals at study start, the age of the children targeted by the medicine was considered. It is expected that the increasing experience gained by Applicants and Regulators will allow further refining the criteria for these juvenile animal studies. Further research on this topic is highly encouraged in the European Regulatory framework.

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

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?

The European Paediatric Initiative

The European Regulation on medicines for pediatric use entered into force on 26 January 2007. It changes dramatically the way medicines are developed for children. This regulation will increase availability of and information on pediatric medicines through high quality, ethical research.

Oral medicines for children in the European paediatric investigation plans

Introduction Pharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review. Methods All PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports. Results A hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified. Conclusion The EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound.

Impact of the European paediatric legislation in paediatric rheumatology: past, present and future

Conducting clinical trials in paediatric rheumatology has been difficult mainly because of the lack of funding for academic studies and the lack of interest by pharmaceutical companies in the small and non-rewarding paediatric market. The situation changed dramatically a few years ago with the introduction of the Best Pharmaceuticals for Children Act in the USA and of specific legislation for the development of paediatric medicines (Paediatric Regulation) in the European Union (EU). The EU Paediatric Regulation had a positive impact in paediatric rheumatology—in particular, on the development of new treatments for children with juvenile idiopathic arthritis (JIA). Some problems remain, however, such as greater harmonisation of the regulatory aspects of medicines, how to handle me-too agents, how to conduct adequate pharmacokinetic studies and develop age-appropriate formulations, ethical problems in study review and implementation, and a change in the current JIA classification. The introduction of specific legislation, coupled with the existence of large international networks such as the Pediatric Rheumatology Collaborative Study Group (PRCSG at http://www.prcsg.org), covering North America, and the Paediatric Rheumatology International Trials Organisation (PRINTO at http://www.printo.it), covering more than 50 countries, has led to great advances in paediatric rheumatology. Future changes might increase the possibility of conducting trials with similar approaches in other paediatric rheumatological conditions and provide evidence-based treatments for children affected by rheumatic diseases.

Pediatric Regulatory Initiatives

A series of government actions have evolved since the 1990s to facilitate the development of medicinal products for pediatric use using a combination of incentives and mandates. The initiatives have been successful in stimulating activity and interest in products developed for pediatric use. The initiatives continue to evolve as experience accumulates and regulatory agencies develop robust cooperative programs. A multidimensional program is necessary to achieve the necessary goal of aligning pediatric therapeutics with adult therapeutics and providing children the most favorable opportunity to benefit and minimize risk to vulnerable populations.

Important issues in the justification of a control treatment in paediatric drug trials

Objective The value of comparative effectiveness trials in informing clinical and policy decisions depends heavily on the choice of control arm (comparator). Our objective is to identify challenges in comparator reasoning and to determine justification criteria for selecting a control arm in paediatric clinical trials. Design A literature search was completed to identify existing sources of guidance on comparator selection. Subsequently, we reviewed a randomly selected sample of comparators selected for paediatric investigation plans (PIPs) adopted by the Paediatric Committee of the European Medicines Agency in 2013. We gathered descriptive information and evaluated their review process to identify challenges and compromises between regulators and sponsors with regard to the selection of the comparator. A tool to help investigators justify the selection of active controls and placebo arms was developed using the existing literature and empirical data. Results Justifying comparator selection was a challenge in 28% of PIPs. The following challenging paediatric issues in the decision-making process were identified: use of off-label medications as comparators, ethical and safe use of placebo, duration of placebo use, an undefined optimal dosing strategy, lack of age-appropriate safety and efficacy data, and drug dosing not supported by extrapolation of safety/efficacy evidence from other populations. Conclusions In order to generate trials that will inform clinical decision-making and support marketing authorisations, researchers must systemically and transparently justify their selection of the comparator arm for their study. This report highlights key areas for justification in the choice of comparator in paediatric clinical trials.

White spots in pharmaceutical pipelines–EMA identifies potential areas of unmet medical needs

Unmet medical needs are a priority for organizations such as the WHO and major public–private initiatives, such as Innovative Medicines Initiative, were established to speed up the development of better and safer medicines for patients. To assist such projects, the EMA in its ‘Road Map to 2015’ considered the mapping of unmet medical needs as a priority. This study has identified medical conditions for which the EMA could not identify developments in the pharmaceutical pipelines, that is, ‘white spots’. Our analysis was made using external data sources as well as mining data of the EMA. The main areas for white spots were oncology, infectious diseases and certain psychiatric conditions. According to our data and a review of literature, in a number of these white spots, diagnostic tools may even be missing. The identification of those conditions will benefit stakeholders, including regulators, research funding bodies and patients’ organizations.

Comments on the EMA draft guideline: Final steps towards a harmonized view between regulators and industry☆

Diana A. van Riet Nales 1,2,∗, Piotr Kozarewicz 3, Siri Wang 4, Agnes Saint-Raymond 5, Jean-Louis Robert 1,6 1 European Medicines Agency, Quality Working Party, London, United Kingdom 2 Medicines Evaluation Board, Department of Chemical Pharmaceutical Assessment, Utrecht, The Netherlands 3 European Medicines Agency, Quality of Medicines, London, United Kingdom 4 Norwegian Medicines Agency, Department for Medicinal Product Assessment, Oslo, Norway 5 European Medicines Agency, Human Medicines Special Areas, London, United Kingdom 6 Laboratoire National de Santé, Department of Control of Medicines, Luxembourg, Luxembourg E-mail address: da.v.riet@cbg-meb.nl (D.A.v.R. Nales).

Fostering responsible research with genome editing technologies: a European perspective

In this consensus paper resulting from a meeting that involved representatives from more than 20 European partners, we recommend the foundation of an expert group (European Steering Committee) to assess the potential benefits and draw-backs of genome editing (off-targets, mosaicisms, etc.), and to design risk matrices and scenarios for a responsible use of this promising technology. In addition, this European steering committee will contribute in promoting an open debate on societal aspects prior to a translation into national and international legislation.