The ethical framework for performing research with rare inherited neurometabolic disease patients

Inherited NeuroMetabolic Diseases (iNMDs) represent a particularly important group of rare diseases being constituted by genetic metabolic disorders that may impact on the brain from birth (sometimes already in utero) and during the whole developmental period causing mental retardation and/or different neurological signs and symptoms, may be progressive and may ultimately end with irreversible consequences and even in early death [2].

Today, as a result of medical research, major progress has been made. The scenario of the ‘personalised medicine’, based on the premise ‘the right treatment for the right patient at the right time’, is proposing the use of the latest advancements in biological knowledge and technology, such as the completion of the human genome mapping, to improve understanding of inter-individual variability, in order to include them in the medicine developmental process. The research based on ‘omics’ technologies, including pharmacogenetics/pharmacogenomics (PGt/PGx), is producing a very high amount of data. In fact, these approaches have been demonstrated to be useful both in pharmacological treatment and in diagnosis.

However, the number of curative interventions remains low and this low number of approved drugs is strictly connected to the difficulties characterising the research in this field that can be summarised as the following.

First of all, when dealing with children, clinical research raises many scientific and ethical concerns, and special provisions should apply [6]. Due to developmental and cognitive limitations and legal incapacity, a child is legally unable to provide informed consent to participate in research that should be done by a legal representative [28]. On the other hand, children are entitled to receive appropriate information about their health and their participation in clinical studies that imply that their views can be sought and taken into account. Challenges and obstacles in accessing the views of children and young people have been identified by the Paediatric Committee (PDCO) and include access, language/ability to express oneself, ethnic and cultural differences, chronological age and maturity, ill-informed or preconceived notions about a child’s level of understanding and maturity [26]. The call for more medical research involving children, as enlightened by the European Directive 2001/20/EC [30] and the Paediatric Regulation [32, 33], has also raised the question whether the law strikes an appropriate balance between the need for clinical trials and the interests and rights of the child.

Secondly, when paediatric patients are affected by rare diseases, difficulties double [5] as children should be considered ‘twice orphan’, and randomised controlled trials, considered as the standard in research design, are even more unfeasible due to the smaller number of patients. It becomes ethically problematic to propose a control arm (in which the investigational product/approach is not provided to a segment of the population) for a study aimed to establish the efficacy of a new product/approach.

The difficulties to propose a control arm are also true for prenatal and neonatal screenings, which represent a fundamental step in the diagnosis of genetic diseases. Screening programs for genetic diseases have multiplied in the last 50 years [50]. Research in this field is often observational with either historical control data or control through comparisons with similar populations without screening [3].

Genetic testing guides the prevention, clinical management and drug treatment based on genetic susceptibilities [4]. Carriers/patients must consider disclosure of information to others and weigh the right to privacy against common interests [17, 39]. In addition, knowledge of one’s carrier status for recessive genetic diseases is useful primarily in making reproductive decisions. Such decisions are within the private domain of the young adults who are dating, mating and forming new families. The privacy of these decisions may be compromised when parents know the carrier status of their children.

Another aspect to be considered is the use of advanced therapy medicinal products (ATMPs), including gene therapy, and the so-called personalised medicine. Today, for this type of diseases, this represents the most innovative research. For example, when a product is autologous (meaning that it ‘originates from the same patient’), who is the owner of the product? The company or the patient?

Finally, the neurological impairment characterising patients affected by iNMDs can lead to mental disability and make both paediatric and adult patients vulnerable (persons relatively or absolutely incapable of protecting their own interests and therefore not capable of giving adequately consent) unable to give their consent or assent. The current legislation [28] defines these patients ‘incapacitated subjects’.

In order to perform well-conducted research in this field, many regulatory/ethical and legal provisions need to be followed by researchers, not limited to good clinical practice [25], to considering all these aspects. For this reason, this work aims the following:

All these conditions share the important ethical issue concerning the need for studying and making available drugs notwithstanding the scarce economic return coming from their development.

In order to reach the aim of this work, the following actions were undertaken:

The actual European regulatory/ethical and legal framework was reviewed. Other relevant international guidelines and texts were taken into account, as well. The following sources were consulted: EudraLex Volume 10—Clinical trials guidelines; International Conference on Harmonisation (ICH) guidelines; World Health Organization (WHO)—Council for International Organizations of Medical Sciences (CIOMS) guidelines; EC Public Health publications; Council of Europe treaties; World Medical Association publications; UNESCO Declarations; and European Medicines Agency (EMA).

Then, the applicability of retrieved documents in the iNMD field was analysed by considering the specific features of iNMDs, i.e.:

An ad hoc bibliographic search was performed in PubMed (Fig. 1). The publications discussing ethical issues related to research involving iNMD patients and the application of the existing provisions in the field were considered compliant with the search.

The following search strategy was used: (“Brain Diseases, Metabolic, Inborn”[Mesh]) AND “Ethics, Clinical”[Mesh] OR (“Brain Diseases, Metabolic, Inborn”[Mesh]) AND “Ethics, Research”[Mesh]. Only publications in English were considered.

Even in this second step, the rarity of conditions, the inheritance and familiar implications, the presence of paediatric patients and the manifestation of neurologic symptoms which can make paediatric and adult patients unable to provide the consent were focused on.

We also looked for data relevant to the aims of this work from already existing EU-funded projects on paediatric and rare disease research. The Community Research and Development Information Service (CORDIS) and Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) were searched by using the following keywords: (paediatric OR rare or genetic) AND disease AND clinical AND research AND ethics. Public websites were consulted, where existing.

The European legal framework offers a number of ethical provisions ruling the clinical research in general as well as specifically applicable to the iNMDs field, i.e. rare inherited diseases with neurological symptoms often involving young and very young patients.

From a general point of view, in Europe, all clinical trials follow the same assessment and authorisation. From 2016, with the entry into force of the new Regulation (EU) 536/2014 [28], a unique central procedure will be in place through a unique portal by submitting a homogeneous package for all Member States. This includes specific conditions to begin clinical research involving vulnerable persons, i.e. minors (art. 32) and incapacitated subjects (art. 31). For paediatric trials, the assessment must take into account PDCO opinions on Paediatric Investigation Plans (PIPs) and must be carried out by ethics committees with paediatric expertise or seeking advice from experts in the field taking into account the risks and benefits of research and other aspects such as the study design, the use of placebo and the monitoring of safety during and after the trial. This represents an important achievement from the ethical point of view and in consideration of the protection of children’s rights [37]. However, uncertainties still remain on how national ethics committees and the PDCO will interact and what would happen if the PDCO and the ethics committee opinions differ [36]. Therefore, given that ethics committees and PDCO evaluate many common elements while having distinct roles and responsibilities, the applications should be harmonised and standardised.

On the basis of our results, we can derive the following considerations regarding the above-mentioned features of iNMDs.

Most of the regulatory documents do not deal with ethical aspects related to rare diseases. Unfortunately, the new clinical trial Regulation (EU) No 536/2014 [28] only mentions the importance of clinical trials and timely availability of drugs for patients with rare and ultra-rare diseases in two recitals, but it does not establish applicable provisions. In fact, it does not make mandatory either a faster assessment of these trials or the involvement of specific expertise in the assessment phase. In line with the regulatory findings, ethical aspects related to the rarity of iNMDs are poorly dealt with in the literature, even though several EU projects are focused on rare diseases.

Specific ethical/regulatory documents are available for paediatric research. The recommendations released by the European Commission in 2008 [21] include the highest standard to be met. They deal with the benefit and risk balance, the process of information and consent/assent according to an age-staggered approach, the ethical review of paediatric protocols, the individual data protection and insurance issues. They mention that children with chronic illness may have increased capacity to make independent judgements based on previous life experience. Currently, this document is under revision and the European Commission launched a public consultation (from 1 June 2016 to 31 August 2016) to seek the views of stakeholders in preparation for the implementation for the new Clinical Trials Regulation (EU) No 536/2014.

However, as underlined in this work and in line with previous considerations [37], they have a poor legislative power and are implemented only partially in the regulation recently released [28].

With regard to the informed consent and assent, it has been recognised that before the decision to participate or abstain from participation, children are entitled to receive oral and written information according to age and level of maturity [21, 24, 28]. However, the existing provisions on informed assent are not fully applicable to iNMDs and are not enough, as the neurological impairment often leads to a different mental maturity of patients, both adult and paediatric, and makes them ‘vulnerable persons’ unable to provide their consent. As demonstrated by the analysis performed, at a regulatory level, this concept has been implemented in different documents [9, 11, 13, 14, 21, 24, 25, 27, 28, 53] and the need for obtaining the consent from a legal representative is made mandatory from the EU Regulation [28].

Other ethical issues arising great interest in the scientific community, as demonstrated in the regulatory framework, the literature and EU projects, include genetic aspects, data protection, confidentiality and the handling of biological samples, including the ‘secondary’ use of stored samples for research purposes after testing is completed. The existing provisions applicable in Europe appear highly relevant as they suggest procedures to safeguard the rights of research participants [9, 13, 52]. However, also these documents have a poor legislative power and their application requires a great effort from researchers, especially in the case of multi-centre and multi-national studies in which national laws also have to be complied with. Importantly, it should be noted that these issues have not ad hoc rules in paediatrics.

The analysis performed in the literature reveals that a great part of publications dealt with informed consent issues, but none mentioned the assent and the involvement of minors in the informed consent/assent procedure.

Finally, even though the literature provides a number of recommendations/suggestions addressed to different stakeholders (researchers/clinicians, policymakers/health institutions, ethics committees, patients and their families), including the implementation of clear ethical rules [38, 50], no publication considers the application of regulatory/ethical/legal provisions in the iNMD field, either in Europe or in any country in the world.

Additional relevant information was found in EU-funded projects. Rare inherited paediatric neurological disorders are the focus of InNerMeD-I-Network [40] and LEUKOTREAT [41] projects.

Because of the paucity of current information about most of these disorders, the ‘Inherited NeuroMetabolic Disease Information Network’ project was launched with the aim of creating the first European network of information related to diagnosis and treatment of iNMDs. One of the goals of the project was to straighten research capacities in the iNMD field and to overcome the existing barriers for developing drugs for small populations. In this context, methodological and ethical recommendations have been publicly released for researchers, including companies and research centres, ethics committees, patients and families to perform well-conducted research involving iNMD patients.

Also, TEDDY [51] and RESPECT [46] FP projects released recommendations on ethical issues in paediatrics with the aims to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families on issues related to paediatric research, such as the informed consent and assent process. Furthermore, the GRiP project (Global Research in Paediatrics - 261060 - FP7-HEALTH-F5-2010) provided documents on the ethical review of multi-jurisdictional trials and models for information sharing on human research among ethics committees and Institutional Review Boards in the paediatric field.

Another important issue raised is the relevance of sharing patient data from different countries from the ethical point of view [41, 45]. This is increasingly widespread in the case of rare disease and particularly challenging when these data are from children and include genetic data.

Importantly, no specific ethical issue on the use of ATMPs for iNMDs and paediatric rare diseases in general is available in the regulatory framework. This claims the need for further specific guidelines/recommendations in this field that could be particularly relevant to iNMDs.

The lack of substantial guidance from the legal and methodological point of view emerges in the regulatory framework, as demonstrated in the literature and underlined in the framework of research projects.

Overall, these EU projects underline the interest from the European Commission in the field. In the framework of the new research programme Horizon 2020, a project on the study of the changes deriving from the application of the new Regulation on clinical trial [28] and the proposed Regulation on privacy and data protection [23] might be expected.

Conclusively, this work highlights the need for a common ethical approach to the clinical research involving iNMD patients and, more in general, rare neurological diseases also affecting children. This approach should represent the basis for developing official ethical recommendations for researchers, companies, ethics Committees, patients and families to be shared with regulatory agencies and public health bodies.