Abstract
The lack of paediatric medicines, including innovative and advanced ones, is a long-lasting and well-known problem at European and international levels. Despite the existing legal frameworks and incentives, children remain deprived of many kinds of therapy because of challenges faced in appropriately study and tailoring medicinal and other products for them. In this context, the necessity to foster paediatric research addressing unsolved and uncovered issues within a ‘translational approach’ has appeared. This article, after having clarified the concept of translational research in the perspective of the establishment of a European paediatric research infrastructure (RI), will identify and point out ethical, legal and regulatory issues particularly relevant in a children’s rights perspective. It concludes asking for the setting up of an adequate model of governance within a future RI, including adequate and independent ethical oversight and a pluridisciplinary common service dealing with ethical, legal and societal issues relevant for children.
1 Introduction1
The lack of paediatric medicines, including innovative and advanced ones, is a long-lasting and well-known problem at European and international levels. The need to include children in drug development programs has been largely recognised over the past few decades, and stringent legal and regulatory frameworks have been established all over the world with significant but insufficient results.
‘Adult instruments are often inappropriate’, and ‘children have been poorly served by research, even though they have specific emotional and physical needs that must be met’.2 ‘In addition, the need for children to have equitable access to medicines will increase with the growth in advanced technologies and personalised medicine’.
Genetics, pharmacogenetics, cell therapies, represent today the most advanced tools incorporated in the drug discovery and development process used for producing the largest part of the innovative medicines on the market and under development. Nevertheless, many products derived by the advancements in the life sciences have been discovered and developed with adult patients in mind. Therefore, children remain deprived of many therapeutics because of the challenges faced to appropriately study and tailor medicinal and other products for children.
In this context, the necessity to foster paediatric research addressing unsolved and uncovered issues within a ‘translational approach’ appeared.
Conceptually, translational medicine, translational research and translational science are often used interchangeably to refer to efforts that intend to bring the benefits of biomedical research to society by bridging the bench to bedside to community. This term includes a wide spectrum of research activities ranging from the discovery and use of biomarkers for accurate detection to the marketing of new medical technologies to the formulation of new clinical guidelines.3 Efforts to promote translational research have proliferated as evidenced by the creation of multiple policy initiatives, educational programs, research institutes, academic journals and funding opportunities.4
To provide Europe with world-class sustainable research, the European Commission supported research infrastructures (RIs), that are facilities providing resources and services for research communities to conduct research and foster innovation, avoiding duplication of effort. They include major scientific equipment or sets of instruments, collections, archives or scientific data, computing systems and communication networks and any other research and innovation infrastructure (such as common services) of a unique nature that is open to external users. They can be used beyond research e.g. for education or public services and they may be single-sited, distributed, or virtual.
In order to facilitate the establishment and operation of research infrastructures with European interest, key facilities are granted, such as the status of the European Research Infrastructure Consortium (ERIC) – a stable legal structure with administrative advantages enjoyed by international organisations.5
The establishment of a European Paediatric Translational Research Infrastructure is foreseen in Europe by supporting the EPTRI project,6 which is aimed at designing the framework for the new RI, providing a conceptual design report (CDR) describing the scientific and technical requirements as well as the key components of the new RI.
This article, after having clarified the concept of translational research in the perspective of the establishment of a European Paediatric Translational Research Infrastructure (2), will now go on to identify and point out ethical, legal and regulatory issues in the children’s rights and well-being perspective (3). It will conclude asking for setting up an adequate model of governance dealing with ethical, legal and societal issues (4) with the aim to also ensure the children’s right to an open future (5).
2 Translational Research, a Wide Concept
Translational science is a relatively novel concept that was introduced to categorise practical, outcome-oriented research. In the biomedical sciences, the concept gained significant momentum in the early twenty-first century when the National Institutes of Health began planning a new “Roadmap” that featured translation as its core mission.7 In the healthcare field, translational research can be described as research on humans whose findings may inform basic science research and lead to a transfer of the results towards clinical therapeutics and novel healthcare policies.
According to the scientific literature, initially translational research was considered as containing two main phases: T1 – bench to bedside (in which new discoveries from the laboratory could be translated towards clinical research – proof of concept, Phase I and II clinical trials); and T2-translation in clinical practice (Phase III clinical trials, studies of clinical efficacy and development of clinical guidelines).
More recently, the process has been further developed by the addition of other stages and the most recent models contain either four or six translational phases. This implies that translational research starts with fundamental research (e.g., genes, molecular processes, biochemical pathways, etc.) and ends at macro level (related e.g., to social healthcare, access to healthcare, drugs, and education) also including and implementing social/economic policies determined by the results obtained in the process.8
‘Public health is de facto a translational industry that concerns itself with bringing about improvement to the health of populations through the best science’.9 Thus, effective translation research policy also requires translating bedside clinical research into effective clinical practice guidelines and into public policy.10
This more comprehensive approach in translation medicine and research is also confirmed by the European Society for Translational Medicine (EUSTM) that defines translational medicine ‘as an interdisciplinary branch of the biomedical field supported by three main pillars: Benchside, Bedside and Community’. EUSTM also underlines the necessity to combine disciplines, resources, expertise, and techniques within these pillars to promote enhancements in prevention, diagnosis and therapies particularly for vulnerable populations,11 such as children.
In the perspective of the establishment of a European research infrastructure (RI) aimed at enhancing technology-driven paediatric research in discovery and early development phases to be translated into clinical research and paediatric use of medicines, we have adopted this more comprehensive approach of translational research in analysing ethical, legal and regulatory issues relevant for paediatrics. To this aim, children’s rights are also elucidated.
3 Children’s Rights: From the ‘Best Interest’ to the ‘Right to an Open Future’
According to human rights instruments, notably the UN Convention on the Rights of the Child,12 children are rights-holders with a progressively evolving ability to make their own decisions. However, on matters concerning their health and general well-being, there is uncertainty as to how the increased recognition of their decision-making capacity should be addressed. Finding the right balance between autonomy and protection is a challenge when considering that children’s rights are situated within a larger set of parental rights and responsibilities that also focus on their best interests. In the space of few years, we have observed an immense change of pace from parents’/guardians’ consent as a sine qua non condition for research study, to a positive minor’s agreement, a practical/ethical consent: the child is the participant, not the parents, who are only the gatekeepers.
The child’s autonomy can be conceptualised as ‘the child’s right to an open future’,13 meaning a right to have one’s future options kept open until one can make one’s own decisions. In some interpretations, the content of the right to an open future therefore includes restrictions on what parents (and others) can do for children, and indicates what they ought to provide children with. Nevertheless, there is no agreement regarding the most appropriate interventions that parents and others should be allowed to authorise in order to safeguard the health of the child.
As acknowledged by the Council of Europe, parenting covers ‘all the roles falling to parents in order to care for and bring up children’, is centred on parent-children interaction, and entails rights and duties for the child’s development and self-fulfilment’.14 ‘Positive parenting’ is promoted, which involves ‘parental behaviour based on the best interests of the child, that is nurturing, empowering, non-violent and provides recognition and guidance’.
Furthermore, the UN Convention on the Rights of the Child (CRC) recognises that each child has the right to the highest attainable standard of health and to healthcare.15 The right to health is closely interconnected with other human rights.16 International and European standards specifically anchor the right to healthcare and to healthcare services.17 The right to healthcare entails the availability, accessibility, acceptability, and quality of such services for children.18
In all the legal instruments and documents elaborating the right to healthcare for children special emphasis has been placed on child-friendly health services, which regard children as rights holders, and position their rights, needs, voices and evolving capacities at the centre of healthcare policies and practices.19
The right of the child to health is of imminent importance to biomedical research and care. The Council of Europe Guidelines for Child-Friendly Health Care (CFHC) specifically acknowledge the principles of participation, non-discrimination, dignity and the best interests of the child in the context of healthcare, and emphasise that children should be treated with care, sensitivity, fairness and respect in any health-related intervention, with special attention to their personal situation and needs.20
Thus, specific measures matching the child’s best interests and taking into account parental authority and the child’s evolving capacities should be taken in the field of biomedicine and research. To this aim, ethical, legal and regulatory issues relevant for children as ‘future generation’ should be identified and analysed in the different phases of translational research.
4 Ethical, Legal and Regulatory Issues of Translational Research Involving Children
As underlined, for all the activities in the biomedical field involving children, the main objective is to guarantee the respect of children’s rights, while ensuring the wellbeing of children and promoting a high level of children health protection. To achieve both clinical and health policy improvements, issues directly derived from different translational phases but also those derived from gaps between different phases should be addressed.
Regardless of the classification scheme, the translation process raises several ethical questions related to the following areas: identification of principles and values that should guide setting of priorities; identification of responsibilities of different stakeholders’ (researchers, research funders, policy makers, decision makers, etc.); identification of mechanisms/processes to be adopted for ethical oversight; choosing/balancing the types of outcome that should be considered.
Any decision adopted within a translational research process should be guided by the following principles:
the allocation of resources to be taken into account in developing drugs;
the obligation to avoid any conflict of interest; the need to reduce funding for undirected basic research;
the obligation to avoid any form of discrimination and stigmatisation (in terms of e.g. access to medicines and healthcare, personal data protection ...);
the respect of the principle of social justice, especially in case of trials in developing or emerging countries.
With reference to the classification scheme, each translational phase raises different ethical, legal and regulatory issues, essentially due to the disparities in legal frameworks, ethical norms, healthcare policies, social expectancies, medical needs and economic priorities across Europe and beyond. In summary, these issues are related to the following areas:
preclinical studies (including research on animals);
risk/benefit assessment (in clinical phase, especially taking into account the requirements of minimal risks/burdens);
research including new technologies and innovative therapies (e.g., use of tissues and cells, gene therapies, devices, gene-editing ...);
storage of samples and biobanking; data protection and confidentiality (especially for processing sensitive/health/genetic/biometric data for research).
Given the high ‘cost of goods’ for drug and therapies, e.g., including new technologies and the limited budget and resources for healthcare, aspects related to the access to drugs (IP issues, choice in developing new drugs/allocation of resources/access to drug policies) have to be addressed as well. Finally, principles of ethics of research (e.g., ‘dual use’, referring to a legitimate scientific work that can be misused to threaten public health or national security, or ‘scientific misconduct’ – referring to any practice that deviates from those accepted by the scientific community and ultimately damages the integrity of the research process) should be taken into account in the assessment within translational research.
Each of the above mentioned phases (from fundamental research to access policies) raises specific issues that need to be further investigated in an ethical, legal and regulatory perspective, taking into account that specific attention should be paid to ensure the well-being and rights of children considered as ‘future generation’. In this perspective, we point out here some of the ethical/regulatory issues of research activities included in a ‘translational research’ pipeline mostly in relation to medical/research practices that, having future or long-term implications, can raise concerns related to the right of children ‘to an open future’.
4.1 Pre-clinical Phase: The Need for Evidence
Starting from the main international ethical codes and declarations on clinical research, there is a consensus that basic laboratory and animal research must precede clinical research in order to develop safe and effective therapies and medical procedures. The Nuremberg Code states that: ‘The experiment should be so designed and based on the results of animal experimentation and knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment’ (Article 3).21
The Declaration of Helsinki includes a similar requirement providing that: ‘Every medical research study involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and communities involved in the research …’ (Article 17).22 Thus, when subjects are recruited for first-in-human trials, it is reasonable to require that the relevant preclinical evidence concerning possible risks be even more robust than when patients with serious underlying pathologies are involved.23
Establishing the scientific validity of preclinical studies supporting the transition to a phase 1 clinical trial in paediatrics is quite complex, especially where emerging technologies or advanced therapies are included. Overall, for decision-makers, the evaluation of preclinical evidence represents a judgment that is by no means simple.24
In a regulatory perspective, regarding the pre-clinical phase including research on animals, according to the Directive 2010/63/EU25 the 3R (replacement, reduction, refinement) approach has to be respected.26 An assessment of these studies, especially if included in a paediatric research pipeline, should also include an ethical evaluation of the justification (e.g., is the study beneficial to humans or animals? benefits can be medical, veterinary, economic, biological or educational?), the risk connected, the kind of benefit and appropriate design.27 Moreover, it should be taken in mind that each choice adopted since the very early stage of the research will have consequences not only on the animals involved but also on the safety of children further involved, with an impact on future generations. This is particularly true in case studies in juvenile animals, tailored to very young groups, necessary to provide safety information.
4.2 Clinical Phase: Risk/Benefit Assessment and Paediatric Expertise
All international texts and guidelines require that an appropriate risk/benefit ratio should be the basis of a clinical trial, especially for studies including children. To avoid exposing children to excessive risk through under-protection or missing opportunities for important advances through over-protection, strict attention should be paid to the criteria used for this evaluation, especially within clinical research phases in paediatrics.
The EU Regulation on Clinical Trials distinguishes between trials with a prospect of direct benefit for participating minors, and research with the prospect of some benefit for the population represented by the minor (Article 32(1g)). Furthermore, it is specified that a clinical trials on minors can be carried out only when there are scientific grounds for expecting that participation in the clinical trial will produce a direct benefit for the minor concerned or some benefit for the population represented by the minor concerned.28 In this last case, a clinical trial will pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with the standard treatment of the minor’s condition. The Clinical Trials Regulation does not define the concepts of either ‘minimal risk and minimal burden’ or of ‘standard treatment’.29
The concept of minimal risk/minimal burden constitute an internationally recognised prerequisite for paediatric research. It is included in many international ethical guidelines (e.g., the Declaration of Helsinki,30 CIOMS guidelines,31 UNESCO Declaration on Bioethics and Human Rights,32 EU Ethical Recommendations)33 in international and European legal instruments, as well as in national laws (e.g. in Austria, Denmark, France, Germany, The Netherlands and Spain, as well as in American and Canadian laws). In many cases these texts do not define what constitutes minimal risk, and when definitions are provided there is a lack of consistency among them. So the two main definitions/interpretations of minimal risk (the ‘absolute’ interpretation34 – from the Code of Federal regulation35 – and the ‘relative’ – from the Council of Europe Additional Protocol on Biomedical Research)36 have different approaches and adopt different comparators, generating ambiguities in the application of these principles and inconsistency in the evaluation of the risk/benefit balance.37
Thus, to ensure the application of the principle of the equality of treatment among children taking part in research, specific consideration shall be given to the assessment of the application for the authorisation of a clinical trial on the basis of expertise or after taking advice on clinical, ethical and psychosocial questions in the field of relevant disease and the patient population (children) concerned. In this perspective, it should be particularly important to establish more agreed criteria also with respect to the concept of ‘standard treatment’ that is particularly heterogenous in paediatrics.
Finally, paediatric expertise in ethics committees and authorities in charge of the evaluation of paediatric protocols should be fostered. Agreed criteria should be developed and adopted in collaboration with experts, patients/ parents’ association and Young Persons’ Advisory Groups (YPAGs), an organisation composed of young people actively participating as partners, advising researchers and their teams on a full range of activities in various research projects and initiatives.38
4.3 Advanced Therapies: Between Risks and Heterogeneity
The last years have seen exponential growth in experimental therapies, broadly defined as regenerative medicine (a very generic definition that includes cell and gene therapy, tissue engineering, and new generation drugs), with a relatively small number of clinical successes and an enormous burden of expectation.39 The translational pipeline from basic research to the delivery of advanced therapies is covered by a variety of European legal instruments.40 Nevertheless, the European legal framework is far from being totally homogeneous in Europe.41 Different (centralised and national) components of the regulatory framework for Advanced Therapies Medicinal Products (ATMPs) development in the EU imply that not all the steps in the translational pipeline are equally addressed from a legal/regulatory point of view.42
Furthermore, if the therapeutic use of cells is regulated by EU law, their research counterparts are not, and largely depend on national laws and regulations, except mainly for what is related to clinical trials and data protection. This leads to heterogeneity in the legal requirements to be fulfilled in the various Members States, which is a factor to be seen as slowing down the innovation process. Moreover, changes that occurred in the scientific, legal and institutional environment of the use of cells lead to the need for an update of regulations with regard to their implementation in national legislation and their impact on research practice and innovation. This is particularly important if we take into consideration the specificity of the ATMPs-associated risk profiles. Distinctive features of ATMPs include complexity of products, limitations on extrapolating relevant information such as immunogenicity, on- and off-target effects and tumorigenicity from animal data, and uncertainty about frequency, duration and nature of side effects.43
Furthermore, existing research in the field is hampered by the frequent absence of strong preclinical evidence, poor trial design, and poor and inconsistent reporting, particularly of non-randomised trials.44 Focusing on the risk profile for cell therapies, the authors of the Lancet Commission Report emphasise that uncontrolled stem cell therapies have a particularly problematic risk structure, and informed consent struggles to adequately protect both individual and children’s best interests outside a strong governance framework. Not all risks are ethically justifiable by the absence of alternatives. Patients must be as aware as possible of the significance and of the uncertain nature of the treatment. Nevertheless, when the information available about risks and benefits is uncertain, it will be difficult, if not impossible, for individuals to control their risks through informed consent alone. The situation is more complicated in the paediatric context, where parents authorise the inclusion of their children in these trials. Children need to be informed according to their age and maturity, in order to be able to provide their assent or express their refusal to be included in, or to withdraw from a trial.
Unlike traditional synthetic products, which are metabolised and expelled from the body, cell-infusion or gene therapy may be irreversible. Furthermore, compared to traditional drugs, pharmacological treatments based on human cell and gene therapy have much more complex characteristics and mechanisms of action that are often difficult to understand and predict. Independent judgement and oversight from ethics committees (ECs)/independent review boards (IRBs) are essential requirements irrespective of whether these products are being used in a clinical trial or in other types of situations such as compassionate use or under the so-called ‘hospital exemption’.
All these issues related to advanced therapies call for coordinated action in order to better realise the translational process that cannot be optimised when the full pipeline is not coherently taken into account in legislation. Specific regulatory tools should be developed and continually updated in line with the progress of the research, taking into account the peculiarities of children considered as ‘future generation’.
To achieve these objectives, consequences of the ambiguity and heterogeneity related to the different phases of the translational pipeline of advanced therapies (e.g., donation, procurement, testing of human tissue and cells, good manufacturing practices, clinical trials, marketing authorisation procedure, pharmacovigilance) or to the use of genetically modified organisms’ (GMOs) framework, need to be further investigated by a coherent and multidisciplinary group of experts with expertise in law, ethics and governance issues. Surveys should be carried out to be able to identify unsolved issues that need to be specifically addressed. Agreed principles contained in the European legal framework (e.g., related to the quality, safety and traceability, voluntary unpaid donors of tissues and cells, different criteria for selection, evaluation and procurement with respect to requirements for different types of donors), should be used as the starting point to develop cross-border standards and favour the integration of European frameworks within a longer-term strategy.
4.4 Emerging Technologies: The Case of Gene Editing
Gene-editing technology is closely related to stem cell and regenerative medicine technologies and is likely to be integrated into future products and applications. This technology has considerable potential for research to better understand the causes of diseases and improve human health by future treatments. In particular, genome editing makes it easier to achieve small mutations and gene repair in human cells compared to current technology. However, the application of genome editing technologies to human gametes or embryos, introducing inheritable changes in the human genome, raises serious ethical, social and safety concerns, about the possibilities of irreversible harm to future persons.
As for applications in the germline and human enhancement, gene editing puts pressure on the debate about deliberately introducing genetic alterations in the human context. Especially the autonomy argument to be able to decide for yourself (and the right of future generations to decide for themselves) applies. Furthermore, pressure for using this technology may become higher at the moment that genome editing is estimated to be 100% safe, and safer than current approaches.45 These concerns have led eminent experts and institutions within and outside the biomedical field worldwide to call for an in-depth analysis of potential risks of genome editing and for international and regional debate on its implications for the human being.
In a regulatory point of view, many potential applications of gene editing are already covered by European legislation. Article 13 of the Oviedo Convention addresses concerns about genetic enhancement or germline genetic engineering by limiting the purposes of any intervention on the human genome, including in the field of research, to prevention, diagnosis or therapy. 46 It prohibits any intervention with the aim of introducing a modification in the genome of any descendants. Furthermore, the Oviedo Convention provides principles that could be used as a reference for the debate,47 called for the fundamental questions raised by these recent technological developments.48
Owing to the degree of uncertainty still surrounding the individual and societal implications of such interventions, main stakeholders’ engagement should precede the enactment of regulation governing their potential transition to the clinical context. Broad societal debate should be supported.49 Particular efforts are therefore needed to engage in open and inclusive consultation with those whose vulnerability to adverse impacts might be increased by the introduction or extension of heritable genome editing interventions.50
Policy frameworks governing human germline editing should make the scientific rationale and the underlying societal values in which they are supported explicit. Clearer guidance needs to be established in relation to the use of new and emerging technologies, including also commercialisation and intellectual property issues. Governance mechanisms should also comprehensively address its applications in the research and clinical contexts, especially if involving vulnerable populations such as children. To this aim, a European Paediatric Translational Research Infrastructure that is also engaged in ethical, legal, regulatory economic and societal issues analysis could play an essential role.
4.5 Research Including Personal Data, a Question of Data Protection
Another issue particularly relevant for developing innovative paediatric research is data protection compliance. To guarantee the privacy and data protection is of paramount importance within research activities, especially for children as vulnerable population, not only in terms of respect of fundamental rights but also in terms of common and agreed standards and practices. Data protection is one of the major issues to be dealt with in a research infrastructure engaged in data sharing and research implying the secondary use of personal data. Despite the EU General Data Protection Regulation (GDPR), many questions are still unsolved regarding the secondary use of personal data for research especially in case of paediatric data. GDPR introduced the concept of broad consent for processing personal data for research purposes. Nevertheless, interpretative issues about this concept exist especially in case of children with evolving capacities, in particular with reference to the modality for consent withdrawal of the minor who reaches the age of legal autonomy when broad consent has been given by the parents.
Thus, specific conditions and adequate safeguards need to be set up to address children’s peculiarities and rights. In an open research infrastructure allowing collaborations among researches, regulators, private companies and other stakeholders, including children and families, the question of data sharing of paediatric data across and outside Europe is also particularly relevant.
Data sharing rules for international transfers need to be specifically addressed, especially in the case of paediatric and sensitive data (health, genetic, biometric data). After the CJEU Schrems case, that invalidated the EU-US Safe-Harbour framework based on the ‘adequacy’ principle, the EU deemed the very notion of security and protection of human beings and the respect of European citizens freedom and fundamental rights as particularly important, especially within the activities implying transfer of personal data.
GDPR introduced some novelties providing that the application and functioning of adequacy decisions have to be analysed every four years by the European Commission. In this context, we can wonder if adequacy could be still considered as the most common and easy basis for the transfer of personal, and moreover sensitive data, for research purposes. Even the consent of the data subject (considered until now the most common way used for data sharing within international health research projects), is likely to be interpreted narrowly, especially for processing the personal and sensitive data (health/genetic/biometric) of children, as a vulnerable population with evolving capacities.51
Thus, clarifications are needed regarding the adoption of common practices and standards. Adequate safeguards within European/international research need to be set up. To reduce the risk of infringements of fundamental and children’s rights (such as interdiction of discrimination and equality of treatment), adequate models of governance need to be developed in collaboration with experts and YPAGs to address data protection issues in specific contexts, such as international research/consortia, new researches such as in silico models, rare diseases, etc.
5 Conclusion
‘The primary societal mission of basic biomedical research and its clinical translation is to alleviate and prevent human suffering caused by illness and injury. All such biomedical research is a collective effort’.52 As described above, there is a great amount of unsolved and uncovered ethical and legal issues related to paediatric translational research. Regulatory certainty and institutional control are essential to avoid the establishment of grey areas of action in which vulnerable patients such as children are at risk of exploitation53 while facing public expectations about medical advance and access. An integrated ethical approach aiming at transparency and regulation of development processes, the support of independent oversight, and the elimination of unregulated and uncontrolled areas of action are necessary to move paediatric research forward.54
The priority to take in mind in dealing with ethical and regulatory issues in paediatric research is the safety of the children participating in that research. To this aim, clear criteria should be established in accordance with existing ethical and legal requirements for balancing the risks and benefits in the evaluation process (benefit of the population groups, cost and location of the study, clinical usefulness and practical application), with the objective of maximising the benefits and minimising the risks.
The objective will be to avoid that the emphasis on advancements in scientific knowledge might prevail over the protection of the participants in research, especially if vulnerable, such as children, also avoiding serious concerns about the possibilities of irreversible harm to future generations. The objective will also be to guarantee the security of children while promoting scientifically sound research in accordance with the principle of the ‘equality of treatment’ of children across Europe. The driving principles should be the best interest of the child and the protection of children as ‘future generation’, these are important principles to be integrated in an ethical/regulatory assessment. This last aspect is essential, and must be taken into account in any decision aimed at regulating advanced therapies research, especially using GMOs and ‘new/emerging technologies’ such as gene editing.
A European Research Infrastructure should play a crucial role in identifying elements to be taken into account by different stakeholders involved in paediatric research, by facilitating coherent and harmonised decisions, as well as the authorisation of paediatric studies. To promote harmonised practices in accordance with ethical and legal norms, taking into account the best interest of the child, should be of paramount relevance, especially within a RI.
To this aim, a ‘common service’ as part of a longer-term strategy in the governance of a paediatric translational research infrastructure should be set up. It should include a group of independent and pluridisciplinary experts (also dealing with biomedical research and healthcare policy in a children-oriented perspective) to be integrated by experts consulted case-by-case, depending on the specifities of the concerns to be dealt with. It should aim at providing the correct strategy to address these issues while ensuring compliance with relevant rules. Representatives of the main stakeholders, including families and children, should be consulted/included in accordance with the principle of the ‘empowerment’ of patients, described in all the relevant European policies in the health sector.
In any case, the group of experts dealing with ethical issues within an RI could replace the role of the Ethics Committees/Institutional Review Board, as regulated in the EU and international legal frameworks.
Finally, initiatives and instruments to facilitate training of researchers, families and children aimed at increasing their awareness about paediatric peculiarities should be promoted. They should also be a good means to promote quality system and cross-border quality, as well as the harmonisation of research practices.
The research leading to these results has received funding from the European Union’s Horizon 2020 programme under Grant Agreement No. 777554 for EPTRI (European Paediatric Translational Research Infrastructure). Support from the TEDDY network (originated from the FP6 Network of Excellence LSHB-CT-2005-005216) is also gratefully acknowledged. The authors would like to particularly thank for rich discussions and support: Evelyne Jacqz-Agrain (AP-HP, France) and María José Mellado Peña (Hospital Universitario Infantil LA PAZ- H. Carlos III, Spain) from the TEDDY network.
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Currently, 20 research consortia in different areas have ERIC status, see: https://ec.europa.eu/info/research-and-innovation/strategy/european-research-infrastructures/eric_en, accessed 8 January 2020.
The European Paediatric Research Infrastructure (EPTRI) is a project that arises from the need to find answers to the serious lack of medicines for children in the EU and worldwide. It aims to propose developmental models for a future research infrastructure focused on paediatric medicines, integrating technology-driven aspects with clinical trials. See https://eptri.eu, accessed 14 October 2019.
J. Maienschein, M. Sunderland, R.A. Ankeny and J.S. Robert, ‘The ethos and ethics of translational research’, The American Journal of Bioethics 8(3) (2008) 43-51.
S. Hostiuc et al., ‘Translational research – the need of a new bioethics approach’, J Transl Med 14 (2016) 16.
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R. Detels and L. Breslow, ‘Current scope and concerns in public health’, in R. Detels (ed.), Oxford Textbook of Public Health (Oxford: Oxford University Press, 2002), 3-20.
R.J. Cohrs et al., ‘Translational Medicine definition by the European Society for Translational Medicine’, European Journal of Molecular & Clinical Medicine 2(3) (2015) 86-88, DOI: http://doi.org/10.1016/j.nhtm.2014.12.002.
Convention on the Rights of the Child (1989), see: https://www.ohchr.org/Documents/ProfessionalInterest/crc.pdf, accessed 20 January 2020.
J. Feinberg, ‘The Child’s Right to an Open Future’, in W. Aiken (ed.), Whose Child? Chidren’s Rights, Parental Authority, and State Power (Totowa, NJ: Rowman & Littlefield, 1980); J. Millum, ‘The foundation of the child’s right to an open future’, J Soc Philos. 45(4) (2014) 522-538.
Recommendation Rec (2006)19 of the Committee of Ministers to member states on policy to support positive parenting.
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See Council of Europe, Guidelines of the Committee of Ministers of the Council of Europe on Child-Friendly Justice, 17 November 2010, para. III(D)(1)-(2); Article 1 Council of Europe Protocol concerning Biomedical Research; Council of Europe Guidelines on Child-Friendly Health Care, (2011), para. III(A)(9), III(B)(10); Council of Europe, Recommendation CM/Rec(2012)2 of the Committee of Ministers to Member States on the participation of children and young people under the age of 18, 28 March 2012, para. II.
T. Liefaard, A. Hendriks and D. Zlotnik, ‘From law to practice: Towards a roadmap to strengthen children’s rights in the era of biomedicine’, Leidein University Report for the Committee on Bioethics (DH-BIO) of the Council of Europe, 2017, online at https://rm.coe.int/leiden-university-report-biomedicine-final/168072fb46, accessed 7 November 2019.
Nuremberg Military Tribunals, 1948-1953, see https://history.nih.gov/research/downloads/nuremberg.pdf, accessed 9 November 2019.
WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects 1964-2013.
C. Petrini, ‘From bench to bedside and to health policies: Ethics in translational research’, Clin Ter. 162(1) (2011) 51-59.
J.V. Lavery, ‘How can institutional review boards best interpret preclinical data?’, 8(3) PLoS Med. (2011) e1001011; J. Kimmelman and A.J. London, ‘Predicting harms and benefits in translational trials: Ethics, evidence, and uncertainty’, PLoS Med. 8(3) (2011) e1001010.
Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes, OJ UE L 276/33.
EMA Guideline on the principles of regulatory acceptance of 3Rs (replacement, reduction, refinement) testing approaches 2014, available at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-principles-regulatory-acceptance-3rs-replacement-reduction-refinement-testing-approaches_en.pdf, acccessed 14 October 2019.
L.U. Sneddon et al., ‘Considering aspects of the 3Rs principles within experimental animal biology’, Journal of Experimental Biology 220 (2017) 3007-3016.
Regulation (EU) N°536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC [2015] OJ L 158/1.
V. Giannuzzi, A. Altavilla, L. Ruggieri and A. Ceci, ‘Clinical Trial Application in Europe: What Will Change with the New Regulation?’, Sci Eng Ethics 22(2) (2016) 451-466.
WMA, ‘Declaration of Helsinki (2013), para. 28.
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UNESCO, ‘Universal Declaration on Bioethics and Human Rights’ (2006), Article 7(b).
European Commission, ‘Ethical considerations for clinical trials on medicinal products conducted with minors, Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use’ (2017), para. 11(1), https://ec.europa.eu/health/sites/health/files/files/eudralex/vol10/2017_09_18_ethical_consid_ct_with_minors.pdf, accessed 15 October 2019.
A.E. Westra et al., ‘How best to define the concept of minimal risk’, J Pediatr 159(3) (2011) 496-500, at 496. It has been also called ‘healthy child interpretation’, see A. Binik, ‘On the minimal risk threshold in research with children’, Am J Bioeth 9(14) (2014) 3-12, at 3.
Code of Federal Regulations (CFR), Section 46.404 Section 46.102 (i); this is almost similar to the previously mentioned definition of the CIOMS, except that the CIOMS guidelines do not refer to daily-life but only to medical and psychological examinations.
Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, Strasbourg, 25 January 2005, CETS n°195, Article 15.2. and Explanatory report, paras. 96, 97, 100.
A. Altavilla and E. Gennet, ‘Paediatric Research under the New EU Regulation on Clinical Trials: Old Issues New Challenges’, Eur. J. Health Law 23(4) (2016) 325-349.
Their support provides fresh and child-oriented perspectives on research study and results in precious knowledge about their needs and expected approach and changes attitudes about the involvement of young people.
G. Cossu, et al., ‘Lancet commission: Stem cells and regenerative medicine’, Lancet 391 (2018) 883-910.
These legal instruments range from regulations on marketing authorisation (Regulation (EC) no. 1394/2007) to Directives about clinical trials (Directive 2001/20/EC) and guidelines of good clinical practice (Directive 2001/83/EC, Directive 2009/120/EC). G. Migliaccio and C. Pintus, ‘Role of the EU framework in regulation of stem cell-based products’, Adv Biochem Eng Biotechnol 130 (2013) 287-99.
M. Favale and A Plomer, ‘Fundamental disjunctions in the EU legal order on human tissue, cells & advanced regenerative therapies’, Maastricht J Eur Comp 16 (2009) 89.
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EMA/CAT/852602/2018. Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials. 2019, online at https://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal, accessed 30 October 2019.
Cossu et al., supra note 39.
Ethical issues in genome editing, Submission to Nuffield Council of Bioethics, see https://nuffieldbioethics.org/assets/pdfs/genome-editing-evidence-Vlaams-Instituut-voor-Biotechnologie.pdf.
Oviedo Convention Article 13 – Interventions on the human genome.
See Article 28 of the Oviedo Convention – Public debate.
Committee on Bioethics (DH-BIO), Statement on Genome Editing Technologies, DH-BIO/INF (2015) 13 FINAL, online at: https://rm.coe.int/168049034a, accessed 15 November 2019.
J.B. Hurlbut et al., ‘Building capacity for a global genome editing observatory: conceptual challenges’, Trends in Biotechnology 36(7) (2018) 639-41.
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A. Altavilla, J. Herveg, V. Giannuzzi, A. Landi and A. Ceci, ‘The secondary use of Paediatric Data under GDPR: Looking for new safeguards for research’, EPLR 4 (2019) 156-164.
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The famous Stamina case in Italy is an example of this. Patients asked for access to an alleged innovative stem cell therapy called ‘Stamina’, based on the use of mesenchymal stem cells (MSC) and intended for the treatment of neurodegenerative diseases. In the context of a highly controversial legal battle again the State, these manipulated cells were administered to numerous patients in public hospitals, without a standardised study protocol upstream. L. Riva et al., ‘Unproven stem cell therapies: Is it my right to try?’, Ann Ist Super Sanità 55(2) (2019) 179-185; P. Bianco, ‘Don’t market stem – cell products ahead of proof’, Nature 499 (2013) 255; P. Bianco et al., ‘Regulation of stem cell therapies under attack in Europe: For whom the bell tolls’, EMBO J 32 (2013) 1489 – 1495.
L. Riva and C. Petrini, ‘A few ethical issues in translational research for gene and cell therapy’, J Transl Med. 17 (2019) 395.
