Descrição

1. SPECIAL ARTICLE
A. Ceci Æ M. Felisi Æ M. Catapano Æ P. Baiardi
L. Cipollina Æ S. Ravera Æ S. Bagnulo Æ S. Reggio
G. Rondini
Medicines for children licensed by the European Agency
for the Evaluation of Medicinal Products
Received: 6 June 2002 / Accepted: 14 August 2002 / Published online: 25 September 2002
Ó Springer-Verlag 2002
Abstract Objective: The aim of this study was to eval-
uate the number and the characteristics of medicines
approved for children in Europe by the European
Agency for the Evaluation of Medicinal Products
(EMEA) and whether the paediatric studies supporting
the authorisation were in accordance with the Note for
Guidance on the Clinical Investigation of Medicinal
Products in children (CPMP/ICH/2711/99). We also
considered any possible difference between the EMEA
and the Food and Drug Administration (FDA) paedi-
atric medicines evaluations.
Methods: We examined the drugs authorised by the
EMEA through the centralised procedure from January
1995 to September 2001 deriving information from the
‘‘European Medicines – Database’’ (EMD) set up in
1998 by the Italian Group for Pharmacoeconomic
Studies (GISF) and sponsored by the Italian Ministry of
Health. The analysis of paediatric data has been man-
aged by experts belonging to the Clinical Pharmacology
Working Group of the Italian Paediatric Society. The
following parameters were assessed: active substance,
year of approval, anatomical therapeutic and chemical
(ATC) code, therapeutic indications, age for which the
drug is authorised, interest to children and paediatric
studies supporting a paediatric authorisation. European
Public Assessment Reports (EPARs) were considered as
reference sources.
Results: The median percentage of drugs authorised for
children from 1995 to 2001 (September) is 35% of the total
of commercially available drugs; only 16 medicines have
been approved for children under 2 years of age (11%),
ten of these being vaccines. Medicines for children shared
out 9 ATC classes, 24 belonging to the J- (anti-infective
agents) -ATC class. Thirty-nine medicines were author-
ised on the basis of at least one clinical trial (27 phase III, 6
phase II, 6 phase I) while eight active substances have been
licensed without any paediatric investigation.
Conclusions: Under the EMEA centralised procedure,
several active substances have been licensed for children.
Consequently serious and life-threatening diseases as
AIDS and diabetes are now treatable, in a legal frame-
work overcoming the orphan status of the past years.
Despite the reported encouraging results, the number of
drugs devoted to children remain low and important
ATC classes, as L-(oncology) or N-(neurology), are still
‘orphans’ of innovative medicines. At the same time few
medicinal products are specifically studied in children.
Consequently, more efforts have to be made to increase
the number of drugs assessed and licensed for the pae-
diatric population, and manufacturers should be
required to supply data on the effects of new drugs in
children when the products are expected to offer a
benefit over existing therapies.
Keywords Children Æ European Community Æ Licensed
medicines Æ Clinical studies
Introduction
For many years, because of the lack of studies specifi-
cally designed to investigate pharmacological and toxi-
cological aspects in paediatric populations, many
approved drugs have been used in children without
proper information on dosage and potential toxicity
[1, 2, 3] or without appropriate dosage forms.
Eur J Clin Pharmacol (2002) 58: 495–500
DOI 10.1007/s00228-002-0511-0
A. Ceci Æ M. Felisi
Department of Pharmacology and Human Physiology,
University of Bari, Bari, Italy
A. Ceci Æ M. Catapano (&) Æ P. Baiardi Æ L. Cipollina
S. Ravera Æ S. Bagnulo
Consortium for Biological and Pharmacological Evaluations,
University of Pavia and the ‘‘S. Maugeri’’ Foundation,
Via Palestro 26, 27100 Pavia, Italy
E-mail: mcatapano@fsm.it
Tel.: +39-0382-25075
Fax: +39-0382-536544
S. Reggio
IRCCS Oasi Maria SS Troina, Italy
G. Rondini
Department of Paediatrics, University of Pavia, Pavia, Italy

2. Consequently, marketed drugs have frequently been
used off-label [4, 5, 6, 7] or unlicensed drugs have been
employed. This attitude seems to lead to an increased
rate of adverse drug reactions and medication errors
[6, 8, 9, 10].
To provide adequate information on paediatric use of
medicinal products, the Food and Drug Administration
(FDA) developed a number of initiatives (1994: Pediat-
ric Labeling Rule [11]; 1997: FDA Modernization Act-
FDAMA, Section 111 [12]; 1998: Mandatory Paediatric
Rule [13]) giving incentives and obligations to the
pharmaceutical industries for conducting paediatric
studies.
The specific issue of paediatric medicines has been
recently considered even by the European Institutions,
defining rules about the principal ethical and method-
ological aspects for clinical trials in children [1997 –
European Agency for the Evaluation of Medicinal
Products (EMEA) Round table of experts [14]; 1999
Note for Guidance on the Clinical Investigation of
Medicinal Products in children (CPMP/ICH/2711/99)
[15]; 2000: Council of the Ministers of Health Resolution
[16]; 2000: Regulation no. 141/2000 [17]; 2001: Directive
EC/2001/20 on the conduct of the clinical experimenta-
tions in humans [18]].
European initiatives, in contrast with those of the
FDA, excluding incentives and obligations, simply
encourage the companies to investigate drugs in children
with the hope that they would result in a change of
attitude by pharmaceutical industries. The aim of the
present study was to evaluate the number and the
characteristics of medicines approved for children in
Europe by the EMEA as well as the number and types of
paediatric studies supporting authorisations.
The medicines approved under the EMEA centralised
procedure represent a homogeneous sample of medicines
useful for this purpose because (a) the centralised pro-
cedure is devoted to innovative drugs for the care of
serious and/or untreatable diseases, (b) the essential
documents used for the marketing authorisation are
currently available and published as European public
assessment reports (EPARs) in the EMEA database and
(c) a single high-level committee is responsible to give
scientific advise for planning clinical studies. In our
analysis we also took into account any possible existing
difference between the EMEA and FDA paediatric
medicines status and evaluations.
Methods
We examined the drugs authorised by the EMEA through the
centralised procedure from 1995 to September 2001, deriving
information from the ‘European Medicines – Database’ set up in
1998 by the Italian Group for Pharmacoeconomic Studies (GISF)
[19] and sponsored by the Ministry of Health with the aim of
collecting information on new and innovative medicinal products
marketed in Europe. EPARs have been considered as reference
sources.
EPAR reflects the scientific conclusion reached by the Com-
mittee for Proprietary Medicinal Products (CPMP) at the end of
the evaluation process for marketing the product. It is made
available by the EMEA for information to the public after deletion
of commercially confidential information. The content of the
EPAR summarises the various reports produced during the cen-
tralised evaluation procedure, resulting from the review of the
documentation submitted by the applicant together with the sci-
entific discussion. It also contains a summary of product charac-
teristics and the information to be included in the patient
information leaflet.
The following parameters were assessed:
• Active substance
• Year of approval
• Anatomical therapeutic and chemical (ATC) code
• Therapeutic indication
• Age/s for which the drug is authorised
• Clinical studies leading to paediatric authorisation
According to CPMP/ICH/2711/99, the ages for which the drug
is intended are defined in completed days, months, or years as
follows:
• New-born infants (0–27 days)
• Infants and toddlers (28 days to 23 months)
• Children (2–11 years)
• Adolescents (12–17 years)
For the purposes of our analysis, we considered four categories
of drugs according to the severity and for interest in treating dis-
eases for children:
• Category 0 = drugs for diseases that do not affect children
• Category 1 = drugs for non-serious diseases that affect both
adults and children or diseases already cured in children
• Category 2 = drugs for serious diseases that affect children and
of significant benefit compared with the existing methods
• Category 3 = drugs for diseases still incurable in children
Category definition was done with the support of the Clinical
Pharmacology Working Group set up by the Italian Society of
Paediatrics. Clinical trials were defined according to the phase of
the study (I, II or III) and to the age of the experimental popula-
tion.
For medicinal products approved by the FDA, we analysed
each product information (PI) document. The PI is the package
labelling reporting the product characteristics. It is written by the
sponsor, approved by the FDA and used during all phases of drug
development; it also contains the design and analysis of clinical
trials that were planned to address and to support the proposed
label. These documents are available on the World Wide Web
(www.rxlist.com, www.micromedex.com). Data management and
analysis were done using the Microsoft Access Office 2000 Software
package.
Results
Since 1995 the EMEA has considered a total of 339
applications for drugs approval, CPMP has provided
217 opinions and 127 active substances, and 14 vaccines
have been granted a community marketing authorisa-
tion. Of these, 47 (33%) are available for use in children,
10 with paediatric dosage forms and 23 with specific
paediatric dosage.
As shown in Table 1:
496

3. i. The percentage of drugs authorised for children per
year varies from 0% to 42%, with a median value of
35%.
ii. Paediatric medicines belong to 9 of 13 ATC classes.
Twenty-four medicines (51%) have been assigned to
J-(anti-infective agents)-ATC code, corresponding to
11 vaccines and 10 antiviral agents for acquired
immunodeficiency syndrome (AIDS) treatment.
Excluding the J-ATC class the percentage of medi-
cines authorised in children falls from 33% to 21%.
iii. Just one medicine refers to category 1 (diseases al-
ready cured), 40 to category 2 (diseases for which no
satisfactory treatment methods exist) and 6 to cate-
gory 3 (diseases still incurable including orphan
diseases).
iv. Sixteen medicines have been approved for children
under 2 years of age (11%), ten of these being vac-
cines. For children under 6 years and 12 years, only
23 (18%) and 33 (26%) medicines, respectively, are
available while the percentage referred to children
over 12 is 25%. For several drugs, the age for which
the medicine is approved does not belong to any of
the age classes listed in the CPMP/ICH/27100/99/EC
document.
In Table 2 the list of Orphan drugs is shown (regis-
tered in Europe) as are drugs for treating rare diseases,
including four drugs belonging to category 2 and eight
drugs to category 3.
Paediatric clinical trials supporting marketing
authorisation were carried out for a total of 36 active
substances including vaccines. All vaccines and 16
active substances had phase-III clinical studies. Six
active substances (sodium phenylbuthirate, etanercept,
telithromicin, temozolomide, insulin aspart, micophen-
olate mofetil) were authorised on the basis of a phase-I
study and six (lopinavir/ritonavir, ritonavir, efavirenz,
nelfinavir mesylate, protein C, stavudine) on the basis of
a phase-II study. Finally, eight medicines (human insu-
lin, ganciclovir, repaglinide, etflornithine, darbepoetin
alfa, factor IX, imiglucerase, lamivudine/zidovudine)
were licensed without any paediatric investigation. The
age of the experimental population was declared in all
but one case, showing that, in 13 cases, it significantly
differed from the age for which the drug has been
licensed. For four active substances (insulin aspart,
stavudine, amprenavir, factor VIII SQ) all groups of age
were included in the clinical studies.
All but four medicines approved by the EMEA for
paediatric use are available in the US market. Moreover
among all the medicines available in both European and
USA markets, four drugs had a negative opinion for
paediatric use by the FDA. On the contrary, three drugs
(abacavir, insulin glargine and desloratadine), approved
in the USA under the FDAMA provisions, were rejected
by the EMEA for the same age group (Table 3).
Discussion
Under the EMEA centralised procedure, 47 medicines
(33%) were licensed for children. This percentage is
significantly higher than that of medicines approved
under the National Procedure and the Mutual Recog-
nition Procedure (MRP) [2, 20]. In fact, in 1996 an Italian
study [2] showed that only 2.1% of 9741 marketed drugs
were labelled for use in paediatric subjects (187 for
children and 18 for infants) . More recently a survey on
drugs approved under the MRP and marketed in
Italy [20] demonstrated that only 19 of 143 (13.2%) were
approved for children during the 1995–2001 period. This
difference was shown to be statistically significant
(P<0.001) [20].
However, our data showed no increasing trend in the
percentage of the EMEA-approved medicines for chil-
dren compared with previously reported data: Impic-
ciatore et al. [20] reported that, of a total of 45
Table 1 Paediatric medicines per year of approval, ATC code,
category of interest in children and medicine availability according
to the groups of age
Paediatric
medicines
and vaccines/
total EMEA
% of
paediatric
medicines on
total EMEA
Year of approval
1995 0/3 0
1996 7/20 35
1997 8/19 42
1998 6/22 27
1999 10/25 40
2000 6/25 24
2001 10/27 37
Total 47/141 33
ATC code
A 7/13 54
B 6/14 43
D 1/2 50
H 1/3 33
J 24/34 71
L 4/25 16
R 2/2 100
S 1/3 33
V 1/16 6
Other 0/29 0
Total 47/141 33
Category of interest in children
0 0/34 0
1 1/11 9
2 40/84 48
3 6/12 50
Total 47/141 33
Groups of age according
to the CPMP/ICH
classification
EMEA-approved
medicines (n)
New-borns (0–27 days) 4
Infants and
toddlers (28 days
to 23 months)
12
Children (2–11 years) 14
Adolescents (12–17 years) 6
Not specified 11
Total 47
497

4. substances licensed by the EMEA until 1998, 34% were
licensed for children [21].
Particularly, the percentage of available medicines
proves to be very low when different groups of age were
considered, falling from 33% to 18% and 11% in chil-
dren under 6 years and 2 years, respectively, while only
four medicines were approved for new-borns. In addi-
tion we noted that, for the majority of medicines, the
ages indicated in the label are not in agreement with the
groups of age listed in the CPMP/ICH/27100/99/EC,
reducing the availability of the drug to a more limited
population.
Several of the new approved medicines are for the
care of serious and life-threatening diseases, such as
AIDS and diabetes, now treatable while in the past were
orphans of specific drugs [21]. A very high percentage of
paediatric drugs was encountered in the J-ATC category
encompassing both the vaccines and drugs for AIDS
treatment. This result could be easily explained because
vaccines represent the only paediatric medicine category
for which the dimension of the market guarantees a
good economic return, while a large amount of incentive
was granted for the development of drugs for AIDS
treatment for research in Europe. This is in contrast with
the absence or the very low percentage of drugs for
treatment of other serious or incurable diseases that
belong to important clinical categories (e.g. central
nervous system and oncology), despite the fact that
many drugs are largely employed in children [22, 23, 24].
The reluctance of pharmaceutical industries to invest
in developing paediatric medicines is furthermore con-
firmed by the absence of paediatric indication in the
group of drugs approved by the EMEA as orphan drugs
(under or before the regulation no. 141/2000 provisions).
Of a total of 11 medicines, 4 are available for children,
while agalsidase (treatment for Fabry disease), levace-
tylmethadol (for opiate addiction), fomivirsen (for local
CMV retinitis in AIDS patients), samarium (for painful
osteoblastic metastases) and tasonermin (for treatment
of soft tissue sarcoma) are not available, notwithstand-
ing the possible paediatric therapeutic interest.
In lack of both interest of industry and public incen-
tives, few clinical paediatric studies have been included in
the documentation for the centralised procedure author-
isation, and medicines for children continue to be gener-
ally understudied. In particular, less than half of the
EMEA-approved paediatric medicines were authorised
after completing phase-III paediatric studies, while 17%
were studied only in adults but authorised in both children
and adults. Moreover, few clinical studies performed in all
groups of age for which the drug was licensed have been
produced. This is of particular concern when the adoles-
cent group is considered, since adolescents are frequently
recruited together with adults while, according to the
CPMP/ICH/2711/99 [15], they are fully entitled to have
access to protocols of study in specific paediatric trials.
In contrast with the European situation described
above, it is pointed out that in USA (September 2001
update), 561 paediatric studies were started up under the
1997 FDA Modernisation Act [12], 20 leading to a
labelling change in dosages or safety announcement. In
addition, 102 studies were completed under the 1998
‘‘Paediatric Rule’’ and more then 32,000 children were
enrolled in studies requested by the FDA or voluntarily
planned by pharmaceutical industries [25].
The European legislative provisions, in contrast with
the 1998 – FDA Paediatric Rule, exclude obligations for
industries to perform paediatric studies for new drugs
that are or could be of interest for children in order to
have a marketing authorisation. The European legisla-
tive provisions also exclude the possibility that the
EMEA could claim for additional studies in case of
Table 2 Orphan drugs (registered in Europe) and drugs for treating rare diseases
Active substance Medicinal product Therapeutic indication Paediatric label-
ling
Cysteamine bitartrate Cystagon* Treatment of proven nephropatic cystinosis 0–12 years
Nonacog alfa BeneFIX* Treatment and prophylaxis of bleeding in patients
with haemophilia B
>6 years
Tasonermin Beromun* Treatment of the irresectable soft tissue sarcoma
of the limbs
None
Imiglucerase Cerezyme* Therapy in patients with a confirmed diagnosis
of type-1 Gaucher disease
Children
Sodium phenylbutyrate Ammonaps* Adjunctive therapy in the chronic management
of urea cycle disorders
0–12 years
Samarium Quadramet* Indicated for the relief of bone pain in patients with
multiplic painful osteoblastic skeletal metastases
None
Fomivirsen Vitravene* Local treatment of cytomegalovirus (CMV) retinitis in
patients with acquired immunodeficiency syndrome (AIDS)
None
Levacetylmethadol Orlaam* Maintenance treatment of opiate addiction in adults
previously treated with methadone
None
Agalsidase Fabrazyme *
Replagal *
Treatment of Fabry disease None
Deferiprone Ferriprox Treatment of iron overload in patients with thalassemia major >6 years
Protein C Ceprotin Treatment of severe congenital protein C deficiency 0–18 years
Temozolomide Temodal Treatment of malignant glioma >3 years
*Orphan or Orphan-like medicinal products registered in Europe
498

5. already marketed drugs that demonstrate to be largely
employed in paediatric populations in accordance with
the demonstrated therapeutic interest. Consequently, the
lack of appropriate clinical studies for paediatric medi-
cines in Europe seems to create a new gap between USA
and Europe, claiming for a new European regulation
that would ensure incentives for research and legal
provisions to require routine studies in paediatric pop-
ulations as part of the marketing authorisation appli-
cation.
Moreover, the different opinions between EMEA
and FDA about the same clinical studies need to be
clarified. This fact could be simply related to the dif-
ferent philosophy of the agencies, but some concern
still exists because the ‘Note for Guidance on the
Clinical Investigation of Medicinal Products in chil-
dren’ (CPMP/ICH/2711/99) [15], which has been set up
to lead a common and scientifically advanced meth-
odology of research, seems to be unsuccessful for this
purpose.
In conclusion, despite the reported encouraging
results, in terms of innovative drugs intended for treat-
ment of serious diseases (AIDS, diabetes), the percentage
of clinical trials supporting marketing authorisation in
children still remains low, and important ATC categories,
such as L-(oncology) or N-(neurology), are still ‘orphans’
of innovative medicines.
To reduce the gap in paediatric medicine availability,
the European Commission–Enterprise Directorate has
recently proposed new regulatory actions [26]. Among
these, the following have to be underlined: incentives for
research, introduction of a period of data protection,
creation of a specific fund that could be used to finance
paediatric research, legal requirements for clinical trials,
central database on off-label uses, establishment of an
EU scientific expert group, follow-up pharmacovigilance
studies for high-risk products and creation of a pan-
European network of clinical excellence for the perfor-
mance of paediatric studies.
These measures seem to entirely fulfil the problems
related to the paediatric medicines in Europe. Therefore,
if these actions were to be promptly adopted, more
effective medicines for children would be possibly as-
sured in the future.
References
1. Wilson JT, Kearns, Murphy D, Yaffe SJ (1994) Pediatric
labelling requirements. Implications for pharmacokinetic
studies. Clin Pharmacokinet 26:308–325
2. Ceci A, Reggiardo G (1997) Utilizzo di prodotti farmaceutici
non documentati nella pratica pediatrica in Italia. Ital J Pediatr
23:959–966
3. Conroy S, McIntyre J, Choonara I, Stephenson T (2000) Drug
trials in children: problems and the way forward. Br J Clin
Pharmacol 49:93–97
4. Conroy S, Choonara I, Impicciatore P et al (2000) Survey of
unlicensed and off label drug use in paediatric wards in Euro-
pean countries. European Network for Drug Investigation in
Children. BMJ 320:79–82
5. McIntyre J, Conroy S, Avery A, Corns H, Choonara I (2000)
Unlicensed and off label prescribing of drugs in general prac-
tice. Arch Dis Child 83:498–501
6. Choonara I, Conroy S (2002) Unlicensed and off-label drug use
in children: implications for safety. Drug Saf 25:1–5
7. Chalumeau M, Treluyer JM, Salanave B et al (2000) Off label
and unlicensed drug use among French office based paediatri-
cians. Arch Dis Child 83:502–505
8. Kaushal R, Bates DW, Landrigan C et al (2001) Medication
errors and adverse drug events in pediatric inpatients. JAMA
285:2114–2120
9. Morales-Olivas FJ, Martinez-Mir I, Ferrer JM, Rubio E, Palop
V (2000) Adverse drug reactions in children reported by means
of the yellow card in Spain. J Clin Epidemiol 53:1076–1080
10. Turner S, Nunn AJ, Fielding K, Choonara I (1999) Adverse
drug reactions to unlicensed and off-label drugs on paediatric
wards: a prospective study. Acta Paediatr 88:965–968
11. Food and Drug Administration (1994) Specific requirements
on content and format of labeling for human prescription
drugs: revision of ‘‘pediatric use’’ subsection in the labeling.
Fed Reg 59:64240–64250
12. 105th Congress (1997) FDA Modernization Act section 111.
Public Law 105–115
13. Food and Drug Administration(1998) Regulations requiring
manufacturers to assess the safety and effectiveness of new
drugs and biological products in pediatric patients: final rule.
Fed Reg 63:66632–66672
14. European Medicine Evaluation Agency (1997) Report on the
experts round table on the difficulties related to the use of new
medicinal products in children held on 18 December 1997.
30 July EMEA/27164/981998 Rev.1, London
Table 3 Active substances with
different labelling approved by
the European Agency for the
Evaluation of Medicinal Prod-
ucts (EMEA) and the Food and
Drug Administration (FDA)
Active substance Labelling
EMEA (EPAR)
FDA (product information
document)
Mycophenolate mofetile Indicated for children >2 years Safety and effectiveness in paediatric
patients have not been established
Insulin aspart Indicated for children >6 years Safety and effectiveness in paediatric
patients have not been established
Indinavir sulphate Indicated for children >4 years Safety and effectiveness in paediatric
patients have not been established
Repaglinide Indicated for children >12 years No paediatric studies submitted
Desloratadinea,b
*
^ Indicated for children >12 years Different dosage for different
age groups
Abacavira
Not recommended in children Indicated for children >3 months
Insulin glarginea
Not recommended in children Safety and effectiveness established
in children <6 years
a
Drugs that have satisfied the
requirements of the FDA’s
implementation of the Paediat-
ric Exclusivity Provision and
already submitted to EMEA
b
In USA loratadine
499

6. 15. CPMP/ICH (2000) Note for guidance on clinical investigation
of medicinal products in the paediatric population. Eudralex
CPMP/ICH/2711/99 – adopted July 2000
16. European Union (2000) Health Council resolution on paedi-
atric medicinal products. December 14, 2000
17. European Parliament and Council Regulation 141/2000/EC,
16 December 1999 on Orphan Medicinal Products. Official
Journal of the European Communities L18/1, 1.5.2001
18. European Parliament and Council Directive 20/2001/EC on the
approximation of the laws, regulations and administrative
provisions of the Member States relating to the implementation
of good clinical practice in the conduct of clinical trials on
medicinal products for human use. Official Journal of the
European Communities L121/34, 1.5.2000
19. Ceci A, Folino-Gallo P, Baiardi P, Capri S, Cipollina L,
Reggio S. (2001) Studio sui farmaci registrati a livello EMEA:
innovativita` , prezzi e rimborsabilita` nei Paesi UE – Rapporto
del GISF (Gruppo Italiano per gli Studi di Farmacoeconomia)
al Ministero della Sanita` , Dipartimento per la valutazione dei
medicinali e la farmacovigilanza
20. Ceci A (2002) Clinical studies at the extreme of age: the situ-
ation in Europe (personal communication). 5th annual EMEA-
IFAPP Conference, 22 February 2002, London
21. Impicciatore P, Choonara I (1999) Status of new medicines
approved by the EMEA regarding pediatric use. Br J Clin
Pharmacol 48:15–18
22. Smyth RL, Weindling AM (1999) Research in children: ethical
and scientific aspects. Lancet 354 Suppl 2:SII21–SII24
23. Park JR, Slattery J, Gooley T, Hawkins D et al (2000) Phase I
topotecan preparative regimen for high-risk neuroblastoma,
high-grade glioma, and refractory/recurrent pediatric solid
tumors. Med Pediatr Oncol 35:719–723
24. Doz F, Gentet JC, Pein F et al (2001) Phase I trial and phar-
macological study of a 3-hour paclitaxel infusion in children
with refractory solid tumours: a SFOP study. Br J Cancer
84:604–610
25. Bisembaum D (2002) Clinical studies at the extreme of age:
Paediatric drug development in the United States: a regulatory
perspective. Personal Communication. 5th annual EMEA-
IFAPP Conference, 22 February 2002, London
26. European Commission Enterprise Directorate-General (2002)
Better medicines for children. Proposed regulatory actions on
paediatric medicinal products. Consultation document. Eudr-
alex 2002
500