Download EU Regulations for Clinical Studies in Pediatric Patients

Regulatory Focus 15:11:39–44, 2010
REGULATORY MANAGER
EU Regulations for Clinical Studies in Pediatric Patients
By Raj Kishore, PhD and Edward Tabor, MD
In 2006, the European Council (EC) and the
European Parliament adopted a regulation
that created major changes in the way clinical
studies in pediatric patients would be planned
and conducted in the EU.1 For many years,
clinical evaluations of drugs and biologics were
conducted primarily in adults because it was
simpler and raised fewer ethical concerns than
conducting studies in children. Nevertheless,
following regulatory approval for use in adults,
these products were often prescribed for children despite the lack of clinical trials in this
population. Physicians often used an empirically
selected lower dose based on the weight of the
child. In some cases, this could have resulted in
exposure to unsafe or ineffective doses because
children may metabolize a drug or biologic differently than do adults.
In September 2004, based on the success of
pediatric drug laws in the US,2,3 the EC adopted
a proposal to develop regulations for pediatric investigations for the EU. The EC passed
Pediatric Regulation (EC) No 1901/2006 in
2006, later amended by Regulation (EC) No.
1902/2006,4 to require clinical studies for pediatric drug development in the EU. The regulation
took effect on 26 January 2007.
Major Provisions of the European
Pediatric Regulation
The European Pediatric Regulation and its
amendment require that manufacturers submit a Pediatric Investigation Plan (PIP) for all
new products and line extensions (new indication, new formulation, new dosage form, etc.)
for existing products. The PIP must outline
studies to be performed or state the reasons
why a waiver or deferral should be granted
and “should be submitted early during product development, in time for studies to be
conducted…before marketing authorization
applications are submitted.”5 However, it has
been recommended that a PIP be submitted
when pharmacokinetic studies have been completed, effectively at the end of Phase 1 studies in
most cases. In addition to providing the design
for each study, the PIP must provide timelines
for the studies.
The regulation also specifies that PIPs must
state which pediatric age groups will be studied;
a waiver or deferral for age groups not intended
for studies should be requested as part of the
PIP. The Marketing Authorisation Application
(MAA) must “cover all subsets of the paediatric population,”6 and thus must contain data
for use in each of the different pediatric age
groups unless waived or deferred. However,
the Pediatric Regulation does not define the different age groups; it only defines the “pediatric
population” as “that part of the population
aged between birth and 18 years.”7 Pediatric age
groups are defined in ICH Guidance E11, Clinical
Investigation of Medicinal Products in the Pediatric
Population,8 as:
• preterm newborn infants
• term newborn infants (0 to 27 days)
• infants and toddlers (28 days to 23
months)
• children (2 to 11 years)
• adolescents (12 to 16-18 years, depending upon the geographic region)
Manufacturers must submit a PIP to the
Paediatric Committee9 (PDCO), an expert committee of the European Medicines Agency
(EMA), created by the Pediatric Regulation to
review PIPs, waivers and deferrals of pediatric
studies. EMA has 30 days in which to validate the PIP for PDCO, and PDCO must issue
a report within the following 60 days. Once
approved by PDCO, the PIP is binding on the
manufacturer unless it is formally revised due to
the availability of new information. Because the
PIP is usually submitted very early in the course
of clinical development of the product, amendments are often necessary. PDCO also reviews
all PIP amendments, and all of its decisions are
posted on a public website.10
Other Provisions of the European
Pediatric Regulation
Waivers from the requirement for pediatric studies in any of the age groups can be granted when
the product is likely to be ineffective or unsafe
in “part or all of the pediatric population,” if
the disease does not occur in pediatric patients
or if the product is not a “significant” advance
over existing treatments for children.11 Waivers
can be given in one or more age groups or for
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one or more indications. The pediatric study
“requirement does not apply to generics or similar biological medicinal products and medicinal
products authorised through the well established
medicinal use procedure, nor to homeopathic
medicinal products and traditional herbal medicinal products authorised through the simplified
registration procedures.”12
Deferrals of pediatric studies can be granted
when the information available about the
product suggests that it would be advisable to
conduct the studies at a later date. Deferrals can
also be issued to delay pediatric studies until
preliminary data on adults suggest it would be
safe to proceed in children, until an age-appropriate formulation is available or merely to avoid
undue delay in making the product available for
adult patients.
The regulation provides incentives for doing
studies in pediatric patients. If a product has
been granted a “supplementary protection certificate,” i.e., a certificate providing additional
years of exclusive marketing in the form of an
extension of patent protection (as a result of the
present application or an earlier application for
use in adults), a six-month extension of the supplementary protection certificate can be given as
a reward for the expense of conducting studies
in pediatric patients, even if the study results do
not support a pediatric indication. However, the
study results, if negative, must be added to the
labeling regardless of the approved indication.
In order to encourage pediatric studies for products that already have orphan designation for
use in adults, the regulation provides for a total
of 12 years of marketing exclusivity (exclusivity
extension of two years) for doing pediatric studies for an orphan indication rather than the 10
years provided in the EU for orphan indications
approved de novo.13 The six-month extension of
the supplementary protection certificate cannot
be added to market exclusivity given because
it is a pediatric orphan drug or to another type
of extension of exclusivity obtained for having
provided “significant clinical benefit in comparison with existing therapies.”14 (In the EU, a drug
or biologic is eligible for orphan designation
if it “is intended for the diagnosis, prevention,
or treatment of a life-threatening or chronically
debilitating condition affecting no more than five
in 10,000 persons in the European Union.”15)
For products already on the market for use
in adults that are not covered by a patent or a
supplementary protection certificate, the regulation created a special application mechanism,
the Paediatric Use Marketing Authorisation
(PUMA). A PUMA may contain data from new
clinical studies, data from pediatric studies in
the literature or data from studies in dossiers of
other approved products. This mechanism was
intended to provide an incentive for small and
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mid-size companies to develop products for use
in children. The regulation permits the use of the
EU Centralised Procedure for applications with
studies conducted under a PIP (whether MAAs
or PUMAs).16 The regulation also cross-references
an earlier regulation to provide 10 years of market protection as a reward for conducting clinical
trials in pediatric patients for products approved
under a PUMA.17
The regulation established a system of
optional, free scientific advice from EMA for
studies in pediatric patients. It also created a
public database to list pediatric studies with the
goal of preventing unnecessary duplication of
studies and of alerting regulators and researchers to areas where developing pediatric products
would be desirable. The results of all ongoing,
discontinued and prematurely terminated clinical trials in pediatric patients must be reported to
this database.
A marketing application based on studies
under a PIP must include a plan for “long-term
follow-up”18 of adverse events and of efficacy
in pediatric patients. Where there are special
concerns, a risk management plan or a plan for
postmarket studies must be submitted.
Comparison of Requirements for
Studies in Pediatric Patients in the
EU and the US
There are many similarities but also some significant differences between pediatric study
requirements in the EU and the US, as shown in
Table 1.
References:
1. Regulation (EC) No 1901/2006 of the European Parliament
and of the Council of 12 December 2006 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. European
Union website. http://eur-lex.europa.eu/LexUriServ/
site/en/consleg/2006/R/02006R1901-20070126-en.pdf.
Accessed 12 October 2010.
2. Best Pharmaceuticals for Children Act of 2002 (Public
Law No: 107-109). 4 January 2002. US Food and
Drug Administration website. http://www.fda.gov/
downloads/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/UCM049874.pdf. Accessed
12 October 2010. (Amended by the Food and Drug
Administration Amendments Act of 2007. 27 September
2007. US Food and Drug Administration website. http://www.fda.gov/downloads/Drugs/
DevelopmentApprovalProcess/DevelopmentResources/
UCM049870.pdf. Accessed 12 October 2010.)
3. Pediatric Research Equity Act of 2003 (Public Law No: 108155). 3 December 2003. US Food and Drug Administration
website. http://www.fda.gov/downloads/Drugs/
DevelopmentApprovalProcess/DevelopmentResources/
UCM077853.pdf. Accessed 12 October 2010. (Amended
by the Food and Drug Administration Amendments Act
of 2007. 27 September 2007. http://www.fda.gov/
downloads/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/UCM049870.pdf. Accessed 12
October 2010.)
4. Amending Regulation (EC) No 1902/2006 on
Medicinal Products for Paediatric Use. European Union
Table 1. Comparison of EU and US Requirements for Pediatric Drug Development
EU Pediatric Drug Development
US Pediatric Drug Development
Covered under a regulation, (EC) No. 1901/2006
(amended by 1902/2006) covering all aspects of
pediatric drug development in one document.
Covered by two separate but complementary laws,
Pediatric Research Equity Act (PREA) requiring pediatric
studies, and Best Pharmaceuticals for Children Act
(BPCA) providing additional marketing exclusivity.
Pediatric population defined as “between birth
and 18 years,” interpreted as ending after age 17
Subpopulation age groups defined in ICH guidance.
Pediatric population defined as birth to 16 years in FDA
guidance.
Subpopulation age groups defined in prior FDA guidance
and in ICH guidance.
PIP recommended for submission before start of Phase
2 and must be approved before submission of MAA. It
can be amended.
Pediatric development plan must be submitted with or
before submission of the New Drug Application.
All PIPs are reviewed by PDCO.
All pediatric development plans are reviewed by the
review division for the disease area being studied. All
Pediatric Study Requests issued by FDA, as well as
deferrals and waivers for pediatric studies, must be
approved by an internal but central FDA Pediatric Review
Committee (PeRC).
Free scientific advice available for pediatric studies.
All scientific advice provided by FDA is free.
Criteria for waiver: 1) ineffective or unsafe in part of
pediatric population; 2) disease does not occur in
pediatric patients; or 3) product is not a “significant”
advance over existing treatments for children.
Criteria for waiver: 1) pediatric studies impossible or
highly impractical (e.g. number of pediatric patients
very small or geographically dispersed); 2) ineffective or
unsafe in part of pediatric population; 3) unlikely to be
used in a substantial number of pediatric patients; or 4)
age-appropriate formulation can’t be made.
Exemptions from Pediatric Regulation: 1) generic drugs;
2) homeopathic medicines; 3) “traditional” herbal
medicines.
Exemptions from PREA requirements: 1) orphan
products; 2) generic drugs.
Provides six months of additional marketing exclusivity
for products for which pediatric information has been
added to labeling based on studies. Two years of
additional marketing exclusivity are provided for orphan
products for pediatric patients (in addition to the 10
years for orphan products for adults).
Provides six months of additional marketing exclusivity
if studies in pediatric patients are completed in
accordance with a written Pediatric Study Request
issued by FDA, but only as an extension of other
granted exclusivity. Results of all pediatric studies must
be included in product labeling.
Ten-year exclusivity is available for off-patent drugs
developed for pediatric patients; does not need to be an
extension of other exclusivity.
No exclusivity is available for developing off-patent drugs
per se.
5.
6.
7.
8.
9.
10.
11.
website. http://eur-lex.europa.eu/LexUriServ/site/en/
consleg/2006/R/02006R1901-20070126-en.pdf.
Regulation (EC) No 1901/2006, op.cit. Preamble,
Paragraph 10.
Regulation (EC) No 1901-2006, op.cit. Article 7, Paragraph
2.
Regulation (EC) No 1901-2006, op.cit. Article 2, Paragraph
1.
ICH Harmonised Tripartite Guideline:Clinical Investigation
of Medicinal Products in the Paediatric Population E11.
International Conference on Harmonisation website.
http://www.ich.org/LOB/media/MEDIA487.pdf.
Accessed 12 October 2010.
Paediatric Committee (PDCO). European Medicines
Agency website. http://www.ema.europa.eu/ema/
index.jsp?curl=pages/about_us/general/general_content_000265.jsp&murl=menus/about_us/about_us.jsp&
mid=WC0b01ac0580028e9d&jsenabled=true. Accessed 12
October 2010.
European Medicines Agency public website for posting
of decisions on PIPs. http://www.ema.europa.eu/ema/
index.jsp?curl=pages/medicines/landing/pip_search.
jsp&murl=menus/medicines/medicines.jsp&mid=WC0b0
1ac058001d129&jsenabled=true. Accessed 12 October 2010.
Regulation (EC) No 1901/2006, op.cit., Article 11,
Paragraph 1.
12. Regulation (EC) No 1901/2006, op.cit., Preamble,
Paragraph 11.
13. Regulation (EC) No 1901/2006, op.cit.Article 37, Paragraph 1.
14. Regulation (EC) No 1901/2006, op.cit.Article 36,
Paragraphs 4–5.
15. Orphan drugs and rare diseases at a glance. European
Medicines Agency website. http://www.ema.europa.eu/
pdfs/human/comp/29007207en.pdf. Accessed 27 October
2010.
16. Regulation (EC) No 1901/2006, op.cit., Preamble,
Paragraph 21.
17. Apparently stipulated by the fact that Article 38 Paragraph
1 of Regulation (EC) No 1901/2006 cross-references the
earlier “Regulation (EC) No 726/2004 of the European
Parliament and of the Council of 31 March 2004 laying
down Community procedures for the authorisation and
supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency”.
European Commission website. http://eur-lex.europa.eu/
LexUriServ/LexUriServ.do?uri=OJ:L:2004:136:0001:0033:E
N:PDF. (See Article 14, paragraph 11). Accessed 12 October
2010. The fact of this PUMA exclusivity is clearly stated on
the EMA website (viz. http://www.ema.europa.eu/htms/
human/paediatrics/pumas.htm. Accessed 12 October
2010.
18. Regulation (EC) No 1901/2006, op.cit. Preamble,
Paragraph 24.
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Authors
Raj Kishore, PhD, is senior director of regulatory affairs at
Quintiles. He has more than 20 years of regulatory experience
at FDA’s Center for Drug Evaluation and Research and in the
pharmaceutical industry. He can be reached at raj.kishore@
quintiles.com. Edward Tabor, MD, is vice president and global
head of regulatory strategy at Quintiles. He was formerly an
FDA division director in both the Center for Drug Evaluation
and Research and the Center for Biologics Evaluation and
Research. He can be reached at [email protected].
© 2010 by the Regulatory Affairs Professionals Society (RAPS).
Reprinted from the November 2010 issue of Regulatory Focus
with the permission of RAPS.
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November 2010