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In Search of Safe and Effective Medicines

Paolo Tomasi at the European Medicines Agency (EMA) assesses the global landscape following the impact of key paediatric regulations and sets out ways to promote and facilitate clinical trials in children

The principle of using children as the subjects of scientific studies has attracted a considerable degree of controversy. In the past, children used to be ‘protected’ from research, having been recognised as subjects who are vulnerable and unable to provide informed consent. Many of the medicinal products currently used to treat the paediatric population have not been studied or authorised for such use. Market forces alone have proven insufficient to stimulate development of medicinal products for the paediatric population.

EU Regulation 1901/2006 – the ‘Paediatric Regulation’ – provides a systematic approach to the development of medicinal products intended for use in the paediatric population (1). This legal framework followed the first US initiative (the Best Pharmaceuticals for Children Act), which has been in place since 1997.

Pharmaceutical companies are now required to perform clinical studies in children before being able to apply for marketing authorisation of a new medicinal product in the EU (or for a new indication, dosage form or route of administration of an authorised, patented product), unless they have agreed a waiver or a deferral with the Paediatric Committee (PDCO) of the European Medicines Agency (EMA).


The term ‘children’ includes the paediatric population from birth to 18 years. This group’s characteristics are extremely diverse; weights can start at less than 1kg but extend up to a typical young adult’s weight, while cognitive development, physical and sexual maturation and biochemical characteristics are all elements that change with each individual. When organising a good clinical trial in children, certain factors require close inspection.

Need, Feasibility and Design of Trials
Once the paediatric need(s) and the study question have been clarified, the possibility of replacing some studies, or reducing the number of patients involved, through extrapolation, modelling and simulation should be discussed. Unnecessary clinical trials in children should be avoided, and the use of extrapolation for efficacy is encouraged by current guidelines (2). If extrapolation is not possible, new clinical data are needed.

In some instances, a feasibility study should be undertaken in order to determine whether it is possible to complete a significant clinical trial. The analysis of feasibility should always be justified with available evidence. A properly conducted feasibility study may constitute the basis to request regulatory agencies to grant a waiver from conducting clinical trials in one or more subsets of the paediatric population. A paediatric trial should not be an adaptation of the adult protocol, but must be conceived and developed in its own right. This may involve particular attention to the exploration of alternative designs.

Bayesian approaches, for example, have been used successfully in sequential dose-finding studies. This may allow a reduction in the number of patients that are required to arrive at a reliable conclusion when performing efficacy studies in children, when the inclusion of weighted prior evidence from studies in adults is admissible (partial extrapolation).

Paediatric studies may need very different primary endpoints from those of adult studies: different effect size; a better spontaneous outcome in the control group; or the inability of the child to perform a particular test. If the primary endpoint suitable for adult trials cannot be used in children, in many cases it should still be included as a secondary endpoint in order to allow comparison among different trials in children (and in adults). The time of assessment for a primary or secondary endpoint can be different in children and adolescents (shorter or longer than in adults).

In terms of sample size determination, sufficient statistical power is sometimes difficult to achieve due to the limitations of the primary endpoint, effect size, variation of the outcome measure, number of available patients, or (usually) a combination of these factors. This should not necessarily constitute adequate justification to declare the study unfeasible: in some situations, an underpowered study may be superior to no data.

The amount of blood that can be drawn from children is limited – a rule of thumb suggests less than three per cent of total blood volume per month (less than 2.4 ml/kg of body weight), and not more than one per cent at any single time (3). Non-invasive methods may be preferable (assays in urine, saliva); additionally, reduction of blood sample volume can be achieved through the use of microassays and microdoses of non-radioactive isotopes for pharmacokinetic studies.

The minimisation of pain and distress should be a central part of paediatric protocols, particularly in younger children who may express pain and distress in different ways, making it difficult to detect and quantify.

An age-appropriate trial setting should be established; the facilities should be friendly and appropriate for the agegroups involved, which means for example, that a paediatric setting for toddlers may not be appropriate for a teenager. Staff, including nursing and auxiliary staff, need to be experienced in managing a clinical research protocol, and specific training should be a requirement. Flexibility should be exercised in order to encourage parent attendance and training.

Practical Conduct of the Trial and Investigators
The ability to select and monitor clinical trial centres is key to the success of a study. Firstly, it is important to identify the right investigators: specialised groups, rather than general paediatricians, may offer the best chances of recruitment and successful completion of the trial. However, the involvement of paediatric research networks probably offers the best opportunities.

Secondly, the training and experience of the investigators, the sponsor’s prior knowledge of the investigator, the setting (for example, primary care centres versus referral hospital) are all factors that may affect the competence and training requirements of the trial investigators, and in turn influence the success of the trial.

Lastly, motivating trial investigators may increase the likelihood that the clinical trial will be run correctly and be completed on time. Motivating investigators through involvement in protocol development, running discussions during the clinical trial monitors’ visits, sending regular trial newsletters, and conducting investigator meetings and workshops should be used, rather than reliance on the incentive of the fees paid to the centre or the investigator. Care should be taken, however, to avoid excessive incentives; these incentives should, in any case, be considered by the ethics committees.


According to the declaration of Ottawa, every effort should be made “to ensure that children share in the benefits from scientific research relevant to their individual age-related health needs” (4). Issues such as consent, assent, risk/benefit and so on, are discussed in pivotal documents which are easily accessible.

Pivotal Documents
The International Conference of Harmonisation (ICH) publishes several guidelines, among which the most relevant is ICH guideline E11, which contains several paragraphs on ethical aspects (2.6.1 to 2.6.5) (2). The clinical trials directive applies to clinical trials with at least one site in the EU (5). It sets out in clear terms the way to protect subjects included in a trial, and Article 4 deals directly with ethical issues in the paediatric population.

Additionally, a document published in 2008 by the European Commission contains the recommendations of the “Adhoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use” (3). This document contains a discussion of all ethical aspects of clinical trials in children, and should constitute required reading for all healthcare staff involved in paediatric clinical research.

Clinical Trials in Developing Countries
Following EU and US paediatric legislation, many more clinical trials have to be performed in children and this will lead to recruitment of patients across the world, possibly giving rise to ethical issues linked to the level of ethical protection in some regions or countries. These are not limited to the paediatric population, but are even more acute due to the vulnerability of children.

When a trial aimed at supporting a marketing authorisation application is performed outside the EU, European legislation requires ethical standards at least equivalent to those in EU. The ethical considerations suggest that the Ethics Committee’s opinion is obtained in the EU in addition to the countries where the trial is going to be performed.

Without a doubt, proper study design, preparation, education and training are the best measures to prevent problems. Good monitoring before, during and after the trial is key in order to ensure that the requirements are met.

Several aspects are critical when considering the ethical conduct of studies in countries outside the EU. For example:

  • Paediatric expertise in the local Ethics Committee/IRB must be available
  • Informed consent by legal representatives (usually parents) and assent from the child is needed. Consent by other relatives (for example grandparents) could be critical in certain societies
  • There must be an absence of inducement: this may be more difficult to achieve where, for example, participation in a clinical trial would be the only way to obtain access to medical care; a related issue is availability of treatment after completion of trial

Increasing international cooperation among regulatory authorities and ethics committees is a key factor when ensuring that a robust framework is established for the conduct of clinical trials and the protection of trial participants.


The EU Paediatric Regulation provides a system of incentives, rewards and obligations to promote the development of medicinal products for use in children. The basic reward is an extension of the supplementary protection certificate (SPC) for six months, when studies have been conducted in compliance with an agreed paediatric investigation plan (PIP) for a patented medicinal product. There are other incentives, such as a two-year extension of market exclusivity for orphan-designated medicinal products, free scientific advice and protocol assistance for paediatric use questions. However, in addition to the main incentives reported above, other provisions of the EU regulatory and scientific framework are aimed at facilitating the conduct of clinical trials in children:

PDCO Opinion on Paediatric Investigation Plans
The procedure for the discussion of the proposed PIP offers the applicant the combined expertise of the EMA scientific staff, more than 50 PDCO members of carefully selected and multidisciplinary expertise, and additional external experts. The output of these experts is condensed in a summary report and constitutes the basis for the PDCO opinion agreeing the studies and measures (including clinical trials) contained in the adopted opinion on the PIP.

The PDCO has established a series of principles for its operation, including the level of detail on clinical trials that need to be included in its opinions. This, along with other factors, can be seen in the template for the PDCO opinion, recently updated and available online (6).

Companies are requested to present their proposed clinical trials in a standardised format (6). This form for non-clinical and clinical trials contains a number of fields (design, objective, inclusion and exclusion criteria, primary endpoint, and so on), used to identify those key binding elements that will be part of the opinion. It is important to note that these key binding elements are only a part of the clinical trial protocol.

As of September 2010 the PDCO has adopted 285 opinions in which a PIP, containing one or more studies in children, was agreed. The PDCO also granted 167 product-specific waivers to the obligation of performing studies for a paediatric condition or indication.

The PDCO has also granted, so far, 141 modifications to a previously agreed PIP, which corresponds to approximately half of the PIP opinions; this figure highlights the degree of flexibility of the process, whereby agreed trials can be modified if needed.

In a substantial number of cases, a placebo rather than active control arm has been requested or agreed by the PDCO. This certainly reflects the lack of medicines authorised for children, but more generally it may also reflect a scarcity of evidence to support the choice of any active control products in the paediatric population (authorised or not). In addition, using an active control comparator generally implies a non-inferiority design of the trial, rather than superiority; unfortunately, non-inferiority designs with sufficiently stringent delta often require larger sample sizes, which may be incompatible with the actual paediatric population available for clinical trials.

Funding of Study for Off-Patent Medicines
The 7th European Framework programme provided funds for the development of offpatent medicines for paediatric use (7). Applicants are requested to submit proposals based on the ‘Priority list of off-patent medicinal products’ created and revised yearly by the EMA. Twelve projects out of 37 proposals were funded in the first three calls, with a total contribution from the EU of €56 million.

Clinical Trials Facilitation Group
The Clinical Trials Facilitation Group (CTFG) is composed of representatives of the clinical trial units of the National Competent Authorities from EU member states, and its aim is to facilitate the approval of clinical trial applications (CTA) in multiple member states through their voluntary harmonisation procedure and voluntary conformity of the involved member states to their agreed evaluation of a trial.

A collaboration exists between the EMA and the CTFG to facilitate access of the CTFG to the results of the evaluation of PIP applications by the PDCO. The aim of this activity is to ensure greater sharing of expertise and a consistent approach of CTFG and PDCO, while facilitating the assessment and approval of CTA by the groups involved.

The EudraCT database is being modified in order to allow public access to information initially on all paediatric clinical trial protocols, and subsequently also to a summary of the results of those studies. This includes clinical trials conducted wholly outside the EU, which are included in a PIP.

EudraCT will allow the sharing of protocol designs from the time of actual initiation of the clinical trial and will ensure the early publication of summaries of the results, whether positive or negative (and so avoiding the ‘publication bias’).

Paediatric Network of Networks
As one of the provisions of the Paediatric Regulation, the EMA is creating and managing the European Network of Paediatric Research at the EMA (ENPREMA). The aims of this network of networks are to:

  • Link existing networks, investigators and centres together with specific paediatric expertise
  • Build up competences at a European level
  • Facilitate the conduct of studies and avoid duplications

More than 50 networks and centres have been identified and invited, and they have submitted their self-assessment documents for inclusion in the network.


Normal pharmacovigilance obligations apply to all marketing authorisation holders for all adverse drug reactions (ADRs) reported in children. The low numbers of children treated with medicinal products in clinical trials makes it more difficult to detect anything less frequent than common reactions. Serious reactions are often rare and may not be recognised until a large number of people have received the medicine. There is, therefore, a need to continue to obtain more safety information from spontaneous reports of adverse drug reactions.

Some adverse drug reactions differ in children compared to adults. Disturbances in growth, bone development, pubertal development or brain maturation for example, are not observed in adults, and can only be detected in children. Longterm follow-up may also be necessary in order to detect such effects. Neonates and infants pose particular problems due to the ongoing maturation of most organ systems and apparata.

A more modern, proactive approach to conducting paediatric pharmacovigilance needs to be developed. Specific recommendations have been provided in the EU in the guideline on conduct of pharmacovigilance for medicines used in the paediatric population. Since information gained based on spontaneous reporting may not be sufficient, special consideration should be given to additional post-authorisation study activities in this population. Cohort and case control studies should be considered. Specialised disease or product registries and drug prescription databases can capture relevant information prospectively.

Long-term pre-registration studies for safety (and maintenance of efficacy) are sometimes required by the PDCO to agree on a PIP. However, in most cases, the key binding element in a PIP only requires evidence that specific paediatric safety aspects of a medicinal product is monitored (for example, periodic safety follow-up of auxological and pubertal parameters) and that the studies have started at the time of application for a marketing authorisation or that it is taken in account in the EU risk management plan.


Addressing the needs of children is an important goal for any society, and this does not only apply to developed countries. Better availability of safe and effective medicines for children, achieved through appropriate studies and research, is one part of this objective. As the Nobel Prize Winner, Nelson Mandela, wrote, “There can be no keener revelation of a society’s soul than the way in which it treats its children”.


  1. EU Regulation 1901/2006, the ‘Paediatric Regulation’,
  2. ICH E11, Clinical investigation of medicinal products in the paediatric population,
  3. European Commission, Ethical considerations for clinical trials on medicinal products conducted with the paediatric population,
  4. WMA Declaration of Ottawa on Child Health,
  5. Clinical Trials Directive, 2001/20/EC,
  6. PDCO opinion,
  7. 7th European Framework programme,

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Paolo Tomasi is Head of Paediatric Medicines at the European Medicines Agency in the Sector Human Medicines Special Areas. He is a physician by training, with a doctorate in Endocrinology and Metabolism, and his main research interests have been in reproductive and paediatric endocrinology, andrology, and internal medicine. He is Clinical Assistant Professor of Internal Medicine and Endocrinology at the University of Sassari, Italy, and is the author of more than 40 publications indexed in Medline.
Paolo Tomasi
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