Transcript Regulatory requirements for the development of medicinal products

Regulatory requirements for the
development of medicinal products for pediatric use
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
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Slide 1 of 25
April 2007
Regulatory requirements for the
development of medicinal products for pediatric use
Presenter:
Dr Tom Sam
Industrial Pharmacy Section
International Pharmaceutical
Federation (FIP)
The significant contributions to this presentation
of the following persons is gratefully acknowledged:
- Nicole Herijgers - NV Organon
- Lisette Vromans - NV Organon
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Slide 2 of 25
April 2007
Outline
1. Regulatory environment
2. Timing of pediatric studies during development
3. Type of development studies needed
4. Addressing pediatric information in the labelling
5. Need for special drug formulations
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Slide 3 of 25
April 2007
Introduction
 Use of unlicensed and off-label medicines in children is widespread
 > 60% of all medicines used in children have never been tested
and are not authorised in the peadiatric population ([i])
 These products have only been tested in adults, not necessarily in
the same indication or same disease.
 Lack of information and appropriate pharmaceutical formulations
may expose children to unwanted side effects or underdosing
without the expected efficacy.
[i] Le Cam, Y. Medicines for children: better, more and faster. Regulatory Rapporteur. May
2005: 8.
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Slide 4 of 25
April 2007
Requirements (1)
 Canada
procedure.
Registration of pediatric drug follows normal
 Australia - Market authorisation may be denied / delayed, if
clinical pediatric data is not included but is deemed appropriate.
 India
- If new drug is intended to treat both adults and
pediatric patients, the pediatric population should be included in the
clinical trials from an early point onwards. If pediatric data is not
included, this needs to be justified in detail.
 China
- Registration of pediatric drug follows normal
procedure. Clinical trials on children are discouraged unless the
drug-use is limited to only the pediatric population.
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Slide 5 of 25
April 2007
Requirements (2)
 Japan
No mandatory pediatric clinical trials. There are
however, ongoing projects organized by the MHLW (Ministry of
Health, Labour and Welfare), which aim to facilitate an accelerated
review of off-label pediatric drugs.
 South Korea -
Non-established legislation for pediatric drugs.
 Switzerland Pediatric studies are not mandatory for drug
registration, unless the drug has potential pediatric use.
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Slide 6 of 25
April 2007
US legislation on pediatric medicines

Pediatric Rule issued by FDA in December 1998 ([i]).
Required the conduct of pediatric studies and development of
pediatric formulations
The Pediatric Rule suspended in October 2002.

Pediatric Research Equity Act (PREA) law in 2003 ([ii],[iii]).

Pediatric Exclusivity Provision - complementary to the PREA,
which provides an incentive for companies who perform clinical trials
in the pediatric population ([iv]).
[i] Pediatric Rule was codified at 21 CFR 314.55 and 601.27 with additional amendments to 21 CFR 201, 312, 314 and 601.
[ii] Pediatric Research Equity Act of 2003 (http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006)
[iii] Draft Guidance for Industry – How to comply with the Pediatric Research Equity Act. September
2005((http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006).
[iv] This provision was originally included in the FDA Modernisation Act 1997(http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March
2006), but after its sunset it has been retained in the Best Pharmaceuticals for Children Act 2002
(http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006).
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Slide 7 of 25
April 2007
Items to be addressed in a proposed
pediatric study request
 Type and objective of studies to be
performed
 Indications to be studied
 Number of patients to be studied
 Regimens
 Route of administration
 Drug-specific safety concerns to be
monitored or assessed
 Age groups in which the studies will be  Statistical information, including power
performed
of study and statistical analyses of the
data
 Study endpoints
 Labeling that may result from the studies
 Timing of assessments (if appropriate)
 Format of report to be submitted to the
 Entry criteria
FDA
 Drug information
 Dosage form
 Timeframe for submitting reports of the
studies
Template for a proposed pediatric study
request is available at
www.fda.gov/cder/pediatric/wr_template.htm
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Slide 8 of 25
April 2007
EU legislation on pediatric medicines (1)
 26 January 2007
European pediatric medicines legislation into force
 Objectives:
– Increasing high quality research in medicines for children
– Promoting development and authorisation
– Improving information on medicines for children
 To be achieved without doing unnecessary studies in
children and without delaying development in adults
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Slide 9 of 25
April 2007
EU legislation on pediatric medicines (2)
Key elements (1)
Pediatric development mandatory for
– all new products
– all new indications, pharmaceutical forms and routes of
administration of existing products that are still
protected by patent
Pediatric development encouraged for off-patent
medicines (PUMA)
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Slide 10 of 25
April 2007
EU legislation on pediatric medicines (3)
Key elements (2)
 First contact with Regulatory Authorities about pediatric
development to take place ‘not later than upon completion
of the human pharmacokinetic studies in adults’
 Regulatory authority translation: contact us after
completion of phase I !
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April 2007
EU legislation on pediatric medicines (4)
Timelines
First PIP
Phase 2
Phase 1
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Slide 12 of 25
April 2007
Registration dossier
Regular updates
Phase 3
EU legislation on pediatric medicines (6)
What is at stake?
 An application …shall be regarded as valid only if it
includes….
– The results of all studies performed and details of all
information collected in compliance with an agreed pediatric
Investigation Plan (PIP)
 Unless there is…
– A decision of the Agency granting a product-specific waiver
– A decision of the Agency granting a class-waiver…
– A decision of the Agency granting a deferral
The documents in the application shall cumulatively cover all subsets
of the pediatric population
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Slide 13 of 25
April 2007
Pediatric Investigation Plan (PIP)
 A research and development programme aimed at
ensuring that the necessary data are generated
determining the conditions in which a medicinal product
may be authorised to treat the pediatric population
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April 2007
Principles of the PIP
 Covers all subsets of the pediatric population
 Covers existing and new indications, forms and routes of
administration
 Focuses on trials that allow labelling the product for appropriate use in
all relevant subsets
 Focuses on development of appropriate formulations if applicable
 Contains all relevant information: favourable or unfavourable,
incomplete or discontinued pharmaco-tox or clinical trials, results form
trials in other indications
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April 2007
Contents of PIP (1)
 Sections A to E plus Annexes (section F)
 A. Administrative and product information
 B. Overall development of the product
– Similarities/differences of disease/condition between populations (adult/pediatric)
– Anticipated similarities/differences effect of product on disease/condition
– Prevalence and incidence in the pediatric population
– Current methods diagnosis, prevention or treatment in pediatric population
– Significant therapeutic benefit/fullfillment therapeutic need (in pediatric population)
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April 2007
Contents of PIP (2)
 C. Applications for product specific waivers
 D 1-4. Strategic evaluation and choices:
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–
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–
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D1. Overall proposed strategy
D2. Strategy in relation to quality aspects
D3. Strategy in relation to non-clinical aspects
D4. Strategy in relation to clinical aspects
Slide 17 of 25
April 2007
Contents of PIP (3)
 D5. Planned measures for the pediatric development
– Overall summary table non-clinical and clinical section
– Outline of each of the planned or performed studies
– Synopsis of the protocol (non-clinical or clinical)
 D6 Timeline of measures in the plan
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Slide 18 of 25
April 2007
Contents of PIP (4)
 E. Application for deferrals
 F. Annexes as appropriate
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–
–
–
–
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References
Investigator’s brochure
Opinions and decisions by Competent authorities
Scientific advice by Competent Authorities
Latest approved Product Information (for authorised product)
Slide 19 of 25
April 2007
Approval needed
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Slide 20 of 25
April 2007
Comparison of pediatric drug regulation
US
Europe
Legislation
Pediatric Research Equity Act 2003
pediatric Regulation
Requirements
Pediatric Advisory Committee issues
Written Requests for NDAs; a
pediatric waiver or investigational
plan must be submitted
Pediatric Committee will review a
Peadiatric Investigational Plan
(PIP)
Off-patent
products
No legislation*
Off-patent products Pediatric Use
Marketing Authorisation (PUMA)
giving 10 years data protection
Incentive
Six-month period of additional
market provisions during which
generic competitors cannot be
marketed
Six-month period of additional
market provisions during which
generic competitors cannot be
marketed
* The Best Pharmaceuticals for Children Act provides a mechanism for public funding (via National Institutes of Health) of
pediatric studies of certain drugs if the manufacturers of those drugs decline to conduct the requested studies
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Slide 21 of 25
April 2007
Outline
1. Regulatory environment
2. Timing of pediatric studies
3. Type of development studies needed
4. Addressing pediatric information in the labelling
5. Need for special drug formulations
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Slide 22 of 25
April 2007
2. Timing of pediatric studies
 US and EU legislation requires that the marketing
authorisation for a new drug contains a pediatric
assessment (i.e. data from pediatric studies)
 unless the applicant has obtained a waiver or deferral
 All subsets of the pediatric population should be
addressed
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Slide 23 of 25
April 2007
Waivers
 Waiver for medicines that are unlikely to benefit children.
 Waiver according to US PREA:
- the product does not represent a meaningful therapeutic benefit therapy over
existing therapies([1])
- the product is not likely to be used by a substantial number of pediatric
patients([2]),
- the studies would be impractical or impossible in the specified population (e.g.
neonates), or there is already existing evidence of ineffective or unsafe use
 Waiver according to EU:
- the pediatric Committee intends to publish lists of waivers of specific medicinal
products and classes of medicinal product
[1] Meaningful therapeutic benefit over existing therapies: i.e. if drug would represent a significant improvement
in the treatment, diagnosis, or prevention of a disease, compared with marketed products adequately
labeled for that use in the relevant pediatric population or the drug is in a class of products or for an
indication for which there is a need for additional options (5).
[2] Substantial: i.e. in general 50,000 patients, but nature and severity of the condition should be taken into
account (5).
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Slide 24 of 25
April 2007
Deferrals
A deferral until a specified date after approval of the drug
can be only be obtained:
 when studies in children will be more appropriate when
there exists some initial experience on use of a products
in adults or studies in children might take longer than
studies in adults.
 In addition, pediatric studies may be delayed when
development of a pediatric formulation is not complete
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Slide 25 of 25
April 2007
Pediatric lists
FDA:
 List of approved drugs for which additional pediatric information is expected to be
beneficial ([i]))
 May help companies to identify important issues and pediatric needs in a
particular therapeutic area
EMEA:
 Pediatric Committee will make an inventory of therapeutic needs for children
before end 2009
 Pediatric Working Party is working on lists (lists already published on
cardiovascular products and pain ([ii],[iii])
[i] FDA’s “Pediatric list” is available on http://www.fda.gov/cder/pediatric/peddrugsfinal.htm (accessed 6 March 2006).
[ii] EMEA assessment of pediatric needs - cardiovascular products. October 2005. EMEA/CHMP/327847/2005. http://www.emea.int (6 march 2006).
[iii] EMEA assessment of pediatric needs - pain. June 2005. EMEA/CHMP/189220/2005. (http://www.emea.int, accessed on 6 march 2006).
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Non-clinical safety studies (1)
 Safety data from previous adult human exposure should be available
before
pediatric clinical trials start
 Appropriate repeated dose toxicity studies, all reproduction studies
and the standard battery of genotoxicity tests should be available prior
to the initiation of trials in
pediatric populations ([i])
 Juvenile animal studies should be considered on an individual basis
when previous animal data and human safety data are insufficient.
[i] ICH M3 Non-clinical safety studies for the conduct of clinical trials. November 2000. (http://www.ich.org accessed on 6 March 2006).
[ii] FDA Guidance for Industry – nonclinical safety evaluation of pediatric drug products. February 2006. Obtained from www.fda.gov/cder/guidance/index.htm (19 march 2006).
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April 2007
Non-clinical safety studies (2)
 Need for non-clinical testing in juvenile animals for pediatric
indications
- detailed recommendations in a specific FDA guideline ([ii])
- draft CPMP guideline ([iii])
 Need for carcinogenicity testing should be addressed prior to longterm
exposure in pediatric clinical trials considering the length of treatment
or cause for concern
[iii] CPMP Draft Guideline on the need for non-clinical testing in juvenile animals on human pharmaceuticals for pediatric indications. September 2005.
EMEA/CPMP/SWP/169215/2005. http://www.emea.eu.int (obtained on 23 May 2006).
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Slide 28 of 25
April 2007
Outline
1. Regulatory environment
2. Timing of pediatric studies
3. Type of development studies needed
4. Addressing pediatric information in the labelling
5. Need for special drug formulations
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Slide 29 of 25
April 2007
Pediatric clinical studies
Age classification of pediatric patients
– pediatric patients cannot be considered as one
homogenous group
– considerable differences in development (e.g. physical,
cognitive and psychosocial)
– the identification of which ages to study should be
medicinal product-specific and be justified
– dividing the pediatric population into many age groups
might needlessly increase the number of patients
required.
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April 2007
Pediatric clinical studies
Age classification of pediatric patients
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Preterm newborn infants; unique spectrum of diseases, rapid development and
differences in their body functions, unique response to treatment, requirements for
forms of medications that can be safely administered given their especially small size.)
Term newborn infants (0 to 27 days); volumes of distribution may be different than
those in older pediatric patients, blood-brain barrier is not fully mature. Oral absorption
may be less predictable, hepatic and renal clearance mechanisms are immature and
rapidly changing.
Infants and toddlers (28 days to 23 months); rapid mental, physical and immune
development. Elimination of drugs from the body may exceed that in adults.
Considerable variability in response to medication, because the development does not
occur at the same rate in all children.
Children (2 to 11 years); large variation and variability in development. Onset of puberty
is highly variable and heralds a time of accelerated growth and marked changes which
may alter response to medications and doses required.
Adolescents (12 to 16-18 years (dependent on region)); sexual maturation: medicinal
products may intervene with the actions of sex hormones and impede development.
Rapid growth and continued neurocognitive development. Increasing independance and
responsibility; willingness to take medication may become a problem
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Slide 31 of 25
April 2007
Pediatric clinical studies
Safety studies in children
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–
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–
–
always necessary to support an indication in this population
age-appropriate, normal laboratory values and clinical measurements should be used
in such studies.
long-term studies or surveillance data (chronic therapy or during the posttherapy
period) may be needed to determine possible effects on skeletal, behavioral, cognitive,
sexual and immune maturation and development.
postmarketing data are also important because at time of approval the pediatric
database is limited
the company should submit a risk management plan to identify the risks and a set of
activities and interventions designed to prevent or minimise risks
pharmacovigilance for medicines used by the pediatric population, because underreporting (i.e. children may be unable to communicate adverse events) and off-label
use may increase the occurrence of adverse drug reactions ([i]).
[i] Guideline on conduct of pharmacovigilance for medicines used by the pediatric population, EMEA, August
2005 (http://www.emea.int.pdfs/human/phvwp/23591005en.pdf, accessed on 6 March 2006).
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Pediatric clinical studies
Efficacy – PK approach (1)
– If 1) the product is to be used in the pediatric population for the same
indication as studied and approved in adults
2) the disease process is similar in adults and pediatric population and
outcome of therapy is likely to be comparable
– then extrapolation from adults efficacy data may be appropriate.
– if a drug’s effect is well characterised with regard to important PK
parameters and these parameters have been correlated well with
activity in adults, PK studies in the pediatric population will reveal
which dose will produce blood levels similar to those observed in adults.
– In this way, adults efficacy data can be extrapolated to the pediatric
population and no special pediatric clinical efficacy will be necessary
(PK approach).
– A similar approach can be used for extrapolation of efficacy from older to
younger pediatric patients.
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April 2007
Pediatric clinical studies
Efficacy – PK approach (2)
– Both EMEA and FDA have recently drafted detailed guidance for pediatric
PK studies ([i],[ii],[iii]).
– In addition, EMEA has published discussion papers on the impact of renal,
liver, heart and lung immaturity when investigating medicinal products for
children ([iv],[v],[vi]).
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–
–
–
–
–
[i] CHMP Draft Guideline on the role of pharmacokinetics in the development of medicinal products in the
pediatric population. EMEA/CHMP/EWP/147013/2004. February 2005. (www.emea.int)
[ii] EMEA concept paper on the development of a committee for proprietary medicianl products (CPMP) points to
consider document on the evaluation of the pharmacokinetics of medicinal products in the pediatric population
(EMEA/18939/03) (http://www.emea.eu.int).
[iii] Draft Guidance for Industry – General considerations for pediatric pharmacokinetic studies for drugs and
biological products. November 1998 ((http://www.fda.gov.cder.pediatric/index.htm)
[iv] EMEA Discussion paper on the impact of renal immaturity when investigating medicinal products intended for
pediatric use. CPMP/PEG/35132/03 December 2004 www.emea.eu.int.
[v] EMEA Draft Discussion paper on the impact of liver immaturity when investigating medicinal products
intended for neonatal use. EMEA/CHMP/PEG/194605/2005. July 2005.
[vi] EMEA Draft concept paper on the impact of lung and heart immaturity when investigating medicinal products
intended for neonatal use. November 2005. EMEA/CHMP/114218/2006. http://www.emea.eu.int.
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Pediatric clinical studies
Efficacy – PK/PD approach / clinical efficacy
– If comparability of disease course or outcome of therapy in pediatric
studies is expected to be similar to adults, but the appropropriate blood
levels are not clear then it may be possible to use measurements of a
pharmacodynamic (PD) effect related to clinical effectiveness to confirm
the expectations of effectiveness and to define the dose and
concentration needed to attain that PD effect (PK/PD approach).
– In all other cases, clinical efficacy studies are needed. It may be
necessary to develop, validate and employ different endpoints for
specific age and developmental subgroups. Measurement of subjective
symptoms such as pain requires different assessment instruments for
patients of different ages.
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April 2007
Pediatric clinical studies
Decision tree for evaluation of clinical efficacy in pediatric population
Similar disease process?
no
yes
Same indication studied?
no
Clinical efficacy studies
yes
Outcome of therapy is
likely to be comparable?
no
yes
Appropriate blood levels
are clear?
no
yes
Linear PK
yes
PK approach
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April 2007
PK/PD approach
no
Pediatric clinical studies
 It is highly recommended that the pediatric clinical program is discussed
with regulatory authorities already at an early stage of development.
- The EU regulation proposes a system of free EMEA scientific advice for issues
related to the pediatric development plan.
- In the US, scientific advice can be obtained during the ‘formal’ meetings with the
FDA, like pre-IND meeting and end-of-phase I or II meeting ([i]).
 There are serious ethical and legal constraints that impact the
performance of research in children ([ii],[iii]). Special measures are needed
to protect the rights of pediatric study participants and to shield them from
undue risk.
[i] FDA Guidance for industry. Formal meetings with Sponsors and Applicants for PDUFA products. February 2000.
(http://www.fda.gov/cder).
[ii] V. Isitt, Legal and ethical problems peculiar to pediatric clinical trials. Part 1: Legal issues. The Regulatory
Review, June 2002 Volume 5 Issue 4; 12-16.
[iii] EU Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical tirals on
medicinal products for human use. Official Journal of the European Communities, 2001, L121/34-44.
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April 2007
Pediatric clinical studies
 In the EU it is proposed that an EU network of investigators and trial
centres will conduct research and development in children in order to
ensure high-quality research. A database of pediatric studies is
proposed to be build onto the EU Community database for clinical trials
(EudraCT).
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Slide 38 of 25
April 2007
Outline
1. Regulatory environment
2. Timing of pediatric studies
3. Type of development studies needed
4. Addressing pediatric information in the labelling
5. Need for special drug formulations
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Slide 39 of 25
April 2007
Pediatric clinical studies
Labeling (1)
– Information about the use of a drug in the pediatric population should
be included in the labeling.
– The US Pediatric Rule prescribes that a special “Pediatric use”
subsection should be included in the labeling ([i]). This subsection
must summarise any limitations on the pediatric indications, need for
specific monitoring, specific hazards of the drug, differences between
pediatric and adult responses to the drug, and other information
related to the safe and effective use of the drug in pediatric patients.
If appropriate, details should be further discussed under the “Clinical
Pharmacology”, “Clinical Studies”, “Contraindications” and/or
“Warnings” section of the labeling. More detailed recommendations
on the inclusion of pediatric PK/PD data in the labeling is provided in
a draft guidance document.
[i] FDA 21 CFR Part 201.23 Specific requirements on content and format of labeling for human prescription
drugs. Revision of “Pediatric Use” subsection in the labeling
(http://wwww.fda.gov.cder/pediatric/pediatric_rule1994.htm)
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pediatric clinical studies
Labeling (2)
 The EU guideline on summary of product characteristics ([i]) provides
guidance on how to include pediatric information in the EU labeling.
Relevant information should be included in section 4.2 “Posology and
method of administration”, with crossreferences to sections 4.1
“Therapeutic information”, 4.3 “Contraindications”, 4.4 “ Special warnings
and precautions for use, 4.5 “Interaction with other medicinal products and
other forms of interaction”, 4.8 “Undesirable effects”, 4.9 “Overdose”, 5.1
“Pharmacodynamic effects”, 5.3 “Pharmacokinetic properties”, and 6.6
“Special precautions for disposal of a used medicinal product or waste
materials derived from such medicinal product and other handling of the
product” if applicable.
 [i] EU Notice to Applicants. A guideline on summary of product characteristics. October 2005.
(www.pharmacos.eudra.org/F2/eudralex/ vol-2/C/SPCGuidRev1-Oct2005.pdf (obtained on 20 May
2006))
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pediatric clinical studies
Labeling (3)
 The draft EU regulation proposes that not only the information
regarding the results of studies in children (whether positive or
negative), but also information on the status of the pediatric
Investigation Plan, waivers and deferrals will be included in the
product information.
 The EMEA Working Group on Quality Review of Documents has
issued a guidance document which addresses the pediatric patient in
the package leaflet ([ii]). It provides suggestions on how to addresss
situations in which the pediatric patient is in the care of a parent or a
carer who is not a health professional.
[ii] EMEA Working Group on Quality Review of Documents. Addressing the pediatric or incapacitated
patient in the package leaflet. 2000. http://www.eudra.org/emea.html).
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Outline
1. Regulatory environment
2. Timing of pediatric studies
3. Type of development studies needed
4. Addressing pediatric information in the labelling
5. Need for special drug formulations
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Pediatric drug formulation (1)
 Many medicines are currently not available in formulations suitable
for administration to children. Children vary greatly in their ability
to use different dosage forms. This is related to their age, physical
development and ability to coordinate, but also to psychological
development and understanding. As a result younger patients that
cannot take the adult formulation may be denied important new
therapies, or they may have to take formulations that may be
poorly or inconsistently bioavailable ([i]).
[i] EMEA Reflection paper: formulations of choice for the pediatric population.
EMEA/CHMP/PEG/194810/2005. June 2005.
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Pediatric drug formulation (2)
 Both US and EU regulation require that an appropriate formulation for the pediatric
population (i.e. appropriate for each age category to be studied) is used (5,7). In the
pediatric drug develop plan (US) and Pediatric Investigation Plan (EU) any measures to
adapt the formulation of the medicinal product to make its use more acceptable, easier,
safer or more effective for different subsets of the pediatric populations should be
described. Since development of pediatric formulations can be difficult and time-consuming,
the development of these formulations should be considered early in development (2).
 The EMEA has recently published a Reflection Paper with some general guidance for the
development of pediatric formulations. Taste, smell and texture are important factors for
orally administered medicines. Rate of dissolution and ability to keep medication at site of
absorption will be important for buccal or sublingual administration. In general,
administration should be as comfortable, painless or stressless as possible, in order that a
child will tolerated repeated administration of medicines. See next slide.
 Pharmacokinetic studies are generally needed to support the development of pediatric
formulations ([i]). Such bioequivalence studies are normally carried out in adults.
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Pediatric drug formulation (3)
Issues to be considered when developing a pediatric formulation*
 What is minimal dosage frequency?
 One dosage form fits all or a full range
 Minimal impact on life style (esp for adolescents)
 Minimum, non-toxic excipients
 Convenient, easy and reliable administration
 Easily produced, elegant and stable
 Cost and commercial viability
* EMEA Reflection paper: formulations of choice for the pediatric population.
EMEA/CHMP/PEG/194810/2005. June 2005.
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Pediatric drug formulation (4)
 FDA and EMEA can waive the requirement to develop an
appropriate formulation for the treatment of children if the
applicant can demonstrate that reasonable attempt to
produce a pediatric formulation necessary for that age
group has failed.
 In that case the manufacturer should provide information
to improve the quality, safety and efficacy of such
manipulations during the time that they are necessary
and unavoidable; e.g. information on issues surrounding
cutting tablets into smaller segments, on suitability of
tablets for crushing and on suitable powder diluents (plus
compatibility and stability of crushed tablets with common
foods and drinks).
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Conclusions (1)
 EU and US marketing authorisations for a new drug should contain a
pediatric assessment (i.e. data from pediatric studies).
 Consider the following issues when developing a new drug for a
pediatric indication:
1) Can a waiver or deferral for studies in pediatric population or subgroups be
obtained?
2) Are non-clinical safety studies required for conduct of pediatric clinical studies?
3) Is the formulation of the drug appropriate for each age category to be studied?
 Outline the pediatric studies in a pediatric Investigational Plan (EU) or
a Pediatric Drug Development Plan (US). Submit these plans to
regulatory authorities at end-of-phase II (or end-of-phase I in case of
serious and life-threatening diseases that lack adequate therapy).
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April 2007
Conclusions (2)
 In both EU and US there is an incentive for studying medicines for
children. In order to qualify for such a reward, the pediatric study should
be agreed upon with regulatory authorities via an agreed pediatric
Investigation Plan (EU) or Written Request (US) prior to carrying out the
study. For global development, it is important that the timing of
requesting a pediatric incentive should be harmonised in both EU and
US, in order to qualify for both the EU and US pediatric incentive.
 Clinical efficacy in the pediatric population can be assessed via
different approaches, depending on the characteristics of the drug (i.e.
PK approach, PK/PD approach, clinical efficacy studies).
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Slide 49 of 25
April 2007
Conclusions (3)
 The specific timing of pediatric clinical studies depends on
- product
- type of disease
- safety considerations and
- efficacy and safety of alternative treatments.
 Safety studies are always necessary in the pediatric population.
 Specific guidance is available on how to include pediatric
information in the labeling.
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Slide 50 of 25
April 2007