REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL State of Paediatric Medicines in the EU - 10 years of the EU Paediatric Regulation
Date: 2017-10-26
Institutions: Directorate-General for Health and Food Safety, European Commission
Subjects: European Medicines Agency, child, drug surveillance, market approval, medical research, medicinal product, paediatrics, public health, testing, young person

EN 

   EN 

   EUROPEAN COMMISSION  Brussels, 26.10.2017  COM(2017) 626 final   REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL State of Paediatric Medicines in the EU - 10 years of the EU Paediatric Regulation   
 
 
1. 

INTRODUCTION 

Nowadays there is broad consensus that children deserve access to medicines that have 
been  specifically  developed  and  researched  for  their  use  in  young  patients.  However, 
until  recently  the  development  and  testing  of  paediatric  medicines  was  far  from 
satisfactory.  Many  of  the  products  used  in  children  were  prescribed  and  administered 
based  on  physicians’  own  experience  rather  than  on  the  results  of  clinical  research. 
Moreover,  medicines  were  often  not  available  in  a  pharmaceutical  form  suitable  to 
children.  Paediatricians  had  to  turn  to  medicines  authorised  for  adults  by  adapting  the 
dosage and  form. For example by crushing  adult tablets and using only  a portion.  This 
off-label  use  of  adult  medicines  comes  with  the  risk  of  inefficacy  and/or  adverse 
reactions in children. Side effects that may not affect adults can be important and serious 
in children. 

Surveys suggested that in many therapeutic areas the off-label use was widespread, often 
reaching  figures  above  50 %.  Childhood  immunisation  was  a  notable  exemption,  being 
one of the success stories of modern medicine. 

There  are  several  reasons  why  paediatric  medicine  development  had  been  largely 
neglected.  Until  the  1980s  it  was  often  argued  that  children  should  be  protected  from 
clinical  research  for  ethical  reasons.  Since  then  there  has  been  a  gradual  shift  to  the 
current consensus that children merit the same level of health care as any other age group 
including  evidence-based  prescribing  of  medicinal  products.  Economic  considerations 
were also a contributing factor as to why companies refrained from proactively investing 
in this sector. The fact that children grow and maturate means that they are not a uniform 
sub-group.  The  needs  and  biological  and  physiological  characteristics  of  neonates  are 
very  different  compared  to  teenagers.  Therefore  additional  age-appropriate  research  is 
often needed, making the process of developing paediatric medicines more complex. 

The  Paediatric  Regulation1  (‘the  Regulation’)  was  adopted  to  address  this  problem. 
Legislative intervention was deemed necessary to reverse previous trends. A consultation 
and  discussion  process  that  lasted  several  years  was  the  basis  of  the  legislation.  It  was 
also inspired by developments in the United States, which started legislative approaches 
to address paediatric product development in the late 1990s. 

2017  marks  the  10th  anniversary  of  the  Regulation.  In  line  with  its  Article  50(3),  this 
report provides an account of its achievements, both in public health and economic terms 
and  an  analysis  on  the  extent  to  which  its  objectives  have  been  met.  While  10  years 
provides a rich database of experience, it remains a relatively short period of time in view 
of the long development cycles of medicinal products, amounting often close to a decade. 

This  report  builds  on  a  10-year  report  prepared  by  the  European  Medicines  Agency 
(EMA)  and  its  Paediatric  Committee,2  an  external  study  on  the  Regulation’s  impact 
ordered by the Commission,3 a public consultation and discussions with Member States, 

1   Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 

on medicinal products for paediatric use, OJ L 378, 27.12.2006, p. 1. 

2   10-year report to the European Commission – General report on the experience acquired as a result of 

the application of the Paediatric Regulation. 

3   Technopolis,  Study  on  the  economic  impact  of  the  Paediatric  Regulation,  including  its  rewards  and 

incentives, 2017. 

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the  European  Parliament,4  patients,  companies,  interested  parties  and  external  partners 
about their experiences on the Regulation’s impact. 

2.  THE PAEDIATRIC REGULATION 

The Regulation is structured around three main objectives: 

  to encourage and enable high-quality research into the development of medicines for 

children; 

  to ensure, over time, that most medicines used by children are specifically authorised 

for such use with age-appropriate forms and formulations; and 

  to  increase  the  availability  of  high-quality  information  about  medicines  used  by 

children. 

To  meet  these  objectives  the  Regulation  sets  up  a  system  of  obligations,  rewards  and 
incentives, and puts in place measures to ensure that medicines are regularly researched, 
developed and authorised to meet children’s therapeutic needs. It is based on the simple 
idea  that  a  company  should  be  obliged  to  screen  every  product  it  develops  for  its 
potential  use  in  children,  thereby  progressively  increasing  the  number  of  products  with 
paediatric indications. 

The Regulation obliges companies to agree at an early stage of development a paediatric 
Research and Development programme (‘paediatric investigation  plan’) with  the EMA. 
The  Regulation  has  a  direct  impact  on  companies’  R&D  expenditure,  as  it  imposes  an 
investment in paediatric research. If a company fails to comply with the agreement, the 
respective  (adult)  marketing  authorisation  may  be  blocked.  The  Regulation  therefore 
goes  beyond  the  mechanisms  set  up  by  the  legislation  on  medicines  for  rare  diseases 
(‘Orphan Regulation’),5 which only provides incentives for companies. 

The  obligation  laid  down  in  the  Regulation  is  complemented  by  other  measures,  in 
particular: 

  a  system  of  waivers  for  medicines  that  are  unlikely  to  benefit  children  and  a 
system  of  deferrals  in  relation  to  the  timing  of  the  paediatric  measures  to  be 
conducted; 

  a  reward  for  complying  with  the  obligation:  a  six-month  extension  of  the 

supplementary protection certificate;6 

  a specific reward for orphan medicines: an extra two years of market exclusivity 

added to the existing 10 years awarded under the Orphan Regulation; 

4  European Parliament resolution of 15 December 2016 on the regulation on paediatric medicines. 

5  Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on 

orphan medicinal products, OJ L 18, 22.1.2000, p. 1. 

6   Regulation  (EC)  No  469/2009  of  the  European  Parliament  and  of  the  Council  pf  6  May  2009 
concerning  the  supplementary  protection  certificate  for  medicinal  products,  OJ  L  152,  16.6.2009, 
p. 152. 

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  a new type of marketing authorisation, the paediatric use marketing authorisation 
(PUMA), to  incentivise the development of paediatric indications  for off-patent 
products; 

  an expert committee, the Paediatric Committee (PDCO), within EMA; and 

  a system of free scientific advice for the industry, provided by EMA. 

In addition, the Regulation promotes high-quality information and high-quality research 
through other measures, such as 

  an  EU  network  of  networks  of  investigators  and  trial  centres  carrying  out 

paediatric research (Enpr-EMA); 

  an EU inventory of paediatric needs; 

  a public database of paediatric studies; and 

  a  requirement  for  companies  to  submit  any  existing  paediatric  studies  on 

authorised medicinal products for scrutiny by regulatory authorities. 

One  of  the  Regulation’s  undisputed  achievements  is  bringing  more  attention  and 
financial  investment  to  paediatric  development.  Companies  were  basically  forced  to 
establish paediatric infrastructure and to build expertise to ensure appropriate paediatric 
research capabilities supporting their product development. 

In  2013,  the  Commission  published  a  first  report  on  the  Regulation’s  impact  and 
concluded  that  there  are  some  promising  signs  of  progress.7  However,  it  found  that, 
because of the length of medicinal products’ development, it will take at least 10 years to 
gain a full understanding of the situation. 

Article  50(3)  of  the  Regulation  requires  the  Commission  to  publish  a  second  report  in 
2017.  The  second  report  should  also  consider  whether  amendments  to  the  Regulation 
should be contemplated. 

3.  MORE MEDICINES FOR CHILDREN 

Figures  show  that  the  Regulation  has  had  a  substantial  impact  on  the  development  of 
paediatric  medicines  in  the  EU.  Pharmaceutical  companies  now  consider  paediatric 
development as an integral part of the overall development of medicinal products, even if 
some  of  them  continue  to  perceive  paediatric  research  as  regulatory-driven  rather  than 
company-driven. 

In 2007-2016 over 260 new medicines for use by children (new marketing authorisations 
and  new  indications)  were  authorised,  most  of  them  linked  to  the  Regulation’s 
requirements.  The  number  of  agreed  paediatric  investigation  plans  (PIPs)  surpassed 
1 000 in 2017, of which 131 were completed at the end of 2016. There is a clear upward 
trend in the number of completed PIPs, with over 60 % finalised in the last three years. In 
addition, competent authorities’ assessments of paediatric studies undertaken before the 

7   Better Medicines for Children – From concept to reality, COM(2013) 443. 

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Regulation  (Article  45)  have  helped  to  consolidate  already  existing  evidence  and  to 
complement product information with paediatric data. 

A  comparison  of  the  situation  before  and  after  the  Regulation  demonstrates  a  clear 
positive effect in terms of new authorised medicines. The same is true for international-
level  comparisons  between  legal  systems  with  paediatric-specific  legislation  and  those 
without:  legal  systems  with  legislative  provisions  in  place  have  a  significantly  higher 
number of new paediatric medicines. 

The  above  quantitative  analysis  shows  clear  progress.  Those  output  figures  are  also  in 
line with expectations taking into account that bringing a medicinal product to the market 
may take up to 10 years, underlining the incremental change the Regulation provides. 

At the same time, issuing a marketing authorisation or adding paediatric information to 
existing  marketing  authorisations  does  not  automatically  translate  into  the  immediate 
availability of the product to all paediatric patients in the EU. This may be due to pending 
reimbursement  decisions  at  national  level  or  prescription  habits,  where  physicians  may 
not  directly switch  to  newly  authorised  products.  In  response  to  a  survey  that  provided 
input to this report,8 the majority of respondents estimated that the increase in available 
medicines  was  in  the  range  of  5-10 %.  On  prescribing  habits,  58 %  of  respondents 
indicated that practitioners are increasingly prescribing approved medicines according to 
their licensed indication for children, as a result of the Regulation. This demonstrates a 
positive  trend,  but  also  underlines  certain  inertia.  The  reduction  of  off-label  use  in 
children  is  finally  not  only  dependent  on  more  authorised  paediatric  medicines,  but  on 
real availability and use at bed-side. 

In  this  context,  it  is  observed  that  companies  often  rely  on  a  staggered  roll-out  of  new 
products with the consequence of delays until the product is finally available throughout 
the  EU.  This  cannot  be  fully  prevented  even  if  the  Regulation  includes  several 
instruments  to  ensure  that,  once  a  PIP  is  completed  and  the  paediatric  medicine  is 
authorised,  the  product  is  placed  on  the  market.  For  example,  the  supplementary 
protection  certificate  reward  under  Article  36  will  only  be  granted  if  the  product  is 
authorised  in  all  Member  States.  Article  33  also  contains  an  obligation  to  place  the 
product on the market within two years of the date on which a new paediatric indication 
is authorised. 

The  timely  availability  of  paediatric  medicines  may  also  be  impacted  by  the  delayed 
completion of the paediatric studies compared to the finalisation and authorisation of the 
corresponding  adult  product.  The  Regulation  includes  provisions  for  deferring  the 
initiation or completion of some or all measures contained in a PIP (Article 20) so as to 
ensure that research is carried out only when safe and ethical. Additionally, it is meant to 
avoid blocking or delaying the authorisation of products for the adult population. 

Experience  shows  that  the  deferral  is  a  widely  used  instrument.  In  practice,  nearly  all 
PIPs for new medicines that are linked to an adult development include a deferral of one 
or  more  measures.  The  deferral  is  in  principle  a  useful  and  appropriate  instrument  and 
there is no evidence that the paediatric requirements have delayed the processing of adult 
applications.  However,  the  Paediatric  Committee  agreed  in  some  cases  to  very  long 
deferrals. This may cause frustration among clinicians and patients, especially if it means 

8   Technopolis study, chapter 5. 

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that  a  promising  paediatric  product  will  only  be  available  years  after  the  adult 
authorisation  comes  through.  Moreover, if  the start  of  a  paediatric  trial  is  delayed until 
after the adult authorisation, experience shows that recruitment of patients in paediatric 
trials  becomes  more  difficult.  Parents  may  fail  to  see  the  added  value  of  agreeing  that 
their child participates in clinical research if the adult product can already be used (off-
label) in  children.  In some cases,  deferrals were also linked to  the late submission  of  a 
PIP.  While  there  is  a  downward  trend  in  late  submissions  (currently  10-20 %),  the 
agreement for deferral in those cases may require closer scrutiny to avoid that those late 
submissions come at the expense of swift progress in paediatric therapies. 

Against this background, the EMA and its Paediatric Committee are currently reviewing 
past  practices  to  ensure  consistency  and  to  avoid  significant  deferrals.  In  view  of 
evolving  science,  it  may  be  argued  that  agreeing  to  long  deferrals  is  tantamount  to 
questioning the significant therapeutic benefit of the product development over existing 
treatments for paediatric patients. In such cases, the added-value of the paediatric studies 
might  be  marginal.  Furthermore,  long  deferrals  may  undermine  the  enforceability  of 
paediatric requirements, and the availability of any reward, especially if the deferral ends 
after the protection periods for the product have expired. 

4.  BETTER MEDICINES FOR CHILDREN 

The last 10 years have seen some considerable progress in the availability of medicines 
for  children  in  certain  therapeutic  fields  because  of  the  Regulation.  Rheumatology  or 
infectious diseases are often referred to as prime examples. The significant surge of new 
treatments for children with rheumatologic diseases following the completion of PIPs has 
transformed a sector, which was previously neglected. 

At  the  same  time,  those  positive  developments  do  not  follow  a  strategic  plan,  but  are 
often  linked  to  developments  in  adult  markets.  As  the  starting  point  for  most  PIPs  is  a 
research  and  development  programme  for  adults,  progress  in  a  paediatric  field  is 
dependent on companies’ adult product pipeline and influenced by revenue prospects in a 
specific  market  segment.  Where  the  adult  needs  or  market  expectations  overlap  with 
paediatric needs, children will benefit directly. However, there are a considerable number 
of diseases that are biologically different in adults and children, where the disease burden 
differs,  or  that  only  exist  in  children.  It  is  in  those  diseases,  where  the  mechanism 
introduced  by  the  Regulation  sometimes  struggles  with  scientific,  clinical  and  market 
realities. 

This  cuts  both  ways.  A  recent  example  where  a  wave  of  new  adult  developments  may 
risk  overloading  the  system  is  type  II  diabetes;  a  disease  that  is  marked  by  its  ever 
growing prevalence among adults since the 1980s. Over the past years, many companies 
concentrated  on  this  therapeutic  area  leading  to  a  peak  in  activities  and  an  evolving 
pipeline of new products. Such waves lead in parallel to an increase in paediatric research 
programmes,  even  if  –  when  seen  from  the  perspective  of  therapeutic  needs  –  having 
fewer of them might have been sufficient, given that type II diabetes is still relatively rare 
in children. The mismatch between disease burden at adult level and in children may also 
lead  to  feasibility  problems  on  conducting  paediatric  trials, as  there  may  be  simply  not 
enough young patients to be enrolled in PIP studies. To overcome such problems it has 
been  suggested  that  companies  should  engage  in  collaborative  research  to  make  better 
use of the limited patient pool. However, companies are hesitant, especially if it concerns 
developments with potential blockbuster status in adults. At the same time, the Paediatric 

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Committee is not in a position to prioritise between PIPs for the same therapeutic area. It 
is  often  a  ‘catch-22’  situation,  as  only  the  results  of  clinical  trials  could  inform  the 
Paediatric Committee in its choice of which compounds may provide the most promising 
results  in  children.  However,  the  intervention  of  the  Paediatric  Committee  and  the 
agreement  of  a  paediatric  investigation  plan  usually  take  place  before  those  results  are 
available,  as  the  purpose  of  a  PIP  is  to  identify  and  agree  the  studies  that  need  to  be 
conducted. 

At  the  other  end  of  the  scale  are  diseases  that  are  unique  to  the  paediatric  population, 
where paediatric development depends typically on the strategic decision of a company 
to invest in this area independently of any on-going adult programme. This is particularly 
true for rare diseases in children, such as paediatric cancer. 

(10 %) 

areas,  with 

(12 %),  oncology 

infectious  diseases 

Reassuringly,  an  analysis  of  the  agreed  PIPs  shows  that  they  cover  a  wide  range  of 
therapeutic 
and 
endocrinology/metabolic diseases (9 %) at the forefront, but no particular area dominates. 
Overall this is a good sign as it demonstrates paediatric activities covering a wide range 
of diseases. However, a high number of agreed PIPs does not automatically mean a high 
number  of  completed  PIPs.  Currently,  the  conditions  with  the  highest  number  of 
completed  PIPs  are  immunology/rheumatology  (14 %),  infectious  diseases  (14 %), 
and 
cardiovascular 
endocrinology/metabolic  diseases  only  corresponding  to  7 %  of  the  completed  PIPs. 
Moreover, the development in terms of agreed and completed PIPs does not necessarily 
correspond with  the paediatric  disease  burden, which underlines the fact  that paediatric 
medicine  development  is  often  driven  by  adult  development.  The  possibilities  of  the 
Regulation  to  steer  activities  towards  certain  therapeutic  areas  are  limited.  It  is  an 
important enabler, but the qualitative impact is still dependent on market forces, drivers 
of growth and strategic considerations of companies. 

10 %),  with 

oncology 

vaccines 

diseases 

(each 

and 

In the discussion on paediatric needs, paediatric oncology is often used as a case study 
for  insufficient  advances  in  an  area  of  high  unmet  paediatric  need.  Although  cancer  in 
children  is  rare,  it  is  still  the  leading  cause  of  death  by  disease  past  infancy  despite 
improved survival rates for some types of cancer in recent decades. 

The  discussion  on  paediatric  oncology  is  often  linked  to  the  waiver  concept  set  out  in 
Article  11  of  the  Regulation,  which  provides  that  the  requirement  for  a  PIP  may  be 
waived  for  specific  products  or  classes  of  products  under  specific  circumstances.  This 
happens if a product is likely to be ineffective or unsafe for children or it does not have a 
significant therapeutic benefit over existing treatments. The obligation is also waived if 
the disease or condition for which the product is intended occurs only in adults. 

The waiver aims to avoid unnecessary or even unethical research and to correctly frame 
the  scope  of  obligations  and  is  considered  as  an  appropriate  instrument.  In  2007-2016, 
EMA granted some class waivers and 486 product-specific waivers for use of a medicine 
in one or more conditions. However, while it is generally appropriate to waive paediatric 
studies,  if  the  target  disease  does  not  exist  in  children,  it  is  not  excluded  that  the 
compound  may  still  be  beneficial  for  children,  albeit  in  a  different  condition.  For 
example, while many paediatric cancers share biological similarities with adult cancers, 
they  occur  in  different  organs  and  are  therefore  usually  considered  as  different 
conditions. Consequently, a company may be entitled to a waiver even if the mechanism 
of  action  of  the  compound  developed  for  adults  and  its  molecular  target  may  also  be 
effective in treating certain paediatric cancers. 

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The last few years has seen a surge of innovative adult cancer drugs entering the market 
with some first-in-class products, creating better treatment options and improved patient 
outcomes  and  longer  survival  rates.  Currently,  cancer  treatments  represent  the  largest 
category of new medicines, also in view of their revenue potential. And it is expected that 
they will continue to transform the therapeutic landscape.9 

Roughly  a  quarter  of  all  medicines  currently  in  late  development  stage  are  cancer 
therapies.  One  indicator  for  the  continued  high  interest  in  cancer  drug  development  is 
also  the  Orphan  Regulation,  where  cancer  therapies  belong  to  the  most  frequently 
designated  orphan  conditions  revealing  a  trend  towards  narrowly  focussed  medicines.10 
However,  this  pace  of  advances  observed  in  adult  therapies  is  so  far  not  mirrored  in 
paediatric patients. In some paediatric cancers, the most used medicines date back to the 
1990s, if they exist at all. 

At  the  same  time,  the  Regulation  has  had  an  impact  and  has  led  to  new  anti-cancer 
products being authorised. Seven developments in PIPs have been completed, providing 
treatment  options  for  high-grade  glioma,  rhabdomyosarcoma,  astrocytoma  and  acute 
lymphoblastic leukaemia. 

The  number  of  agreed  PIPs  for  anti-cancer  medicines  (68)  covering  more  than  30 
different  mechanisms  of  action  are  a  promise  for  further  improvements  in  the  future. 
Some  of  those  PIPs  are  based  on  the  mechanism  of  action  principle,  i.e.  while  the 
company could have potentially relied on a waiver, it committed to paediatric research in 
view of the potential benefit of the compound to treat childhood cancers. 

A  contributing  factor  to  those  commitments  may  have  been  secondary  effects  of  the 
Regulation,  which  by  definition  encouraged  companies  to  strengthen  their  expertise  in 
paediatric drug development. This may have impacted strategic decisions of companies 
in  favour  of  covering  paediatric  needs,  in  particular  through  the  use  of  innovative  trial 
designs,  such  as  basket  trials,  by  which  a  compound  is  tested  against  multiple  cancer 
types  to  inform  an  early  selection  of  the  most  promising  developments.  Moreover,  the 
EU provides targeted funding for cancer research, including through its European Fund 
for Strategic Investments.11 

The above results are mixed, which has led some to advocate for a stronger reliance on 
the mechanism of action principle and legislative changes to the waiver concept in order 
to  force  companies  to  invest  more  in  the  development  of  paediatric  cancer  medicines. 
This  could  however  impact  the  predictability  of  the  scope  of  a  PIP  and  may  lead 
companies to reconsider the overall product development. 

EMA  reviewed  in  2015  its  class  waiver  decision  in  light  of  the  mechanism  of  action 
principle, thereby limiting its scope. This approach may help to engage with companies 
that develop anti-cancer medicines. If those companies still want to rely on a waiver they 
must  justify  it  through  a  direct  application  to  the  Paediatric  Committee  (via  a 

9   QuintilesIMS Institute, Outlook for global medicines through 2021, December 2016. 

10   European Commission, Inventory of Union and Member States incentives to support research into, and 

the development and availability of, orphan medicinal products, SWD(2015)13. 

11   https://ec.europa.eu/commission/news/investment-plan-europe-eib-grants-financing-apeiron-2017-aug-

28_en. 

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product-specific waiver). The process allows direct discussion to highlight the paediatric 
potential,  despite  that  waiver  application.  It  will  also  force  companies  to  contact  the 
committee at an earlier stage in the development to get certainty about the requirements 
under the Regulation. The effects of this class waiver review have yet to be seen as the 
three-year  transitional  period  has  yet  to  lapse,  but  the  approach  may  allow  for  a  better 
buy-in by companies rather than imposed statutory rules. 

In  addition,  it  is  still  not  fully  understood  why  companies  refrain  from  reaping  the 
benefits of the Orphan Regulation for paediatric cancers in a similar way that they do for 
adult cancers. A considerable number of new adult cancer products thrive on the stimulus 
provided  by  the  Orphan  Regulation,  while  this  is  not  matched  for  paediatric  cancers, 
albeit all qualify as rare in the sense of the Orphan Regulation. 

5.  ADVANCING PURE PAEDIATRIC DEVELOPMENTS 

The positive impact of the Regulation and the change in culture that it has stimulated are 
most  visible  in  the  integration  of  paediatric  development  in  the  overall development  of 
new  medicines.  It  is  less  obvious  in  pure  paediatric  developments,  which  are  not  a 
derivative  of  an  adult  project,  but  where  a  company  aims  at  developing  a  child-only 
medicine for a particular paediatric disease. 

The  available  data  does  not  provide  sufficient  evidence  for  any  firm  conclusion.  Some 
argue  though  that  for  child-only  products  the  PIP  process  adds  an  additional  layer  of 
complexity  for  a  product  that  was  destined  to  treat  children,  potentially  prolonging 
developing timelines. While EMA and the Paediatric Committee may still provide useful 
guidance  and  will  ensure  a  development  that  covers  all  relevant  paediatric  subsets,  the 
impact is less significant compared to adult-based developments. That said, at least in the 
initial  years  of  the  Regulation,  companies  may  have  prioritised  paediatric  projects  that 
are  linked  to  an  adult  development  over  paediatric-only  projects  to  ensure  its  timely 
completion. While this could change over time, especially for rare paediatric diseases it 
seems necessary to better understand the combined impact of the Orphan and Paediatric 
Regulation  and  how  they  correlate  to  assess  the  added  value  of  those  statutory 
instruments in paediatric only diseases. 

There  is  one  category  of  paediatric-only  developments  where  the  Regulation  tries  to 
generate specific interest, but has so far failed. It introduced the concept of a paediatric 
use marketing authorisation (PUMA). The main goal of the PUMA concept (Article 30) 
is  to  stimulate  research  in  existing  compounds  that  are  off-patent    and/or  to  help 
transform known off-label use into authorised use that is safer and better framed through 
the marketing authorisation. Once approved, the PUMA provides the manufacturer with a 
ten-year period of marketing protection during which generic copies cannot be placed on 
the market. 

To  date  only  three  PUMAs  have  been  granted.  This  is  clearly  below  expected  levels, 
given  that  ear-marked  EU  funding  from  the  FP7  programme  has  been  provided  for 
several  years  for  off-patent  medicines.  While  EMA  agreed  more  than  20  PIPs  with  a 
view to submitting a PUMA, it remains uncertain how many will ever be completed and 
lead to the commercialisation of a new product. 

In  an  attempt  to  create  additional  interest,  the  Commission  and  EMA  clarified  in  2014 
that a PIP for a PUMA does not have to necessarily cover all age groups, but the impact 

9 

 
 
has so far been limited. While this may allow companies to focus research on the most 
prevalent paediatric subsets, it risks further reducing the target population and potential 
revenues. 

The  PUMA  concept  struggles  with  similar  issues  like  any  scheme  meant  to  encourage 
companies to invest in additional research for known compounds that have been on the 
market  for  a  long  time  (repurposing).  Medicine  developers  fear  that  a  PUMA  will  not 
necessarily prevent physicians from continuing to use competitor products with the same 
active  ingredient  but  authorised  for  other  indications  off-label,  at  lower  costs,  nor 
substitution for cheaper forms at the level of pharmacies. Moreover, national health care 
payers are generally hesitant to agree a premium price for such products. 

Given  the  current  limited  number  of  granted  PUMAs  it  is  neither  possible  to  check 
whether  those  risks  are  substantiated  nor  the  economic  value  of  the  PUMA  reward. 
While  the  available  data  shows  that  the  products  authorised  through  PUMAs  have 
received positive reimbursement decisions in several Member States and represent good 
business  cases,  it  may  simply  be  the  exception  to  the  rule,  partly  supported  by  the 
specificities of the products rather than the PUMA concept alone. 

This  shows  that  the  commercial  success  of  a  PUMA  is  influenced  by  complex  factors 
that can be hardly addressed at EU level. They concern downstream decision-making at 
national  level,  which  is  outside  the  scope  of  EU  law.  Legislative  incentives  cannot 
compensate for economic success. There have been suggestions that a PUMA might be 
effective  where  a  child-specific  formulation  or  dosage  form  is  required,  but  while  this 
hypothesis  is  valid  in  theory,  experience  shows  that  the  PUMA  label  does  not  fully 
exclude physicians continuing to prescribe non-child-adapted products. 

6.  THE COSTS OF PAEDIATRIC MEDICINES 

The Regulation places an additional burden on pharmaceutical companies by asking them 
to  carry  out  paediatric  research,  which  they  might  not  have  undertaken  otherwise.  It 
requires  additional  investment  and  compliance  monitoring.  The  Regulation  however, 
links this obligation with a reward system in order to allow companies to recuperate the 
additional upfront costs incurred as a result of it through prolonged protection periods. In 
this  regard,  the  EU  system  differs  from  the  US  system,  where  paediatric  requirements 
imposed by US Food and Drug Administration (FDA) do not attract a reward, with the 
exception of those where a company voluntarily engages in additional research following 
a corresponding ‘Written Request’ by US FDA. 

The reward becomes available once the PIP is completed and its results are reflected in a 
corresponding marketing authorisation. The company is entitled to the reward even if the 
results of paediatric studies finally fail to support a paediatric use of the compound, as it 
is  meant  to  compensate  for  the  research  as  such,  not  a  particular  outcome.  The 
Regulation  differentiates  between  two  main  rewards,  the  SPC  reward  and  the  orphan 
reward.  They  are  mutually  exclusive  and  serve  different  purposes,  but  have  both  the 
effect of delaying the market entry of competitor products. Hence, the additional revenue 
provided  by  the  rewards  are  finally  covered  by  national  health  care  payers  and/or 
patients, as society does not benefit from increased competition and lower prices for the 
duration of the exclusivity extension. 

10 

 
 
Under  Article  36  of  the  Regulation,  the  company  may  obtain  a  six-month  extension  of 
the duration of the SPC. SPCs are an autonomous sui generis right linked to the existence 
of a basic patent. They compensate a patent holder for the lengthy periods for obtaining 
marketing authorisation during which the patent owner cannot commercially exploit the 
patent.  The  SPC  therefore  provides  a  patent  right-like  position  for  a  variable  duration 
(from zero to a maximum of five years). It is this period that will be prolonged through 
the  SPC  reward  or  that  may  be  turned  positive  if  it  was  previously  negative.12  It  is 
interesting  to  note  that  the  legislature  chose  an  external  reward  system  linked  to  the 
patent status of a product over the pharmaceutical-specific reward system of regulatory 
data protection. 

The  orphan  reward  (Article  37)  consists  of  a  two-year  extension  of  the  orphan  market 
exclusivity  period  i.e.  up  to  12  years.  One  of  the  reasons  for  introducing  an  orphan-
specific reward was that, when the legal proposal for the Regulation was discussed, the 
majority of orphan designated products were off-patent. It was therefore felt appropriate 
to  provide  for  an  alternative  reward  in  order  to  ensure  that  manufacturers  of  orphan 
medicinal products may also have access to compensation. 

The system of the Regulation is built on the assumption that products falling within the 
PIP  requirement  should  be  eligible  for  the  reward,  once  the  paediatric  development  is 
completed. However, in reality not all companies were able to obtain a reward. Figures 
suggest that up to now only 55 % of the completed PIPs benefited from a reward. Most 
of them took the form of a prolongation of the SPC. In a few cases the market exclusivity 
period of an orphan medicinal product was granted. While it is expected that over time 
the proportion of products that benefit from the reward will increase, as companies start 
to plan better and earlier their paediatric research, it is unlikely that the success rate will 
ever reach 100 %. 

6.1.  The supplementary protection certificate reward 

The SPC prolongation is often considered as the most precious reward. Until the end of 
2016 more than 40 medicines benefited from the SPC reward and companies applied for 
respective certificates at national level. The number of SPC prolongations granted in the 
last 10 years (more than 500) shows that companies regularly receive the reward from the 
national patent office to which they apply. This points to a functioning reward system.  

At the same time, the use of an external reward system linked to another legal instrument, 
leads  to  complications  and  inefficiencies.  For  example,  SPCs  are  national  titles,  which 
means that extensions must be obtained from the national patent office in each Member 
State  in  which  an  SPC  exists,  and  thus  considered  by  some  as  an  overly  complex 
procedure.  

Moreover, filing for the SPC extension must happen two years before the expiry of the 
certificate. In some  cases,  this resulted in  companies missing  out  of the reward as  they 
failed to complete the PIP on time. On the other hand, this deadline stimulates companies 
to  speed  up  the  completion  of  paediatric  research  and  ensures  that  generic  competitors 
learn  sufficiently  in  advance  about  any  prolongation  of  the  protection  period  that  may 
impact the market launch of generic copies. 

12   European  Court  of  Justice  in  Case  C-125/10  Merck  Sharp  &  Dohme  v  Deutsches  Patent-  und 

Markenamt, ECLI:EU:C:2011:812. 

11 

 
 
                                                 
The SPC Regulation is currently subject to an evaluation initiated by the Commission to 
assess the usefulness of the instrument.13 Its results and the consequences for the future 
of  the  SPC  system  are  not  yet  known,  but  expected  in  the  coming  months.  Any 
modernisation  or  recalibration  may  address  some  inefficiencies  of  the  SPC  system,  but 
may also have a direct impact on the functioning of the paediatric reward system and thus 
on the Regulation itself. It is therefore important to take the results of that evaluation into 
account in any policy decision about the Regulation. 

The  monetary  value  of  the  SPC  rewards  depends  largely  on  the  overall  revenue  that  a 
particular product brings in during the period in which it is protected by an SPC. Generic 
competition will be delayed for the entire product (including the adult use), securing the 
marketing  authorisation  holder  an  additional  period  of  premium  revenues.  Historically, 
this period corresponds with the peak in sales. However, new market trends may lead to a 
decrease  in  revenue  return  times.  The  market  position  of  a  product  may  be  diminished 
over time by the market entry of new innovative products in the same therapeutic class. 

To  estimate  the  economic  benefit  to  companies  deriving  from  the  reward  it  is  first 
necessary to establish the regulatory costs incurred by companies to comply with a PIP. 
Based on an external study ordered by the Commission14 the total costs of the Regulation 
for  the  whole  industry  is  estimated  to  be  EUR  2.1  billion  per  year.  This  figure  derives 
from an extrapolation based on 85 real PIPs. The total R&D costs on average amount to 
EUR 18.9 million per PIP, with each plan including an average of three clinical studies. 
On  top  of  this,  companies  incur  overhead  costs  of  around  EUR  720 000  in  relation  to 
filing of the initial submission of a PIP and for subsequent modifications. 

While  those  averages  build  on  a  relatively  robust  sample  size,  risks  of  over-  or 
underestimation  cannot  be  fully  excluded.  Moreover,  estimations  based  on  averages 
means  that  there  are  deviations,  especially  on  the  costs  for  clinical  trials  (phase  II  and 
phase  III),  which  account  for  the  largest  portion  of  R&D  costs.15  Nevertheless,  those 
figures  suggest  that  the  additional  costs  borne  by  industry  as  a  consequence  of  the 
Regulation only lead to a limited increase in the total costs of medicine development. 

To compare those costs with the value of the SPC reward eight medicinal products have 
been specifically analysed. This selection includes products that received SPC extensions 
and lost their protection before the end of 2014. The sample size is naturally quite small, 
as  only  a  fraction  of  products  with  completed  PIPs  have  yet  lost  exclusivity  rights  and 
hence, provide data on the impact on such loss on revenues. While the figures for those 
products may need to be interpreted with some caution, given that companies may have 
prioritised  in  the  early  years  products  with  the  highest  estimated  return  of  investment 
resulting  from  the  SPC  prolongation,  they  provide  some  interesting  insight  in  the 
economic value of the reward by comparing the actual revenues with the SPC extension 
with hypothetical revenues without such extension.  

The  data  shows  that  the  price  drop  of  branded  products  often  starts  in  the  first  quarter 
after the loss of exclusivity, but limited in scale (up to 20 %), before decreasing further. 

13   DG  GROW,  Optimising  the  Internal  Market’s  industrial  property  legal  framework  relating  to 

supplementary protection certificates (SPC) and patent research exemptions, 16.2.2017. 

14   Technopolis study, chapter 2. 

15   Technopolis study, chapter 2.2. 

12 

 
 
                                                 
There  are  significant  differences  between  products  and  countries,  most  likely  linked  to 
the  competitiveness  of  the  particular  therapeutic  market  and/or  national  policies  to 
stimulate  generic  substitution,  leading  to  a  high  variation  of  the  economic  value  of  the 
SPC extension as a percentage of the total revenue (between 10 and 93 %). Overall, the 
adjusted economic value of the SPC reward for the eight products concerned amount to 
EUR  926  million,  with  revenues  especially  geared  towards  some  blockbuster  products 
included in the sample size. 

While this figure may be compared with the average R&D costs per PIP (18.9 million), a 
more  granular  approach  may  focus  on  a  product-based  benefit-cost  ratio  of  the  eight 
developments. This means comparing the estimated benefits for society and child health 
resulting  from  the  enforced  paediatric  development  with  the  costs  to  society  from  the 
extra monopoly rent obtained by the company through the reward system. 

Such  comparison  is  exploratory  in  nature,  as  it  has  to  put  a  monetary  value  on  the 
positive impact in terms of improved treatment for children and a reduction of off-label 
use and also the potential of adverse drug reactions. Based on a model developed as part 
of the economic study, two out of the eight products show a strongly favourable benefit-
cost ratio for health systems when calculated over a 10-year period, i.e. the benefits for 
society  and  health  in  monetary  terms  outweigh  the  additional  costs  due  to  the  extra 
monopoly  rent.  All  other  products  have  a  negative  benefit-cost  ratio  over  10  years, 
especially  those  for  which  the  completion  of  the  PIP  did  not  result  in  a  new  paediatric 
indication. While it is still useful to know with certainty that an adult product should not 
be used in children, the economic value of such information is much smaller compared to 
products, which provide new treatment alternatives for paediatric patients. 

Those product-based results may however need to be adjusted with those products, which 
had  to  comply  with  the  PIP  obligation,  but  were  not  able  to  obtain  a  reward  in  the 
relevant  period  (around  45 %).  They  resulted  in  valuable  paediatric  information 
becoming available without society contributing to the incurred costs through additional 
monopoly  rents.  If  those  products  are  parts  of  the  equation,  results  improve  but  the 
benefit-cost ratio is still negative. 

In  addition,  the  Regulation  may  generate  economic  spill-over  effects  due  to  additional 
R&D  investment  towards  new  and improved  medicines that  triggers  further  investment 
and contributes to the creation of jobs, growth and innovative activity across sectors. A 
more conservative estimated rate of return from an annual EUR 2.1 billion investment in 
paediatric  R&D  could  after  10  years,  yield  a  total  societal  return  of  around  EUR  6 
billion.16 This estimated societal return is significantly higher than the economic value of 
the SPC extension, suggesting that in monetary terms, the benefits of the Regulation for 
society outweigh the costs of the additional monopoly rent. 

6.2.  The orphan reward 

So  far  seven  products  obtained  the  orphan  reward  of  two  additional  years  of  market 
exclusivity,  with  the  first  product  in  2014.  However,  in  some  instances  companies 
voluntarily waived  the orphan designation in  order to  make  the product eligible for the 
SPC reward. This may be explained by the fact that the SPC reward protects the entire 
product family of a specific compound across different therapeutic indications, while the 

16   Technopolis study, chapter 6. 

13 

 
 
                                                 
orphan reward is limited to protecting the orphan use. Therefore, where medicines have 
both common and rare conditions, revenues from a 6 month SPC prolongation might be 
higher than from an additional two years market exclusivity in the orphan condition. 

A  contributing  factor  may  be that more  and  more  of  newly  authorised  orphan  products 
are on-patent (currently more than 90 %), which is a positive news, as it shows that the 
system  provided  by  the  Orphan  Regulation  attracts  innovative  products  based  on  new 
research.  On  the  other  hand,  it  points  to  a  weakness  of  the  orphan  reward,  which  is 
mainly  geared  towards  off-patent  products  and  has  no  built-in  flexibility  to  allow 
companies to keep the orphan status of the product, while opting for the SPC reward. 

At this stage and without further studies, it is not possible to estimate the economic value 
of the orphan reward, based on a similar sample size as for the SPC reward, given that 
most of the products are still under protection. Therefore, it is not possible to analyse the 
actual impact of the loss of exclusivity on revenues. There is for example no guarantee 
that generics will enter the market in the same speed as for non-orphan products or at all 
in  view  of  the  rarity  of  the  disease  and  the  limited  size  of  the  relevant  market. 
Nevertheless, a similar economic model might be used for estimating the economic value 
as the approach used for the calculation of the SPC reward, with the main difference that 
the delay is two years instead of six months. 

7. 

IMPROVED IMPLEMENTATION 

The  Regulation  gives  EMA  and  its  Paediatric  Committee  primary  responsibility  for 
handling PIPs, deferrals and waivers. Hence, EMA plays a key role in the Regulation’s 
implementation. Efforts have been made to learn from the first years of implementation 
and  to  simplify  PIP  opinions  to  reduce  the  need  for  modification  if  there  are  non-
significant changes to the programme. These efforts have helped to decrease the overall 
ratio of changes, even if the figures show that on average a PIP has been modified at least 
once.  The  most  common  causes  are  on  the  timelines  (43 %)  or  the  number  of  children 
enrolled in a study (14 %). 

Additionally, the revision of the Commission’s guidelines on the format and content of 
paediatric investigation plans in 201417 introduced measures to streamline the process of 
agreeing  the  plans.  Moreover,  in  2015  EMA  piloted  early  interaction  meetings  with 
companies to enable the integration of paediatric needs in the early phases of medicine 
development.  Based  on  this  experience  the  concept  of  engagement  in  project-focused 
development  discussion  is  currently  being  revisited  to  enable  discussion  on  the 
appropriate  timing,  and  integration  of  paediatric  measures  in  the  context  of  the  overall 
development. 

Ensuring product discussion and knowledge exchange across the various committees and 
working  parties  within  their  respective  remits  is  an  essential  part  of  the  EMA’s 
coordination  function.  In  the  area  of  paediatric  development,  this  particularly  concerns 
the engagement of the Paediatric Committee with other scientific committees or advisory 
working  parties.  Continuous  improvement  activities  are  ongoing  to  enable  such 
collaboration.  

17   Guideline  on  the  format  and  content  of  applications  for  agreement  or  modification  of  a  paediatric 

investigation plan, OJ C 338, 27.9.2014, p. 1. 

14 

 
 
                                                 
To  increase  cooperation  across  regions,  a  discussion  forum  to  regularly  exchange 
information  mainly  via  teleconferences  (‘paediatric  cluster’)  was  formed  in  2007, 
including members of the US FDA and EMA. The cluster has since been joined by the 
Pharmaceuticals  and  Medical  Devices  Agency  (PMDA)  Japan,  Health  Canada,  and  the 
Australian Therapeutic Goods Administration (TGA) as an observer. In 2013 EMA and 
launched  so-called  ‘common  commentaries’  on  paediatric 
its  US  counterpart 
development  plans  that  have  been  submitted  to  both  the  EMA  and  FDA  and  that  are 
therefore  being  reviewed  by  both  agencies.  While  informal  and  non-binding,  these 
commentaries and discussions between the two agencies have helped to align views and 
to avoid contradictory requirements on the paediatric development programme. 

However,  it  remains  a  challenge  for  EMA  and  its  Paediatric  Committee,  as  well  as  for 
companies, to consider key aspects of medicine development when certain information is 
not yet known and when discussions are still based on assumptions and scarce data. This 
is  true  especially  as  one  of  the  objectives  of  paediatric  development  plans  is  to  create 
legal  certainty  on  regulatory  authorities’  expectations  towards  companies.  On  the  other 
hand, only early planning makes it possible for paediatric development to be seamlessly 
integrated into overall product development instead of being an afterthought. In principle, 
it  should  also  lead  to  more  (cost-)efficient  R&D,  as  it  allows  for  example  to  consider 
integrating paediatric patients (e.g. adolescents) in adult trials and into early formulation 
development planning, therefore reducing overall development costs. 

8.  MORE CLINICAL TRIALS WITH CHILDREN 

The  Regulation  aims  to  ensure  that  evidence  of  the  quality,  safety  and  efficacy  of 
medicinal products is generated before a product is used by children. This means more 
clinical research carried out in children prior to the authorisation of medicines. Available 
figures show a notable increase. The proportion of clinical trials in the European clinical 
trial database EudraCT that  include children has increased by 50 %  in  2007-2016 from 
8.25 % 
research  with  previously  neglected  paediatric 
subpopulations  has  risen  considerably.  Prior  to  the  Regulation  research  with  neonates 
was almost non-existent in medicine development. 

to  12.4 %.  Moreover, 

Generally speaking, EU legislation is well equipped to ensure that paediatric research is 
scientifically valid and ethically sound. These aspects are considered not only by EMA’s 
Paediatric  Committee  in  its  assessment  of  PIPs,  but  also  by  national  ethics  committees 
and regulatory authorities that are responsible for authorising individual clinical trials. 

The  Regulation  has  fostered  expert  discussion  about  the  optimal  design  of  paediatric 
trials.  This  includes  initiatives  related  to  the  exchange  of  good  practices,  and 
development of new scientific guidelines. A contributing factor has been the creation of a 
network  of  research  networks  at  the  EMA  (Enpr-EMA),18  which  due  to  its  successful 
work  now  expanded  beyond  Europe,  with  the  registration  of  American,  Canadian  and 
Japanese national and multi-speciality networks. 

The further development of innovative trial concepts as well as modelling and simulation 
strategies  to  reduce  the  number  of  necessary  study  participants,  were  also  stimulated. 
Additionally, the Regulation brought attention to the debate about the role that children 

18   European Network of Paediatric Research at the European Medicines Agency. 

15 

 
 
                                                 
should  play  in  research  decisions.  Initiatives  range  from  the  creation  of  young  people 
advisory  groups  to  discussion  of  appropriate  information  about  clinical  studies  for 
patients and parents, to practical issues, such as consent forms. 

Still  paediatric  trials  pose  particular  challenges.  For  example,  recruitment  difficulties 
frequently lead to delays in conducting and completing them. Paediatric trials also tend to 
be  multi-centre  trials,  sometimes  with  just  a  few  patients  per  site,  which  can  create 
operational challenges, including with maintaining the necessary staff and expertise on-
site.  To  support  paediatric  clinical  trial  infrastructure  further,  the  EU-financed  private-
public  partnership  the  ’innovative  medicines  initiative’  launched  at  the  end  of  2016  a 
project to create a sustainable Pan-European paediatric clinical trial network.19 

Moreover,  with  its  recent  initiative  to  establish  European  Reference  Networks,20  the 
Commission  supports  virtual  networks  involving  healthcare  providers  across  Europe  to 
tackle complex or rare diseases and conditions that require highly specialised treatment 
and a concentration of knowledge and resources. Some of the thematic networks included 
in the project focus specifically on rare paediatric diseases. They will foster cooperation 
and pave the way for additional clinical research which might previously not have been 
feasible. 

Overall,  the  Regulation  has  boosted  paediatric  research.  It  is  however,  recognised  that 
such research is geared towards product development. For some diseases or therapeutic 
areas,  a  good  understanding  of  the  underlying  disease  is  still  lacking.  Additional  basic 
research on the diseases themselves would therefore be beneficial to enable and inform 
appropriate product development. This cannot be guaranteed through the Regulation, but 
requires additional efforts and funding from public and private sources. 

9.  FUTURE CHALLENGES 

The  way  pharmaceuticals  are  developed  may  change  over  time  due  to  scientific 
advances,  technological  developments  and  changing  business  models.  Recent  trends 
include the stratified development of medicines or the concept of personalised medicine, 
which  aims  to  optimise  the  use  of  medicines  by  targeting  them  to  patients’  individual 
genes to  ensure that  they will be truly responsive to  treatments. They may also see the 
increased  market  entry  of  technology  firms  to  support  therapies  through  technology 
enabled patient support and services. 

While  most  of  these  new  development  paradigms  seem  perfectly  compatible  with  the 
mechanism introduced by the Regulation, they may influence the way companies decide 
on  investment  priorities  and  design  clinical  trials.  In  the  short  term  those  trends  are 
unlikely to affect the Regulation as the number of new medicines in late stage pipeline is 
historically large, with an expected 45 new active substance forecast to be launched per 
year  until  2021.  However, the  PIP process  needs  to  provide  the  necessary  flexibility  to 
accommodate  those  trends,  while  at  the  same  time  ensuring  that  children  fully  benefit 
from those emerging concepts such as personalised medicine. 

19   https://www.imi.europa.eu/. 

20   Created  under  Article  12  of  Directive  2011/24/EU  on  the  application  of  cross  border  healthcare, 

https://ec.europa.eu/health/cross_border_care/policy_en. 

16 

 
 
                                                 
On a more granular level, it also needs to be taken into account that the implementation 
of  the  Regulation  presupposes  a  significant  investment  of  resources  not  only  from 
EMA,21  but  also  by  Member  States,  by  appointing  members  to  the  PDCO  and 
contributing  to  the  assessment  of  paediatric  investigation  plans  or  historical  or  new 
paediatric trial results submitted by companies. The Regulation states that applicants can 
avail  of  these  procedures  without  incurring  any  fees,  which  is  part  of  the  incentives  to 
enable paediatric development. While there is no evidence that the absence of fees had so 
far a negative impact on the quality of the assessment, the long-term impact on the proper 
functioning  of  the  system  is  yet  unknown.  In  its  ongoing  evaluation  of  the  EMA  fee 
system the Commission will also verify the costs of assessing PIPs. 

10.  CONCLUSION 

The  Paediatric  Regulation  had  a  considerable  impact  on  the  development  of  paediatric 
medicines in the EU. It ensured that paediatric medicine development became an integral 
part of the overall development of medicines. This result would have not been achieved 
without specific legislation and underlines its continued relevance. Moreover, measures 
taken to improve its implementation have over time strengthened its effectiveness. 

terms, 

the  Regulation  provides  overall  positive  results  from  a 
In  economic 
socioeconomic perspective demonstrating the appropriateness of this direct investment in 
improving  the  availability  of  paediatric  medicines.  The  combination  of  obligations  and 
rewards seems effective to shift focus to paediatric product development. Still the use of 
rewards  was  limited  to  55 %  of  the  completed  PIPs  and  there  are  instances  of  over-  or 
under  compensation  pointing  to  certain  limitations  of  the  current  system.  Additionally, 
the PUMA concept with its specific reward has failed to deliver. 

The  increase  in  paediatric  research  and  the  number  of  new  products  with  specific 
paediatric indications is encouraging and will ensure that over time the off-label use of 
adult  medicines  in  the  paediatric  population  will  decrease.  Those  positive  results  do 
however  not  evenly  spread  among  all  therapeutic  areas,  but  concentrate  in  some,  often 
linked to research priorities in adults rather than children. 

This  shows  that  the  Regulation  works  best  in  areas  where  the  needs  of  adult  and 
paediatric patients overlap. Especially, in diseases that are rare and/or unique to children 
and  which  in  many  cases  are  equally  supported  through  the  orphan  legislation,  major 
therapeutic  advances  often  failed  to  materialise  yet.  Why  this  is  the  case  and  why  the 
orphan reward is in some instances not able to drive paediatric development in a similar 
way than adult orphan development requires further scrutiny. 

Therefore  and  before  proposing  any  amendments,  the  Commission  intends  to  take  a 
closer  look  at  the  combined  effects  of  the  Orphan  and  Paediatric  Regulation  through  a 
joined  evaluation  of  those  two  legal  instruments  aimed  at  supporting  medicine 
development  in  subpopulations  of  particular  need.  Given  that  weaknesses  identified  in 
this report often relate to paediatric diseases that qualify as orphan condition, only such 
combined effort will guarantee to adjust the right parameters, if required. 

21   In  line  with  Article  48  of  the  Regulation  the  EU  budget  contribution  paid  to  EMA  supports  the 

operation of its paediatric activities. 

17 

 
 
                                                 
This report marks not the end, but an essential intermediate step in the debate on a joint 
vision  about  the  future  parameters  for  paediatric  and  orphan  medicines.  The  further 
evaluation supporting this process aims at providing results by 2019 so to allow the next 
Commission  to  take  informed decision  about possible policy options. It will also allow 
the forthcoming results of the SPC evaluation for the future of the Paediatric Regulation 
to be taken into account. 

In the meantime, the Commission is committed to a positive agenda of concrete actions 
in  order  to  streamline  the  current  application  and  implementation  together  with  EMA22 
wherever needed. This includes: 

  providing  additional  transparency  of  new  products  authorised  with  paediatric 

indications; 

  analysing the experience with use of deferrals and consider changes in practice to 

 

ensure speedier completion of PIPs; 
revisiting processes and expectations in the context of handling of applications for 
PIPs and if necessary adapt the corresponding Commission guideline; 

  exploring  opportunities  to  discuss  paediatric  needs  in  an  open  and  transparent 
dialogue involving all relevant stakeholders like academia, health care providers, 
patients/care givers, paediatric clinical trial networks, industry and regulators; 
  delivering  regular  updates  about  development  and  trends  of  the  paediatric 

medicines landscape in the EU; and 
fostering international cooperation and harmonisation. 

 

Additionally,  it  will  further  support  high-quality  healthcare  and  research  for  children 
through  projects  such  as  the  European  Reference  Networks,  which  connect  health  care 
providers  and  centres  of  expertise.  Those  networks  have  the  potential  of  significantly 
improving access to diagnosis and treatment in the short term and to make a difference in 
terms of child health. 

22   In this context business continuity priorities may need to be taken into account due to the relocation of 

EMA. 

18