Regulatory aspects of drug development in children: change and resistance to change

Keywords::

• child
• drug
• regulatory

Dramatic changes in the way medicines are developed for children are taking place, and children are now being placed at the forefront after years of neglect. We hold the view that the changes made in the last 20 years may have the highest impact on the regulatory framework. Changes had to be obtained through requirements compensated by rewards because guideline recommendations and laments from healthcare professionals had proved ineffective. The changes were welcomed by some stakeholders, health professionals and patients (and their families), but they also triggered frustrations and difficulties from the pharmaceutical industry, some legitimate, others less so [1]. This was not unexpected.

The first regulatory initiatives were launched successfully by the US FDA in the 1990s, based mainly on a voluntary process [101]. Under the Best Pharmaceuticals for Children Act, a company may comply with a written request to obtain 6 months of supplementary exclusivity. The balance of requests versus costs was considered positive by the FDA [2]. The other side of the US regulatory coin, the Pediatric Research Equity Act (PREA; 2003, renewed in 2007) requires pediatric assessment unless there is a deferral or a waiver of studies, but is devoid of a reward. The FDA review of the PREA demonstrated that the requirements were not initially applied fully or in keeping with the language of the Act, and this may have given the impression that the PREA was not a real requirement for industry [102].

Until 2006 in Europe, the International Conference on Harmonization (ICH) E11 guideline, in force since 2000, had practically no effect on pediatric submissions in Europe. Between 1995 and 2005, 44% of the 243 medicines authorized by the EMA had a potential pediatric use but no data [EMA, Unpublished Data]. At the end of 2006, the European Union (EU) adopted a regulation with a considerably wider scope than the US legislation [3]. The reasons to support the legislative initiative differ significantly between stakeholders. The Regulation brings higher requirements to industry but retains the principle of rewards; it requires not only agreement on the pediatric development and compliance with the agreed plan before filing the adult marketing authorization, but also that the pediatric investigation plan (PIP) covers all subsets, from the rarely studied neonate to the adolescent, in all pediatric and adult conditions, with an age-appropriate formulation. The main European reward is an extension of intellectual property rights by 6 months (extension of the Supplementary Protection Certificate [SPC]) as in the USA. Despite the increased requirements, the protection offered by the European regulation has been criticized as less rewarding [104]. The SPC extension is difficult to obtain due to a short time frame for requests, it has to be requested at an individual national level and the financial return may be less despite identical duration, due to lower than average price levels in Europe. Many medicines ineligible to receive the extension of the SPC still need to be developed for children. Although not based on evidence, criticisms have been made that the balance of requirements versus rewards is tipped towards requirements in Europe.

Worldwide in 2008, in addition to the US and EU initiatives, the WHO issued a list of essential medicines for children, and launched its own initiative ‘Making Medicines Child Size’, advocating the pediatric development of and access to appropriate quality medicines especially for emerging countries [105]. Countries such as Japan and Canada are considering the measures necessary to obtain appropriate prescribing information. The nearly simultaneous approaches taken by regulatory authorities have created a synergy and the basis for global pediatric development. Pediatric medicines available to one region should become available to others, but unnecessary replication of trials should be avoided. This may mitigate the difficulties in getting the European reward.

Producing more, and hopefully better quality, evidence to support the prescription of medicines to children is a public health benefit and is seen as an ethical duty. However, protecting vulnerable children against avoidable risks in clinical trials is just as much an ethical duty. In this respect, the EMA Paediatric Committee is taking specific and systematic measures to protect children exposed to research. Taking into consideration global development and the current increase in clinical trials being performed in third-world countries, there is also concern for children from third-world countries who may be even more vulnerable. The recent EMA’s initiative on Clinical Trials in Third World Countries is one of the attempts from regulatory authorities to address these concerns [105]. Additionally, the intensive collaboration between regulatory agencies aims to avoid unnecessary repetition of pediatric trials.

The implementation of the pediatric regulation has exemplified the difficulties of systematic pediatric development. Companies must present a PIP early during adult development, after completion of adult pharmacokinetic studies, understood to mean at approximately the end of Phase I for new medicines and the plan will need to be modified as knowledge of the medicine increases. The plan must include age-appropriate formulations and timelines for studies. In practice, a plan is often extremely complex and extensive, as it systematically discusses the main subsets from adolescents and children, down to infants and neonates, unless there are grounds for a waiver. This plan must be agreed by the expert Paediatric Committee at the EMA. Studying medicines in children, including neonates, is indisputably challenging, but indisputably necessary, as most of the therapeutic needs are not covered. The younger the age group, the greater the unknown and the more difficult it is to plan appropriate development. Both industry and the committee are working hard to meet these challenges. The lack of outcome measures and comparators and the reluctance to use placebo, or even to accept randomized controlled trials, especially in neonates, are major hurdles. Long-term safety would require collection of data over decades. Our limited knowledge on the influence of, or impact on, maturing organs also justifies more research; noninvasive methods are rarely available and micro-assays are underused. In addition, it is not easy to design sufficiently powered trials. Overall, the pediatric population accumulates two ‘trial-adverse’ characteristics, heterogeneity, for example, owing to maturation and limited numbers of children available for research.

Competition between trials of similar medicines in similar diseases will take place within the population affected; this competition is a complicating factor, both unwanted and counterproductive, if the resulting trials are too small to provide robust results. The Paediatric Committee is unable to select one medicine among several, as it cannot influence submissions by industry, does not have information on subsequent submissions and in most cases does not have the information to decide which medicine is the most likely to demonstrate a positive risk-to-benefit balance.

As a consequence, the requirements from the Paediatric Committee share all the issues identified for pediatric trials, which mostly amount to feasibility of the trials agreed. If no committee is above criticism, industry’s initial proposals are also not without limitations. The committee normally refuses adult protocols that are simply ‘translated’ into pediatrics. Whilst advocating for better evidence, the Paediatric Committee is also of the view that extrapolation of efficacy data obtained in adults or older children may be justified in a number of situations. Until recently, a systematic approach to extrapolation, using, for example, disease modeling and simulation had not been established and guidance was missing. There is now work in progress in both the USA and Europe.

Performing the necessary trials requires the necessary infrastructure and competence for pediatric research. Pediatric research is still fragmented and difficult, although it has been developed in a few areas, such as oncology or vaccines. The EU Paediatric Regulation has tasked the EMA with a new responsibility of establishing a network of pediatric research networks. The network is now taking shape, but it will take a few more years to measure the impact of such collaboration. In parallel, an international initiative to develop the pediatric research capacity in Europe and elsewhere is being funded by the European Commission and is expected to help produce high-quality research. Academic researchers are not the sole stakeholders and work remains to be carried out to engage community practitioners and families in pediatric research, as well as to provide training to ethics committees judging pediatric protocols.

Greater transparency is a major force for change, and we believe this is an irreversible process. However, releasing early information to the public, which includes the company’s competitors, has its drawbacks. The EU Paediatric Regulation gave precedence to disclosure over commercially sensitive information and has created high expectations from patients and health professionals. The benefits of transparency include avoiding the unnecessary repetition of trials in children, ensuring that negative results are published and informing potential investigators and participants of current trials. It is also acknowledged that development plans are revealed when the opinions from the Paediatric Committee are made public. In the past, these plans, including their timelines, were considered commercially sensitive. Details of trials agreed in collaboration with clinicaltrials.gov will be further revealed in EudraCT, the EU Clinical Trials database, by end of 2010.

Complementing other regulatory initiatives, but clearly having more demanding requirements, the EU Paediatric Regulation is responding to the public health needs of children at a cost for industry. It has been argued that the resources put forward for pediatric development are taken from other adult developments or that investing in drafting early PIPs for all medicines is a waste of resources, as the majority of medicines will fail in Phase II or III and the PIP will become redundant. It is also argued that companies know next to nothing about the product until Phase III; however, pediatric clinical development can still be described early as it is mostly dependent on the pediatric disease itself for end points, comparators and safety, for example. Other voices have – often timidly – argued that the reflection triggered by the PIP had actually helped companies to better define adult development. We support the view that anticipating pediatric use has benefits and saves costs for the formulation development, planning of toxicology and pharmacokinetics and integration of modeling.

The EU Paediatric Regulation includes requirements for the European Commission to report on the experience acquired by January 2013 and to measure the impact after 10 years – by January 2017. It can be expected that some stakeholders will propose changes to the legislation.

Is it possible to identify some results of the regulation as of now? The first measure should be the number of pediatric trials conducted or registered. Despite having PIPs agreed since 2008 in Europe, the resulting increase in the number of pediatric trials is lower than expected. In 2008 and 2009, 4680 and 4513 trials, respectively, with at least one site in the European Economic Area, were authorized. Among those, there were 336 (7.2%) and 419 (9.3%) pediatric trials, that is, trials including participants aged under 18 years. This represents an increase of 25% in a year [EMA, Unpublished Data]. The effect of the regulation measured by this indicator is still modest, even if it can be argued that more pediatric trials are and will be performed outside Europe and are not visible in EudraCT, as the database does not yet allow the registering of trials performed outside the EU. The measure of other indicators, such as the number of medicines authorized for children, capacity building, education of the public vis-à-vis participation in research and filling gaps in knowledge, will take longer still.

Overall, the pediatric regulation is producing positive results for children’s medicines, even if it is still far too early for a demonstration of the full impact. The regulation is stimulating interest and awareness for pediatric medicines. Funding for further research into outcomes measures, physiology, pharmacokinetic and disease modeling, and for the ethics of pediatric trials is available. The Regulation has been extremely well received by many stakeholders, not only health professionals and patients’ organizations, but also individuals in pharmaceutical companies who relate easily to research benefiting their own children. We continue to believe that the pediatric regulatory revolution will deliver high-quality information and more medicines with age-appropriate formulations for the benefit of children in Europe and beyond.

Disclaimer

The views presented in this editorial are those of the author and should not be understood or quoted as being made on behalf of the EMA and/or its scientific committees.

Financial &competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.