REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL Better Medicines for Children — From Concept to Reality General Report on experience acquired as a result of the application of Regulation (EC) No 1901/2006 on medicinal products for paediatric use
Date: 2013-06-24
Institutions: European Commission
Subjects: European Medicines Agency, consumer information, market approval, medical research, medicinal product, paediatrics, product quality, testing, therapeutics

EUROPEAN 
COMMISSION 

Brussels, 24.6.2013  
COM(2013) 443 final 

REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND 
THE COUNCIL 

Better Medicines for Children — From Concept to Reality 

General Report on experience acquired as a result of the application of Regulation (EC) 
No 1901/2006 on medicinal products for paediatric use 

(Text with EEA relevance) 

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REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND 
THE COUNCIL 

Better Medicines for Children — From Concept to Reality 

General Report on experience acquired as a result of the application of Regulation (EC) 
No 1901/2006 on medicinal products for paediatric use 

(Text with EEA relevance) 

1. 

INTRODUCTION 

‘Better  Medicines  for  Children’  was  the  ambitious  title  of  a  consultation  paper  of  February 
2002,  in  which  the  European  Commission  presented  its  vision  for  regulatory  actions  on 
paediatric medicinal products1. At that time, many of the products used in children were not 
specifically studied or authorised in children. Instead, doctors often used products authorised 
for  adults,  sometimes  in  different  dosages,  with  the  associated  risks  of  inefficacy  and/or 
adverse reactions. 

The consultation paper built on a 5-year discussion process that started in 1997 with a round 
table  meeting  at  the  premises  of  the  European  Medicines  Agency  (EMA)  and  was  the 
blueprint  for  the  subsequent  legislative  act.  It  outlined  many  of  the  measures  that  are  to  be 
found  in  the  Paediatric  Regulation  (Regulation  (EC)  No  1901/2006  of  the  European 
Parliament  and  of  the  Council  on  medicinal  products  for  paediatric  use2,  hereinafter  ‘the 
Regulation’). 

The  Regulation  was  adopted  some  five  years  after  the  consultation  paper,  on  12  December 
2006. It entered into force on 26 January 2007 and its main provisions were applicable from 
26 July 2008 (Article 7) and 26 January 2009 (Article 8), respectively. 

Five years on, it is time to take stock of developments and report to the European Parliament 
and the Council on the experience acquired as a result of the Regulation, in accordance with 
its Article 50(2). Are we already seeing the emergence of ‘better medicines for children’? 

This report does not yet provide comprehensive answer, as it is subject to certain limitations; 
it  should  therefore  be  regarded  as  an  interim  report  that  presents  a  first  impression  of  the 
experience  gained.  In  view  of  the  development  cycles  of  medicinal  products,  it  will  take  at 
least  10  years  to  gain  a  full  understanding  of  the  impact  of  the  legislation.  This  factor  has 
already  been  accounted  for  in  the  legislation  which  requires  the  Commission  to  provide  a 
second,  more  comprehensive  report  in  2017  which,  in  accordance  with  Article  50(3)  of  the 
Regulation, must include an analysis of the economic impact of the rewards and incentives, 
together  with  an  analysis  of  the  Regulation’s  implications  for  public  health,  with  a  view  to 
proposing  any  necessary  amendments.  However  at  this  stage,  some  analyses  and  interim 
conclusions can be made. 

This  document  has  been  prepared  in  consultation  with  Member  States,  the  EMA  and 
interested  parties.  The  Commission  particularly  values  the  ‘5-year  Report  to  the  European 

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http://ec.europa.eu/health/files/pharmacos/docs/doc2002/feb/cd_pediatrics_en.pdf. 
OJ  L  378,  27.12.2006,  p. 1;  amended  by  Regulation  (EC)  No  1902/2006  of  the  European  Parliament 
and of the Council of 20 December 2006, OJ L 378, 27.12.2006, p. 20. 

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Commission’  presenting  the  views  of  the  EMA  and  its  Paediatric  Committee3,  and  the 
responses to the public consultation the Commission undertook at the end of 20124. 

2. 

THE PAEDIATRIC REGULATION 

In 2010 around 21 % of Europeans were children, representing more than 100 million people. 
Children  represent  a  vulnerable  population  group  with  developmental,  physiological  and 
psychological  differences  from  adults.  They  are  not  merely  ‘small  adults’.  Age-  and 
development-related  research,  and  the  availability  of  suitable  medicinal  products,  is 
consequently particularly important. 

Studies carried out before the Regulation was adopted showed that over 50 % of the medicines 
used for children had not been tested for use in this specific age group. What is more, only a 
limited number of medicinal products had been developed specifically with children in mind. 
Companies had already developed a range of products against a number of diseases prior to 
the Paediatric Regulation, particularly in sectors such as childhood immunisation by means of 
the  availability  of  child-appropriate  medicines  was  generally 
vaccines.  However, 
unsatisfactory.  Accordingly,  the  Regulation  was  seen  as  a  response  to  the  absence  of 
sufficient  numbers  of  suitable,  authorised  medicinal  products,  with  appropriate  dosages  and 
pharmaceutical forms, to treat conditions in children in the European Union (EU). 

There  are  several  reasons  for  the  lack  of  paediatric  medicines.  It  would,  however,  be  too 
simplistic to pin the blame on pharmaceutical companies for not carrying out enough research 
and  development  (R&D)  to  adapt  medicinal  products  to  the  needs  of  the  paediatric 
population.  This  reluctance  has  long  mirrored  a  general  social  and  ethical  paradigm  that 
children  should  be  protected  from  clinical  research.  Only  in  the  last  two  decades  has  there 
been a shift to the current consensus of better protecting children through clinical research. 

Economic factors certainly rendered paediatric R&D less attractive in terms of achieving an 
adequate return on investment. Children are not a homogenous sub-group — subpopulations 
range  from  neonates 
teenagers,  with  different  biological  and  pharmacological 
characteristics. Age-appropriate research makes the process more expensive and complex for 
organisations that are active in this sector. 

to 

However, the absence of specifically tested products often left healthcare professionals with 
no  alternative  but  to  use  products  ‘off-label’,  with  the  associated  non-negligible  risks  of 
inefficacy or adverse reactions. Such a situation was contrary to the general goal to provide 
high-quality medicinal products to the entire EU population. 

To  address  this  problem,  the  Regulation  establishes  a  system  of  obligations,  rewards  and 
incentives,  together  with  horizontal  measures  to  ensure  that  medicines  are  regularly 
researched, developed and authorised to meet the therapeutic needs of children. Other than the 
Orphan  Regulation5,  which  is  limited  to  providing  various  incentives,  the  Paediatric 
Regulation has a direct impact on companies’ R&D expenditure. While not questioning that 
medicinal  development  is  company  driven,  it  compels  companies  to  consider  the  potential 
paediatric use of medicinal products they develop. 

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5-year report to the European Commission — General report on experience acquired as a result of the 
application  of  the  Paediatric  Regulation,  prepared  by  the  European  Medicines  Agency  with  its 
Paediatric  Committee,  http://ec.europa.eu/health/files/paediatrics/2012-09_pediatric_report-annex1-
2_en.pdf. 
http://ec.europa.eu/health/human-use/paediatric-medicines/developments/2013_paediatric_pc_en.htm. 
Regulation  (EC)  No  141/2000  of  the  European  Parliament  and  the  Council  of  16  December  1999  on 
orphan medicinal products, OJ L 18, 22.1.2000, p. 1. 

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The key objectives of the Regulation are: 

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• 

to ensure high-quality research into the development of medicines for children; 
to  ensure,  over  time,  that  the  majority  of  medicines  used  by  children  are  specifically 
authorised for such use with appropriate forms and formulations; 
to ensure the availability of high-quality information about medicines used by children. 

The key measures included in the Regulation are: 

•  setting up an expert committee within the EMA: the Paediatric Committee; 
• 

requiring  companies  to  submit  data  on  the  use  of  a  medicine  in  children  in  accordance 
with an agreed paediatric investigation plan when applying for marketing authorisation for 
medicines and line-extensions for existing patent-protected medicines; 

•  a system of waivers from the requirement for medicines unlikely to benefit children and a 
system of deferrals in relation to the timing of the requirement, to ensure that medicines 
are  tested  in  children  only  when  it  is  safe  to  do  so  and  to  prevent  the  requirements 
delaying the authorisation of medicines for adults; 

•  a reward for complying with the requirement in the form of a six-month extension to the 

Supplementary Protection Certificate; 

•  a reward, in respect of orphan medicines, for compliance in the form of an extra two years 
of  market  exclusivity  added  to  the  existing  ten  years  awarded  under  the  EU’s  Orphan 
Regulation; 

•  a  new  type  of  marketing  authorisation,  the  Paediatric  Use  Marketing  Authorisation 

(PUMA), to attract new paediatric indications for off-patent products; 

•  measures to maximise the impact of existing studies on medicines for children; 
•  an EU inventory of the therapeutic needs of children to focus the research, development 

and authorisation of medicines; 

•  an EU network of investigators and trial centres to carry out the required R&D; 
•  a system of free scientific advice for the industry, provided by the EMA; 
•  a public database of paediatric studies; 
•  a provision on EU funding for research to stimulate the development and authorisation of 

off-patent medicines for children. 

The  Regulation  gives  the  EMA  and  its  Paediatric  Committee  primary  responsibility  for 
handling paediatric investigation plans, deferrals and waivers. This provides the Agency with 
concrete decision-making powers. 

The operational costs of the Paediatric Regulation are partly covered by a contribution from 
the EU budget (see Table 8), as its main activities do not attract any fees. For the period 2007-
12, the EU budget contribution amounted to more than EUR 39 million. In addition, Member 
States’  national  competent  authorities  contribute  resources  in  kind,  especially  staff  time  for 
the assessment of paediatric investigation plans (see Table 12). 

3. 

MAJOR MILESTONES IN IMPLEMENTING THE REGULATION 

To implement the Paediatric Regulation successfully, complementary measures needed to be 
adopted and supplementary action taken as stipulated in the legislation. 

The Agency implemented the Regulation in a timely manner. The Paediatric Committee was 
duly established and held its first meeting on 1-2 July 2007, and has met monthly since. The 
Commission guideline on the format and content of applications for a paediatric investigation 

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plan (Article 10) was published in September 20086. The Agency put in place the necessary 
procedures and database for the scientific evaluation of paediatric investigation plans and for 
the adoption of decisions under the Regulation. 

The European Network for Paediatric Research at the EMA (Enpr-EMA) was set up after the 
EMA Management Board adopted the implementing strategy in 2008, launched in 2009 and 
has met regularly since 2010 (Article 44). 

The  results  of  the  survey  of  all  existing  uses  of  medicinal  products  in  the  EU  paediatric 
population were published in December 20107 (Article 42) and were used as a basis for the 
inventory of therapeutic needs (Article 43). 

In March 2011, the European Union Database on Clinical Trials (EudraCT) was modified and 
made publicly accessible via the public website ‘clinicaltrialregister.eu’, for protocol-related 
information on paediatric trials included in paediatric investigation plans or submitted under 
Article 46. Information relating to results should be available by the end of 2013. To that end, 
the Commission published in 2009 guidance on the information concerning paediatric clinical 
trials to be entered into EudraCT and on the information to be made public by the EMA8. In 
2012  and  2013,  further  specifications  on  the  posting  and  publication  of  result-related 
information9 and the format of data fields followed10 (Article 41). Subject to a confirmatory 
announcement from the Agency, clinical trial sponsors have to submit all results of paediatric 
trials to the EMA without delay, regardless of whether they were conducted inside or outside 
the EU, with a view to their publication in ‘clinicaltrialregister.eu’11. 
Commission Regulation (EC) No 658/200712 was amended in 201213 (Article 49) to allow the 
Commission to impose financial penalties for infringements of the Paediatric Regulation. 

With  regard  to  labelling  medicinal  products  with  a  paediatric  indication  with  a  symbol 
(Article  32),  the  Paediatric  Committee  advised  the  Commission  against  using  one  as  the 
precise  meaning  of  a  symbol  may  be  misunderstood  by  parents  or  carers.  That  is  why  the 
Commission informed stakeholders in 2008 that it is not in a position to select a symbol. 

Where  existing  medicinal  products  are  authorised  for  a  new  paediatric  indication  in 
accordance with the requirements of the Regulation, the marketing authorisation holder has to 
place the product with this new paediatric indication on the market within two years. For this 
purpose, in 2013 the Agency set up a register14 of the applicable deadlines (Article 33). 

The  Paediatric  Regulation  has  unfortunately  not  yet  been  incorporated  in  the  Agreement  on 
the  European  Economic  Area  because  the  EU  and  the  three  EEA-EFTA  states  —  Iceland, 

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Communication  from  the  Commission  —  Guideline  on  the  format  and  content  of  applications  for 
agreement or modification of a paediatric investigation plan and requests for waivers or deferrals, OJ 
C 243, 24.9.2008, p. 1. 
http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101006.pdf. 
OJ C 28, 4.2.2009, p. 1. 
Commission Guideline — Guidance on posting and publication of result-related information on clinical 
trials  in  relation  to  the  implementation  of  Article  57(2)  of  Regulation  (EC)  No  726/2004  and  Article 
41(2) of Regulation (EC) No 1901/2006, OJ C 302, 6.10.2012, p. 7. 
http://ec.europa.eu/health/files/eudralex/vol-10/2013_01_22_tg_en.pdf. 
https://www.clinicaltrialsregister.eu. 
Commission  Regulation  (EC)  No  658/2007  of  14  June  2007  concerning  financial  penalties  for 
infringement  of  certain  obligations  in  connection  with  marketing  authorisations  granted  under 
Regulation  (EC)  No  726/2004  of  the  European  Parliament  and  of  the  Council,  OJ  L  155,  15.6.2007, 
p. 10. 
Commission Regulation (EU) No 488/2012 of 8 June 2012, OJ L 150, 9.6.2012, p. 68. 
Register of deadlines to place a product on the market (EMA/137292/2013). 

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Liechtenstein  and  Norway  —  have  been  unable  to  agree  on  the  appropriate  terms  of 
adaptation, especially in relation to Article 49(3) of the Regulation. 

4. 

MAIN ACHIEVEMENTS 

4.1. 

Better and safer research 

Before  the  Paediatric  Regulation  entered  into  force,  many  pharmaceutical  companies 
considered the adult population their key market. Research into the potential use of an adult 
product  in  the  paediatric  population  was  often  side-lined  or  not  considered  at  all.  With  the 
obligations  introduced  by  the  Regulation,  forcing  companies  to  screen  every  new  (adult) 
product for its potential paediatric use, the situation has been turned around. Feedback from 
companies  confirms  a  fundamental  change  of  culture:  undertakings  now  consider  paediatric 
development to be an integral part of the overall development of a product. 

The  requirement  to  develop  and  discuss  with  the  Paediatric  Committee  a  paediatric 
investigation plan, which normally should be submitted not later than upon completion of the 
human  pharmaco-kinetic  studies  in  adults,  obliges  companies  to  think  about  paediatric  use 
early on so as to avoid any delays in general product development. The plan brings with it a 
research  and  development  programme  which  aims  to  ensure  that  the  necessary  data  are 
generated for the authorisation of paediatric indications. 

By the end of 2012 the Agency had agreed 600 paediatric investigation plans (see Table 1). 
Of these, 453 were for medicines that were not yet authorised in the EU (Article 7), while the 
remainder  related  to  new  indications  for  patent-protected  products  (Article  8)  or  paediatric-
use marketing authorisations (Article 30). 

These  plans  cover  a  broad  range  of  therapeutic  areas.  At  the  forefront  are  Endocrinology-
Gynaecology-Fertility-Metabolism  (11 %),  Infectious  diseases  (11 %)  and  Oncology  (11 %), 
but no particular area dominates (see Table 3). 

In order to take account of new information during medicine development, agreed paediatric 
investigation plans need to be modified. Statistics show that several requests for modification 
are submitted for each agreed plan (see Table 2). To date, the Committee has already adopted 
more opinions on modifications than on the initial agreement of the investigation plan. 

By  end  of  2012,  33  of  all  approved  paediatric  investigation  plans  had  been  completed  (see 
Table 4), which has led to the approval of new medicines with specific paediatric indications. 

4.1.1.  European Union funding to support research 

The  EU  supports  research  into  paediatric  medicinal  products  through  its  multi-annual 
Framework  Programme  for  Research  and  Technological  Development.  Under  Article 40  of 
the Regulation, the Union has a specific obligation to fund research into off-patent medicinal 
products. Support is granted to projects which have successfully undergone a peer review by 
independent  experts  in  response  to  calls  for  proposals,  announced  regularly  by  the 
Commission.  In  order  to  ensure  that  funds  are  directed  into  researching  medicinal  products 
with  the  highest  needs,  the  Paediatric  Committee  has  adopted  a  priority  list  of  off-patent 
active substances15 for which studies are required. 

To  date,  16  projects  covering  at  least  20  off-patent  active  substances  have  received  EU 
funding, amounting to total support of EUR 80 million (see Annex III). 

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http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/10/WC500004017.pdf. 

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4.1.2. 

Scientific advice 

Applicants may request scientific advice from the EMA and/or national competent authorities 
on  pharmaceutical,  non-clinical  or  clinical  issues  relating  to  the  development  of  medicines. 
Scientific advice is a well-known and successful procedure for answering specific questions at 
any  stage  of  the  research  and  development  process.  Since  the  Paediatric  Regulation  entered 
into  force,  paediatric-related  advice  and  protocol  assistance  from  the  Scientific  Advice 
Working Party, which is provided free of charge, increased significantly (see Table 5) despite 
the fact that issues of pharmaceutical, non-clinical and clinical development are also part of 
the  discussions  of  a  paediatric  investigation  plan.  To  facilitate  collaboration  with  the 
Paediatric Committee, joint procedures have been created within the EMA. 

4.1.3.  Clinical trials with children 

Medicines for use in children need to be tested with appropriate formulations in the paediatric 
population  to  ensure  their  safe  and  effective  use.  Hence  it  is  generally  accepted  that  the 
Paediatric Regulation will lead to more clinical trials in children. The figures in the EudraCT 
database  have  not  yet  shown  an  increase  in  paediatric  trials.  The  number  remained  stable 
between 2006 and 2012, averaging 350 trials per year with some fluctuations (see Table 6). It 
should be pointed out, however, that while the number of paediatric trials remained stable, the 
number of clinical trials in all populations decreased between 2007 and 2011. 

Moreover,  until  recently  EudraCT  was  limited  to  paediatric  trials  commencing  in  the  EU. 
Data on paediatric trials that are part of a paediatric investigation plan and conducted outside 
the EU have only become publicly available since spring 2011. 

It  should  also  be  noted  that  the  initiation  of  a  considerable  percentage  of  clinical  trials 
included  in  a  paediatric  investigation  plan  has  been  deferred  in  order  to  avoid  delays  in  the 
authorisation  of  the  corresponding  product  for  adults.  Hence,  the  impact  of  the  Paediatric 
Regulation on paediatric trials will become more apparent in EudraCT in the years to come. 
There has, however, been an evident increase in the number of paediatric study participants, 
in particular for the age group from 0 to 23 months, who were normally not included in trials 
prior  to  2008  (see  Table 7).  Allowing  neonates  and  infants  to  benefit  from  research  is  a 
positive sign as these have been the most neglected groups so far. 

4.1.4.  Optimised framework and coordination 

The Paediatric Regulation fosters a comprehensive network of expertise in paediatric matters 
within  the  EU.  In  this  context  the  role  of  the  Paediatric  Committee  is  pivotal,  as  it  brings 
together a high level of expertise and competence. 

The Committee has contributed to the scientific guidelines published by the EMA and has so 
far convened 22 expert workshops on the development of medicines for children. 

In  addition,  the  European  Network  for  Paediatric  Research  at  the  EMA  (Enpr-EMA)  was 
established in 2009. While a closely-knit network of experts existed prior to the introduction 
of the Regulation in disease areas such as paediatric oncology, Enpr-EMA provides the added 
value  of  a  holistic  approach  by  bringing  together  national  and  European  networks, 
investigators  and  centres  with  specific  expertise  in  designing  and  conducting  high-quality 
studies in children. 

However, question still remain as to whether this expertise translates into sufficient capacity 
within the EU to conduct trials in specialised investigation settings. Well-developed research 
networks capable of facilitating the necessary research to fulfil the commitments included in 
paediatric investigation plans do exist in some but not all Member States. 

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4.1.5. 

International cooperation 

On an international level, the EMA has developed international links with medicines agencies 
in the United States, Canada and Japan. Of particular interest is the cooperation with the US 
Food  and  Drug  Administration  given  that,  already  in  the  late  1990s,  the  United  States 
introduced  legislation  that  stimulated  the  development  of  medicinal  products  for  paediatric 
use by means of a combination of incentives and obligations. This cooperation is also of great 
interest to stakeholders as it may give companies the possibility of satisfying the legislation in 
both regions with the same studies. 
In addition,  the EMA  participates actively in the Paediatric medicines regulatory network16, 
which was created in 2010 as part of the WHO’s Better Medicines for Children initiative. 

4.2.  More medicines available for children 

Over  12  years  (from  1995  to  2006),  108  of  all  317  indications  of  262  centrally  authorised 
medicines  included  the  paediatric  population.  Since  the  Paediatric  Regulation  entered  into 
force, 31 out of 152 new medicines have been authorised for paediatric use; 10 of which met 
the conditions of Article 7. This is not more than a 'snapshot' of the effects of the Regulation 
as this figure is likely to increase in the future, as a considerable number of the new, already 
authorised, medicines are subject to an investigation plan where completion was deferred to 
avoid  delays  in  the  authorisation  of  the  adult  product.  It  follows  that  in  the  years  to  come 
many more of those 152 new medicines are expected to be authorised for paediatric use. 

Annual  reports  on  deferred  paediatric  studies  of  authorised  medicines  indicate  that  the 
majority of paediatric investigation plans are running  to  schedule.  Paediatric research is on-
going at the same rate across therapeutic areas such as oncology, vaccines and immunology-
rheumatology-transplantation. 

Furthermore,  by  the  end  of  2011,  72  new  paediatric  indications  had  been  approved  for 
medicines  already  authorised,  including  30  indications  (18  centralised)  arising  from  the 
obligation  in  Article  8.  Moreover,  26  new  pharmaceutical  forms  were  authorised  for 
paediatric use, including 18 adapted forms for centrally authorised medicines. 

As far as Paediatric Use Marketing Authorisation is concerned, to date only one authorisation 
has been granted. This falls short of initial expectations. 

A detailed inventory of centrally authorised products is provided in Annex II. 

– 

Rewards and incentives 

Companies  that  have  complied  with  the  obligations  of  the  Regulation  may  benefit  from  a 
reward once the product concerned is authorised or the product information is amended. The 
reward  takes  the  form  of  a  6-month  extension  of  the  supplementary  protection  certificate 
(SPC) provided for by Regulation (EC) No 469/200917 or, in the case of an orphan medicinal 
product, by an extension of the ten-year period of orphan market exclusivity to twelve years. 

No orphan rewards have been awarded yet. In this regard it is observed that some companies 
withdrew  the  orphan  designation  of  a  product  in  order  to  qualify  for  the  SPC  reward  rather 
than the orphan reward, which seems to be more attractive from an economic perspective. As 
far as SPC extensions are concerned, national patent offices in 16 Member States had, by the 

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http://www.who.int/childmedicines/paediatric_regulators/en/. 
Regulation  (EC)  No  469/2009  of  the  European  Parliament  and  of  the  Council  of  6  May  2009 
concerning the supplementary protection certificate for medicinal products, OJ L 152, 16.6.2009, p. 1. 
This Regulation is a codification of Council Regulation (EEC) No 1768/92. 

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end of 2011, granted 6-month extensions to 11 medicinal products, which resulted in a total of 
more than 100 national SPCs. 

It should be pointed out that a ruling of the European Court of Justice further increased the 
value of the paediatric reward, as it made clear that the initial certificate could have a negative 
or  zero  duration,  which  could  then  become  positive,  once  the  paediatric  extension  was 
granted18. 

4.3. 

Increased information on medicines used in children 

To provide better information on the use of medicinal products in children, Article 45 of the 
Paediatric Regulation requires companies holding data on the safety or efficacy of authorised 
products in the paediatric population to submit these studies to the competent authorities. In 
this way the data can be assessed and, where appropriate, the authorised product information 
amended.  Article  46  of  the  Regulation  also  requires  companies  to  submit  newly  generated 
paediatric data. 

Since  2008,  more  than  18 000  study  reports  on  roughly  2 200  medicinal  products  have  been 
submitted, revealing the large amount of existing paediatric information available at company 
level. 

These  study  reports  have  been,  and  continue  to  be,  assessed  by  the  competent  authorities 
thanks  to  an  impressive  work-sharing  project  (see  Tables 10  and  11).  For  nationally 
authorised products, this has led to the publication of assessment reports covering more than 
140  active  substances  and,  in  a  considerable  number  of  cases,  to  recommendations  for 
changes  to  the  summaries  of  product  characteristics  of  authorised  products,  resulting  in  65 
actual  changes.  For  centrally  authorised  products,  by  2011  the  Agency  had  completed  the 
assessment  of  all  the  data  submitted  under  Article  45,  covering  55  active  substances  in  61 
centrally  approved  medicinal  products.  The  summaries  of  product  characteristics  of  12 
medicinal products were changed following the assessment. 

5. 

LESSONS LEARNT 

5.1. 

Better access to treatment 

One of the  explicit  goals of  the Paediatric Regulation is to increase the number of products 
that are researched, developed and authorised for use in children, and to reduce the off-label 
use of medicinal products in the paediatric population. 

The  main  tool  to  achieve  this  result  is  to  oblige  companies  to  establish  a  paediatric 
investigation  plan  for  each  newly  developed  product  or  for  the  line  extension  of  an  already 
authorised product that is still under patent protection. The plan is meant to ensure — under 
the supervision of the Paediatric Committee — that the necessary data are generated so as to 
determine the conditions under which a medicinal product may be authorised to treat children. 
Since 2008, more than 600 paediatric investigation plans have been approved. However, only 
a minority of them has been completed to date; the vast majority are still on-going. This is due 
to the long development cycles of medicinal products, often lasting more than a decade and 

18 

Case C-125/10 Merck Sharp & Dohme v Deutsches Patent- und Markenamt, not yet published in the 
ECR, paragraph 37: ‘if the SPC application had to be refused because the calculation provided for in 
Article 13(1) of Regulation No 1768/92 results in a negative or zero duration, the holder of the basic 
patent could not obtain an extension of protection conferred by such a patent, even if it conducted all 
the  studies  according  to  the  approved  paediatric  investigation  plan,  under  Article  36  of  Regulation 
No 1901/2006.  Such  a  refusal  would  be  liable  to  adversely  impact  on  the  useful  effect  of  Regulation 
No 1901/2006 and might jeopardise the objectives of that regulation, namely the compensation of effort 
made to evaluate the paediatric effects of the medicinal product at issue.’. 

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the near-systematic deferral of paediatric studies. The high number of deferrals may not have 
been initially expected, but are currently a reality, as for most of the medicinal products that 
have been authorised so far, the R&D programme started before the entering into force of the 
Regulation. Consequently, the paediatric requirements could not be taken into account from 
the beginning of the product development. 

While  the  Paediatric  Regulation  has  led  to  some  new  authorisations  that  include  paediatric 
indications,  the  regulatory  instrument  is  recent,  and  it  will  probably  take  at  least  a  decade 
before  it  can  be  judged  in  terms  of  its  output.  In  terms  of  pharmaceutical  forms,  there  is 
however already a visible positive impact. 

In this context, criticism has been voiced that the Regulation will fail to ensure a breakthrough 
in areas of particular paediatric need, such as paediatric oncology. This argument is related to 
the fact that the starting point for the majority of paediatric investigation plans is an ongoing 
R&D  programme  for  a  medicinal  product  for  adults.  An  intrinsic  consequence  of  this 
approach is that these products primarily target adult conditions. They are developed in areas 
where there is a need (or a market) in the adult population. This need in the older population 
does not necessarily correspond to the paediatric population’s need. 

Moreover, the Regulation grants waivers from its obligations where the disease or condition 
for  which  the  specific  medicinal  product  is  intended  occurs  only  in  adult  populations.  This 
legislative approach creates friction in the case of diseases that are specific and exclusive to 
children.  It  also  limits  the  powers  and  possibilities  of  the  Paediatric  Committee  when 
reviewing and agreeing to a paediatric investigation plan as regards the scope of studies that 
the  Committee  may  request  from  applicants  following  the  objective  and  scientific-based 
assessment of the compound concerned19. 

These constraints and boundaries have to be taken into account when judging the impact the 
Regulation  is  likely  to  make.  In  addition,  the  effect  of  instruments  such  as  the  Orphan 
Regulation  have  to  be  considered  given  that,  for  example,  all  paediatric  cancers  are  rare 
diseases and fall under the EU policy framework on rare diseases. 

All in all, the achievements highlighted in chapter 4 of this report and the number of products 
with  new  paediatric  indications  show  that  there  are  some  encouraging  signs  after  this  first 
five-year period; it is however, too early for comprehensive answers. 

5.2. 

The PUMA concept: a disappointment 

The Paediatric Regulation introduced a new type of marketing authorisation — the Paediatric 
Use Marketing Authorisation (PUMA). As an incentive to carry out research into the potential 
paediatric  use  of  off-patent  medicinal  products  that  have  been  authorised  for  adults,  this 
marketing authorisation offers 8 years of data and 10 years of market exclusivity to any new 
off-patent product developed exclusively for use in the paediatric population. Thus, the main 
goal of the PUMA concept is to stimulate research in existing products. This scheme has been 
supported  by  EU  funding  through  the  EU  Framework  Programmes  for  Research  and 
Technological Development. 

However, to date only one PUMA has been granted, with a few more projects currently in the 
pipeline. 

Neither  industry  nor  academic  networks  have  embraced  this  opportunity  as  fully  as  the 
Regulation intended. It would seem that the incentive of data and market exclusivity does not 
work for these products, or  at least that the market  opportunities in this sector are  currently 
considered  insufficient  to  outweigh  the  inherent  economic  risks  of  pharmaceutical 

19 

Case T-52/09 Nycomed v EMA, not yet published. 

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development.  Researchers  are  not  engaging  in  trials  with  medicines  that  have  been  on  the 
market for years. Companies seem to fear that market exclusivity will not prevent physicians 
from continuing to use competitor products with the same active ingredient off-label, at lower 
costs,  or  that  substitution  for  cheaper  adult  forms  takes  place  at  the  level  of  pharmacies. 
Moreover, national pricing and reimbursement rules in Member States often do not allow for 
the additional research needed to obtain the PUMA to be rewarded in price negotiations20. 

Against this background the PUMA concept has failed so far to fulfil the initial expectations. 

The  EMA  will  in  future  accept  paediatric  investigation  plans  for  a  PUMA  that  cover  only 
certain  age  groups  and  not  the  entire  paediatric  population.  This  may  offset  some  of  the 
reservations that currently hamper better endorsement of the PUMA concept. 

5.3. 

No impact on adult development 

Studies  prior  to  the  adoption  of  the  Regulation  have  suggested  a  theoretical  risk  that  the 
requirements for research in children could lengthen the overall drug development process21. 
The  Regulation  has  met  this  risk  head-on.  In  order  to  avoid  any  delays  in  authorising 
medicines for other populations, it allows for the granting of deferrals relating to the initiation 
or completion of some or all of the measures contained in a paediatric investigation plan. 

Experience shows that the deferral is a widely used instrument, which suggests that the risk of 
delays in the processing of adult applications is minimal. There have been some transitional 
problems in cases where the adult programme was already  established  when the Regulation 
entered into force, but these issues seem to have been resolved. 

A  concern  that  was  raised  initially  was  that  some  companies  would  become  reluctant  to 
develop  new  indications,  pharmaceutical  forms  and  new  routes  of  administration  in  small 
markets  and  for  products  with  low  sales,  to  avoid  being  bound  by  the  paediatric  obligation 
under Article 8 of the Regulation. However, there is no evidence of such effect. Moreover, it 
may also be argued that the incentive of a potential six-month extension of the SPC served to 
counterbalance such an effect as it may have led companies to examine more thoroughly the 
benefits of a line extension, taking into account the economic value of the paediatric reward. 

Still,  industry  stakeholders  claim  that  in  rare  cases  the  development  for  new  medicinal 
products has been delayed or abandoned in the expectation or as a consequence, of additional 
costs and requirements associated with paediatric development. Overall, there is, however, no 
evidence  that  the  Regulation  has  a  considerable  negative  impact  on  products  for  other 
populations. 

Rather, there are some concerns that the requirements under the Regulation may cause delays 
in  the  authorisation  of  products  with  paediatric-only  indications,  as  they  bring  added 
complexity  to  the  R&D  and  regulatory  process  for  products  that  already  directly  target 
children. The added value of the submission of a paediatric investigation plan in these cases 
will be assessed further in the 2017 report. 

5.4. 

Reaping the benefits of existing information 

There was widespread speculation prior to the adoption of the Paediatric Regulation as to how 
many studies would be submitted by pharmaceutical companies in accordance with Articles 

20 
21 

See the results of the public consultation conducted by the Commission in preparation of this Report. 
Cf. Commission Staff Working Document. Proposal for a Regulation of the European Parliament and of 
the  Council  on  medicinal  products  for  paediatric  use  and  amending  Council  Regulation  (EEC)  No 
1786/92,  Directive  2001/83/EC  and  Regulation  (EC)  No  726/2004.  Extended  impact  assessment 
(COM/2004/599/F). 

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45 and 46. The fact that competent authorities received more than 18 000 studies reveals the 
considerable amount of paediatric information that existed at company level. 

Certainly,  it  is  true  that  not  all  the  information  submitted  met  modern  requirements  for 
scientific  data  and  clinical  research,  and  that  the  work-sharing  process  of  evaluating  the 
information is rather long and resource intensive. 

Nevertheless, compared to the PUMA concept, this scheme proved more successful in terms 
of  output,  and  in  recommending  and  implementing  changes  to  the  summary  of  product 
characteristics  of  authorised  products.  In  its  public  consultation,  the  Commission  called 
Articles 45 and 46 the ‘hidden gems’ of the Regulation. 

One  drawback  that  remains,  however,  is  reluctance  by  marketing  authorisation  holders  to 
update the summary of product characteristics on a voluntary basis. This said, the Regulation 
contains  mechanisms  to  overcome  such  reluctance  as  it  empowers  competent  authorities  to 
directly update the summary and vary the marketing authorisation accordingly. Moreover, in 
accordance with Article 23 of Directive 2001/83/EC22 and Article 16 of Regulation (EC) No 
726/200423, marketing authorisation holders are obliged to ensure that the product information 
is kept up to date with the current scientific knowledge. While preference should be given to 
cooperative  approaches,  the  enforcement  tools  may  need  to  be  used  if  companies  do  not 
overcome their reservations. 

On  the  whole,  the  requirements  of  Articles  45  and  46  have  provided  an  efficient  and 
appropriate instrument for collecting and evaluating existing paediatric studies. 

5.5. 

Clinical trials with children 

It  is  generally  accepted  that  the  Paediatric  Regulation  will  lead  to  more  clinical  trials  with 
children,  but  that  its  aims  should  be  achieved  without  subjecting  children  to  unnecessary 
clinical trials. 

The youngest paediatric-age subsets, including neonates, are particularly sensitive. It will be a 
constant  challenge  to  balance  the  therapeutic  needs  of  these  age  groups  with  their  specific 
vulnerability when considering and deciding on the appropriateness of specific clinical trials 
or the specific settings of studies in this age subset. Efforts are therefore continuously being 
made  to  explore  alternative  means,  e.g.  the  use  of  extrapolation,  modelling  and  simulation 
techniques  to  reduce  the  number  of  study  subjects  as  much  as  possible.  The  Paediatric 
Committee  is  actively  contributing  to  facilitate  the  development  and  use  of  such  means, 
including non-conventional trial design. 

Another  challenge  is  how  to  avoid  duplicating  trials  for  different  paediatric  investigation 
plans  from  different  applicants.  Companies  embarking  on  product  development  in  similar 
areas  may  be  required  by  the  agreed  paediatric  investigation  plan  to  conduct  studies  within 
similar  settings.  While  collaborative  approaches  between  companies  would  be  highly 
desirable,  and  have  occurred  on  rare  occasions,  they  often  conflict  with  companies’ 
understandable  reluctance  to  share  data  with  competitors  in  the  early  stages  of  product 
development  and  participate  in  direct  comparisons.  This  situation  could  lead  to  competition 
among  companies  to  find  investigators  and  study  participants  as  well  as  the  duplication  of 
trials which are unnecessary from a scientific and ethical point of view. 

22 

23 

Directive  2001/83/EC  of  the  European  Parliament  and  of  the  Council  of  6  November  2001  on  the 
Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67. 
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying 
down  Community  procedures  for  the  authorisation  and  supervision  of  medicinal  products  for  human 
and veterinary use and establishing a European Medicines Agency, OJ L 136, 30.4.2004, p. 1. 

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The  Paediatric  Committee  is  able  to  waive  paediatric  trial  requirements  where  the  specific 
medicinal  product  does  not  represent  a  significant  therapeutic  benefit  over  an  existing 
treatment  for  paediatric  patients,  including  once  the  product  is  authorised  (Article  11). 
However, this option does not provide a way out in the early stages of product development, 
where the Committee has to ensure equal treatment and non-discriminatory approaches. 

The  key  to  avoiding  such  unnecessary  trials  is  transparency  with  regard  to  ongoing  and 
completed trials. The situation continues to be monitored. 

Finally,  it  is  in  the  interest  of  the  EU  that  paediatric  trials  stemming  from  paediatric 
investigation plans are conducted within the EU. This has less to do with the standards under 
which a trial is conducted, given that clinical trials carried out outside the EU have to meet the 
ethical and scientific requirements of the EU provisions on clinical trials24, than with the fact 
that  studies  within  the  EU  may  provide  patients  there  with  early  access  to  innovative 
medicines. To date, there is insufficient data on the ratio between paediatric trials conducted 
within and outside the EU. However, in view of the upgraded functionalities of the EudraCT 
database, it is expected that more data will be available in 2017 for the second report. 

5.6. 

Spreading  the  news  —  getting  new  information  to  patients  and  healthcare 
professionals 

If the Regulation is to be a success, it is not only necessary that data on the use of a specific 
product  in  the  paediatric  population  are  collected,  but  that  these  data  are  then  also 
appropriately communicated to, and used by, paediatricians in their day-to-day work for the 
benefit of their patients. 

In this regard some studies published in the medical literature suggest a failure on the part of 
practitioners to recognise the actual amount of off-label prescribing to children. Moreover, it 
is claimed that the prescribing habits of practitioners are often strongly influenced by personal 
experience rather than by evidence-based information for paediatric medicine25. 

These studies, in making generalisations, may not have taken into account the heterogeneity 
of healthcare professionals, whose receptiveness varies greatly according to their work setting 
and  specific  area  of  specialisation.  At  the  same  time,  such  observations  may  point  to  a 
substantial hurdle in achieving the goal of the Paediatric Regulation. 

National  competent  authorities  as  well  as  organisations  for  healthcare  professionals  seem 
particularly  qualified  to  consider  appropriate  ways  of  ensuring  an  adequate  flow  of 
information. Some Member States have already established a number of tools to communicate 
effectively  and  efficiently  with  healthcare  professionals,  e.g.  by  means  of  regular  meetings, 
web-based information distribution systems or national formularies. 

5.7. 

Is the burden greater than rewards? 

There can be no doubt that the Paediatric Regulation places a considerable additional burden 
on  pharmaceutical  companies  with  its  obligations  regarding  research  on  products  for  use  in 
children.  However,  this  approach  was  adopted  because  market  forces  alone  proved 
insufficient to stimulate adequate research. 

The Regulation requires companies to submit paediatric investigation plans at an early stage 
of product development. However, research on some active substances may be discontinued 

24 

25 

Directive 2001/20EC of the European Parliament and of the Council on the approximation of the laws, 
regulations, and administrative provisions of the Member States relating to the implementation of good 
clinical  practice  in  the  conduct  of  clinical  trials  on  medicinal  products  for  human  use,  OJ  L  121, 
1.5.2001, p. 34. 
5-year report to the European Commission (see footnote 3), page 41. 

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at  later  stages  should  further  studies  fail  to  show  potential  with  respect  to  the  safety  and 
efficacy of the product. For every successful authorised medicinal product there are many that 
fail to make the finishing line. 

Hence, not all approved paediatric investigation plans will be completed, as companies may 
decide  to  stop  the  corresponding  adult  development.  It  is  too  early  still  to  obtain  reliable 
statistics  that  show  the  ratio  between  completed  and  non-completed  paediatric  investigation 
plans, but in the current context not all approved plans will eventually result in an approved 
medicine with a paediatric indication. 

In terms of output, this entails some unnecessary effort in compiling and screening paediatric 
investigation  plans.  To  what  extent  this  is  offset  by  the  benefit  of  early  submission,  which 
ensures  that  the  paediatric  development  fits  smoothly  into  the  overall  product  development, 
need further monitoring. 

A  further  point  of  concern  is  the  high  number  of  modifications  to  paediatric  investigation 
plans.  Figures  seem  to  suggest  that  nearly  all  plans  have  to  be  modified  at  least  once. 
Conceptually  though  this  does  not  come  as  a  surprise,  in  view  of  the  early  submission  of 
paediatric  investigation  plans,  the  length  of  adult  and  paediatric  developments  and  the 
substantial deferrals granted. An R&D plan frequently has to be adapted or amended to take 
account of initial results. Recruitment problems or necessary design changes in the trials may 
also  lead  to  modifications.  While  it  is  acknowledged  that  substantial  amendments  or 
modifications to the plan have to be subject to discussions with the Paediatric Committee, this 
is less obvious for minor changes. In this context, the level of detail required by the EMA has 
been repeatedly criticised. In the past five years, the EMA and its Paediatric Committee have 
made efforts to provide for some flexibility in the plan so to allow a margin of manoeuvre that 
takes account of uncertainties in relation to certain parameters of a trial. 

In any case, the Commission intends to review its Communication on the format and content 
of  applications  for  agreement  or  modification  of  a  paediatric  investigation  plan  to  take  into 
account the experience gained, including the considerable number of modification requests. 

On a positive note, it can be noted that companies are applying for the rewards provided by 
the Regulation, primarily the 6-month extension of the Supplementary Protection Certificate, 
which have been introduced to offset the additional burden. The economic value of the reward 
depends  on  the  turnover  of  the  product  concerned.  In  the  case  of  blockbuster  products  the 
amount may be considerable, while for niche products the effect is small. 

An in-depth evaluation of the economic impact will be included in the 2017 report in order to 
draw conclusions on the balance between burden and rewards, and public health benefits. 

6. 

OUTLOOK — A FAIRY-TALE ENDING AHEAD? 

‘Better Medicines for Children — From Concept to Reality’ is the title of this report. Readers 
may suggest that, based on the evaluation referred to above, it would be more appropriate to 
add a question mark. It is evident that it is too early still to make a firm statement. Despite 
more than five years of experience, the true impact of the Regulation on the health of children 
will only become apparent over time as experience is accumulated in the longer term. 

There are encouraging signs though. Paediatric development has become a more integral part 
of the overall development of medicinal products in the EU. A number of new products with 
paediatric  indications  and  age-appropriate  pharmaceutical  forms  have  been  authorised  and 
made available to patients. A high number of agreed paediatric investigation plans indicates 
that further products are in the pipeline. 

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However, it needs to be pointed out that it would be wrong to expect the Regulation to be able 
to solve all problems. Instead, it is a major catalyst to improve the situation of young patients. 

Finally, some weaknesses and deficits have also become apparent in the last five years. Their 
impact on the overall performance of the Regulation has to be closely monitored. On the basis 
of the actions outlined above, the Commission intends to fine-tune the current implementation 
together with the EMA. 

Even  if  better  medicines  for  children  are  not  yet  a  reality,  it  should  be  the  ambition  of  all 
stakeholders involved that this piece of legislation will be for the greater good of children, so 
that in the 2017 report, the discussion will focus not on whether a question mark should be 
added to the title of the report, but on whether it should be an exclamation mark instead! 

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ANNEX I — Figures and Tables 

Table 1: Agreed paediatric investigations plans (PIPs) 2007-2012 

250

200

150

100

50

0

2007

2008

2009

2010

2011

2012

Agreed PIPs (total number)

Agreed PIPs submitted under Article 7 (without waivers)

Agreed PIPs submitted under Article 8 (without waivers)

Source: EMA Paediatric database. The numbers on agreed PIPs correspond to EMA decisions. 

Table  2:  Agreed  paediatric  investigations  plans  (PIPs)  compared  to  full  waivers  and 
modifications 2007-2012 

250

200

150

100

50

0

2007

2008

2009

2010

2011

2012

Agreed PIPs (total number)

Submitted modifications of an agreed PIP

Agreed Full waivers

Source: EMA Paediatric database. The numbers on agreed PIPs and waivers correspond to EMA decisions. 

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Table 3: Therapeutic areas addressed by the paediatric investigation plans (2007-2011) 

Dermatology
6%

Vaccines
7%

Haematology-
Haemostaseology
8%

Cardiovascular 
Diseases
8%

Gastroenterology-
Hepatology
5%

Neurology
5%

Pneumology —
Allergology*
4%

Other
19%

Oncology
10%

Immunology-
Rheumatology-
Transplantation
9%

Infectious 
Diseases
10%

Endocrinology-
Gynaecology-Fertility-
Metabolism
10%

Oto-rhino-laryngology
3%

Pain, Anaesthesiology
3%

Uro-nephrology
3%

Psychiatry
2%

Neonatology** —
Intensive Ca re 2%

Other 
7%

Source: EMA Paediatric database. * Excluding allergen products. ** Applications that exclusively address a use in neonates. 

Table 4: Number of compliance opinions adopted by the Paediatric Committee per year 

10

9

8

7

6

5

4

3

2

1

0

2008

2009

2010

2011

2012

Source: EMA Paediatric database. 

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Table  5:  Scientific  advice  and  protocol  assistance,  including  follow-ups  (provided  by  the 
EMA  Scientific  Advice  Working  Party  and  the  Committee  for  Human  Medicinal  Products, 
per year) 

500

400

300

200

100

0

388

400

433

420

321

277

259

0

0

21

0

32

0

74

68

80

80

91

94

57

67

2006

2007

2008

2009

2010

2011

2012

Total number of advice (Scientific Advice and Protocol Assistance)*

Sum of paediatric-only and mixed (adult and paediatric development questions)
advice*
Paediatric-only or mixed advice that involved a Paediatric Committee member(s) as
expert(s)**

Source: EMA databases. * Year of advice letter. ** Year of start of procedure. 

Table 6: Paediatric clinical trials by year of authorisation 

2005 

2006 

2007 

2008 

2009 

2010 

2011 

2012 

254 

316

355

342

404

379

334 

332

2 

1

2

6

16

30

76 

76

Paediatric trials 

(number) 

Paediatric trials that 

are part of an 

agreed PIP* 

Proportion of 

paediatric trials that 

are part of an 

1 % 

0 %

1 %

2 %

4 %

8 %

23 % 

23 %

agreed PIP among 

paediatric trials* 

Total number of 

trials (adults and / 

3 350 

3 979

4 749

4 512

4 445

4 026

3 809 

3 698

or children) 

Proportion of 

paediatric trials of 

8 % 

8 %

7 %

8 %

9 %

10 %

9 % 

9 %

all trials 

Source: EudraCT Data Warehouse using a predefined query on 6 March 2013 and counting the first authorised trial only, in the case of more 
than one Member State. 

* This partial information requires sponsors to use a Clinical Trial Application form that was only available from November 2009, for use 
with version 8 of EudraCT (available from 2011). 

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Table 7: Number of children to be enrolled in clinical trials 

Number of 

subjects 

Preterm newborns 

Newborns 

Infants and toddlers 

Children 

Adolescents 

Sum of above 

Reference: number 

of paediatric trials 

2006 

2007 

2008 

2009 

2010 

2011 

2012 

0 

0 

330 

2 142 

368 

2 840 

0 

0 

21 

181 

111 

313 

0 

5 

20 

200 

205 

207 

64 

59 

2 230 

1 577 

82 

169 

351 

2 281 

1 105 

2 788 

1 712 

1 172 

3 141 

2 055 

10 325 

20 677 

2 861 

9 054 

13 193 

430 

4 137 

5 517 

25 553 

39 895 

316 

355 

342 

404 

379 

334 

332 

Source: EudraCT Data Warehouse using a pre-defined query on 6 March 2013, modified by excluding studies for ‘immunological medicinal 
products’ 

Table 8: EU budget contribution to the Paediatric Regulation and the EMA expenditure 

10

9

8

7

6

5

4

3

2

1

0

2006

2007

2008

2009

2010

2011

2012

EU budget contribution (in Million €)

EMA  expenditure for paediatrics (in Million €)

EMA  expenditure for paediatrics including support (in Million €)

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Table  9:  Percentage  of  European  Medicines  Agency's  human  resources  working  in  the 
paediatric area from 2006 (inner circle) to 2012 (outer circle) 

0,52% (2006)

7,33% (2012)

Table  10:  Member  States  acting  as  rapporteurs  for  the  assessment  of  studies  submitted  in 
accordance with Article 46 (paediatric work-sharing procedures) 

60

50

40

30

20

10

0

UK DE SE NL FR DK IT BE PL ES NO SK FI

IE RO AT HU EL CZ PT LV BG

Study included in worksharing

Rapporteur appointed

EN 

20 

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Table  11:  Member  States  acting  as  rapporteur  for  the  assessment  of  studies  submitted  in 
accordance with Article 45 (paediatric work-sharing procedures) 

60

50

40

30

20

10

0

UK DE NL DK AT FR PL SE ES

IE CZ MT IT BE SI EE FI HU NO RO BG EL LV PT IS

SK

Wave 1 Wave 2 Wave 3 Wave 4 Wave 5 Wave 6 Wave 7 Wave 8 Wave 9

Wave 10 Wave 11 Wave 12 Wave 13 Wave 14 Wave 15 Wave 16 Wave 17 Wave 18

Table  12:  Member  States  acting  as  rapporteurs/peer  reviewers  in  EMA's  Paediatric 
Committee procedures (initial PIP/waiver or modification of an agreed PIP) 

500
450
400
350
300
250
200
150
100
50
0

A
u
s
t
r
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Initial PIP applications

PIP modifications

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EN 

21 

   EN 

 
 
 
 
 
 
 
 
 
ANNEX II — Detailed inventory of centrally authorised medicinal products for 
paediatric use since the entry into force of the Paediatric Regulation 

Table  13:  Medicinal  products  authorised  centrally  since  2007,  which  include  a  paediatric 
indication 

Active substance(s) 

Trade name 

Year of 
authorisation 

Retapamulin 
Nelarabine 
Human papillomavirus 
vaccine [types 16, 18] 

Hydroxocobalamin 
Idursulfase 
Gadoversetamide 
Betaine anhydrous 
Stiripentol 
Mecasermin 
Rufinamide 
Hydroxycarbamide 
Human normal 
immunoglobulin (ivig) 
Fluticasone furoate  
Human normal 
immunoglobulin 
Lacosamide 
Micafungin 
Sapropterin 
Sugammadex 
Tocofersonal d-alpha 
tocopheryl polyethylene 
glycol succinate 
Mifamurtide  
Rilonacept 

Tacrolimus 
Pneumoccocal 
polysaccharide 
conjugate vaccine 
(adsorbed) 
Canakinumab 

Pneumoccocal 
polysaccharide 
conjugate vaccine (13-
valent, adsorbed) 
Meningococcal group a, 
c, w135 and y 
conjugate vaccine 
Velaglucerase alfa 

Influenza vaccine (live 
attenuated, nasal) 
C1 inhibitor, human 

Dihydroartemisinin / 
piperaquine phosphate 

Altargo  
Atriance  
Cervarix 

Cyanokit 
Elaprase 
Optimark 
Cystadane 
Diacomit 
Increlex 
Inovelon 
Siklos 
Flebogamma 
DIF 
Avamys 
Privigen 

Vimpat 
Mycamine 
Kuvan 
Bridion 
Vedrop 

Mepact 
Rilonacept 
Regeneron 
Modigraf 
Synflorix 

Ilaris (PIP not 
yet completed) 
Prevenar 13 
(PIP not yet 
completed) 

2007 
2007 
2007 

2007 
2007 
2007 
2007 
2007 
2007 
2007 
2007 
2007 

2008 
2008 

2008 
2008 
2008 
2008 
2009 

2009 
2009 

2009 
2009 

2009 

2009 

Menveo 

2010 

Vpriv (PIP not 
yet completed) 
Fluenz (Waiver) 

Cinryze (PIP 
not yet 
completed) 
Eurartesim (PIP 
not yet 
completed) 

2010 

2011 

2011 

2011 

22 

EN 

Requirement to 
fulfil Paediatric 
Regulation at first 
authorisation? 
No 
No 
No 

Indication is 
paediatric-only 
or ‘mixed’ (adult 
and paediatric)? 
Mixed 
Mixed 
Mixed 

No 
No 
No 
No 
No 
No 
No 
No 
No 

No 
No 

No 
No 
No 
No 
No 

No 
No 

No 
No 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Mixed 
Mixed 
Mixed 
Mixed 
Paediatric only 
Paediatric only 
Mixed 
Mixed 
Mixed 

Mixed 
Mixed 

Mixed 
Mixed 
Mixed 
Mixed 
Paediatric only 

Mixed 
Mixed 

Mixed 
Paediatric only 

Mixed 

Paediatric only 

Mixed 

Mixed 

Paediatric only 

Mixed 

Mixed 

   EN 

 
Active substance(s) 

Trade name 

Year of 
authorisation 

Midazolam 
Everolimus 

Tobramycin 

Nomegestrol / estradiol 
Colistimethate sodium 
Mercaptopurine 
Catridecacog 
Efavirenz 
Ivacaftor 

Desloratadine 

Desloratadine 
Perampanel 

Buccolam 
Votubia 
(PIP not yet 
completed) 
Tobi Podhaler 
(PIP not yet 
completed) 
Ioa, Zoely 
Colobreathe 
Xaluprine 
NovoThirteen 
Efavirenz Teva 
Kalydeco 
Desloratadine 
ratiopharm 
Desloratadine 
Actavis 
Fycompa 

2011 
2011 

2011 

2011 
2012 
2012 
2012 
2012 
2012 

2012 

2012 
2012 

Requirement to 
fulfil Paediatric 
Regulation at first 
authorisation? 
Yes (PUMA) 
Yes 

Indication is 
paediatric-only 
or ‘mixed’ (adult 
and paediatric)? 
Paediatric only 
Mixed 

Yes 

Yes 
Yes 
No 
Yes 
No 
Yes 

No 

No 
Yes 

Mixed 

Mixed 
Mixed 
Mixed 
Mixed 
Mixed 
Mixed 

Mixed 

Mixed 
Mixed 

Table 14: List of centrally authorised medicinal products for which the therapeutic indication 
was extended to or amended for the paediatric population 

Active substance(s) 

Trade 
name 

Levetiracetam 

Keppra 

Date 

2007/ 
2009 

Pneumococcal 
saccharide 
conjugated vaccine, 
adsorbed  

Prevenar 

2007 

Infliximab 

Remicade 

2007 

Darbepoetin alfa 

Aranesp 

2007 

Fosamprenavir 

Telzir 

2007 

Lamivudine / 
zidovudine 

Combivir 

2007 

Desloratadine 

Aerius 

2007 

Subject of the extension 

Extension of the indication to include adjunctive 
therapy in the treatment of primary generalised 
tonic-clonic (PGTC) seizures in adults and 
adolescents from 12 years of age with idiopathic 
generalised epilepsy; 
Extension of indication to include the adjunctive 
treatment of partial seizures with or without 
secondary generalisation in children from 1 month to 
<4 years old 
Extension of the indication to include new information 
on efficacy against disease caused by Streptococcus 
pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 
23F in otitis media; 
Extension of indication from active immunisation 
against bacteraemic pneumonia to active 
immunisation against pneumonia 
Extension of indication to include treatment of severe 
active Crohn’s disease in children aged 6 to 17 years 

Extension of indication for CRF patients, which 
restricted the use of Nespo to paediatric subjects ≥ 
11 years of age 
Extension of indication of Telzir in combination with 
ritonavir for the treatment of Human 
Immunodeficiency Virus Type 1 (HIV-1) infected 
adults in combination with other antiretroviral 
medicinal products to include paediatric populations 
Extension of indication to include paediatric patients 
and replacement of film-coated tablets by scored 
film-coated tablets 
Extension of indication from ‘chronic idiopathic 
urticaria’ to ‘urticaria’ 

EN 

23 

   EN 

 
Active substance(s) 

Trade 
name 

Date 

Subject of the extension 

Insulin glulisine 

Apidra 

2007 

Human papilloma 
virus vaccine [types 
6, 11, 16, 18] 
(recombinant, 
adsorbed) 
Adalimumab 

Gardasil 

2008 

Humira 

2008/
2011 

Caspofungin 

Cancidas 

2008 

Etanercept 

Enbrel 

2008/
2011 

Miglustat 

Zavesca 

2009 

Tacrolimus 

Protopic 

2009 

Tipranavir 

Aptivus 

2009 

Omalizumab 

Xolair 

2009 

Aripiprazole 

Abilify 

2009 

Peginterferon alfa-2b  PegIntron 

2009 

Ribavirin 

Rebetol 

2009 

Abatacept 

Orencia 

2010 

Atazanavir sulphate 

Reyataz 

2010 

Measles, mumps and 
rubella vaccine (live) 
Nitric oxide 

M-M-
RVAXPRO 
Inomax 

2010 

2011 

Extension of indication to include 6 year olds and 
older children based on the results of 2 paediatric 
studies 
Extension of indication to include the prevention of 
high-grade vaginal dysplastic lesions (VaIN 2/3) 

Extension of indication to include treatment of active 
polyarticular juvenile idiopathic arthritis in 
adolescents from 13 to 17 years of age; 
Extension of indication to include treatment of active 
polyarticular juvenile idiopathic arthritis in the 
paediatric population aged from 4 to 12 years. 
Extension of the indication to include the paediatric 
population 
Extension of indication to include the treatment of 
chronic severe plaque psoriasis in children and 
adolescents from the age of 6 years who are 
inadequately controlled by, or are intolerant to, other 
systemic therapies or phototherapies; 
Extension of indication to include lower age range for 
polyarticular juvenile idiopathic arthritis ‘from the age 
of 4 years’ to ‘from the age of 2 years’ 
Extension of indication to include the treatment of 
progressive neurological manifestations in adult 
patients and paediatric patients with Niemann-Pick 
type-C disease 
Extension of indication to ‘maintenance treatment’ 
further to completion of one study in adult patients 
and one in paediatric patients 
Extension of indication to include the treatment of 
HIV-1 infection in highly pre-treated adolescents 12 
years of age or older with virus resistant to multiple 
protease inhibitors 
Extension of indication to children from 6 to <12 
years of age as add-on therapy to improve allergic 
asthma control 
Extension of indication to include treatment of 
schizophrenia in adolescents 15 years and older 
Extension of indication of the combination therapy 
peginterferon alfa-2b and ribavirin to include 
treatment of the paediatric population 
Extension of indication of the combination therapy 
peginterferon alfa-2b and ribavirin to include 
treatment of the paediatric population 
Extension of indication to include the treatment of 
moderate to severe active polyarticular juvenile 
idiopathic arthritis in paediatric patients 6 years of 
age and older who have had an insufficient response 
to other DMARDs including at least one TNF inhibitor 
Extension of indication for Reyataz capsules to 
include the treatment of HIV-infected children and 
adolescents above the age of 6 in combination with 
other antiretroviral medicinal products 
Extension of indication to include administration to 
healthy children from 9 months of age 
Extension of indication to include the treatment of 
pulmonary hypertension peri- and post heart surgery 
in children 

EN 

24 

   EN 

 
Active substance(s) 

Trade 
name 

Date 

Subject of the extension 

Tenofovir disoproxil 
fumarate 

Viread 

2011 

Paliperidone 

Invega 

2011 

Sildenafil 

Revatio 

2011 

Human normal 
immunoglobulin 
(ivig) 

Kiovig 

2011 

Tocilizumab 

Roactemra  2011 

Pneumococcal 
polysaccharide 
conjugate vaccine 
(adsorbed) 
Insulin detemir 

Synflorix 

2011 

Levemir 

2011 

Eculizumab 

Soliris 

2011 

Human 
papillomavirus 
vaccine [types 16, 
18] (recombinant, 
adjuvanted, 
adsorbed) 
Etanercept 

Cervarix 

2011 

Enbrel 

2012 

Measles, mumps, 
rubella and varicella 
vaccine (live) 

Proquad 

2012 

Amendment of indication based on the results of a 
safety and efficacy study in treatment-experienced 
adolescents aged 12 to 18 years old 
Extension of indication to include treatment of 
psychotic or manic symptoms of schizoaffective 
disorder 
Extension of indication in paediatric patients aged 1 
year to 17 years old with pulmonary arterial 
hypertension 
Extension of indication to include treatment of 
multifocal motor neuropathy and 
hypogammaglobulinaemia in patients after allogeneic 
haematopoietic stem cell transplantation in adults 
and children 
Extension of indication to include treatment of active 
systemic juvenile idiopathic arthritis in patients 2 
years of age and older, who have responded 
inadequately to previous therapy with NSAIDs and 
systemic corticosteroids 
Extension of indication to increase the upper age 
limit of infants and children from 2 years to 5 years 

Extension of indication as add-on therapy to 
liraglutide treatment; 
Extension of indication to children aged 2-5 years 
Extension of indication to include atypical haemolytic 
uremic syndrome (aHUS). Additional vaccination and 
antibiotic prophylaxis recommendation have also 
been added in section 4.2 for treatment of aHUS in 
adults and children 
Extension of indication to children from 9 years 

Extension of the Juvenile idiopathic arthritis (JIA) 
indication to include children and adolescents with 
extended oligoarticular JIA from the age of 2 years, 
children and adolescents with enthesitis-related 
arthritis from the age of 12 years, and children and 
adolescents with psoriatic arthritis from the age of 12 
years 
Extension of the age range in the indication to 
children from 9 months of age onwards under special 
circumstances, i.e. outbreak control 

For  a  more  detailed  inventory,  including  information  on  nationally  authorised  products  and  new  routes  of  administration  or  new 
pharmaceutical forms, please refer to Annex II of the ‘5-year Report to the European Commission’ of the EMA. 

EN 

25 

   EN 

 
ANNEX III — List of funded projects 

List of projects on off-patent medicines funded by the European Commission through the EU 
Framework Programme Health: area 4.2 results, off-patent medicines calls 2, 3, 4 and 5. 

•  HEALTH.2007-4.2-1  Adapting  off-patent  medicines  to  the  specific  needs  of  paediatric 

populations. 

•  HEALTH.2009-4.2-1  Adapting  off-patent  medicines  to  the  specific  needs  of  paediatric 

populations. 

•  HEALTH.2010.4.2-1  Off-Patent  Medicines  for  Children.  FP7-HEALTH-2010-single-

stage. 

•  HEALTH.2010.4.2-2 International paediatric initiative. Network of Excellence. 
•  HEALTH.2011.4.2-1  Investigator-driven  clinical  trials  on  off-patent  medicines  for 

children. 

Table 15: Funded off-patent medicines projects (beginning up to 1 January 2012) and agreed 
PIPs, if available. 

No.  Acronym 

Year 

Objectives 

start 

Agreed 

PIP 

1 

KIEKIDS 

2011 

To develop an innovative, age-adapted, flexible and safe 

NA 

paediatric formulation of ethosuximide for the 

treatment of absence and of myoclonic epilepsies in 

children 

2 

NEO-CIRC 

2011 

To provide safety and efficacy data for dobutamine, to 

EMEA-

perform pre-clinical studies, to develop biomarker(s) of 

001262-

hypotension and to adapt a formulation for newborns 

PIP01-12 

3 

TAIN 

2011 

To develop a neonatal formulation of hydrocortisone 

EMEA-

for the treatment of congenital and acquired adrenal 

001283-

insufficiency and for use in oncology (brain tumours and 

PIP01-12 

leukaemia) 

4 

GRIP 

2011 

To implement an infrastructure matrix to stimulate and 

NA 

facilitate the development and safe use of medicine in 

children 

5 

DEEP 

2011 

To evaluate Pharmacokinetics (PK) & Pharmacodynamics 

EMEA-

(PD) of deferiprone in in 2-10 years old children in 

001126-

order to produce an approved paediatric investigation 

PIP01-10 

plan to be used for regulatory purposes 

6 

TINN2 

2011 

To evaluate PK & PD of azithromycin against urea 

plasma and in BPD in neonates 

7 

HIP Trial 

2010 

To evaluate the efficacy safety, PK, PD of adrenaline 

and dopamine in the management of neonatal 

EMEA-

001298-

PIP01-12 

NA / 

EMEA-

hypotension in premature babies and to develop and 

001105-

adapt a formulation of both suitable for newborns in 

PIP01-10 

order to apply for a Paediatric Use Marketing 

Authorisation 

8 

PERS 

2010 

Focuses on two indications, the use of risperidone in 

EMEA-

children and adolescents with conduct disorder who are 

001034-

not mentally retarded, and the use of risperidone in 

PIP01-10 

adolescents with schizophrenia 

EN 

26 

   EN 

 
No.  Acronym 

Year 

Objectives 

start 

9 

NeoMero 

2010 

European multicentre network to evaluate 

Agreed 

PIP 

EMEA-

pharmacokinetics, safety and efficacy of meropenem in 

000898-

neonatal sepsis and meningitis 

PIP01-10 

10  NEMO 

2009 

To evaluate the efficacy safety, PK, PD, mechanisms of 

NA 

action of bumetanide in neonatal seizures, including the 

effect on neurodevelopment and to develop and adapt a 

bumetanide formulation suitable for newborns in order to 

apply for a Paediatric Use Marketing Authorisation 

11  NEUROSIS 

2009 

Efficacy of budesonide in reducing bronchopulmonary 

EMEA-

dysplasia 

001120-

PIP01-10 

12 

EPOC 

2009 

To evaluate pharmacokinetics and pharmacodynamics of 

NA 

doxorubicin 

13 

LOULLA & 

2008  Development of oral liquid formulations of 

NA / NA 

PHILLA 

methotrexate and 6-mercaptopurine for paediatric 

acute lymphoblastic leukaemia 

14  NeoOpioid 

2008 

To compare morphine and fentanyl in pain relief in 

EMEA-

pre-term infants 

15  O3K 

2008  Oral liquid formulations of cyclophosphamide and 

temozolomide 

16 

TINN 

2008 

Aims to evaluate PK & PD of ciprofloxacin and 

fluconazole in neonates 

NA = not available or not applicable 

000712-

PIP01-09 

EMEA-

000530-

PIP02-11 / 

NA 

NA  

•  HEALTH.2011.2.3.1-1 Investigator-driven clinical trials of off-patent antibiotics 

Table 16: Investigator-driven clinical trials of off-patent antibiotics 

No.  Acronym 

Year 

Objectives 

start 

Agreed 

PIP 

1 

MAGICBULLET  2012 

Optimisation of treatment with off-patent antimicrobial 

NA 

agents of ventilator-associated pneumonia 

2 

AIDA 

2011 

Assessment of clinical efficacy by a pharmacokinetic / 

NA 

pharmacodynamic approach to optimise effectiveness 

and reduce resistance for off-patent antibiotics. 

NA = not available 

EN 

27 

   EN