Clinical research in paediatric subjects has grown significantly in recent decades, and public health authorities recognise the need of performing more trials in this vulnerable subset of the population that is underrepresented in clinical trials.1,2 Off-label drug prescription is frequent in the paediatric population, for instance of growth hormone replacement therapy and other drugs used in paediatric endocrinology practice.3,4

Children have particular physiological, psychological and developmental characteristics that require performance of specific clinical trials of new drugs and vaccines to determine their pharmacodynamics, pharmacokinetics and safety profile and improve treatment options in this age group.5 Paediatric clinical research has unique and complex ethical implications. Due to the vulnerability of minors and their lack of a legal right to consent, measures must be taken to protect their rights and to minimise the risks that they are exposed to.

Minor consent or assent is an essential requirement for research in paediatrics and clinical decision-making that is contemplated in international codes of ethics (2013 Declaration of Helsinki, Council for International Organizations of Medical Sciences, ICH-GCPs International Conference Harmonization-Good Clinical Practices, 2015 Nuffield council on Bioethics) and current law at the state level.

Consent and assent are not the same. Consent represents a formal decision to allow participation in research provided by an adequately informed individual that has the legal ability to agree to such participation. Assent involves a similar agreement but by an individual that does not have the legal capacity to consent and who requires the consent of a legally authorised individual (in the case of a minor, the parents or legal guardians). In the words of the Declaration of Helsinki, “when a potential research subject who is deemed incapable of giving informed consent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorised representative.”

The consent/assent process in a minor involves significant challenges for researchers, among them the comprehension of the written information provided to the patient. Usually, written information is not adapted to the reading level of potential participants (adults and minors alike), which hinders comprehension and therefore the ability to consent.6–8

When it comes to minors, regardless of the legal age of consent (for, when they are not of age, assent should still be obtained if they are able to provide it), it is essential to provide information fitting their comprehension level through the correct choice of language, format and volume of information, in addition to verifying their understanding of the contents.9 It is important to consider differences in their decision-making capacity based not only on age but also on their level of development, social, environmental and family-related factors and their medical condition.10

Generally, children start developing the ability to understand research procedures and how they may differ from routine medical care from age 7 years, so they could start to agree to participation at this age; some authors propose personalising this process, adapting it to each child.11–13

At present, no standardised tool is available to assess the ability of minors to make decisions and there is a lack of consensus on the age of consent to either medical research or medical care, and the determination of the maturity, understanding and competence of the minor rests on judgment of the researcher or clinician.10

The aim of our study was to analyse the following aspects through a literature review: 1) the current ethical guidelines and law on informed consent (IC) in minors regarding medical care decisions and/or participation in clinical research and 2) studies that use objective tools to assess the competence of minors for IC in decisions related to medical care and research protocols.

Study design and inclusion criteria: a single reviewer analysed scientific articles and grey literature according to the following protocol:

The findings of our review corroborate that despite there being a general international framework of ethics, each country has developed domestic laws regarding when minors can autonomously provide consent and for which health-related decisions.

In the United States and Europe, the concept of the autonomy of the minor is more developed, although most medical interventions require the consent of parents or adult legal representatives of the minors (especially in the USA, due to the widespread practice of defensive medicine).27 Exceptions to this requirement basically apply to voluntary termination of pregnancy and birth control, which in some instances do not require parental consent, and research, where protection of minors is particularly strong. Adults must make decisions based on the best interests of the minor, a fundamental legal principle that entails the contemplation of the specific case and the rights and needs of the minor at hand. At the practical level, this is where conflicts may arise between different stakeholders: clinicians, parents and the minors themselves with severe medical conditions or with no other treatment options, situations whose resolution may require the involvement of a health care ethics committee.28

The situation is different in developing countries where the practice of clinical research is relatively new, family and parents may play a more important role due to cultural, social and health care-related factors and clinical trials may be the only way to access certain treatments. However, Latin American countries, whose legislation was included in our review, have laws that recognise the rights, autonomy and active participation in decision-making of minors, defining the concepts of best interests of the minor, the mature minor and progressive autonomy29; although Chile and Uruguay would need the development of a specific legal framework for clinical research in minors.

In Europe, the analysis of the 9 states that have ratified the European convention for the protection of human rights and biomedicine reveals significant differences: only 3 (Spain, Denmark and Portugal) establish an age below the age of majority to consent to health care interventions, and another 3 (Czech Republic, Estonia and Lithuania) take into account age and maturity of the patient to determine the capacity for consent in health care.

In Spain, minors can generally consent to health care interventions starting from age 16 years or after legal emancipation, with the exception of clinical trials and assisted reproductive technology procedures, consent for which can only be given after reaching the age of majority,30 and interventions carrying serious risks to health, in which case the onus of decision-making is on the parents, although it is also necessary to consider the opinion of the minor from age 16 years.

After the reform of 2015, the duty to seek and consider the opinion of the minor aged more than 12 years was removed from the law on patient autonomy, although some authors consider that these minors may be sufficiently competent to make decisions about medical treatment in certain cases.24

In the case of clinical trials, IC by the parents or legal representatives of the minor is required (until the age of majority of 18 years) in addition to assent from minors over 12 years (although the legal text does not use this word, but “consent”). Royal decree 1090/2015 also establishes that the opinion of minors under 12 years must be taken into account if they are deemed mature enough.

Age is not the sole factor that determines the decision-making capacity of minors. The assessment of this competence is complex, as maturity is a developmental process that involves the maturation of moral judgment, cognitive development, emotion and the health condition of the minor.25 However, it is reasonable to say that conventional morality develops sometime between 10 and 12 years of age. The findings of our review corroborate that from age 12 years, minors have the capacity to make health-related decisions, as evinced by studies that used the paediatric adaptation of the MacArthur scale. This instrument, which is based on a cognitive model of mental capacity, is a semi-structured interview with items grouped in 4 dimensions: understanding, appreciation, reasoning and expressing a choice. Although this scale is more widely used in adult psychiatric patients,8 it has also proven to be a valid and reliable instrument with consistent psychometric properties in children and adolescents. In addition, there is evidence that this tool offers a high sensitivity and specificity between ages 9.6 and 11.2 years, which suggests that in this age range, as long as the personal capacity to consent of the minor can be demonstrated, consent or assent should be obtained from the minor. Although the EVC scale developed by Espejo et al. could be valid and reliable for the assessment of competence in adolescents, it is restricted by design to decisions regarding health care and has not been used in clinical research or in children under 12 years, so its applicability is more limited.

Few studies to date have used existing instruments to assess competence, and their sample sizes were small, so additional research needs to be conducted at a larger scale on the assessment of competence for consent in minors with the ultimate purpose of providing a solid instrument to researchers and clinicians and to guide changes in legislation on IC.

Our review of studies that used instruments validated in the paediatric population in the specific context of medical research showed that the semi-structured MacArthur interview adapted to adolescents is most accurate, thorough and consistent for the evaluation of the minor’s decision-making capacity. While awaiting data from further studies to improve the evidence on the subject, minors aged more than 12 years can be considered competent to make health-related decisions, while the individual decision-making capacity of minors aged 9–12 years can be assessed using the aforementioned instrument.

The legal regulation of IC in paediatric research should take into account the current scientific evidence and establish the assent of the minor as an absolute requirement for recruitment, in every case in individuals aged more than 12 years, and starting from age 9 years if the minor exhibits the capacity to assent.

To assess this capacity in the minor, researchers and clinicians alike should use validated and appropriate tools, such as the semi-structured MacArthur interview, which has proven useful for the purpose.

The authors have no conflicts of interest to declare.