FAQ

A clinical trial is a study conducted to evaluate a drug. Each study is designed to answer scientific questions and find new and better ways to cure people. With any new drug there are benefits as well as possible risks. There may also be some risks that are not yet known. Clinical trials help us find out if promising new treatments are safe and effective for patients. During a clinical trial, more and more information is gained about a new drug, its risks, and how well it may or may not work. You may be interested in or asked to enter a trial. Learn as much as you can about the clinical trial before deciding. Only patients that volunteer take part in a clinical trial.

Paediatric clinical trial is a study conducted in paediatric patients, i.e. children and adolescents from 0 to 18 years of age. Generally the paediatric clinical trial needs to be tailored to the patient group as well as to the disease and therapeutic area. When designing a paediatric clinical trial, it is also important to consider each paediatric class, since children are not small adults and respond very differently to medicines at various ages and stages of their development.

Many medicines administered to children have not been specifically developed for them. This means that no paediatric clinical trials were conducted to determine if the drug is safe and effective in children. Medicines authorized for adults are usually administered to children by decreasing dosages on the basis of weight, which is extremely hazardous. Serious consequences, inefficacy and side effects often stem from incorrect dosage. This use, defined as off-label in children, is widespread and has been an increasing concern over the last years. In the European Union (EU), fifty per cent or more of medicines used in children have never actually been studied in this population, but only in adults, and not necessarily in the same indication (or the same disease). The general lack of information and appropriate pharmaceutical formulations to support the administration of many medicines in children may expose them to unwanted side effects or under-dosing without the expected efficacy. The risk of adverse drug reactions (ADRs) related to the unlicensed and off-label use of drugs in children is elevated. The need for more studies to obtain paediatric information for medicines used in children is now a matter of consensus on a global basis.

Yes, the European Community provide several incentives. Among these, there are the funds granted through the Framework Programmes, available to individuals, academics or research centres and networks, or to both small and large companies. In particular, funding is directed to the performance of clinical trials investigating off-patent medicines (drugs no longer covered by a patent) used off-label in paediatrics. A maximum of 6 million Euros per project and a total of 30 million Euros for the next 2 years are provided.

All research involving human subjects should be conducted in accordance to three basic ethical principles:

• Respect for the person. This notion includes: respect for autonomy, which requires that those who are capable of deliberation about their personal choices should be treated with respect for their capacity for self-determination; and protection of persons with impaired or diminished autonomy, which requires that those who are dependent or vulnerable should be afforded security against harm or abuse.
• Beneficence. This principle refers to the ethical obligation to maximize benefits and to minimize harms and requires the risks of research to be reasonable in the light of the expected benefits, the research design to be sound, and the investigators to be competent both to conduct the research and to safeguard the welfare of the research subjects.
• Justice. This notion refers to a fair distribution of burdens and benefits of research.

The legal definition of a minor may differ according to Member States’ legislations. It generally refers to a person who has not reached the legal age of adulthood (usually 18 and above, rarely 16). In the Clinical Trials Directive (Dir. 20/2001/EC) we find both the terms children and minors, while in the ICH E11 guideline (ICH Topic E11, 2000) the paediatric population is defined according to different age categories from birth up to 16-18 years (dependent on region).

A paediatric clinical trial may be undertaken only if:

• the informed consent of the parents or legal representative has been obtained; consent must represent the minor’s presumed will and may be revoked at any time, without detriment to the minor;
• the minor has received information regarding the trial, the risks and the benefits, according to its capacity of understanding and from staff with experience with minors;
• the explicit wish of a minor who is capable of forming an opinion and assessing this information to refuse participation or to be withdrawn from the clinical trial at any time is considered by the investigator, or where appropriate the principal investigator;
• no incentives or financial inducements are given except compensation;
• some direct benefit for the group of patients is obtained from the clinical trial and only where such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods; additionally, such research should either relate directly to a clinical condition from which the minor concerned suffers or be of such a nature that it can only be carried out on minors;
• the corresponding scientific guidelines of the Agency have been followed;
• clinical trials have been designed to minimize pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress have to be specially defined and constantly monitored;
• the Ethics Committee, with paediatric expertise or after taking advice in clinical, ethical and psychosocial problems in the field of paediatrics, has authorized the protocol; and the interests of the patient always prevail over those of science and society.

The Clinical Trials Directive defines the Ethics Committee: “An independent body in a Member State, consisting of healthcare professionals and non medical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent.”

The reference document is “ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL PRODUCTS WITH THE PAEDIATRIC POPULATION”, released by the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC1 relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, chaired by the European Commission. The document provides recommendations on various ethical aspects of clinical trials performed in children from birth up to the legal age of adulthood.

The Clinical Trials Directive does not provide any definition of legal representative, as this varies according to the Member State’s legislation. In most clinical trials performed in children, the legal representative will be one or both parents.

An ADR is a response to a medicinal product which is noxious and unintended and which occurs at doses normally used for the prophylaxis, diagnosis or treatment of a disease or for the restoration, correction or modification of a physiological function.

The definition of medication error released by The National Coordinating Council for Medication Error and Prevention NCCMERP is: “… any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems including: prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use”.

The factors that predispose children to ADRs are similar to those in adults, but can be enhanced by age-related differences in physiological function, differences in patterns of the disease,. Recent studies conducted in the general population confirm that age is a significant correlate for ADR incidence.

The definition of a serious ADR in children does not different from the one in adults. A serious ADR is any problematic medical occurrence that:

• results in death;
• is life-threatening;
• requires inpatient hospitalisation or prolongation of existing hospitalisation;
• results in persistent or significant disability/incapacity: is a congenital anomaly/birth defect.

An unexpected ADR is one whose nature, severity or outcome is not consistent with domestic labelling or marketing authorization, or expected from the pharmacological/toxicological characteristics of the drug. An increased frequency of expected ADRs should also be considered as unexpected for the purposes of expedited reporting.

A regulation is a legislative act of the European Union which becomes immediately and simultaneously enforceable as law in all Member States. Regulations are to be distinguished from Directives which, at least in principle, need to be transposed into the national law.

Before any medicine is authorised for use in adults, the product must undergo extensive testing including pre-clinical tests and clinical trials to ensure that it is safe, of high quality and effective. The same procedure however was not always be applied to medicines used to treat children. Studies showed that over 50% of the medicines used in children were not tested for use in this specific age group. The absence of suitable authorised medicinal products to treat conditions in children results from the fact that frequently pharmaceutical companies do not perform the necessary research and development to adapt medicinal products to the needs of the paediatric population. This leaves health care professionals with no alternative other than to use products “off-label” or to use unauthorised products with the associated risks of inefficacy and/or adverse reactions.

REGULATION (EC) No 1901/2006 of 12 December 2006 on medicinal products for paediatric use entered into force on 26 January 2007, i.e. 30 days after publication in the Official Journal of the European Union.

The objective of the Paediatric Regulation is to improve the health of children in Europe by:

• increasing the development of medicines for use in children;
• ensuring that medicines used to treat children are: 1. subject to high quality research, 2. appropriately authorised for use in children;
• improving the information available on the use of medicines in children.

The achievement of such objectives should be gained without subjecting children to unnecessary clinical trials or delaying the authorisation of medicines in the adult population.

• Obligation of paediatric research (PIP – Paediatric investigation Plan) for every new drug developed for adults and having a potential use for children;
• Creation of an inventory of specific needs for paediatric medicinal products;
• Creation of a Paediatric Committee (PDCO) including patient representatives at the European Medicines Agency (EMEA);
• Six-months extension of the patent for the paediatric formula of existing ‘still under-protection’ adult medicine;
• Two-years extension of market exclusivity for orphan drugs for children (12 years in total instead of the 10 years for adult orphan drugs);
• Financial support via the EU Framework Programmes for research on old (off-patent) drugs to study and develop paediatric use;
• Implementation of a process to avoid unnecessary clinical studies on children;
• Specific label products studied in children and authorised: the Paediatric Use Marketing Authorization (PUMA).

Started as a Network of Excellence funded under the Sixth EU Framework Programme for Research and Technological Development (FP6), the Task-force in Europe for Drug Development for the Young (TEDDY) is today an independent multidisciplinary, multinational network aimed at facilitating the performance of good quality paediatric studies and research.

The TEDDY objectives are:

• to promote and conduct clinical research on medicinal products in children in compliance with EU legislation and guidelines;
• to collaborate with existing paediatric networks and research organization in the framework of the European network of paediatric research at the EMEA and other International initiatives, such as GRIP;
• to develop educational tools (tailored to Industry, Public Agencies, researchers, health professionals, Ethics Committees) in order to favour awareness on the topics of paediatric research.

EPMD is the European Paediatric Medicines Database created by TEDDY. It collects information on the drugs authorised by the EMEA under the centralised procedure.

The objectives of the EPMD are:

• to create a harmonised, integrated and reliable European source of information by collecting data from different sources (national authorities, regulatory bodies, pharmaceutical companies;
• to support the transparency of the information concerning the innovative drugs currently used in children, including information concerning performed studies or restrictions on use;
• to identify therapeutic areas uncovered by innovative drug treatments for children;
• to provide health professionals, paediatricians, institutional bodies, companies, patients’ associations, parents and children with appropriate information concerning the rational use of paediatric medicines;
• to provide the knowledge necessary for the creation of the information centre.

The EPMD also aims at identifying unmet medical needs and providing appropriate information concerning the rational use of paediatric medicines for health professionals, paediatricians, institutional bodies, companies, patients’ associations, parents and children.