Objective Paediatric clinical trials are often conducted as multinational trials. Informed consent or assent is part of the ethics committee approval for clinical trials. The consent requirements vary between countries due to national laws and regulations, which are not harmonised in Europe. These discrepancies can present challenges for paediatric clinical trials. The aim of this study was to assemble these consent and assent requirements across the European Economic Area. The collated national requirements have not been publicly available before, despite a real need for this data.
Methods National consent and assent requirements for paediatric clinical trials were analysed and collated for 25 European Union Member States and 2 European Free Trade Association countries until the end of 2014. The data were retrieved from existing databases and through communication with the competent authorities and selected ethics committees. Results from a literature search for international or national guidelines, declarations and conventions and academic societies' publications served as comparison material.
Results Consent and assent requirements are heterogeneous across these countries. We compiled our findings in ‘The Informed Consent and Assent Tool Kit’, a table including 27 national consent and assent requirements listed by individual country.
Conclusions Wide variation in paediatric consents and assents presents challenges for multinational paediatric trials in Europe. The toolkit is available for all those involved in paediatric clinical trials and ethics committees, providing a new platform for proactive feedback on informed consent requirements, and may finally lead to a needed harmonisation process, including uniform standards accepted across Europe.
- clinical trials
- informed consent of minors
- regulations and guidelines
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What is already known on this topic?
There are noticeable differences between national consent and assent requirements for paediatric clinical trials in Europe due to national laws and regulations.
The international and the ethics societies’ guidelines are not based on uniform standards and rarely provide detailed consent or assent recommendations for children.
A single source of comprehensive multinational data on informed consent and assent requirements of paediatric clinical trials across Europe is not publicly available.
What this study adds?
The ‘Informed Consent and Assent Tool Kit’ is a publicly available resource for stakeholders involved in the running of paediatric clinical trials in Europe.
These data provide a new platform for proactive feedback from stakeholders to maintain a common resource and approach to consent and assent requirements in Europe.
These data hope to promote discussion for long-term decisions and practical changes leading to uniform ethics committee procedures across the European Economic Area.
Clinical trials (CTs) in children are often conducted as multinational, multicentre trials, necessitated by small patient populations, rarity of disease and limited specialist facilities. As CTs need a separate competent authority (CA) and ethics committee (EC) approval in each participating country, the pharmaceutical industry and investigators spend much time and resources preparing documentation and correspondence to these submissions.
In January 2007, the European Union (EU) Paediatric Regulation ((European Commission) No 1901/2006)1 came into force requiring the conduct of more paediatric CTs to facilitate the development and accessibility of medicinal products for children. A further EU CT Regulation will come into force after 28 May 2016,2 but while this harmonises the clinical trial application (CTA) process, it does not address the diversity in review and conduct of EC approvals at each site.
The process of obtaining EC approval (with consent or assent requirements for children) is not harmonised in the EU. Despite internationally accepted ethical principles3–11 and several EU-level guidelines,12–16 this area presents a major challenge for paediatric CTs across the EU. Although the doctrine of consent is an ethical cornerstone of medical research conducted in humans, special provisions for children vary between and, in some cases, within countries due to differences in national laws and practices.
Within the European Economic Area (EEA), three regulatory frameworks govern the conduct of paediatric research: the Convention on Human Rights and Biomedicine (the Oviedo Convention);12 Directive 2001/20/EC (European Commission Directive)14 and the Paediatric Regulation ((European Commission) No 1901/2006).1 Discrepancies exist between these three frameworks. For example, the veto power of a child to participate in research is not covered in the Paediatric Regulation, while the Oviedo Convention allows a more extensive decision-making capacity by the child than the European Commission Directive, which relies on investigator’s consideration of the explicit wish of a child. The aim of this work is to describe the heterogeneity in consent and assent requirements for paediatric CTs and to provide a tabulated summary of these requirements by country as a tool for stakeholders preparing paediatric CT submissions in the EEA.
The working group (WG) of the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) collected specific legal requirements of consent and assent for children and adolescents from the national legislations of 25 EU member states and 2 European Free Trade Association (EFTA) countries (Norway and Iceland) during 2014. The primary data source was a repository of EC submissions from national authorities provided by the Contract Research Organization (CRO), PRA Health Sciences (PRAHS).17 Secondary sources were publicly available data found on national websites of regulatory authorities, such as Medicines Agencies and National Ethics Committees. Additional data came through Regulinx,18 a UK-based company specialised in consulting on regulatory affairs, and from the Finnish Investigators Network for Pediatric Medicines (FinPedMed).19
Table 1 provides a snapshot of the information collated in 2014. The data are arranged by country under three main headings. The first heading, ‘Consent/Assent from child’, includes data on the legal age of consent and mandatory or suggested age ranges defined for assent (or consent if assent is not used). The second heading, ‘Consent from parent(s)/guardian(s)’, includes legal requirements for the number of required signatories. The third heading, ‘General informed consent information’ includes official language requirements and consent template(s), guidelines or additional national information with existing web links.
In addition, the WG systematically searched online sources to identify subject-related articles, learned societies’ recommendations and ethical guidelines, conventions and recommendations. The search was conducted in the PubMed (US National Library of Medicine, National Institutes of Health) database, EU Commission website, national competent authorities’ websites and Google sources using the keywords: ethics, guideline, regulations, paediatric, minors, children, biomedical research, clinical trials, human rights and children’s rights. The search resulted in 28 relevant documents related to medical research ethics on humans and, more specifically, on children. Ten had a worldwide scope, nine a continental or national scope, and nine were publications from academic societies.2–14 ,20–34 These documents were compared with the current official and legal recommendations by verifying the consent-related and assent-related texts of these documents.
Finally, personal experiences of the WG members (ie, in the conducted multicentre trials and communication with ECs) were used for supplementary comparison. Once all the data sources for consent and assent requirements in the EEA had been collated, the WG compared and analysed the sources of discrepancy in practice across the jurisdictions. This revealed several discrepancies, which are addressed in the discussion section.
Assent and consent: differences in use and definitions
Both the term ‘consent’ and ‘assent’ are interpreted differently in legal texts between EEA countries. Generally, each country's national legislation includes legal age ranges and requirements for either consent or assent from a child, in addition to any legal (parental or guardian) signatures. The definition of these two terms rests on the need of these signatures: either given by the trial subject alone, or in conjunction with the parents/guardians. Usually, consent is defined according to the legal age limit of majority, which differs between countries. This is not the case in all countries, like the Netherlands where infant informed consent is needed, in addition to parental consent in children between 12 and 17 years of age. Assent is a non-legal agreement, and an additional parental/guardian signature (consent) is always required before the participation of the child in a trial is legally accepted.
Differences in consent and assent age limits and legal signatures
In most of the EEA countries, 18 years is the legal age for independent consent, but the following exceptions should be noted: 14 years in Austria, 15 years in Finland and Denmark and 16 years in the UK. These exceptions come with certain limitations and with the obligation to notify parents/legal guardians. However, across all the EEA countries, 32 different age groupings to the legal age exist for recommended additional assent or consent needed from the child participating in the CT. These groupings include, for example, 4–11 years, 12–14 years and 14–17 years. Only three countries (Croatia, Lithuania and Slovakia) have not specified age groups for assent or consent.
Differences are also seen in the requirement of signatures from parents or legal guardians. Seventeen countries (63%) require signatures of both parents in addition to the child’s own assent or consent. Specific guidelines with consent form templates and additional aid material (eg, pictures) for children in paediatric CTs have been generally accepted by some EU member states (eg, Finland and UK).
The United Nations Convention on the Rights of the Child defines a child as everyone under 18, unless, ‘under the law applicable to the child, majority is attained earlier’.3 For children below that age, there are noticeable differences between national and organisational regulations on ethical consent in paediatric CTs. These concern specifically non-uniform age limits and age ranges, different definitions for legal consent and the requirement of parental or legal guardian signatures.
It appears that these criteria, for unknown reasons, are not uniformly defined in European guidelines or recommendations. We also found that the international and the ethics societies’ guidelines and recommendations rarely detail consent or assent procedures for children,7 ,13 ,27–31 but often very generic instructions without specific definitions.2–6 ,8–12 ,20–26 ,32–34 For the greater part, these criteria do not seem to be based on the developmental stage of the child and his/her competency level for informed consent or assent. Competency, in addition to health condition, is important for determining further actions if trial subjects reach the age of majority during the study and need to give their own (legal) consent to continue.2
The terms ‘consent’ and ‘assent’ are also not defined in general guidelines and are not harmonised across the EEA. Some European countries use the term consent for both minors (older children below legal adult age) and parents (legal guardians). Usually, the term assent refers to a child's or minor's agreement to the trial (not legally valid on its own), while consent is documented through legal signature(s) by the parents (guardians) or the child, when the child is above the legal age.
There are more than 1000 ECs in Europe,35 which result in substantial variability of EC compositions and practices,36–38 with consequently a certain degree of inconsistency in the required consent and assent documentation for multinational and multicentre trials. Moreover, much time and resources may be needed to obtain approvals. To manage these inconsistencies and to reduce the duplicative workload, sponsors are recommended to perform an iterative or sequential review at each participating institution or country.
The European Medicines Agency (EMA) has evaluated the impact of the Paediatric Regulation after its first 5 years of being in force.39 So far, the regulation has not yet led to more paediatric CTs in Europe, although there are plans to conduct CTs with enrolment of more children.39 Still, the initiation of new CTs may be hampered by the practical obstacles of complex EC processes.
Currently, it is not possible to seek European-wide legislative changes for EC practice harmonisation, as the practice for one EC will not necessarily work for another without concerted effort to achieve harmony. However, an expert group has designed model consent and assent forms for different paediatric age groups,40 which could be applied across Europe. Furthermore, better definitions of the concepts of ‘understanding’, ‘capability’, ‘capacity for autonomous decisions’ and ‘moral understanding of altruism’ could greatly support a harmonisation process.
To solve these problems, we suggest the following measures:
Uniform, commonly accepted standards and guidance across Europe/EEA
Definition of the lowest age limit to consent and assent requiring own signatures in addition to parental (legal) consent until the legal age of majority permits independent consent
Fundamental discussion to create more detailed definitions of assent and consent and to decide whether these terms could be harmonised and used with similar principles for paediatric population
Standardised structure and reading level requirements of consent and assent documents, including recommendations for legal guardian’s (parental) signatures
A master consent/assent template in all national languages being publicly and readily available.
‘The Informed Consent and Assent Tool Kit’ was updated mainly until the end of 2014. As national-level regulations and laws may change over different intervals, the accuracy of the data and linked documents are dependent upon regular review. The Enpr-EMA's central aim is to enhance and promote the conduct of paediatric CTs in Europe. This toolkit being publicly available free of cost on the Enpr-EMA website meets this aim. Please go to: http://www.ema.europa.eu/Partners&Networks/Networks/Enpr-EMA/Enpr-EMA activities, or directly at: http://tinyurl.com/h2xrlvr. With this toolkit, we hope that all stakeholders will proactively provide feedback via the Enpr-EMA, to keep this toolkit up to date and fostering discussion on harmonisation of EC procedures needed for paediatric trials across Europe.
Special thanks go out to other partners of our original working group, Ivana Silva (EMA), Dr Richard Trompeter (GOSH/IPTA, UK) and Dr Alan Boddy (previously Newcastle University/currently, the University of Sydney) for their help in preparing the initial report for Enpr-EMA.
Contributors Literature search was done by PL, AN, JM, PS and DN; data collection and figures were done by PL, JM, PS and AN; Data interpretation, writing and approval of final version were done by all authors.
Funding This research has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 261060 (Global Research in Paediatrics—GRiP network of excellence).
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.