Medical Research Involving Minors

I. Medical aspects

Especially since the second half of the twentieth century, medical research has led to the development of numerous therapeutic, diagnostic and preventive techniques. These advances have also been reflected in paediatrics. Yet the balance of progress in this field, compared with other areas of medicine, has been considerably more modest. In a paper from 1968 the paediatrician Harry Shirkey coined the phrase "therapeutic orphans" in order to highlight the extent to which children are neglected - in comparison to adults - when it comes to the development of new medical products and procedures.

It continues to be the case that the treatment of minors with drugs frequently takes place using so-called off-label or off-licence products i.e. with substances that are either not licensed for paediatric use at all due to a lack of clinical trials or at least do not have the appropriate licence for the specific area of application. Paediatricians then have to decide on the administering of a drug based on empirical values. Most significantly, they also have to determine the dose without recourse to scientifically secure data.

Even though the off-label or off-licence use of drugs is widespread in paediatrics, this can only be a makeshift solution from the medical standpoint. Children are not "little adults", especially from the perspective of developmental physiology, which is, amongst others, highlighted by the German Academy for Pediatrics and Adolescent Medicine (DAKJ) in a statement on medical research involving minors. With reference to the international human rights conventions of the United Nations, the German academy both advocates better qualifications of physicians and nursing staff and pleads for the parliamentary representation of children’s rights in the German federal parliament ("Bundestag"). As numerous examples have demonstrated, it is therefore often not possible to simply adjust the dosage of drugs that are successfully used on adults. Cases like the “grey baby syndrome” or the off-label prescription of antidepressants to minors exemplify these controversies. A further problem consists in that the off-label use of drugs can only take place under certain conditions which were set by the Federal Social Security Court during two verdicts in 2002 and 2006 respectively, to the disadvantage of the 'Gesetzliche Krankenversicherung' (GKV) which stands for statutory health insurance.

In this context it cannot even be considered appropriate to use the blanket term "children". On the contrary, it is vital to differentiate between several developmental phases up to adulthood, each of which has its own distinct physiological characteristics. Only by conducting targeted clinical trials on minors will it be possible to really remedy the problem of children as "therapeutic orphans".

In certain areas of paediatrics, most notably in paediatric oncology, large numbers of clinical trials are already being carried out today. Indeed, estimates suggest that in the United States, for example, roughly 70% of all child cancer patients are treated as part of clinical trials. This does, however, raise the question of whether crucial distinctions between medical research and medical practice are being ignored. In Germany, too, clinical tests on minors are being carried out. According to an evaluation amongst VFA-businesses this is, however, the case stagnantly and only on a small scale.

II. Legal aspects

1. European law

On 16th April 2014, the European Parliament and the Council of the European Union enacted  Regulation (EU) No 536/2014  (“on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC”). This Regulation replaces EC Regulation No 1901/2006 which had the intention to "facilitate the development and accessibility of medicinal products for use in the paediatric population, to ensure that medicinal products used to treat the paediatric population are subject to ethical research of high quality and are appropriately authorised for use in the paediatric population, and to improve the information available on the use of medicinal products in the various paediatric populations". Therefore the regulation contains both, obligations and incentives. For obtaining marketing authorisation either the results of clinical studies in according with a paediatric investigation plan, or a certificate of exemption for medicines that are of no paediatric use, must be presented. For medicines protected by a patent or a Supplementary Protection Certificate (SPC), the extension of exclusive rights is provided.

The new Regulation (EU) No 536/2014 repeals Directive 2001/20/EC and complements it for example with respect to informed consent in clinical trials (Article 29). The key objective of the Regulation is to harmonize how  clinical trials in the European Member States are applied for and approved of. Concomitantly, a better protection of vulnerable groups of patients is intended.

The stipulations of the EU enactment were implemented into national law because of the Fourth Law on pharmaceutical amendments and other regulations from the 20 December 2016. It particularly includes numerous amendments of the German Medicinal Products Act (Arzneimittelgesetz – AMG).

2. National law

With the implementation of the "Reichsrichtlinien zur Forschung am Menschen" [Reich Directives on Research on Human Beings] of 1931 Germany was the first country in the world to adopt statutory regulations governing research on human subjects. Even earlier, the Minister for Spiritual, Educational and Medical Affairs had issued a government guideline in the form of the "Anweisung an die Vorsteher der Kliniken, Polikliniken und sonstigen Krankenanstalten" [Order Issued to the Directors of Hospitals, Outpatients' Clinics and other Infirmaries]. While the aforementioned order prohibited all research on minors without exception, the "Reichsrichtlinien" provided for permission in cases where the experiments presented no danger whatsoever to the minor subjects.

Germany does not currently have any comprehensive special statutory regulations governing research on human beings as is, for instance, presently being discussed in Switzerland within the scope of a new article to the constitution and its respective law. Special laws are in place, first and foremost, for the clinical testing of pharmaceuticals (Pharmaceutical Act - AMG) and medical devices (Medical Devices Act - MPG). Further provisions pertaining to research on human subjects are contained in the Radiation Protection Law (Strahlenschutzgesetz - StrlSchG) and the Radiation Protection Ordinance (Strahlenschutzverordnung - StrlSchV). The present paper, however, will only explore in greater detail the standards established by the Pharmaceutical Act.

The protection of the human subject in clinical trials of pharmaceuticals is dealt with in §§ 40-42a of the AMG. It is stipulated here, inter alia, that a risk/benefit analysis must be performed prior to commencement of a clinical trial and that subjects must give their informed consent ito participation after receiving relevant information. In addition, a favourable opinion is required from an independent Ethics Committee Research on minors is discussed specifically in §§ 40 IV and 41 II.

The basic principle is that clinical trials on minors are subject to additional restrictions compared to those conducted on adults; cf. in particular § 40 IV Item 2, which states that clinical trials on minors are only permissible if testing on adults (or indeed other research methods) does not promise adequate test results based on the insights of medical science. What is more, § 40 IV Item 1 requires that the drug be intended for the identification or prevention of diseases in minors and that use of the drug - based on the insights of medical science - be indicated in order to identify diseases in the minor subject or protect them against diseases. Formulated slightly differently this means: clinical trials involving minors are only permitted if adults cannot be considered as test subjects for methodological reasons, if the object of the trial promises a therapeutic, diagnostic or preventive benefit for minors and, what is more, if usage on the participating child subjects themselves is medically indicated. For example, the testing of a new diagnostic method on a healthy child is not permitted pursuant to § 40 IV Item 1, but the testing of new vaccines probably would be permissible because they promise a medical benefit for the child subject themself. § 40 IV Item 3 sets out rules governing consent in the case of minor subjects. This consent is given in the first place on a proxy basis by the minor's legal representative; it must, however, comply with the presumed wish of the minor. Yet the minor too must also be adequately informed prior to commencement of a clinical trial by a trial team member experienced in dealing with minors in a manner appropriate to their age and intellectual maturity. A refusal to participate on the part of the minor must be respected. If the minor subject themself is in a position to grasp the nature, significance and implications of the clinical trial in question (and to direct their wishes accordingly), the minor's consent must also be obtained.

While § 40 AMG contains general preconditions for a clinical trial, § 41 sets out special requirements; more precisely, it refers to cases where sick persons are to be used as test subjects. If minors are involved in this context, the drug to be tested must - based on the insights of medical science - be indicated in order to save the life of the person concerned, restore their health or alleviate their suffering (§ 41 II Item 1) or it must be associated with a direct medical benefsubgroup of minorsit for the group of patients who suffer from the same disease as the affected person (§ 41 II Item 2 a). In the latter case the research must also be absolutely indispensable for the confirmation of already existing data (§ 41 II Item 2 b), the research must relate to a clinical condition from which the affected minor themself suffers (§ 41 II Item 2 c) and the research may only entail minimal risks and minimal burden (§ 41 II Item 2 d). In this context, a merely minimal risk exists if - given the nature and scope of the intervention - it is to be expected that it will at most lead to slight and temporary health impairment. Likewise, minimal burden may be presumed if the discomfort for the affected person will at most be temporary and very slight.

The legalization of so-called research "beneficial to group interests" , which came about only with the 12th Amendment of the Pharmaceutical Act in 2004 pursuant to § 41 II Item 2, is extremely controversial. Because of the Fourth Law on pharmaceutical amendments and other regulations from the 20 December 2016, significant changes were made in the Pharmaceutical Act (AMG). These amendments apply to ethics commissions, but are also related to research involving adults who lack the capacity to consent. Based on the adjusted regulation, research which includes aforesaid adults and benefits group interests can be admissible under certain conditions. In this context, it has been criticized that the subgroup of minors not been treated equally to other subgroups of people who lack the capacity to consent. Thus, research beneficial to group interests with adults incapable of giving consent is only admissible if the experiments have a direct medical benefit for the test subjects. However, this does not apply to minors. A reason for this stipulation might be the intention to reduce off-label use of pharmaceuticals when it comes to treating minors. Furthermore, a minor’s capacity of giving consent is usually evaluated by age limits while the capacity of adults is considered on a case-by-case basis. Moreover, an existing incapacity of giving consent is taken into consideration when it comes to evaluating adults.

Pursuant to § 42 I, a positive vote from an Ethics Committee is a precondition for lawful conduct of a clinical trial. If the clinical trial in question involves minors and the committee does not have specialist knowledge in the field of paediatrics, it must call upon the services of an expert or request a specialist opinion.

3. Guidelines and opinions

Probably the most influential international guideline covering research on human beings is the "Declaration of Helsinki" issued by the World Medical Association, which was first adopted in 1964 and has since been updated on several occasions. Here, too, it is the assumption of Item 27 that research on minors is only legitimate if comparable results cannot be obtained through experiments on adults (capable of giving consent). Furthermore, the research should be associated with at least a group benefit for minors as a population as well as with minimal risk and minimal stress for the minors. In addition, Item 28 requires that a legal representative gives their consent to the participation of the minor subject and that - if possible - the affected minor themself should also assent to participation.

In contrast to the German Medicines Law, the declaration of Helsinki does not distinguish between healthy and sick study participants, adults and minors or research that benefits the subject and research that benefits a group. These distinctions are crucial to the German Medicine Law with respect to the research practice.

There is critique concerning the practicability of the principles as they are established in the declaration. One argument is that, concerning the informed consent of the subject, there are not enough exceptions, which makes a strict compliance of the principles ethically questionable. This argument also concerns subjects who are able to give their informed consent. According to critics, inconsistencies within the declaration, for instance the connection of research intervention and clinical treatment, are a weakness of the declaration (last amended 2008) as well as the deviation from the mainstream opinion of the medical among experts. Because of this, the declaration is, according to the critics, not suitable as an ineluctable ethical medium. 

The "Convention on Human Rights and Biomedicine" adopted in 1997 by the Council of Europe constitutes another influential international document governing research on human beings, although it still has to be ratified by Germany. In the first place this text also defines general rules for research on human subjects (Art. 16). The requirements include inter alia the lack of any alternative to the human experiment, a favourable risk/benefit balance and informed consent on the part of the person concerned. Art. 17 contains further provisions relating to research on subjects unable to give informed consent, including minors. Once again, the conditions set out for permissibility are that comparable research on test subjects able to give informed consent is not possible, consent has been given by a legal representative and the person concerned does not refuse to participate. What is more, there is a requirement that participation must be associated with a direct medical benefit for test subjects unable to give informed consent (Art. 17 I). In exceptional cases, however, Art. 17 II provides that research which only holds the prospect of a group benefit should be permitted - albeit only if the research is expected to significantly enhance scientific understanding of the condition, illness or disorder of the person concerned and if the research entails only minimal risks and minimal burden. Not least on account of the provisions of Art. 17, the Convention on Human Rights and Biomedicine has met with sharp criticism in Germany. Critics see it as the precursor for a legal foundation justifying - in their eyes unacceptable - research on persons unable to give informed consent. It is nevertheless the case that with the 12th Amendment of the Pharmaceutical Act similar provisions have since been adopted in national law (see above).

In 2004 the Central Ethics Committee for the Observance of Ethical Principles in Medicine and Adjacent Fields (Zentrale Ethikkommission zur Wahrung ethischer Grundsätze in der Medizin und ihren Grenzgebieten - ZEKO) set up by the German Medical Association published an opinion on research involving minors. It called upon lawmakers to define the conditions, basic procedure and major criteria for research involving minors (§ 4.1). In the opinion of the ZEKO, research does not make minors into an object as defined by court practice in relation to Art. 1 I Basic Law (GG). This is only the case if the research is not associated with any benefit for the patient or their group of patients (§ 4.2). The ZEKO stipulates determination and evaluation of the possible benefits and possible risks/burden, the lack of an alternative research method (§ 4.3) and the assent of the minor subject's parents (§ 4.4) as preconditions for the acceptability of research beneficial to group interests that involves minors. Research projects may only be conducted, the ZEKO continues, if the proportionality of benefits and risks is "commensurate" and the risks and burden are (normally) only minimal (§§ 4.5, 4.6). For the purpose of minimizing psychological risks and burden, the ZEKO recommends the participation of independent persons who are experienced in dealing with minors, enjoy the trust of the minor in question and can safeguard the latter's interests (§ 4.7). Furthermore, the ZEKO requires that minors be integrated into the decision-making process to the extent permitted by their level of comprehension (§ 4.8). Finally, once a project has been completed, the participants and legal guardians should be informed of the results in an appropriate manner (§ 4.9). 

In 2012 the work group of medical ethics commissions published a reissue of its advice for the assessment of clinical studies by ethics commissions. The advice refers to the often lacking connection of international and national guidelines to German law, for instance the higher level of protection for individuals who are not able to give their informed consent, which is established by the German Medicines Law.

In 2011 the Council of Europe published a guideline for ethics commissions which examines clinical studies prior to conduct. In Chapter 7.2 the authors explicitly refer to the involvement of children into clinical studies.

III. Ethical aspects

The issue of the ethical acceptability of biomedical research involving minors constitutes an extraordinarily difficult problem within the ethics of research and has hence long been a subject of intense debate. The special difficulty of the problem lies in the clash between two conflicting moral intuitions: on the one hand, minors must be regarded as needing special protection, which would lend plausibility to a general ban or at least a far-reaching restriction of biomedical human experiments in the filed of paediatrics. On the other hand, the extensive restriction of paediatric research implies considerably slower medical progress in this area, if not a complete standstill, and imposes limitations on the ethical imperative that the benefits and risks of applied therapeutic methods must be reviewed by means of clinical studies.

Informed consent constitutes one of the central principles in the ethics of research on human beings. Accordingly, human experiments can only be considered ethically acceptable in principle if the test subjects in question have been advised in advance of the nature, significance and implications of an experiment and have then given their informed consent to participation. This idea is reflected in all pertinent codes of research ethics and in the relevant statutory regulations. In contrast to adults, minors are frequently themselves unable to give informed consent on account of their lack of cognitive abilities. Consequently, according to one possible position, research on minors is ethically unacceptable at least in those cases when it is not associated with a direct medical benefit for the minor test subjects; in this understanding, only "therapeutic research" would be permissible. Such a position was put forward, for example, by the American bioethicist Paul Ramsey in his book "The Patient as Person" published in 1970.

That medical research on minors is necessary in order to develop new and effective techniques in paediatrics can be regarded as generally accepted. Since, however, this in no way involves a value-neutral goal, but on the contrary the provision of effective treatment options is highly desirable from the moral standpoint, many ethicists have sought arguments to counter the position of fundamental inadmissibility put forward by Ramsey and others. What is not disputed in this context is that the consent of a legal representative and the lack of alternatives are necessary conditions. Furthermore, a rough distinction can be made between four approaches: 1. assumed consent, 2. educational benefit as a ground for justification and 3. the concept of minimal risk and 4. parents as (preliminary) lobbyists for their children.

1. Assumed consent

The first approach proceeds from the presumption that in light of the moral value attached to participation in a human experiment the minor's consent may be assumed. Richard McCormick elaborated this position as a direct response to Ramsey's theory of fundamental unacceptability. According to McCormick's central argument, there is absolutely no need to assume that a minor test subject would refuse to participate in a medical experiment. On the contrary, it may be assumed that the minor would give his or her consent if he/she had the requisite faculties because such a decision would be morally correct. For this reason, McCormick concludes, Ramsey's theory of the ethical unacceptability of research on minors for the benefit of others is incorrect. One readily obvious criticism of this approach is that no comparable assumption is made in the case of adults who are able to give informed consent, and hence there is no reason to accept why this should be permissible in the case of minors.

2. Educational benefit as a ground for justification

The point of departure for a second approach is the assertion that research involving minors can be considered ethically acceptable if the research is associated with a direct benefit for the minor test subjects. While the presumption in this context is usually a direct medical benefit, proponents of this approach claim that other types of benefit can and must also be taken into account here. A participation in a human experiment does, for instance, also have an educational benefit for minor test subjects, inasmuch as basic social skills such as altruism and solidarity are fostered. Thus, experiments that do not have a direct medical benefit can also be considered to be ethically acceptable. This appears plausible when one remembers that in many instances children are subjected to norms that are informally considered important or accepted without their being asked, since otherwise it is scarcely possible to socialize and educate children. At issue here is firstly whether an educational benefit can really acquire the asserted legitimizing force, while on the other hand many critics claim that an understanding of altruistic actions can only be assumed from a certain level of maturity onwards and hence research on younger children cannot be justified on the basis of this approach.

3. The concept of minimal risk

A third approach that has taken on special prominence in the US debate starts out from the risk profile of human experiments. If, so the argument goes, a human experiment entails only minimal risks and burden which in some cases can only be seen as intervention in the context of a strictly defined definition of intervention, the requirement for personal consent may be dispensed with and the consent of the legal representative suffices for ethical justification. In the first place, this approach raises the issue of whether the use of humans in medical experiments without their consent is not fundamentally problematic from an ethical perspective, irrespective of any risks and burden. If this is the case, the invoking of only minimal risks and burden cannot provide an ethical justification. What is more, this approach encounters problems arising out of the definition of risk. In particular, many contributors to the debate consider it questionable whether it is possible to define with adequate clarity what constitutes only a minimal risk and whether an objective determination lends itself to adequately accommodating the evaluations of individual test subjects. Even as regards the judgment of group-beneficial research projects with a risk higher than minimum, the views of German ethics commissions were diverging, according to a recent study.

Empirical studies show that standards as 'minimal risk' or 'minimal stress' are interpreted differently. Therefore, these abstract distinctions become more concrete by an increasing number of clinical examples and are connected with further guidelines.

4. Parents as (preliminary) lobbyists for their children

The medical ethicist Giovanni Maio on the other hand questions, whether research, which is not associated with the benefit of the child, indeed poses an ethically unjustifiable instrumentalization of minor test subjects. According to Maio, there is a tension between the prohibition of the instrumentalization of a test subject and the imperative of investigating possible help for children in the future. Maio claims that only the violation of the child’s dignity makes the involvement of minors illegitimate. This is why he wants to let parents decide, whether the research is appropriate.

Depending on their mental maturity, the minor test subjects should also be involved into the decision, although in practice it is often difficult to determine, whether or not a child is mature enough for the consent into a survey. If a child refuses to participate in the survey though, this decision should be respected even before the child’s maturity has been ascertained.

IV. Special Cases on Studies with Minors

Although the same legal and ethical standards apply for all sections of pediatrics, two priorities can be distinguished. Regarding the establishment of surveys, the pediatric oncology stands out significantly from the other fields. As a consequence of the realization of multicentric studies, new treatment options have been achieved in course of which the cure rate of minors suffering from cancer was increased from 15% in the early 1970s to round about 70% today. However, physicians and ethicists are confronted with the difficult task of informing parents and children as well as balancing the protection of test subjects and the knowledge gained by the study. The high quantity of studies furthermore raises the question, whether or not there is a disregard of significant differences between medical research and medical practice.
According to experts, many medicaments are used in the field of neonatology, which have not been tested on groups of patients before. The occasionally grave consequences for newborns make experts wonder, if all neonatological treatments should be carried out as part of clinical studies. However, the distinction of research and medical practice would be up for discussion here as well.

Wird geladen