The 5 Challenges Pharmaceutical Industry Has to Face in Paediatric Research

Nikolaos E. Papachatzakis1, Kalliopi Sofou2

Abstract
In the era of biotechnology and sequencing of the human genome, paediatric research
is still crying out for attention from drug manufacturers and governmental agencies.
At the same time, Europe is welcoming the new legislation with the ultimate hope to
stimulate development of adequately tested and authorized medicines for paediatric
use. The issues that the pharmaceutical industry encounters remain more challenging
then ever.
How will the technical obstacles around paediatric study design and long-term
pharmacovigilance be overcome?
Will the new EU legislation manage to offset the regulatory burden and the
development costs?
Are the informed consent and assent process and its ethical implications finally
resolved?

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Introduction
Over half a century after the Nuremberg Code, with thalidomide disaster still haunting
our memory, paediatric drug development is still struggling to find its way to evolve.
Despite the public and scientific call for appropriately tested and authorized paediatric
therapies, the majority of medicines administered to the paediatric population are still
prescribed on an unlicensed basis. This ‘off-label’ use, even though lacking rigorous
scientific scrutiny, accounts for almost half percent of drug use in paediatric wards,
while the respective rate in neonatal intensive care exceeds an average of 90
percent1,2. The growing recognition for the need of systematic efforts by all
stakeholders to enhance paediatric clinical research has often been heralded by
reluctance and legislative delays.

After almost one decade of discussions about the need and content of a harmonized
approach to the conduct of paediatric clinical trials across the European Union, the
new EU Regulation on Paediatric Medicines (Regulation (EC) No 1901/2006) finally
came into full force, on January 26th, 20073. Since then, the European Medicines
Agency (EMEA) has been reinforced by the establishment of the Paediatric
Committee (PDCO), whose main responsibility is to provide scientific input on drug
development for paediatric use [Appendix I]4.

In order to align with this initiative, the pharmaceutical industry is challenged to

address several critical issues, the five major of which we attempt to identify and
further discuss in the current article.

Study Design
The first challenge that the pharmaceutical industry has to face in order to ensure
sound paediatric research is the study design. Although the new Regulation introduces
a solid framework for the conduct of paediatric clinical trials, the absence of precise
and sound design methods presents important countervailing considerations. The role
of placebo in paediatric clinical trials is an elaborate example. Is the clinical benefit of
a placebo-controlled trial counterbalancing the potentially increased risk of harm
during exposure to placebo? Do we need placebo-controlled trials when there is no
existing comparator, as in the case of antiviral agents5? The development of
guidelines for the ethical use of placebo controls per disease area would be a

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promising step; still, this initiative will require extensive discussions and advisory
boards among experts in order to reach consensus6.

An additional constraint is that for many conditions the target paediatric population is
relatively small. And there may be a number of distinct age ranges to be considered
within this population. Thus, the need for innovative study designs such as cross over
studies, with specific stratification methods, is imperative7. As pediatric age groups
vary from premature infancy to late adolescence, multiple dosage forms must be
foreseen in study design, along with bioavailability and stability evaluation for
different formulations8. The lack of validated assessment tools in this population, such
as scales and questionnaires, imposes even higher obligations not only to
pharmaceutical companies but to academic institutions as well.

Informed Consent/Assent

Informed consent is considered the cornerstone of biomedical research on human

subjects. The difference between informed consent and assent is that the latter, by
definition, is the voluntary permission granted by an individual without legal
authority9. In order to be genuine, informed consent should incorporate the following
four essential components:

1. Disclosure of all relevant information about the research

2. Comprehension of this information by the prospective participant in order to

make an informed decision

3. Freedom of the prospective participant from any coercion, undue influence,

inducement or intimidation

4. Explicit and formal consent by the participant, usually in written form10.

The ultimate purpose of such a multi-step process is to protect and promote the ethical
principle of autonomy. However, the process itself raises important ethical issues,
when it comes to the conduction of research in children and adolescents. And, first of
all, when is a child capable of providing informed assent? Unless circumstances
prevent this, children over the age of six must assent to participate in a trial9. In
general, consent is sought only from one parent or legal guardian. Children are far
more willing than their parents to participate in clinical studies, as shown in an

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unpublished study of an antibiotic authorized for adult use, conducted in 2001. Only
23 percent of parents gave their consent for their child to participate in the trial, as
opposed to an almost double percentage of children willing to participate5.

The procedure becomes more complicated as patient information must be adjusted to

age and presented to children in a simple and comprehensible manner. Obtaining
parental consent on the other hand raises other questions such as whether this is a
valid and unforced decision, considering the emotional and ‘timing’ stress the parent
is under. Indeed, one of the most intriguing challenges for the pharmaceutical industry
is to facilitate the informed consent/assent process, while protecting the privacy rights
of the child.

Pharmacovigilance
The third challenge for the pharmaceutical industry is the new pharmacovigilance
requirements, which each of 27 EU member states must comply with. As stated in
Paragraph 24 of the Regulation, “it is essential to ensure that pharmacovigilance
mechanisms are adapted to meet the specific challenges of collecting safety data in
the paediatric population, including data on possible long-term effects.” And
continues by adding that “where there is a particular cause for concern, the applicant
should submit and implement a risk management system and/or perform specific post-
marketing studies as a condition for the granting of the marketing authorization”.3

In order to secure long-term follow-up of adverse reactions, pharmaceutical

companies are encouraged to develop and implement appropriate procedures to
continue beyond patent expiry. This is particularly the case when the potential for
long-term toxicity is of great concern. In view of delayed or chronic toxicities
including effects on growth and development, a case-by-case approach should be put
in place. Specific guidance on pharmaceutical industry requirements and
commitments remains to be issued11.

Timelines
Regulatory workload has always been considered one of the most crucial challenges
for the pharmaceutical industry. A first look at the new EU Regulation fails to raise
any hopes of regulatory acceleration. It is now mandatory for pharmaceutical

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companies to submit a Paediatric Investigation Plan (PiP) to the Paediatric Committee
no later than the first phase of testing a new drug in adults is completed3. However,
this may be too early for some therapeutic areas, where a marketing company may
choose to wait in order to collect more safety and efficacy data from the adult
population. Prior to submitting the PiP, meaning “a research and development
program aimed at ensuring that the necessary data are generated determining the
conditions in which a medicinal product may be authorized to treat the paediatric
population”, the pharmaceutical company must notify EMEA two months in advance
of its intention to submit an application for a PiP12. After submission and approval by
the PDCO, follows the standard procedure of submission and approval by Local
Ethics Committees and Regulatory Authorities. It is noteworthy that, as from July
26th 2008, if a company submitting a Marketing Authorization Application in Europe
does not have an approved PiP in place, the new drug will be automatically rejected,
leading to significant losses in terms of time and investment13.

Economic burden
Although there are financial motives, these may not fully offset the development cost
for unmet medical needs proposed by the PDCO; let alone the major investment of a
marketing company in a PiP that may eventually be rejected. As stated in the
Paragraph 32 of the Regulation, “an inventory of the therapeutic needs of the
paediatric population should be established by the Paediatric Committee after
consultation with the Commission, the Member States and interested parties, and
should be regularly updated. The inventory should identify the existing medicinal
products used by the paediatric population and highlight the therapeutic needs of that
population and the priorities for research and development. In this way, companies
should be able easily to identify opportunities for business development..”3.

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Moreover, as stated in paragraph 33, “clinical trials in the paediatric population may
require specific expertise, specific methodology and, in some cases, specific facilities
and should be carried out by appropriately trained investigators”3. Pharmaceutical
companies need not only to integrate paediatric assessments into the standard drug
development, but also certify the competence of highly trained personnel, within and
outside the pharmaceutical field.

Conclusion
It is unfortunate but true that children have not benefited from advances in drug
development to the same extent as adults14. Being of lower marketing potential,
paediatric clinical trials have been systematically supplanted. As paediatric research
proceeds, the need to develop successful strategies in order to ensure that children and
adolescents will benefit from a safe and controlled clinical environment becomes even
more imperative. Successful implementation of the new EU Regulation requires close
and effective collaboration between all stakeholders concerned, meaning the
paediatric population and their parents/care-givers, regulatory authorities, the
pharmaceutical industry, health professionals, patient organizations, national health
care systems and the media. As for the pharmaceutical industry challenges, ‘Alea
Jacta Est’!

References

1. Clinical Trials and Children's Medicines. ABPI briefing paper.

http://www.abpi.org.uk/publications/briefings/clinical&child_brief.pdf

2. European Commission Staff Working paper 13880-04 2004

3. 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

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-
1/reg_2006_1901/reg_2006_1901_en.pdf

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4. The Paediatric Committee (PDCO)
http://www.emea.europa.eu/htms/general/contacts/PDCO/PDCO.html

5. Gill D, Kurz R: Practical and ethical issues in pediatric clinical trials. Applied
Clinical Trials 2003;Sep 1

6. Flynn JT: Ethics of placebo use in pediatric clinical trials: The case of
antihypertensive drug studies. Hypertension 2003;42;865-869

7. Smit-Marshall P: Pediatric policies grow up. Applied Clinical Trials 2007;Jul

1

8. ICH E11, Clinical Investigation of Medicinal Products in the Pediatric

Population. Guidance for Industry, 2000

9. Gans-Brangs KR, Plourde PV: The evolution of legislation to regulate

pediatric clinical trials: Present and continuing challenges. Advanced Drug
Delivery Reviews 58 (2006) 106– 115

10. Council for International Organizations of Medical Sciences (CIOMS).

International ethical guidelines for biomedical research involving human
subjects. Geneva: CIOMS, 2002

11. O’Donnell P.: Preparing for Europe’s pediatric rules. Applied Clinical Trials
2007;Aug 1

12. EC/1901/2006: Practical Aspects.

http://www.emea.europa.eu/pdfs/human/paediatrics/practical_aspects.pdf

13. Frequently asked questions on regulatory aspects of Regulation (EC) No

1901/2006 (Paediatric Regulation) amended by Regulation (EC) No
1902/2006
http://www.emea.europa.eu/pdfs/human/peg/52008506en.pdfEC/1901/2006

14. Schreiner MS. Safety and effectiveness data: will children gain access? Am
Heart J. 1998;136:4–5.

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 Authors Details
1
Nikolaos E Papachatzakis is a freelance Medical Writer based in Gothenburg,
Sweden.
2
Kalliopi Sofou is a Medical Advisor based in Athens, Greece.

Conflict of Interests

The authors declare that no competing interests exist.

Affiliation/Regulation
Council for International Organizations of
Medical Sciences (CIOMS)
EC/1901/2006
EC/1901/2006: FAQs
EC/1901/2006: Practical Aspects
APPENDIX I
Link
http://www.cioms.ch/index.html
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-
1/reg_2006_1901/reg_2006_1901_en.pdf
http://www.emea.europa.eu/pdfs/human/peg/52008506en.pdf
http://www.emea.europa.eu/pdfs/human/paediatrics/practical_aspects.pdf

EU Directives
European Federation of Pharmaceutical
Industries and Association
European Medicines Agency (EMEA)
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev1.htm
http://www.efpia.org/content/
http://www.emea.europa.eu/

Good Clinical Practice (GCP) http://www.emea.europa.eu/Inspections/GCPgeneral.html

International Conference on
http://www.ich.org/cache/compo/276-254-1.html
Harmonization (ICH)
http://www.emea.europa.eu/htms/general/contacts/PDCO/PDCO.html
Paediatric Committee (PDCO)

US Food and Drug Administration (FDA) http://www.fda.gov/