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 and concerning the operation of the compliance check and on criteria for assessing significant studies
Date: 2008-09-24
Institutions: European Commission
Subjects: drug surveillance, exchange of information, market approval, medical research, medicinal product, paediatrics, pharmaceutical legislation, testing

24.9.2008

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Official Journal of the European Union

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II

(Information)

INFORMATION FROM EUROPEAN UNION INSTITUTIONS AND BODIES

COMMISSION

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
and concerning the operation of the compliance check and on criteria for assessing significant
studies

(2008/C 243/01)

1. INTRODUCTION

Regulation (EC) No 1901/2006 of the European Parliament and
of the Council on medicinal products for paediatric use and
amending Regulation (EEC) No 1768/92, Directive 2001/20/EC,
Directive 2001/83/EC and Regulation (EC) No 726/2004 (1)
(hereinafter ‘the paediatric regulation’) entered into force on
26 January 2007. The paediatric regulation aims to facilitate the
development and accessibility of medicinal products for use in
the paediatric population, to ensure that medicinal products
used to treat the paediatric population are subject to research of
high quality and are appropriately authorised for use in the
paediatric population, and to improve the information available
on the use of medicinal products in the various paediatric popu-
lations. These objectives should be achieved without subjecting
the paediatric population to unnecessary clinical
trials and
without delaying the authorisation of medicinal products for
other age populations.

industry for

these objectives the paediatric regulation creates a
To meet
number of requirements on the pharmaceutical
industry for
when medicinal products are developed and creates rewards for
the pharmaceutical
fully complying with the
requirements for studies in children. The paediatric regulation
creates a new type of marketing authorisation, the paediatric use
marketing authorisation (PUMA) as an incentive for the develop-
ment of off-patent medicines for children. The paediatric regu-
lation also creates a framework to manage the operation of the
paediatric regulation including the paediatric committee within
the European Medicines Agency (hereinafter ‘the Agency’).

Pursuant to Article 10 of the paediatric regulation, this guideline
provides the detailed arrangements concerning the format and

(1) OJ L 378, 27.12.2006, p. 1.

content of applications for agreement or modification of a
paediatric investigation plan and requests for waivers and defer-
rals. The guideline also lays down the arrangements for the
operation of the compliance check referred to in Articles 23
and 28(3) of the paediatric regulation (2). Finally, pursuant to
Article 45(4) of the paediatric regulation the guideline provides
the assessment criteria for the significance of studies started
before and completed after the entry into force of the paediatric
regulation (3).

Definitions relevant to this guideline are provided in Direc-
tive 2001/83/EC, Directive 2001/20/EC, Regulation (EC)
No 141/2000 as well as the paediatric regulation. In addition,
the following terms and definitions are used in this guideline.

(a) condition: any deviation(s) from the normal structure or
function of the body, as manifested by a characteristic set of
signs and symptoms (typically a recognised distinct disease
or a syndrome);

(b) paediatric investigation plan indication:

the proposed
indication(s) in the paediatric population for the purpose of
a paediatric investigation plan, and at the time of paediatric
the
investigation plan submission.
medicinal product is intended for diagnosis, prevention or
treatment of a condition;

should specify if

It

(2) Article 10 of the paediatric regulation states: ‘In consultation with the
Member States, the Agency and other interested parties, the Commis-
sion shall draw up the detailed arrangements concerning the format
and content which applications for agreement or modification of a
paediatric investigation plan and requests for waivers or deferrals must
follow in order to be considered valid and concerning the operation of
the compliance check referred to in Articles 23 and 28(3)’.

(3) Article 45(4) of the paediatric regulation states: ‘In consultation with
the Agency, the Commission shall draw up guidelines to establish
assessment criteria for the significance of studies for the purposes of
applying paragraph 3’.

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(c) proposed therapeutic indication: the therapeutic indica-
tion in adults and/or paediatric populations as proposed in
the paediatric investigation plan at the time of submission
of a paediatric investigation plan;

(d) granted therapeutic indication: the therapeutic indication
in adults and/or paediatric populations that is included in
the marketing authorisation. This will be the result of the
assessment of the quality, safety and efficacy data submitted
with the marketing authorisation application;

(e) measures: as used in Article 15(2) of the paediatric regu-
lation includes studies, trials, data and pharmaceutical devel-
opment proposed to generate new scientific information
aiming at ensuring that the necessary data are generated
determining the conditions in which a medicinal product
the paediatric population
may be authorised to treat
including the development of age appropriate formulation
in all subsets of the paediatric population affected by the
condition, as specified in a paediatric investigation plan.

2. SECTION 1: FORMAT AND CONTENT OF APPLICATIONS
FOR AGREEMENT OR MODIFICATION OF A PAEDIATRIC
INVESTIGATION PLAN AND REQUESTS FOR WAIVERS AND
DEFERRALS

2.1. General principles and format

It is acknowledged that the amount of information available
relevant
to applications for agreement or modification of a
paediatric investigation plan and requests for waivers and defer-
rals will differ substantially depending on whether a medicinal
product
is in early clinical development or already has a
marketing authorisation and is being investigated for new or
extended uses. Because the same format for applications for
paediatric investigation plans, waivers and deferrals should be
it will not
used whatever the stage of product development,
always be possible to provide comprehensive information in
some Sections of the application. In this situation an absence of
data or information should be indicated in the relevant Section.
However, when available, all information relevant to the evalua-
tion of the paediatric investigation plan, as well as requests for
deferrals or waivers should be included in the application
whether
favourable or unfavourable to the product. This
includes details of any incomplete or discontinued pharmaco-
toxicological
relating to the
medicinal product, and/or completed trials concerning indica-
tions not covered by the application.

test or clinical study or

trial

The same application format should be used whether requesting
agreement to a paediatric investigation plan, a waiver, a deferral
or a combination thereof. Different parts of the application are
provided to fulfil the different types of request, as follows:

— Part A: Administrative and product information,

— Part B: Overall development of

the medicinal product

including information on the conditions,

— Part C: Applications for product specific waivers,

— Part E: Applications for deferrals,

— Part F: Annexes.

Because the same application format is used some Sections of
the application will not be applicable to specific types of appli-
cation.

One single application should cover all subsets of the paediatric
population as required by Article 7(2) of the paediatric regu-
lation with either a waiver or a paediatric investigation plan
(with or without a deferral). Applications for products falling
within the scope of Article 8 of the paediatric regulation should
cover
the existing and the new indications, pharmaceutical
forms and routes of administration. In this case one comprehen-
sive paediatric investigation plan should be included in the
application. Similarly, when it is intended to develop several
indications simultaneously, only one comprehensive paediatric
investigation plan should be included in the application.

The paediatric population is defined in Article 2 of the paedia-
tric regulation as ‘that part of the population aged between
birth and 18 years’. This is understood to mean up to but not
including 18 years. The paediatric population encompasses
several subsets defined for example in international guide-
lines (1): the pre term and term neonate from 0 to 27 days, the
infant from 1 month to 23 months, the child from 2 years to
11 years and the adolescent from 12 up to 18 years. However,
when it is considered to be more appropriate, to use different
subsets this may be acceptable but the choice of subsets should
be explained and justified.

When drafting paediatric investigation plans for paediatric use
marketing authorisations,
those drafting are encouraged to
consider whether there may be a therapeutic need for the
medicinal product in each paediatric subset.

submission of applications

To facilitate the practical
European Medicines Agency (EMEA) has made
online forms
(available
trics/pips.htm).

the
available
this guideline
at: http://www.emea.europa.eu/htms/human/paedia-

follow the structure of

that

2.2. Part A: Administrative and product information

It is acknowledged that at an early stage of product development
it may not be possible to provide comprehensive answers to all
Sections of Part A of the application. However, all Sections of
Part A should be completed and where information is not avail-
able, this should be stated.

2.2.1. A.1: Name or corporate name and address of the applicant

and contact person

The name and address of the applicant for the Paediatric Investi-
gation Plan, Waiver or Deferral should be provided. The appli-
cant may be any legal or natural person or a company estab-
lished within the European Economic Area. The person
authorised to communicate with the Agency on behalf of the
applicant during the procedure, and after the Agency decision, if
different, should be provided.

— Part D: Paediatric investigation plan,

(1) ICH Guideline E11 available at: www.ich.org

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In view of the fact that Agency decisions will be made public,
the applicant is encouraged to provide a contact point (tele-
phone/fax/e-mail) for enquiries from interested parties that the
Agency will then make public with the decisions.

2. Article 8 of the paediatric regulation, a medicinal product
authorised in the Community (EEA) and covered by a supple-
mentary protection certificate or a patent which qualifies for
the grating of the supplementary protection certificate; or

It should be stated whether or not the applicant qualifies under
Commission Regulation (EC) No 2049/2005 (1) as a micro,
small or medium sized enterprise.

3. Article 30 of the paediatric regulation, a product being devel-

oped for a paediatric use marketing authorisation.

2.2.2. A.2: Name of the active substance

INN should be provided.

The active substance should be stated by its recommended Inter-
national Non-proprietary Name (INN), accompanied by its salt
or hydrate form if relevant. If the ‘recommended’ INN is not yet
If no INN
available the ‘proposed’
exists, the European Pharmacopoeia name should be used or if
the substance is not in the European pharmacopoeia, the usual
common name should be used. In the absence of a common
name,
scientific designation should be given.
Substances not having an exact scientific designation should be
described by a statement of how and from what they were
prepared, supplemented where appropriate by any relevant
details. A company or laboratory code cannot be used as the
sole identifier of the active substance.

exact

the

Considering the timing for submission of applications, only
preliminary names of the active substance might be provided. In
this situation and in the event that the application is resub-
mitted (e.g. for modification of a paediatric investigation plan) it
is suggested to record all successive name changes in the docu-
ment.

2.2.3. A.3: Type of product

group

and Anatomical

In addition, where possible t

(ATC) code have been assigned,

The type of product for which the application is for (e.g. a
chemical entity, a biological product, a vaccine, a gene therapy
product, somatic cell therapy medicinal product etc) should be
specified.
the pharmacological
target and mechanism of action should be specified. Where a
Therapeutic
pharmacotherapeutic
Chemical
these should be
included. For products not yet authorised in the Community or,
for authorised products where a new indication is proposed for
development, the condition(s), whether in adults or children,
that the medicinal product is intended to diagnose, prevent or
treat, as envisaged at the time of submission, should be stated,
following an agreed classification system, such as the World
Health Organisation International Classification of Diseases
(ICD-10).

all

on

paediatric

regulation

information

For medicinal products that will be caught by Article 7 or 8 of
the
different
formulations under development irrespective of future use in
the paediatric population should be provided. In addition, for
applications relating to products that will be caught by Article 8,
pharmaceutical
authorised
information
on
form/route(s) of
in
administration should
Section A.6. For products being developed for paediatric
use marketing authorisations information on the proposed
strength(s), pharmaceutical form(s), and route(s) of administra-
tion should be provided.

be provided

strength(s),

2.2.5. A.5: Regulatory information on clinical trials related to the

condition and to the development in the paediatric population

In this Section regulatory information on clinical trials related
to the condition and to the development in the paediatric popu-
lation should be provided in a tabular format. For clinical trials
conducted inside the EEA, please provide a table of clinical trials
relevant to the condition in children, and in adults if relevant to
the development in the paediatric population. For clinical trials
conducted outside the EEA, please provide a table of clinical
trials performed in children only and relevant to the condition.

The information provided, whether relating to studies conducted
in the EEA or outside the EEA should include a statement on
whether each clinical trial was conducted according to Good
Clinical Practice (GCP).

2.2.6. A.6: Marketing authorisation status of the medicinal product

Information of
medicinal product should be provided in a tabular format.

the marketing authorisation status of

the

For medicinal products not yet authorised which will subse-
the
quently be caught by the requirements of Article 7 of
paediatric regulation, the marketing authorisation status outside
the EEA should be provided.

2.2.4. A.4: Details of the medicinal product

The precise information to be provided will depend on whether
the application relates to:

1. Article 7 of the paediatric regulation, a medicinal product

not yet authorised in the Community (EEA);

(1) OJ L 329, 16.12.2005, p. 4.

For medicinal products on the market and covered by a supple-
mentary protection certificate or a patent which qualifies for the
grating of the supplementary protection certificate, which will
subsequently be caught by Article 8 of the paediatric regulation,
in the EEA should be
the marketing authorisation status
provided and regarding authorisation status outside the EEA
only information on authorisations
in children should be
included.

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For products being developed for paediatric use marketing
authorisations information should be provided on authorised
medicinal products in the EEA containing the same active
substance.

Details of any regulatory action to restrict for safety reasons the
use of
the medicinal product outside the EEA should be
provided. This will include any product withdrawal, restriction
of indication or new contraindication for the medicinal product.

2.2.7. A.7: Advice from any regulatory authority relevant

to the

development in the paediatric population

The paediatric committee should be provided with any deci-
sions, opinions or advice (including scientific advice) given by
competent authorities, including those of third countries, on the
paediatric development of the medicinal product. This should
include any written request for paediatric information issues by
a regulatory body. A copy of any relevant documents should be
included in Part A.10 of the application.

2.2.8. A.8: Orphan drug status in the EEA

It should be clear whether the medicinal product has been
designated an orphan medicinal product by the European
Commission's decision. For orphan designated products the
number
in the Community Register of Orphan Medicinal
If orphan designation is being
Products should be provided.
sought this should be indicated and for pending applications the
EMEA Orphan Designation Procedure Number
should be
provided.

2.2.9. A.9: Planned application for marketing authorisation/line

extensions/variation

The planned submission date for the marketing authorisation or
variation application,
should be provided
as appropriate,
together with an indication of whether the application can be
expected via the centralised or mutual recognition/decentralised
route. For medicinal products not yet authorised which will
subsequently be caught by the requirements of Article 7 of the
paediatric regulation, the date of completion of adult pharmaco-
kinetic studies should be provided.

2.2.10. A.10: Annexed documentation where appropriate

The following documents, if available, should be annexed in this
Section:

— a letter of authorisation for

the person authorised to

communicate on behalf of the Applicant,

— a copy of any Scientific Advice given by the EMEA

Committee on Human Medicinal products (CHMP),

— a copy of any Scientific Advice given by any EEA National

competent authorities,

— a copy of United States Food and Drug Administration
(FDA) written request and/or of any advice/opinion/decision

relating to paediatric information given by a regulatory
agency outside the EEA,

— a copy of any Commission Decision on Orphan Designa-

tion,

— a copy of any previous EMEA decision on a Paediatric Inves-
the paediatric

tigation Plans or a negative opinion of
committee on such plans,

— a copy of a representative Summary of Product Characteris-

tics recently granted in the EEA.

2.2.11. A.11: Table of translations of the EMEA decision

If the EMEA Decision is requested in an official EU language
other than English then the name of the active substance, the
condition, the pharmaceutical form and route of administration
should be provided in that language.

2.3. Part B: Overall development of the medicinal product

including information on the conditions

For medicinal products being developed for applications that
will fall under the requirements of Articles 7 and 8 of the
paediatric regulation Part B should list for each indication and
each subset of the paediatric population, how the requirements
of Articles 7 and 8 will be met. This part should also include
details on the diseases/conditions in the paediatric population
including their similarity between adult and paediatric popula-
tions and within the different paediatric subsets, prevalence,
incidence, diagnosis and treatment methods, and alternative
treatments.

Where the medicinal product is developed for use in children
only some of the information requested in Part B may not be
available and this should be clearly indicated.

2.3.1. B.1: Discussion on similarities

and

differences

of

the

disease/condition between populations

For each disease or condition already the subject of an
authorised indication, as well as for each disease or condition
which is the subject of new development (i.e. for new medicinal
products or new indications for authorised medicinal products)
the application should state whether they occur in the paediatric
population. A description of the diseases or conditions should
be provided, with a view to discuss any potential differences or
similarities:

— between the adult and the paediatric populations,

— between the different paediatric subsets.

Emphasis should put on the seriousness of the disease, aetiology,
epidemiology, clinical manifestations and prognosis, and patho-
physiology in the paediatric subsets. This may be based on
published references, or textbooks.

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Information on the earliest age of onset of the diseases/condi-
tions or the age range concerned should be provided, as well as,
if possible, incidence and/or prevalence in the Community, espe-
cially if it is intended to apply for a product specific waiver
covering specific paediatric subsets. This information can be
based on published references if available.

A brief description of
the pharmacological properties and
mechanism of action should be provided. Any anticipated differ-
ences and similarities of the safety and efficacy profile (known
or expected) of the product should be described focussing on a
comparison:

— between the adult and the paediatric population,

— between the different paediatric subsets.

2.3.2. B.2: Current methods of diagnosis, prevention or treatment in

paediatric populations

For each disease or condition already authorised, as well as for
each disease or condition which is the subject of new develop-
ment (i.e. for new medicinal products or new indications for
authorised medicinal products) the diagnosis, prevention and
treatment interventions available in the Community should be
identified, making reference to scientific and medical literature
or other relevant information. This should include unauthorised
treatment methods if they represent the standard of care, for
if they are mentioned in internationally recognised
example,
treatment guidelines. This should be presented in tabulated
format for ease of reference.

Of the available treatments identified, in the case of authorised
medicinal products, when the information is accessible the list
should include those authorised by the national authorities in at
least one Member State and those authorised in the framework
of centralised procedure in accordance with Regulation (EC)
No 726/2004. This can be presented as an overview table. In
order that the paediatric committee has an overview over the
existing diagnosis, prevention or treatment of the condition, as
far as possible, other methods of diagnosis, prevention or treat-
ment for the disease or condition in question, such as surgical
interventions, radiological techniques, diet and physical means
used in the Community, should be indicated. In this context, for
medical devices the invented name(s) and the approved use(s)
should be provided. For medical devices which fall within the
scope of Directive 93/42/EEC, the list should include all devices
placed on the market according to this Directive, and in the case
of active implantable devices which fall within the scope of
Directive 90/385/EEC, those placed on the market or put into
service in accordance with this Directive.

If methods for diagnosis, prevention or treatment of the condi-
tion in question have been included in the inventory of thera-
peutic needs established pursuant to Article 43 of the paediatric
regulation then this information should be highlighted.

2.3.3. B.3: Significant
therapeutic need

therapeutic benefit and/or

fulfilment of

On the basis of Article 6(2) (1), 11(1)(c) (2) and 17(1) (3) of the
paediatric regulation, whether the use of the medicinal product
either through use as an authorised product or through the
conduct of clinical trials in children is expected to be of signifi-
cant therapeutic benefit to children and/or fulfil a therapeutic
need in children will be assessed by the paediatric committee
and this assessment will be pivotal in determining whether a
paediatric investigation plan receives a positive opinion or
whether a waiver is granted.

should

application

To enable the paediatric committee to make its assessment
the
include
the
medicinal product which is the subject of the application with
the current methods of diagnosis, prevention or treatment of
the diseases/conditions that are the subject of the intended indi-
cations in children, referred to in Section B.2.

comparison

of

a

When considering significant therapeutic benefit the paediatric
committee will take into account the nature of the condition to
be treated (diagnosed or prevented) and the available data on
the medicinal product concerned.

On this basis, significant therapeutic benefit could be based on
one or more of the following:

(a) reasonable expectation for safety and efficacy for a marketed
or new medication to treat a paediatric condition where no
authorised paediatric medicinal product is on the market;

(b) expected improved efficacy in a paediatric population
compared to the current standard of care for the treatment,
diagnosis or prevention of the condition concerned;

(c) expected improvement in safety in relation to either adverse
reactions or potential medication errors in a paediatric
population compared to the current standard of care for the
treatment, diagnosis or prevention of
condition
concerned;

the

(d) improved dosing scheme or method of administration
(number of doses per day, oral compared to intravenous
administration,
leading to
improved safety, efficacy or compliance;

reduced treatment duration)

(e) availability of a new clinically relevant age-appropriate

formulation;

(1) Article 6(2) of the paediatric regulation provides that ‘When carrying
out its tasks, the Paediatric Committee shall consider whether or not
any proposed studies can be expected to be of significant therapeutic
benefit to and/or fulfil a therapeutic need of the paediatric population’.
(2) Article 11(1)(c) provides a ground for granting a waiver ‘that the
specific medicinal product does not represent a significant therapeutic
benefit over existing treatments for paediatric patients’.

(3) Article 17(1) provides that the opinion on a paediatric investigation
plan ‘… as to whether or not the expected therapeutic benefits justify
the studies proposed’.

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(f) availability of

clinically relevant

and new therapeutic
knowledge for the use of
the medicinal product in the
paediatric population leading to improved efficacy or safety
of the medicinal product in the paediatric population;

(g) different mechanism of action with potential advantage for
the paediatric population(s) in terms of improved efficacy or
safety;

the therapeutic indication and the subset of the paediatric popu-
lation are already covered by a class waiver (2). Where the
requirements of Articles 7 and 8 of the paediatric regulation are
partially covered by class waiver but a product specific waiver is
necessary to satisfy the requirements, the class waivers should
be referred to when specifying the scope of the product specific
waiver.

(h) existing treatments are not

satisfactory and alternative
methods with an improved expected benefit-risk balance are
needed;

Companies are encouraged to inform the paediatric committee
when new information becomes available which suggests that a
class or product specific waiver should be reviewed in accord-
ance with Article 14(2) of paediatric regulation.

(i) expected improvement in the quality of life of the child.

As experience with the use of the medicinal product in the
paediatric population might not be available or might be very
limited at an early stage of the development of a medicinal
product, significant therapeutic benefit might also be based on
well-justified and plausible assumptions. In order to allow the
paediatric committee to make its assessment the application
should explore these assumptions based on reasoned arguments
and relevant literature. If significant therapeutic benefit cannot
be justified at that early stage of the development of a medicinal
product, the paediatric committee will consider a waiver or
deferral, as appropriate.

If the therapeutic need is included in the inventory of thera-
peutic needs established by the paediatric committee pursuant
to Article 43 of the paediatric regulation, the application should
refer to the inventory (1). Where the applicant considers the
proposed paediatric development to fulfil a therapeutic need
and this therapeutic need is not yet included in the inventory as
established by the paediatric committee, sufficient information
to explain this assumption should be provided.

2.4. Part C: Applications product specific waivers

A waiver may be issued with reference either to one or more
specified subsets of the paediatric population, or to one or
more specified therapeutic indications, or to a combination of
both (Article 11(2) of the paediatric regulation). Requests for
product specific waivers should clearly define their scope in
terms of paediatric subset and indication.

As waivers may subsequently be used to satisfy, either in part or
in full the requirements of the second subparagraph of Article 8
of the paediatric regulation, the route of administration and
pharmaceutical form should be specified.

2.4.2. C.2: Grounds for a product specific waiver

The grounds for a waiver are defined in Article 11 of
paediatric regulation.

the

2.4.2.1. C.2.1: The

specif ic medicinal product or
likely to be
the

class of medicinal products
ineffective or unsafe in par t or all of
paediatr ic population

is

Article 11(1)(a) of the paediatric regulation provides a specific
ground for granting a waiver as ‘that the specific medicinal
product or class of medicinal products is likely to be ineffective
or unsafe in part or all of the paediatric population’. On this
basis a request for a waiver may be based on evidence of lack of
efficacy in the paediatric population(s). The application should
take account, for the different paediatric subsets, of the serious-
ness of
the condition/disease and the availability of other
methods as stated in Part B. All available evidence should be
submitted (cross-referring to the
information in Part B)
describing the lack of efficacy in the paediatric population as a
whole or in subsets, as applicable. The justification should be
based on effects observed in non clinical models, studies and
trials, when available.

The justification for a waiver based on evidence that the product
is unsafe may differ depending on the existing experience with
the product as the full characterisation of the safety profile of a
medicinal product usually only occurs after a product has been
Justification for a waiver on these
placed on the market.
grounds may include the pharmacological properties of
the
product or class of product, results from non-clinical studies,
clinical
trials or post-marketing data. The applicant should
specify whether a specific safety issue is known or suspected.

2.4.1. C.1: Class waiver

No product specific waiver may be necessary to satisfy the
requirements of Article 7 and 8 of the paediatric regulation if

At an early stage of development, the absence of any available
data on the safety or efficacy in the paediatric population will
not be accepted as the sole as justification for a waiver.

(1) Article 43 of the paediatric regulation provides that the inventory be

(2) Class waivers will be made public on the EMEA website in accordance

published by the EMEA by 26 January 2010 at the latest.

with Article 12 and 25(7) of the paediatric regulation.

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2.4.2.2. C.2.2: The disease or condition for which the
is

specific medicinal
class
intended occurs only in adult populations

product

or

Article 11(1)(b) of the paediatric regulation provides a specific
ground for granting a waiver as ‘the disease or condition for
which the specific medicinal product or class is intended
occurs only in adult populations’. On this basis justification may
be based on detailed justification on the incidence or prevalence
of the disease in different populations. For waivers covering the
the paediatric population the justification should
totality of
the
particularly focus on the
condition/disease. For waivers for specific subsets the justifica-
tion should focus on the incidence or prevalence in the different
paediatric subsets delineated in Part B.

age of onset of

earliest

2.4.2.3. C.2.3: The specific medicinal product does
not represent a signif icant therapeutic benefit
paediatr ic
treatments
over
patients

existing

for

Article 11(1)(c) of the paediatric regulation provides a specific
ground for granting a waiver as ‘that the specific medicinal
product does not represent a significant therapeutic benefit over
existing treatments for paediatric patients’. On this basis justifi-
cation for a waiver may be based on a lack of significant thera-
peutic benefit.

is

requested, particularly where

therapeutic
Where a waiver based on a lack of significant
benefit
are
submitted before clinical trial data are available, justification for
a waiver could be based on a detailed discussion of the existing
treatment methods, as well as extrapolations from non-clinical
or adult clinical data if available.

applications

2.5. Part D: Paediatric investigation plan

2.5.1. D.1: Overall strategy proposed for the paediatric development

Whereas Part B relates to the overall development of
the
medicinal product including development work relating to the
adult population as well as information on the medical condi-
tions, Part D should focus specifically on the development of
the medicinal product for the paediatric population.

2.5.1.2. D.1.2: Selected age group(s)

The paediatric investigation plan should cover all subsets of the
paediatric population which are not covered by a waiver. The
age ranges to be studied should be justified and may vary
depending on the pharmacology of the product, the manifesta-
tion of the condition in various age groups and other factors.
Unless otherwise justified the application should refer to the age
classification of ICH/CHMP guideline E11. However, these age
classes are wide and may include different maturation levels. In
addition to age, the classification of the paediatric population
may be based on other variables such as gestational age,
pubertal stage(s), and renal function.

2.5.1.3. D.1.3:

Infor mation on the

quality, non-

clinical and clinical data

the development of

application should outline

the
The
including the pharmaceutical development
medicinal product,
which is relevant
for paediatric development and its results
when available. An outline of the planned studies in adults
should also be provided. This could take the form of an ‘investi-
gator brochure’ style summary. The full study reports of non-
clinical and clinical studies undertaken need not be provided but
should be made available upon request. The application should
take into account any existing scientific guidance/advice and
justify any deviation for the development.

In addition the application should include a review of any infor-
mation on the product in the paediatric population, making
reference to scientific and medical
literature or other relevant
information, such as reports from off label or unlicensed use, or
accidental exposures, as well as known class effects.

2.5.2. D.2: Strategy in relation to quality aspects

the product

This Section should address the chemical, pharmaceutical, biolo-
gical and biopharmaceutical aspects related to the administra-
tion of
to the relevant paediatric subsets. The
discussion will take into account the pharmaceutical develop-
ment of the product and,
in addition to the normal require-
ments for
the pharmaceutical development, should address
critical issues such as:

— need for specific formulations or dosage forms in relation to
the chosen age group(s) and discussion of the benefit of the
chosen formulation or dosage form,

— qualitative and quantitative composition if available,

2.5.1.1. D.1.1: Paediatr ic investigation plan indica-

tion

— availability/timeframe for the development of an age appro-

priate dosage form,

The proposed indication(s) should be stated in the paediatric
population for the purpose of a paediatric investigation plan,
covering part of or all subsets, as appropriate. This part should
specify whether the medicinal product is intended for the diag-
nosis, prevention or treatment of
the diseases/conditions in
question.

— potential issues in relation to the formulation (e.g. appropri-

ateness of excipients for the paediatric population),

— administration of the medicine to paediatric subsets (e.g. use
of specific administration devices, ability to mix with food,
anticipated container closure systems etc.),

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its ‘fitness for purpose’,

— the acceptability of the formulation (including palatability)
— i.e.
justified from a physico-
chemical, biological and physiological point of view. In case
it is not possible to develop a formulation which is relevant
and acceptable for paediatric use on an industrial scale, the
application should state how it
intends to facilitate the
extemporaneous magistral preparation of an individual
ready-for-use paediatric formulation.

The addition of a paediatric indication may result in the need
for a new pharmaceutical form or new strength, for example a
liquid rather than a tablet, or a tablet of a new dose strength,
because the existing pharmaceutical form or strength may be
unsuitable for use in all or part of the relevant paediatric popu-
lations. This means that the suitability of existing pharmaceu-
tical forms/strengths should always be discussed in the paedia-
tric investigation plan. Consideration should be given to any
ethnic or cultural difference in route of administration, accep-
table dosage forms and excipients.

2.5.3. D.3: Strategy in relation to non-clinical aspects

This Section should discuss the strategy for the non-clinical
development, which is needed in addition to classical non-cli-
nical development or to already existing data. If human safety
data and previous animal studies are considered insufficient for
reassurance on the likely safety profile in the intended paediatric
age group, juvenile animal studies should be considered on an
individual basis. The following elements should be considered,
taking into consideration existing scientific guidance:

— pharmacology:

— the need for proof of concept for the use in paediatric
in vitro

for example using non-clinical

populations,
and/or in vivo models,

— the need for pharmacodynamic studies (e.g. to establish
a dose relationship for a pharmacodynamic endpoint, if
there is a reliable animal model to justify the choice of
juvenile animal
the most relevant species for potential
studies),

— the need for safety pharmacology (studies using non-cli-
nical in vitro and/or in vivo models to investigate specific
function of the physiological system),

— pharmacokinetics:

— the need for additional

local tolerance studies e.g. for

topical application dosage forms.

2.5.4. D.4: Strategy in relation to clinical aspects

This Section should discuss and justify the strategy for the
clinical paediatric development,
in relation to the standard
development (including that in adults and in relation to existing
data).

This Section should present the overall clinical approach to
support the product development in the paediatric investigation
plan indications and age subset(s). This should include critical
aspects of study design, and should present the strengths and
limitations of
It should
address the appropriateness of endpoints according to age (the
actual design of each individual study should be described in
Section D.5). Details of the formulation to be used should be
given and plans for bridging between the different formulations
should be addressed.

the proposed clinical development.

In its strategy, the application should discuss possible extrapola-
tion from adult data to paediatric patients, as well as from older
age groups to younger ones. The interrelation (in terms of
common studies, data and timelines) between development in
adults and paediatric populations should be explained.

The application should address the rationale to support dosing,
formulation(s) and route(s) of administration. The discussion
should reflect which data are needed in order to conduct the
studies so that bridging to the timing of the studies in the
overall development plan can be made.

The application should justify that the subjects intended for
inclusion in the trials are representative of the population in
which the product will be used. Trials should be performed in
the least vulnerable groups whenever possible (i.e in adults
rather than in children, in older children rather than younger
ones). If results cannot be extrapolated to younger groups, this
should be justified.

The following aspects should be considered, where relevant:

— pharmacodynamic studies:

— pharmacodynamic differences between adult and paedia-
tric populations (e.g. influence of maturation of recep-
tors and/or systems),

— the need for specific studies justifying the most relevant

species for potential juvenile animal studies,

— extrapolation from different populations (from adult
and/or for older paediatric age groups) including, where
appropriate, the use of pharmacodynamic modelling,

— toxicology:

— the need for specific toxicity studies including toxicoki-

netics in juvenile animals,

— the need for specific studies in certain age groups,

— discussion of any biomarkers for pharmacokinetics/phar-

macodynamics,

— the need for toxicity studies to address specific endpoints
e.g. neurotoxicity, immunotoxicity or nephrotoxicity at a
particular developmental phase,

— use of

the pharmacodynamic approach, particularly

when pharmacokinetics cannot be measured,

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— pharmacokinetic studies:

committee opinion and subsequently the EMEA Decision on the
paediatric investigation plan.

— the possibility to extrapolate efficacy and safety from
adult or older age group based on pharmacokinetics,

— the possibility to use sparse pharmacokinetic sampling,

— the use of pharmacokinetics/pharmacodynamics studies
to bridge efficacy and safety in adults or older age group,

— the possibility to support pharmacokinetics in certain
age groups using information, or to extrapolate pharma-
cokinetics from other populations,

— discussion of age groups where more extensive studies
are needed e.g. due to expected high kinetic variability,

— use of population pharmacokinetics,

2.5.5.1. D.5.1: Overall Summar y Table of all planned
clinical

non-clinical

ongoing

and

and/or
studies

While it is acknowledged that the proposed timing of measures
in a paediatric investigation plan will be estimates, particularly
for medicinal products in early development, it should be noted
that this Section is critical to the development of the paediatric
committee opinion and subsequently the EMEA Decision on the
paediatric investigation plan.

— the possibility to extrapolate interactions, organ function
impairment and effects of pharmacogenetics, and the
need for specific studies,

A table should be included providing an overview of all
measures planned and/or ongoing by the application in the
paediatric population.

— efficacy and safety studies:

— discussion of the need for specific dose-finding studies,

— discussion of issues of relevance across the proposed
studies, such as the use of placebo or active control, age
appropriateness of endpoints, use of surrogate markers,
use of alternative study design and analysis, potential
need for short term and long term safety and potential
risks by age group,

— if there is an approved EU-risk management plan for a
product which is already authorised for use in the adult
population, any risk minimisation activities appropriate
for
the paediatric population should be taken into
account in developing the paediatric investigation plan.
there are pharmacovigilance studies in the EU-risk
If
management plan which involve a paediatric population,
they should also be cross-referred to in the paediatric
investigation plan.

The need for long-term safety studies in the paediatric popula-
tion should always be discussed in the paediatric investigation
plan. If such studies are considered necessary, the details should
also be provided in the EU-risk management plan, or its update,
submitted at the time of the application for marketing authori-
sation, but in principle would not form part of the agreed
paediatric investigation plan.

Finally the measures proposed to protect the paediatric popula-
tion during development for example the use of less invasive
methods, use of a data and safety monitoring board for certain
studies, and issues related to the feasibility of the proposed
studies
recruitment or quantity of blood sampling
compared to blood volume) should be discussed.

(e.g.

2.5.5. D.5: Measures for the development in paediatric population

It should be noted that this Section, together with Section D.5.1
the paediatric
and Part E is critical

to the development of

This table should present the timelines of the measures included
in the paediatric investigation plan. Particular emphasis should
be placed on the timing of
the measures in the paediatric
investigation plan compared to the development for adults, as
expressed for example in ICH/CHMP guideline (E11). The
predicted timing of marketing authorisation applications which
fall under Articles 7, 8 and 30 of the paediatric regulation
should be provided and the timing of
the measures in the
paediatric investigation plan should refer to these applications.
The application should propose timelines for initiation and
completion of each measure, including specific dates. The appli-
cation should include in its proposal a reasonable amount of
time for unforeseen circumstances to complete, analyse and
report the studies to be included in the application.

2.5.5.2. D.5.2: Outline of each of the planned and/or
ongoing studies and steps in the phar maceu-
tical development

The studies which should be outlined here are strongly depen-
dent upon the proposed strategy mentioned in Section D.2
therefore the examples given below are not exhaustive.

If the basis of the paediatric product is an authorised adult
product with a simple reduction in content of active substance,
or reduced amount administered, then pharmaceutical develop-
ment studies may be minimal
in the context of a paediatric
investigation plan. Otherwise, if the strategy is to create a new
pharmaceutical form (e.g. new dosage form, or new route of
administration) then the necessary pharmaceutical development
studies may need to be more extensive. In any case, the full
range of pharmaceutical development
to confirm
process and product uniformity and stability would be required
at the stage of application for Marketing Authorisation. Agency
guidelines in this area are available should be consulted to
decide which studies could be relevant within the strategy
proposed in Section D.2.

studies

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Proposed studies of particular relevance to the development of
paediatric products may include:

— compatibility and stability in the presence of

relevant
common foods and drinks particularly if food is used to
facilitate administration of the dosage form,

— compatibility with administration systems

e.g. medical

devices,

— taste-masking or palatability.

2.5.5.3. D.5.3: Synopsis/outline of protocol of each of
non-clinical
and/or

ongoing

planned

the
studies

Sufficient information to adequately describe the study should
be detailed as relevant, for example:

— type of study,

— objective(s),

— test system/species,

— method of administration,

— duration of dosing.

2.5.5.4. D.5.4: Synopsis/outline of protocol of each of
the planned and/or ongoing clinical studies
or tr ials

2.6. Part E: Applications deferrals

Pursuant to Article 20(1) of the paediatric regulation, at the
same time as the paediatric investigation plan is submitted, a
request may be made for deferral of the initiation or completion
of some or all of the measures set out in that plan.

With reference to the timelines stated in Section D.5.1, any
request for deferrals of the start or the completion of measures
should make clear to which indication, route of administration
and pharmaceutical form the deferred timeline relates to. When
requesting a deferral, the application should specify the age
group to which it applies. For timelines, specific months and
years should be given, and timelines may also be expressed in
relation to the development in adults.

Requests for deferrals should be justified on scientific and tech-
nical grounds or on grounds related to public health and the
paediatric regulation requires that a deferral be granted when:

— it is appropriate to conduct studies in adults prior to initi-

ating studies in the paediatric population,

— studies in the paediatric population will

take longer to

conduct than studies in adults.

Other examples of scientific and technical
justification for a
deferral may include when additional non-clinical data are
considered necessary or when major quality problems currently
prevent development of the relevant formulation(s).

The following should be detailed as relevant according to the
study and as appropriate to the phase of product development:

2.7. Part F: Annexes

— type of study,

— study design,

— type of control (placebo or active control with dose to be

used) and justification,

— location (regions),

The annexes to the application should include the following
documents, if available:

— references (i.e. published literature),

— investigator brochure,

— latest approved EU-risk management plan for a product

— test(s) products; dosage regimen; route of administration,

already authorised.

— objective(s) of the study,

— number of subjects (M/F), ages, number per ICH age groups

2.8. Modification of an agreed paediatric investigation plan

or other relevant age group,

— duration of treatment including the duration of post-treat-

ment observation,

— main inclusion/exclusion criteria,

— parameters or endpoints (primary, secondary),

— sample size (more or less detailed as appropriate),

— power calculation: describe effect size expected,

— options in case of recruitment issues, interim analyses and

stopping rules,

— statistical methods (Statistical methods used to compare
groups for primary outcome, and for additional analyses if
relevant).

Paediatric investigation plans should be submitted early during
product development, in time for studies to be conducted in the
paediatric population, where appropriate, before marketing
authorisation applications are submitted. Such early submission
of a paediatric investigation plan will ensure early dialogue
between the applicant and the Paediatric Committee. As the
development of medicinal products is a dynamic process depen-
dent on the result of ongoing studies, provision is made in
Article 22 of the paediatric regulation for modifying an agreed
plan where necessary (1).

(1) Article 22 of the paediatric regulation states ‘If, following the decision
agreeing the paediatric investigation plan, the applicant encounters
such difficulties with its implementation as to render the plan unwork-
able or no longer appropriate, the applicant may propose changes or
request a deferral or a waiver, based on detailed grounds, to the Paedia-
tric Committee. […]’.

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Submission of an application to propose changes to the paedia-
tric investigation plan, or a request for deferral or a waiver will
be particularly important if the new information may have an
impact on nature or timing of one of the key measures explicitly
highlighted in the EMEA decision on the paediatric investigation
plan.

paediatric population concerned, including any measure to
adapt the formulation of the medicinal product so as to
make its use more acceptable, easier, safer or more effective
for different subsets of the paediatric population have been
carried out in accordance with the paediatric investigation
plan decision.

In the case of an application for modification of a paediatric
investigation plan, the content of the application should follow
the same structure as for an initial paediatric investigation plan
request for agreement only relevant Sections supporting the
change should be completed. The application should provide the
reference of the previous paediatric investigation plan decision.

When the paediatric development has to stop for example for
safety reasons, a modification of
the paediatric investigation
plan or a request for a waiver should be requested. Any modifi-
cation of the paediatric investigation plan should have taken
the marketing authorisation
place before the submission of
application.

3. SECTION 2: OPERATION OF THE COMPLIANCE CHECK

The requirements of Articles 7 and 8 of the paediatric regu-
lation as well as applications for paediatric use marketing
authorisations (provided for in Article 30 of the paediatric regu-
lation) are the subject of compliance checks by the competent
authorities. These compliance checks are described in Articles 23
and 24 of the paediatric regulation. Article 23 provides for the
the possibility of an
timing of
opinion of the paediatric committee on compliance and clarifies
when and by whom this opinion can be requested. Pursuant to
Article 23(3) second subparagraph, Member States shall take
account of the opinion of the paediatric committee. Article 23
does not provide for re-examination of the paediatric committee
opinion on compliance.

the compliance check,

for

One compliance standard is checked by the competent authori-
ties in a two step process:

— step one, pursuant to Article 23, compliance is checked at
validation for applications under Article 7, 8 and 30 of the
paediatric regulation. Non-compliance of these applications
will lead to non-validation of the application,

— step two, pursuant to Article 24 of the paediatric regulation,
detection of non-compliance during the scientific assessment
of a valid application will result in non-inclusion in the
statement
marketing authorisation of
referred to in Article 28(3) and the product shall not be
eligible for the rewards and incentives provides for in Arti-
cles 36, 37 and 38 of the paediatric regulation.

compliance

the

The determination of compliance in both steps described above
will include:

— whether or not

to
Article 7(1) of the paediatric regulation cover all subsets of
the paediatric population,

submitted pursuant

the documents

If at the time of the evaluation of the data generated as a result
of an agreed paediatric investigation plan, it is shown that the
studies have not been conducted in accordance with the paedia-
investigation plan decision compliance will not be
tric
confirmed and the
referred to in
Article 28(3) of the paediatric regulation will not be included in
the marketing authorisation.

compliance

statement

Compliance can be judged only if
full study reports are
provided. To facilitate the work of competent authorities and,
when appropriate,
the paediatric committee in reaching an
opinion on compliance, presentation of a compliance report at
the time of the submission of the application is encouraged. If
the paediatric committee opinion is sought by the applicant for
a marketing authorisation or variation under Article 23(2)(a),
prior to the application a copy of this opinion will be annexed
to the application as provided for by Article 23(2),
last sub-
paragraph.

For medicinal products that fall under the scope of Articles 7
or 8, the compliance report should indicate in the form of a
table how each subset of
the paediatric population and for
applications falling under Article 8 of the paediatric regulation,
how each of the existing and new indications, pharmaceutical
forms and routes of administration have been covered by the
documents referred to in Article 7(1) of the paediatric regu-
lation. A separate table should be included covering the decision
on the paediatric investigation plan, the marketing authorisation
or variation applicant's position on compliance with the key
elements, and, when submitted with the marketing authorisation
application, a cross-reference for each key element of the paedia-
tric investigation plan to the location within the relevant
module in that marketing authorisation application. In case of
modifications to a paediatric investigation plan, the table should
be based on the latest decision of the Agency.

It should be noted that:

— for applications falling within the scope of Article 8 of the
paediatric regulation, whether
the documents submitted
pursuant to Article 7(1) cover the existing and the new indi-
cations, pharmaceutical forms and routes of administration,
and

— the relevant Competent Authority or

the Agency will
perform a detailed check of each key element of the EMEA
decision on the paediatric investigation plan against what
has actually been submitted,

— for medicinal products with an agreed paediatric investiga-
tion plan, whether all of the measures in that plan (studies,
trials and timelines) proposed to assess the quality, safety
and efficacy of the medicinal product in all subsets of the

— because the decision on the paediatric investigation plan will
include the minimum critical elements for each of
the
measures, the marketing authorisation or variation applicant
will need to comply with each item,

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— if the EMEA Decision on the paediatric investigation plan
includes measures using conditional
language such as
‘could’, or ‘such as’ then the compliance may be confirmed
even if these measures were not followed as suggested,

rather than by the number of studies. In exceptional cases, a set
of non-significant studies might be considered as significant if
the results taken together are expected to provide important and
clinically relevant information.

To qualify for the rewards and incentives of Articles 36, 37
and 38 significant studies need to be completed after the entry
into force of
the paediatric regulation. A study will be
considered as completed when the last visit of the last patient
has occurred, as foreseen in the latest version of the protocol (as
submitted to competent authorities) and falls after the date of
entry into force of the paediatric regulation. Open extensions of
studies
for patients
included, will not be considered as continuing after the entry
into force if this was not part of the protocol submitted to the
relevant competent authorities.

treatment maintenance

consisting of

The Agency or competent authorities will assess the significance
of each study proposed in a paediatric investigation plan on a
case-by-case basis. However, the examples below are provided as
a guide to the assessment of the significance of studies.

The following study types will generally be considered as signifi-
cant:

1. comparative efficacy studies (randomised/active control or

placebo);

2. dose-finding studies;

3. prospective clinical safety studies, if the results are expected
to make a major contribution to the safe use of
the
medicinal product in the paediatric population (this includes
studies on growth and development);

4. studies to obtain a new age-appropriate formulation, if the
formulation is expected to be of clinical relevance for the
safe and effective use of the medicinal product in the paedia-
tric population;

5. PK/PD studies: well founded pharmacokinetic/pharmacody-
namic clinical studies if they are likely to provide meaningful
data which would avoid the need for a clinical efficacy study
and therefore spare the numbers of children who may need
to be enrolled in a larger trial.

In order to be considered as significant, the studies should
normally cover all paediatric subsets affected by the condition
where sufficient data are not available, unless a waiver has been
granted. However, on a case by case basis, studies conducted in
a single subset of the paediatric population could be considered
as significant if sufficiently extensive or if they make an impor-
tant contribution to treatment of children or if they are carried
out in a subset considered particularly difficult to study, for
example neonates. Where sufficient data for one or more of the
paediatric subsets are already available, duplication of studies
should be avoided and therefore unnecessary studies will not be
considered as significant.

— in the case of a paediatric committee opinion on compliance
under Article 23 of the paediatric regulation, the grounds
for accepting or denying compliance will be clearly stated in
the opinion.

Where a paediatric investigation plan contains no study
completed before the entry into force of Regulation (EC)
No 1901/2006,
the statement of compliance referred to in
Article 28(3) of the paediatric regulation will be the following:
‘The development of
this product has complied with all
measures in the agreed paediatric investigation plan [reference
number]. For the purpose of the application of Article 45(3) of
Regulation (EC) No 1901/2006, all studies in the agreed paedia-
tric investigation plan [reference number] were completed after
the entry into force of that Regualtion’.

Where a paediatric investigation plan contains some studies
completed before the entry into force of Regulation (EC)
No 1901/2006,the statement of compliance referred to in
Article 28(3) of the paediatric regulation will be the following:
‘The development of
this product has complied with all
measures in the agreed paediatric investigation plan [reference
number]. For the purpose of the application of Article 45(3) of
Regulation (EC) No 1901/2006, significant studies in the agreed
paediatric investigation plan have been completed after the
entry into force of that Regulation’.

4. SECTION 3: ASSESSMENT CRITERIA FOR THE SIGNIFI-
CANCE OF STUDIES STARTED BEFORE AND COMPLETED
AFTER THE ENTRY INTO FORCE OF THE PAEDIATRIC
REGULATION

4.1. Background

For studies started before the entry into force of the paediatric
regulation (1) to be the basis of granting the rewards and incen-
tives of Articles 36, 37 and 38 of the paediatric regulation they
need to be completed after the entry into force and to be judged
significant (Article 45(3) of the paediatric regulation).

The statement of compliance referred to in Article 28(3) of the
paediatric regulation will indicate whether the studies included
in the paediatric investigation plan which were initiated prior to
and were completed after the entry into force of the regulation
are considered significant in the meaning of Article 45(3) of the
paediatric regulation.

4.2. Assessment criteria

In general, the significance of studies is determined by the
clinical relevance of data generated for the paediatric population

(1) The 26 January 2007.