International Journal of Pharmaceutics xxx (2014) xxx–xxx

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More than 5 years of European Paediatric Regulation: Statistics andindustrial experience

Gesine Winzenburg *Technical Research & Development, Novartis Pharma AG, Basel CH 4002, Switzerland

A R T I C L E I N F O

Article history:Received 19 December 2013Received in revised form 28 March 2014Accepted 31 March 2014Available online xxx

A B S T R A C T

The aim of the European paediatric legislation is to ensure high quality paediatric clinical research, andsubsequently increase availability of authorised medicines that are appropriate for children and producebetter information on medicines.One of the main pillars of the regulation is the paediatric investigation plan (PIP), a new key document inthe general drug development process. PIP submission and approval are now mandatory to ensureregistration of a new drug in the EU.A short summary of the achievements from the introduction of the regulation in 2007 is given. Inaddition, PIP case studies are presented to illustrate the challenges associated when working within theframework of the new process.

ã 2014 Elsevier B.V. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsev ier .com/locate / i jpharm

1. Introduction

In 2007 the European Paediatric Regulation (EMA, 2006) waslaunched to provide better medicines for children. This regulationis based on incentives and obligations for pharmaceuticalcompanies.

The main objectives of the regulation are (1) to promote highquality clinical trials in children to ensure quality, safety andefficacy of medicines for children (2) to generate more informationfor the administration of medicines for children and (3) to fosterthe development of age appropriate formulations in children(EMA, 2013a).

The achievements from more than 5 years of the regulation arehighlighted in this report. However, developing a paediatricprogram and executing a PIP are associated with a variety ofchallenges. Thus, general aspects and issues related to the quality,non-quality and clinical part of a PIP are also discussed to shareindustrial experience. These are further exemplified with 3 PIP casestudies.

2. Achievements

Over 600 PIPs have been approved (Fig. 1), the majority (76%)was for medicines that were not yet authorized at the time ofevaluation, 22% of PIPs were related to life cycle management and

* Novartis Pharma AG, 4056 Basel, Switzerland. Tel.: +41 795892060.E-mail address: Gesine.Winzenburg@novartis.com (G. Winzenburg).

http://dx.doi.org/10.1016/j.ijpharm.2014.03.0580378-5173/ã 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: Winzenburg, G., More than 5 years of EuJ Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.03.058

2% for off-patent drugs. The majority of PIPs was submitted intherapeutic areas of oncology, cardiovascular diseases andendocrinoloy–gynaecology–fertility–metabolism (EMA, 2013a).

By the end of 2012, 33 PIPs (5.5%) were completed resulting inthe approval of new medicines with specific paediatric indications(EMA, 2013a). With the increasing number of agreed PIPs, thenumber of modifications is increasing in order to take account ofnew data and knowledge. Meanwhile, the number of PIPmodifications is higher than newly agreed PIPs. A reason for thiscould be difficulties to execute the initial PIP (formulationchallenges, delay of study start, change in clinical study design).Of course not all approved PIPs will result in an approved medicinewith a paediatric indication e.g. because of lack of efficacy in adultsor safety concerns in the paediatric population.

Twelve products received a 6-month extension of the SPC and20 off-patent drugs received EU funding (in total 80 million EUR).The funding is needed to foster the development of these drugs asthey are often not available in an age-appropriate dosage form ordose strength and have never been adequately studied in children.So far only 1 paediatric use marketing authorisation (PUMA) hasbeen granted (BuccolamTM, EMA, 2013a; Rawcliffe et al., 2013)indicating that the PUMA concept does not yet have the results thatwere anticipated. However, more of these products will hopefullybe approved in the next 5 years.

Currently clinical trials in children account for less than 10% ofall drug trials in Europe, with an average of 360 a year (EMA,2013a). However, the proportion of clinical trials in children iaincreasing (Table 1). Since most paediatric clinical trials aredeferred to avoid the delay of MA in adults, an increase of clinical

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Fig. 1. Agreed paediatric investigation plans compared to full waivers and modifications 2007–2012 (EMA, 2013a).

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trials in children will likely come in the future. With this in mind, aEuropean network of national paediatric and internationaldisease-specific networks with expertise in performing drug trialson children (Enpr-EMA) was created at EMA (EMA, 2012).

3. Challenges in developing a paediatric program

In general, the PIP should be submitted at the end of humanpharmacokinetic studies in adults and before proof of concept, i.e.before clinical efficacy of the new compound has been shown(Creba et al., 2011). The PIP discusses, among other things, theproposed targeted indication in children (“condition”) frompreterm newborns to adolescent. Furthermore, the PIP lists thedevelopment measures for paediatric use including quality (e.g.development of an age-appropriate formulation), non-quality (e.g.juvenile animal studies) and clinical studies. Ninety-two percent ofPIPs assessed by a specialized formulation working group (FWG) ofthe paediatric committee raised at least one issue, mainly relatedto excipients, appropriateness of formulation or route of adminis-tration, dosing accuracy and acceptability (Quijano Ruiz et al.,2014)

Furthermore, more than one disease might be qualified as beingwithin the “condition” the drug is being developed for and oftenmore than one subset of the population needs to be considered.Therefore, one formulation will not fit for all populations ordiseases. Hence, different formulation strategies need to beassessed which is extremely challenging since less information

Table 1Number of children to be enrolled in clinical trials (EC report, 2013).

Number of subjects 2006 2007 2008

Preterm newborns 0 0 0

Newborns 0 0 5

Infants and toddlers 330 21 20

Children 2142 181 200

Adolescents 368 111 205

Total 2840 313 430

Number of paediatric trials 316 355 342

Please cite this article in press as: Winzenburg, G., More than 5 years of EuJ Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.03.058

is available regarding the dose in paediatric patients. In addition,the acceptability of dosage forms is different in different agegroups (CHMP EMA, 2006; EMA, 2013b). Despite formulationissues the non-quality part needs to be considered carefully sincelimited information is available about impact on maturation oforgans in all population subsets (CHMP EMA, 2008; Lima et al.,2010). The latter will have an impact on the non-clinical programas well as the dimensions of the clinical program.

4. Cases studies

The first example shows the difficulties in developing drugs forcancer in children <6 years of age. Often these drugs are poorlywater soluble, need a high dose and can’t be formulated easily intoan age-appropriate oral liquid. Due to the toxic properties of thecompound, the exposure to dusty drug substance must be avoided,and a two-component product was developed for paediatric use. Adevice qualification program covering e.g. dosing accuracy,material compatibility, risk assessment and user requirementswas performed to ensure selection of an appropriate measuringdevice. Clear instructions for use were generated and verified.Finally, the administration via a nasogastric tube and theacceptability of the formulation will be investigated in a clinicaltrial.

The second example illustrates a parenteral dosage formdevelopment. The drug is developed for a very rare paediatricdisease only in children aged 2–18 years. The dosage form available

2009 2010 2011 2012

207 82 2281 171264 169 1105 117259 351 2788 3141

2230 2055 10325 206771577 2861 9054 131934137 5518 25553 39895404 379 334 332

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for adults is a powder for solution for injection in one dosestrength. An additional dose strength was requested to ensureaccurate dosing in the youngest age group. The development wasstarted but stopped based on a PK study in younger childrendemonstrating no need for a lower dose strength. The PIP wasmodified accordingly.

Further challenges were the suitability of excipients (CHMPEMA, 2007) including long-term use, drug substance quality, anddose accuracy and wastage. As mentioned earlier, the EMA is highlyconcerned about excipient safety in paediatric medicines hencepreclinical safety testing was conducted with all excipients. Sincethe compound contains benzoyl alcohol (BA) in levels below 2 ppmlevel, which is critical in children aged <3 years due to insufficientmetabolism (Breitkreutz and Boos, 2007), the quality of drugsubstance needed to be improved. The route cause investigationidentified filters as a contamination source because they aresupplied in 1% BA solution. Intensified rinsing and washing stepsdo not remove the hydrophobic excipient hence BA-free filtersystems were implemented for the manufacturing process of thecompound.

The last example covers multiple indications in paediatriconcology for children �1 year of age. In contrast to the first PIPexample, the "sprinkle capsule" approach for children unable toswallow the intact capsule was feasible and accepted by PDCO. Theinitial PIP requested the manufacturer to study the bioavailabilityof the compound if administered as an intact capsule or aftersprinkling the capsule content on soft food in adult volunteers, tostudy PK/PD, efficacy and safety in children from birth to less than18 years. However, dosing of cancer drugs in children below 1-yearis challenging due to significant changes in body composition,metabolism, hepatic and renal function. Furthermore, patientsbelow 1 year of age have not been reported due to the rarity of thedisease. This resulted in a request for modification of the PIP and awaiver for children below 1 year of age was granted. Another issuewas the patient enrollment which was extremely slow due to therarity of patients (9 children/2 years enrolled, including 2 children<10 years). The collaboration with the scientific community andthe addition of clinical sites as well as a change in samplingprocedure to reduce patient burden, facilitated study enrollment.As the drug was investigated in multiple indications as second-linetreatment but became first-line treatment in one indication basedon additional data in adult patients, the paediatric program wasimpacted. The target population was expanded and inclusioncriteria had to be precised. The process of final agreement withhealth authorities to align between written request and PIP was atime-consuming process.

5. Conclusion

Improving pharmaceutical dosage forms and formulation forpaediatric use is part of the objectives of the regulation. As a result,some drugs have already received new paediatric authorisation,new age-appropriate formulations or updates of product informa-tion with new paediatric data. The increase in PIP modifications

Please cite this article in press as: Winzenburg, G., More than 5 years of EuJ Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.03.058

compared to newly submitted PIPs indicates the challenges relatedto the development of paediatric medicines. The cases presentedbriefly illustrate aspects related to the quality part of the PIP.Important quality attributes are excipient safety, route ofadministration and acceptability of dosage form as function ofage. Formulations should be developed which cover all paediatricage ranges for the targeted condition. Often more than one dosageform or dose strength or suitable administration device needs to bedeveloped. To ensure the accurate and consistent administration ofpaediatric formulations it is important to provide clarification ondosing accuracy and to minimise the risk of dosing errors. Thepaediatric development program can be small or substantial.Modification of an agreed PIP is feasible and need to be triggered bythe applicant.

References

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Committee for Medicinal Products for Human Use, EMA, 2006: Reflection paper:formulation of choice for the paediatric population (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003782.pdf). (assessed 08.12.13.).

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