The influence of the European paediatric regulation on marketing authorisation of orphan drugs for children

Rare diseases are defined as life-threatening or chronically debilitating conditions with such a low prevalence that special combined efforts are needed to ensure adequate medical care. As a guide, a prevalence of less than 5 per 10,000 citizens in the European Union (EU) is considered low [1]. A low prevalence still equals to approximately 250,000 patients in the Community for diseases near the cut-off point. Much rarer diseases only affect a few dozen patients in the whole EU. There are between 5000 and 8000 rare diseases identified so far, affecting an estimated 30 million EU citizens [2]. Over 80% of rare diseases have a genetic background, with the great majority being single-gene defects, although multifactorial and chromosomal defects exist. Other non-genetic rare diseases are due to degenerative and proliferative causes, infectious diseases, treatment-related toxicities, alimentary deficiencies, rare poisonings and injuries [2],[3]. Rare diseases can occur at any age but approximately half of these have their onset at birth or during childhood [4].

Drugs for rare diseases are classified as orphan drugs (ODs). Developing ODs is very challenging. This is mainly due to the various factors that limit clinical studies such as the small number of patients, the heterogeneous and scattered populations, ethical issues (i.e. the use of placebo), lack of validated biomarkers and end-points, poor diagnostics and limited clinical expertise [5], but also by the lack of return of investment in the small target population [6]. To stimulate research, development and placing on the market of ODs, in 2000, incentives were put in place for drug developers, such as a ten-year marketing exclusivity, access to centralised authorisation procedures and fee reductions for regulatory activities (such as protocol assistance, MA applications and inspections) by the European Medicines Agency (EMA) [6]. Another mechanism that may boost the discovery and development of ODs is “repurposing”. This refers to the exploitation of known drugs for new indications [7]. Repurposing receives attention in both the United States and Europe, although differences exist between both continents with respect to policies for repurposing of medicinal products [8]. Several initiatives have been created to identify possible targets for drug repositioning [7]. One of them is the US Food and Drug Administration (FDA) Rare Diseases Repurposing Database to encourage repurposing for rare diseases [9]. There are many examples of ODs that were successfully developed from repurposed drugs [10],[11].

The development of drugs for children with rare diseases poses even more challenges than it does for adults. The biology of the growing child, its changing physiology and psychology are much different from adults and requires research that is dedicated to children [12]. Such research is confronted by technical difficulties and legal and ethical constraints. As a consequence, there is little or no investment in research and development of drugs for the paediatric population. More than half of medicines used for children were never or incompletely studied in this population; their use in children is either unlicensed or off label, i.e. out of the scope of the drug’s authorised label for age, route of administration, dose frequency, formulation or indication [13]. Use of unlicensed drugs or off-label use is especially common for children with rare diseases and is potentially inefficacious and hazardous [14].

The European Regulation (EC) No 1901/ 2006, hereinafter referred to as the ‘Paediatric Drug Regulation’ [1] came into force on 26 January 2007 with the objective to improve the health of European children by facilitating the development, accessibility and safe use of new drugs for children aged 0 to 17 years, through clinical studies. These objectives should be achieved without subjecting children to unnecessary clinical trials and without delaying the authorisation for other age populations. This regulation obliges applicants to submit study results to the EMA for each new medicine, new indication, new route of administration or new formulation, according to an agreed Paediatric Investigation Plan (PIP). This PIP describes the planned paediatric studies and their timelines. It should ideally cover all age groups from birth to adolescence. Paediatric studies may be (partially) ‘waived’ if studies are not feasible, appropriate or safe for (a subset of) the paediatric population or ‘deferred’ if it is appropriate to conduct studies in adults prior to initiating studies in children or if studies in children will last longer than studies in adults. The PIP should also describe the need for the development of age-appropriate formulations and/or additional non-clinical information (such as developmental toxicity studies in juvenile animal). When the PIP is completed and all requirements are met, applicants are rewarded with a six month extension of patent protection. Off-patent products developed exclusively for use in children are granted eight year data- and ten year market exclusivity for the paediatric indication (the Paediatric Use Marketing Authorisation (PUMA)). ODs are rewarded with two additional years of market exclusivity. The Paediatric Drug Regulation was introduced in stages (see Table 1) distinguishing new medicinal products from already authorised medicinal products.

The implementation of the Paediatric Drug Regulation has paid off for non-orphan medicinal products. Five years after its implementation, more medicines have become available for children and more research has been conducted in children [15]. Over 600 PIPs have been agreed upon and 30% of those PIPs include studies with neonates, the most neglected group. In addition, more paediatric clinical trials were conducted and the proportion of clinical trials including children increased over the last 6 years, to approximately 10% [15].

For ODs, the impact of the Paediatric Drug Regulation has not been studied. In this manuscript, we describe the drug application process from orphan drug designation (ODD) to marketing authorisation (MA) and analyse the effect of the Paediatric Drug Regulation on the success rate and time course of obtaining MA.

More than 80 ODs, covering nearly 100 indications, were authorised in Europe since 2000. Half of these products are available for (a subgroup of) children. Another 34 authorised ODs are currently undergoing further investigations in children. The introduction of the Paediatric Drug Regulation was associated with a longer time to MA for OD, did not significantly increase the number of ODDs with potential paediatric indications and did not lead to more MAs for paediatric indications.

In this study we were able to quantify the time to authorisation and the number of paediatric ODs, but could not extract the quality of research conducted in children given the relatively young EU Paediatric Drug Regulation. The use of Cox regression to analyse time to MA as a survival function is appropriate and the data set is large enough to draw valid conclusions. There is some autocorrelation between indications for children and adults within the same drug. This means that the time to MA for a paediatric indication is linked to that for adult indications of the same drug, because, in part, they share study results. The data set illustrates that ODs often obtain MA for adults first, for which clinical studies are easier to conduct, and later for children. A control group would have been desirable, but since non-ODs do not have the same starting point (time of obtaining ODD), comparison in this context is not possible and data would have to be based on different criteria which is beyond the scope of this study.

Administrative processes are not static, they change over time, and that also applies to the approval of ODs. This implies that the time to MA, modelled as survival time in our Cox regression model, may not be completely independent of time. This time dependency was addressed by using after/before 2007 as a separate categorical variable. Since the granted therapeutic indication at the time of MA is the result of the assessment of the quality, safety and efficacy data submitted with the marketing application, this may be different (narrower) to the indications proposed at the time of ODD application [17]. After 2007, the Paediatric Committee (PDCO) safeguards that for any potential paediatric medicinal product an investigation plan is made.

The situation for patients with rare diseases has, without a doubt, improved dramatically after 2000, the year in which the EU Orphan Drug Regulation was implemented. Before 2000 only eight products, so called orphan-like drugs, were authorised for the treatment of rare diseases with the support of the EMA [18]. Four of these orphan-like drugs were authorised for use in children. In contrast, the United States introduced the Orphan Drug Act almost 20 years earlier, in 1983 [19]. Over the period 2000–2009, 148 (13%) of 1138 ODDs received MA in the U.S., of which 81% were potentially beneficial for children [20]. In the same period in the EU only 55 of 703 of ODDs were authorised and only 52% of the products were authorised in children.

The Paediatric Drug Regulation, implemented to increase the availability of effective and safe drugs of good quality for children, was also beneficial for ODs. The majority of ODs with potential paediatric use that were off label to children at the time of MA (40% of all ODs) is currently in development for the paediatric population. Also, 40% of ODs authorised for children are undergoing further investigations to either expand the intended treatment group to include younger children and/or to develop an age appropriate formulation for youngsters. This would presumably not have taken place without the instalment of the Paediatric Drug Regulation.

A drawback is the high number of deferrals for both ordinary and orphan products. In deferrals, either initiation or completion of paediatric studies is postponed until the medicinal product is authorised for use in adults, to ensure that it is safe to do research in children and that availability for adults is not delayed.

In the 5 year progress report on the paediatric regulation, the EMA concluded that authorisation of medicines for adults was not delayed. However, in our analysis, products authorised before 2007 had a shorter time to MA than those authorised after the Paediatric Drug Regulation came into force. Apparently the Paediatric Drug Regulation added complexity to the R&D and regulatory process of orphan medicinal products, exemplified by the applicants’ investments time and effort in drafting a PIP.

Others also expressed concern that the EU Paediatric Drug Regulation retards drug development and authorisation for adults by demanding paediatric trials, especially for rare diseases [21],[22]. It is not only the Paediatric Drug Regulation that causes delay. There are potential other product- and company-related factors such as the indication for which a drug is being developed, the type of drug product in development, the company’s experience in developing OD and the size of the companies submitting the MA application [23]–[25], and incentives such as those for Small and Medium Sized companies implemented in December 2005 [26]. Other economic and bureaucratic issues such as the increasing amount of regulations where applicants have to comply with during drug development in general have their effects. However, the increased approval time after 2007 can also be an artefact, caused by the submission of ODD applications increasingly earlier in the developmental phase.

Given the relatively young EU Paediatric Drug Regulation, there are few data on PIP completion and outcome in rare diseases, especially since deferrals lead to an additional seven years before expected completion of the files for paediatric indications. So far, only one product successfully reached completion of development. Furthermore, no orphan-designated medicine has yet obtained the orphan incentive of two additional years of market exclusivity. The impact of introducing PIPs will become apparent in the next few years when more PIPs are expected to be completed and will learn whether applicants are compliant with measures and timelines agreed upon in PIPs.

We could not demonstrate that repurposing is an effective strategy for the development of drugs for rare diseases in children. Drug repurposing is considered an interesting acceleration and facilitation of OD development at lower cost and with lower risk of failure, since these drugs have already been studied [7]. Although repurposed drugs have already been studied in animals and/or humans to some extent, a positive benefit/risk balance has to be established for the intended paediatric population. Since research in children on average takes another seven years after safety and efficacy have been confirmed in adults, this is considered to be the rate-limiting step, irrespective of repurposing.

There is a need for novel research tools to support decisions that balance between exposing children to experiments and the obvious need to provide children with authorised good quality drugs. Comparative trials are considered the primary instrument to collect the evidence needed for MA. However, for rare disease this is often not feasible. In most cases, the studies requested in the PIPs were open label uncontrolled studies. Most studies were designed to collect as much data as possible, ranging from pharmacokinetics and dose finding to safety and efficacy. When experimental research is not feasible, on-going data collection through registry/observational programs (such as named patient programmes (NPP) or compassionate use) are in place to characterise both long-term safety and efficacy as well as to determine patient characteristics and disease progression [27],[28]. There are differences in implementation of legislation throughout the EU. For example, the French authorities explicitly mention that investigation is not the goal of an NPP and that an NPP may not replace a clinical trial [29].

Several novel research strategies have been proposed, such as meta-analytic approaches, extrapolation, modelling and simulation. With the use of sparse sampling, population pharmacokinetics/pharmacodynamics (POP-PK/PD) and/or physiologically based pharmacokinetic models, extrapolation from adults to children, interpolation between paediatric age subgroups and the optimal use of scientific literature and in vitro/preclinical data, drug development is enriched while minimising the burden of studies in children [30]. Since the implementation of the Paediatric Drug Regulation, especially simulation and modelling are increasingly used for paediatric drug development [15].

Non-clinical juvenile studies are often used to bridge the knowledge gap between mature and immature systems, to detect safety issues early and to predict the dose in children. A recent survey showed that in the majority of juvenile toxicity studies, findings were comparable to those for adults, yielding no new information [31]. Furthermore, novel toxicity was uncommon and could have been predicted from either known pharmacology or from adult data. On the other hand, in a preliminary review of 5 completed juvenile animal studies required in PIPs, unexpected organ toxicity and increased sensitivity was observed in 3 medicinal products, stressing the importance of conduction juvenile animal studies [15]. It confirms that drug development is not a “one size fits all” process. A case-by-case evaluation process is necessary, especially for paediatric ODs.

Part of paediatric drug development is to avoid duplication and to ensure that ongoing and planned paediatric research is transparent. To this purpose, in March 2011, the EU Clinical Trials Register (EU-CTR) was made publicly accessible (EU-CTR) for paediatric trials included in a PIP [15]. The website (available at https://​www.​clinicaltrialsre​gister.​eu) provides public access to information extracted from the EU clinical trials database (EudraCT), such as protocols and known results. The clinical trials included are those with agreed PIPs from investigator sites within and outside the European Economic Area (EEA). As soon as a paediatric trial is approved, it becomes accessible in the database.

The EU Paediatric Drug Regulation did not increase the number of ODDs with potential paediatric indications nor did it lead to more MAs for paediatric indications. It was associated with a longer time to MA for both adult and paediatric orphan indications. Nonetheless, the Paediatric Drug Regulation has ensured the further paediatric development of drugs still off-label to children. The impact on the quality and volume of research in the paediatric population through PIPs will become clear in the coming few years. Case-by-case assessment, based on innovative research tools is necessary to collate the best evidence while protecting children from unnecessary experiments.