Article Text
PDF
Abstract
Independent ethics committees play an important role in clinical trials as well as in all health-related research. Internationally, the national laws of the individual countries have guided their local development and organisation over the decades. Directive 2001/20/EC of the European Parliament and of the Council explicitly recognised the ethics committees’ duty to protect the rights, safety and well-being of human subjects involved in trials and to provide public assurance of that protection. Regulation (EU) 536/2014, which repealed the aforesaid directive, provides that a clinical trial must be subjected to scientific and ethical review, without specifically defining what they consist in. The divide between the evaluation of the ethical value and the scientific value of a study is very faint and, for some, it may even appear a meaningless distinction. While Regulation (EU) 536/2014 requires Member States to ensure that ethics committees are involved in the assessment process within their national territory, it does not require such ethical assessment to be binding. This article proposes a possible system for interaction between ethics committees and local regulatory authorities in which the meaning and purpose of the ethical assessment are conceptually clearly defined and not narrow.
- Clinical Trial
- Ethics (see Medical Ethics)
- Law (see Medical Law)
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
STRENGTHS AND LIMITATIONS OF THIS STUDY
The article delves into a topic on which there is no full understanding and procedural consistency at the European level.
The article suggests a model to be discussed and shared.
The article does not delve into the internal discussion and legislation specific to each European country, especially when this is not available in English.
Introduction
Today, the commonly accepted basis for conducting clinical trials on humans is firmly founded on the protection of human rights and the dignity of the human being. The reference principles are clearly set out in the leading international guidance documents, such as the 2013 version of the World Medical Association’s Declaration of Helsinki and Good Clinical Practice (GCP).1 Historically, the need to establish mandatory principles of behaviour is usually associated with the Nuremberg trials of 19462 as a means of avoiding abusive situations in particular in favour of those in conditions of vulnerability.3 Since then, there have been many regulatory efforts around the world to protect individuals in medical research and practice.4 GCP is an internationally recognised set of ethical and scientific quality requirements, which are mandatory for providing public assurance that the results of clinical trials are reliable.5 Certification of compliance with GCP is required for all submissions approved by regulatory agencies in the European Union, the USA, Japan and Canada.
It is also worth mentioning the International Ethical Guidelines for Health-Related Research Involving Humans, developed by by the Council for International Organisations of Medical Sciences in concert with the WHO. These guidelines state that the ethical justification for undertaking health-related research involving humans is its scientific and social value. However, scientific and social value cannot legitimate subjecting study participants or host communities to mistreatment or injustice.6 The highest standards of care and protection should not be waived under any circumstances, even during a pandemic situation, such as that of the COVID-19 emergency, which forced ethics committees to adopt new work methods, and the pressure exerted on medical research must not result in trials that do not comply with all applicable ethical standards.7 8
Full compliance with these requirements does not seem to be something that can be taken for granted even today.9 It is not possible, in fact, to state that the ethical principles recognised as fundamental are applied in a satisfactory and equitable way around the world and that no improvements to the supervision and review processes are necessary.10 11 The very way in which independent review is conducted is far from procedurally incontrovertible.12 There is a long-standing debate regarding the assessment of the quality of the work carried out by the ethics committees and the need to empirically verify whether this work actually improves the protection of individuals.13–16
It is, therefore, still necessary to identify the best practices or standards to be adopted in order to ensure adequate protection and to build community trust in research.
Before a clinical trial can start, the sponsor must apply for and be granted clinical trial authorisation from the competent regulatory authority. Each EU Member State has its own regulatory authority. In addition to this authorisation, as is stated in the GCP guidelines, before initiating a trial, the investigator must obtain a favourable opinion from the Institutional Review Board/Independent Ethics Committee (IRB/IEC).
Worldwide, IRBs17 or Research Ethics Committees (RECs)5 have the duty to ensure ‘the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. The legal status, composition, function, operations and regulatory requirements pertaining to independent ethics committees may differ among countries, but should allow the independent ethics committees to act in agreement with GCP as described in this guideline’.5
GCP has been incorporated into European legislation; in particular, the ‘Clinical Trials Directive’—Directive 2001/20/EC of the European Parliament and of the Council—refers explicitly to it and defines the ethics committee as ‘an independent body in a Member State, consisting of healthcare professionals and non-medical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent’ (Art. 2, k).18
In 2014, Directive 2001/20/EC was replaced by Regulation (EU) No. 536/2014 on clinical trials on medicinal products for human use, which brought important changes to the organisational structure of clinical trials in Europe.19 20 Although it came into force on 16 June 2014, its implementation was postponed until 31 January 2022, in which it was conditional to the development of a fully functional EU Clinical Trials Information System. The regulation has binding legal force for all EU Member States and stipulates that the study protocol must contain ‘a statement that the clinical trial is to be conducted in compliance with the protocol, with this Regulation and with the principles ofgood clinical practice ’ (Annex 1, D 17(a)).
As mentioned previously, GCP attaches considerable significance to the ethical assessment by the ethics committees, making them guarantors of the general protection of the participating subjects, going well beyond the mere aspect of correct information for informed consent purposes. Ethics committees are not the only subjects that have moral duties and responsibilities towards study participants, as these lie also with all interested parties, including the investigators, sponsors and regulators.
It is conceptually inappropriate to consider that the certain aspects of a study design have to do with science and others with ethics, that is, the statistical method regards science and the informed consent process regards ethics.21 22 A poorly designed study will not be scientifically valid because it will neither bring reliable results nor will it be ethically valid because it will reflect professional negligence, a waste of resources or, in the worst case, the dissemination of unreliable results. A wide range of aspects contributes to determining the value and acceptability of a study and some of which are complex to evaluate,23 24 such as, for example, the possible prevalence of commercial interests (eg, in a study in which the benefits to individuals or potential patients are negligible) or the true value of the research for society in relation to the use of public resources.4 25
A well-devised research protocol that does not protect the subjects involved may be scientifically valid, but it is not ethically acceptable in a society that puts the well-being and dignity of individuals first. The function of RECs constitutes the introduction, into an experimental process that could be imperfect, of a control system. ‘Ethics’ here refers precisely to the scrutiny of a behaviour to appreciate its value in relation to shared principles and reference points. Ethics is not an abstract, philosophical dimension—at least in this particular context—it merely refers to the best possible behaviour expected from someone in a given situation.
In this article, it is assumed that the behaviour of an investigator can be examined along three necessarily interrelated axes. The first axis is that of scientific action: it concerns the use of a rigorous methodology and the application of scientifically recognised principles. The second axis is that of human protection: it concerns respect for the rights and dignity of the subjects involved. The third axis is the regulatory one: it concerns knowledge and compliance with current regulations. In this perspective, the review by the independent committee should take place following these three axes of action; it is the impartial eye on the investigator’s planned behaviour. It might be more appropriate to refer to it not as an ‘Ethics Committee’, but simply as a ‘review committee’.26
Regulation (EU) No. 536/2014: critical issues
According to Regulation (EU) No. 536/2014, a clinical trial must undergo scientific and ethical review. It prescribes a precise and detailed procedure for the submission and assessment of authorisation requests. A sponsor who intends to initiate a clinical trial must submit an application dossier to the Member States involved via the EU portal. The reporting Member State appointed (Regulation, Art. 5) will be responsible for validating and evaluating applications, with the involvement of the other states involved in the clinical trial. Validation must take place within 10 days from the submission of the application dossier and the Member States involved may forward to the rapporteur Member State any comments relating to the validation of the application within 7 days of submission of the application dossier.
This is followed by the assessment phase. The issues to be considered in the assessment phase are detailed in Part I (Regulation, Art. 6) and Part II (Regulation, Art. 7). Part I represents a general analysis of the study protocol: it includes general aspects, such as those related to therapeutic benefits, risks to participants and safety and quality of the therapeutic agent. This part is assessed by the ‘reporting Member State’ and is valid for the entire EU. Part II covers local feasibility, such as local subject recruitment methods, the informed consent process and subject compensation, which is assessed separately by each state.
For clinical trials involving more than one state, Part I assessment process shall include three phases (Art. 6): (a) an initial assessment phase carried out by the rapporteur Member State within 26 days from the validation date; (b) a coordinated review phase conducted within 12 days from the end of the initial assessment phase and involving all Member States and (c) a consolidation phase carried out by the rapporteur Member State within 7 days from the end of coordinated review phase.
Each Member State concerned shall assess, in relation to its own territory, the application for authorisation with regard to the aspects included in Part II (Art. 7) and must complete its assessment within 45 days from the validation date by submitting it through the EU portal.
At the end of the assessment process, the rapporteur Member State shall draw up an assessment report. It must contain one of the following conclusions concerning the aspects addressed in Part I (Art. 6): a) the conduct of the clinical trial is acceptable pursuant to the requirements set out in the regulation; (b) the conduct of the clinical trial is acceptable pursuant to the requirements set out in the regulation, but subject to compliance with specific conditions that must be specifically listed in the conclusion or (c) the conduct of the clinical trial is not acceptable pursuant to the requirements set out in the regulation.
Regulation (EU) 536/2014 refers to the ‘ethics committee’ as ‘an independent body established in a Member State in accordance with the local law and empowered to give opinions for the purposes of the Regulation, taking into account the views of laypersons, in particular patients or patients' organisations’.
In relation to the role of ethics committees, regulation requires Member States to organise the involvement of these bodies in the evaluation process.
It allows Member States full discretion regarding the pronouncement of the ethics committees and prescribes that ‘the ethical review shall be performed by an ethics committee in accordance with the law of the Member State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II of that assessment report as referred to in Article 7 as appropriate for each Member State concerned’ (Art. 4). The individual states must ‘determine which body or bodies are appropriate for the purpose of evaluating an application for authorization to conduct a clinical trial and to organise the participation of ethics committees’ (recital no. 18).20
This provision leaves the authorisation process undefined, particularly regarding the relations between the competent authorities and the ethics committees.27–29 It neither defines the meaning of the assessment required of the ethics committees nor whether it is binding or non-binding and nor whether ethics committees should liaise with the sponsor directly or through the competent authority. Some authors have emphasised that the uncertainty regarding these points could lead to diversities between the various countries as well as to situations of marginalisation and ineffectiveness of the action of ethics committees,30 31 whereas it would be desirable to work on quality standards and accreditation systems for these bodies.32–34
The possible decision to implement a narrow model, only involving ethics committees in Part II, could certainly lead to a situation in which participating subjects are not adequately protected in breach of the Declaration of Helsinki and other international research ethics guidelines.3
Such a possible decision would also appear difficult to justify, given that the scientific and methodological elements contained in Part I are closely associated with the protection of the subjects involved and, therefore, with the ethicality of the research. Part II assessment activity is closely intertwined with Part I assessment activity, such as formulating the risk–benefit profile and disclosing it during the informed consent process.
The structure and legal basis of RECs in the various EU Member States vary significantly. As far back as 2013, the European Network of RECs emphasised the importance of having these bodies review both Parts I and II of the trial authorisation dossier and of making the authorisation to conduct a biomedical research project conditional to their issuance of a favourable opinion. It is essential to clarify the exact impact of an REC assessment for the granting of a favourable opinion for the whole assessment process.35
The new framework requires the committee to issue a single opinion that applies to the entire territory of the Member States participating in a multicentre trial, regardless of whether the trial then takes place at different sites within that state. All Member States are, therefore, in the position of needing to adapt their national legislation on ethics committees in order to achieve a system capable of providing the enactment of the aforementioned single opinion.
Before Regulation (EU) No. 536/2014 came into force, in order to start a clinical trial in Italy, it was necessary to obtain authorisation from the competent authority, the Italian Medicines Agency (AIFA) and from ethics committee.36 The opinion of the ethics committee was binding and covered all aspects of the submitted study, that is, all those now provided for in Parts I and II of the regulation.
At the current time, it has still not been established what form the ethical assessment should take.
It would be appropriate, at European level, to maintain a clear distinction between the work of the competent authority and that of the ethics committee, and for the latter’s assessment to be traceable at all times, rather than be incorporated into the final assessment. A possible interaction model is proposed below.
Possible model for the role of ethics committees
As mentioned previously, since the regulation makes no specific provision in this sense, each Member State is at liberty to define its own procedures for involving the ethics committees, as well as the specific procedure through which the ethics committees must carry out their evaluation; with regards to Part I, in particular, the regulation does not explicitly provide for the opinion of the ethics committee to be binding.
This has led to significant heterogeneity among European states.
Currently, in Italy, the ethics committees evaluate the aspects included in Part II autonomously and independently. They may also comment on Part I, but the competent authority responsible for completing Part I assessment could hypothetically avoid taking into account comments raised by ethics committees. The significance of their role in this case is, therefore, rather undefined. We believe that, despite the local organisational and structural differences, action must be taken at the European level to harmonise the operation of ethics committees, particularly with regards to clinical trials.
In the model postulated and described here, the rapporteur Member State must immediately involve a local ethics committee, which must assess the protection afforded to the subjects of the clinical trial (figure 1). This assessment should form a separate part in the drafting of Part I assessment that the Member States shares with all the other Member States in the coordinated review phase and should contain a reasoned conclusion on the feasibility of the study (figure 2). In this way, the ethics committee’s assessment would not be incorporated into that carried out by the competent authority, rather, it would maintain an autonomous character and, above all, its own conclusion. The other Member States involved could then consult it and use it to make their own further considerations. Box 1 shows a possible example of a format for the evaluation of Part I by the ethics committee.
The validation process of a trial authorisation request submitted by the sponsor. The left part of the figure represents the timing of Regulation (EU) No. 536/2014, and the right part represents a possible model that provides for the immediate involvement of an ethics committee. CTIS, clinical trials information system.
The different phases of the assessment process of the aspects covered by Part I of the Regulation (EU) No. 536/2014 (Art. 6). The left part of the figure represents the timing of the regulation, and the right part represents a possible model of involvement of the ethics committee.
Evaluation scheme for ethics committees, Part I, Reg. 536/2014.
ASSESSMENT REPORT PART I.
SECTION FOR ETHICS COMMITTEE:
Compliance with Good Clinical Practice ensures the reliability of the trial. Research Ethics Committees (RECs) have the duty to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance by, among other things, reviewing and providing a favorable opinion on the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
The Ethics Committee (reference),
With reference to compliance with the principles of WMA Declaration of Helsinky, the Good Clinical Practice and the requirements set out in the Regulation 536/2014, art. 6, expresses the following assessment of the study (reference):
Ethics Committee ASSESSMENT:
the conduct of the clinical trial is acceptable;
the conduct of the clinical trial is acceptable but subject to compliance with specific conditions which shall be specifically listed;
the conduct of the clinical trial is not acceptable;
Reasons for the assessment and any requests:
It would be of fundamental importance to establish, consistently between the Member States, whether or not the assessment report—particularly the aspects covered by Part I—of the ethics committee is binding as this serves to define the very meaning given to these bodies. We believe that in the context of clinical trial regulations, ethics committees are oversight rather than advisory bodies, which also means they take on a guarantor role towards the public. A negative opinion issued by these bodies cannot in actual fact be a negligible opinion, but rather a reason why it is right, as a precautionary measure, not to initiate the trial.37
Conclusion
Regulation (EU) No. 536/2014 brought important changes to the organisational structure of clinical trials in the European Union. This reform has also affected the way ethics committees work, imposing a reflection on the meaning of their assessment. The regulation requires that a clinical trial be subject to scientific and ethical review, but does not specify in detail how they should be conducted, leaving it to the Member States to establish their own organisational model and how the competent authorities and IECs should interact. It is important to point out that Regulation No. 536/2014 does not require that a favourable ethics evaluation be binding for the beginning of a trial. Some authors have expressed concern that the discretion left to the Member States could lead, in some of them, to a weakening of the ethics committees’ ethical function and assessment. GCPs attribute a broad meaning to the assessment by the independent committees, a supervisory role to ensure the general protection of the participating subjects, which can potentially affect all aspects of the study and, therefore, go beyond the aspect of correct information for informed consent purposes. It is conceptually inappropriate to hold that the certain aspects of a clinical study regard science and others regard ethics, that is, the statistical method regards science and the informed consent process regards ethics.
As an adjective, ethics refers to the goodness of all dimensions of a trial. The ethics of a study refers to every aspect of the behaviour that is expected of an investigator. In this article, we assume that such behaviour can be examined along three necessarily interconnected axes: the axis of scientific action, that of the protection of subjects and that of compliance with legal provisions. If we focus on the part concerning the methods for acquiring informed consent, particularly for incapacitated subjects, we will be analysing above all the axes of protection. However, any consideration of the quality of existing behaviour will be an ethical consideration. Considerations regarding, for example, the publication of negative results are also important ethical considerations.
The IECs, understood as third parties, should be called on to express an opinion on clinical trials regarding the aspects included in both Part I and Part II of Regulation (EU) No. 536/2014. In the model proposed here, they should be involved from the validation phase and the assessment expressed should constitute a recognisable document in its own right, rather than being incorporated into the assessment by the rapporteur Member State.
This approach would help to ensure a clear conceptual definition of the role and function of these bodies, as is recognised internationally. The application of a uniform model in all EU Member States would encourage the development of standardised procedures aimed at achieving similar standards of protection in the different states. However, future research would be useful in order to investigate how multidisciplinary committees should actually act to ensure a high-quality review and how to develop consistency among them.
Ethics approval
Not applicable.
References
Footnotes
Contributors LR and CP contributed to the conceptualization of the work and the structuring of the concluding proposals. LR drafted the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.