The Clinical Trials Regulation is intended to harmonise and streamline the review and conduct of clinical trials in the European Union. In this paper, we identify and analyse several serious issues concerning the division imposed by the Regulation between scientific review and ethical review. We conclude that these problems may compromise the objectives of the Regulation.
- Clinical trials
- Ethics Committees/Consultation
- Policy Guidelines/Inst. Review Boards/Review Cttes.
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The new Clinical Trials Regulation (536/2014) (CTR) is intended to harmonise conduct of clinical trials across the European Union. In this paper, we analyse the CTRs provisions and highlight some key problems regarding scientific and ethical review of applications. Despite the CTRs attempt to streamline authorisation of clinical trials, the division imposed between part 1's scientific design/relevance and risk/benefit assessment and part 2's focus on consent issues is problematic. Scientific design is also an ethical issue, and consent cannot be considered fully without also considering risks and benefits. While having two parts reviewed simultaneously is an admirable attempt to speed up review, the body reviewing part 2 might raise concerns that are really the domain of part 1, and vice versa. There is also no provision within the CTR for raising concerns between the bodies constituted to review parts 1 and 2. Another problematic issue is that the CTR has no provisions for objecting to a project on general ethical grounds, for example, if it involves xenotransplantation of chimeric organs. Ultimately, it would be better for parts 1 and 2 to be considered by the same body, or indeed for the CTR to be revised rather than attempt to divide responsibilities in this way.
Scientific versus ethical review
Article 4 of the CTR sets out requirements that each member state (MS) must follow. The key distinction is that ethics committees are supposed to conduct ethical review (part 2 of the assessment report on a given application), while scientific review is the province of part 1:
A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this Regulation. 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.
Despite the general distinction between part 1 and part 2, this text states that ethics committees can also consider part 1 issues in its deliberations. But what are the specific topics for consideration in part 1 and part 2? Article 6 sets out the comprehensive requirements for part 1 review:
The reporting Member State shall assess the application with regard to the following aspects: (a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor;
(b) Compliance with Chapter V with respect to the following:
(i) The anticipated therapeutic and public health benefits taking account of all of the following: — the characteristics of and knowledge about the investigational medicinal products;
— the relevance of the clinical trial, including whether the groups of subjects participating in the clinical trial represent the population to be treated, or if not, the explanation and justification provided in accordance with point (y) of paragraph 17 of Annex I to this Regulation; the current state of scientific knowledge; whether the clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment and authorisation of the placing on the market of medicinal products; and, where applicable, any opinion formulated by the Paediatric Committee on a paediatric investigation plan in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council (1);
— the reliability and robustness of the data generated in the clinical trial, taking account of statistical approaches, design of the clinical trial and methodology, including sample size and randomisation, comparator and endpoints;
(ii) the risks and inconveniences for the subject, taking account of all of the following:
— the characteristics of and knowledge about the investigational medicinal products and the auxiliary medicinal products;
— the characteristics of the intervention compared to normal clinical practice;
— the safety measures, including provisions for risk minimisation measures, monitoring, safety reporting and the safety plan;
— the risk to subject health posed by the medical condition for which the investigational medicinal product is being investigated;
(c) Compliance with the requirements concerning the manufacturing and import of investigational medicinal products and auxiliary medicinal products set out in Chapter IX;
(d) Compliance with the labelling requirements set out in Chapter X;
(e) The completeness and adequateness of the investigator's brochure.
Thus, we have five main topics: low-risk trials; prospective benefits and risks; compliance with manufacture and distribution requirements and the investigator's brochure. The prospective benefits and risk section is itself four times the length of the other four combined, and it is here that several problems are encountered. Under the heading of benefits, the review body is to consider evidence concerning the agent under investigation and the relevance of the study. This makes sense, but it is somewhat strange to consider ‘the reliability and robustness of the data generated in the clinical trial, taking account of statistical approaches, design of the clinical trial and methodology’ under the heading of ‘benefit’. While it is true that a poorly designed study cannot be beneficial as it cannot answer its question, the potential relevance and benefit of a trial should be assessed on the assumption that its design is sound. Design is extremely important, but should not be subsumed under the heading of benefit. This oddity is made even more apparent by the fact that statistics and design are not mentioned under (ii), risks and inconveniences for the subject. It is quite right that relevance and benefit are not mentioned here, but if statistics and design are relevant to assessing prospective benefit, they are also relevant to assessing potential harm.
These might seem like trifling technical issues, but they are significant in the sense that they indicate that the structure of one of the key parts of the CTR has not been properly thought through. Another indicator of this is that the reference to chapter V in Article 6 means that design considerations are subsumed under the heading of benefit, and also that benefit itself is considered under the mantle of ‘Protection of Subjects and Informed Consent’. In essence, the structure of the document is protection and consent>therapeutic and public health benefits>relevance/design/statistics. It is rather atypical (to say the least) for research guidance to structure its requirements in this way; normally, design, prospective benefit to society or patients, and informed consent would not be ranked like this. Indeed, consent and risk and benefit considerations would normally be the domain of the ethics committee.
This confusing structure is made even more complicated by the fact that both Articles 6 and 7 refer to the rules laid out in chapter V, meaning that both review bodies must apply the same rules regarding consent and protection of participants to their supposedly different remits. Let us look at the first section of chapter V as an example: it sets out eight different rules that must be followed:
A clinical trial may be conducted only where all of the following conditions are met:
(a) the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored;
(b) the subjects, or where a subject is not able to give informed consent, his or her legally designated representative, have been informed in accordance with Article 29(2) to (6);
(c) the subjects, or where a subject is not able to give informed consent, his or her legally designated representative, have given informed consent in accordance with Article 29(1), (7) and (8);
(d) the rights of the subjects to physical and mental integrity, to privacy and to the protection of the data concerning them in accordance with Directive 95/46/EC are safeguarded;
(e) the clinical trial has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as possible for the subjects and both the risk threshold and the degree of distress are specifically defined in the protocol and constantly monitored;
(f) the medical care provided to the subjects is the responsibility of an appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner;
(g) the subject or, where the subject is not able to give informed consent, his or her legally designated representative has been provided with the contact details of an entity where further information can be received in case of need;
(h) no undue influence, including that of a financial nature, is exerted on subjects to participate in the clinical trial.
In terms of Articles 6 and 7, this is something of a ‘pick'n'mix’. Most of the rules concern consent, and are clearly the domain of a part 2 review body. However, rules (a) and (e) are clearly the purview of the part 1 review body. The way they are listed together in chapter V clearly suggests that these rules are closely linked, and indeed inter-related, which makes the planned division of review of adherence to these rules between part 1 and part 2 review bodies somewhat mystifying.
What of the requirements for part 2 review? These are set out in Article 7 of the CTR:
Each Member State concerned shall assess, for its own territory, the application with respect to the following aspects:
(a) compliance with the requirements for informed consent as set out in Chapter V; [Protection of Subjects and Informed Consent];
(b) compliance of the arrangements for rewarding or compensating subjects with the requirements set out in Chapter V and investigators;
(c) compliance of the arrangements for recruitment of subjects with the requirements set out in Chapter V;
(d) compliance with Directive 95/46/EC [Data Protection Directive];
(e) compliance with Article 49 [suitability of individuals];
(f) compliance with Article 50 [suitability of trial sites];
(g) compliance with Article 76 [compensation arrangements];
(h) compliance with the applicable rules for the collection, storage and future use of biological samples of the subject.
In essence, this unreasonably limits the ethics committee to consideration of consent issues, confidentiality issues and suitability and recruitment of participants. This amounts to a drastic curtailment of the issues that ethics committees normally, and indeed must, consider.
Handicapped ethics committees
The specific remit for ethics committees is limited in two different senses. The first is that it is too limited in a general ethical sense, in that ethics committees cannot object on other grounds than those mentioned in Articles 6 and 7. Some ethics committee members might object to the particular type of research being considered, for example, if it involves xenotransplantation or the use of embryonic stem cells. Under the terms of the regulation, any ethical concerns like these should not be considered in the committee's decision. A potential loophole that might allow ethics committee members to circumvent this problem would be to argue on relevance grounds against any such project; that is, society would never use such a drug or intervention because of its ethically problematic nature. However, this seems to be an unsatisfactory solution.
The second, potentially more important problem is that very specific scientific concerns that are normally within the specific purview of ethics committees are not its responsibility in the CTR. Ethics committees might well object to the design, relevance or risk of the study,1 and thus (wish to) reject an application on ‘Part 1’ grounds. For example, the experts on an ethics committee might realise that similar research has already been conducted, making a repeat study irrelevant; or that the risks posed are not outweighed by prospective benefit to society even if the study is novel; or that the study is statistically underpowered and thus cannot confirm its hypothesis. Furthermore, ethics committees cannot pass judgement on the information provided to participants without assessing the design, relevance and risks/benefits of a given study; otherwise, they would just have to assume that everything on every participant information sheet were true. While the CTR does allow ethics committees to consider part 1 issues like these, they should really be listed as a specific responsibility of the ethics committee.
The CTR is not alone in confusing the issue of scientific and ethical review; the UK's governance arrangements for research ethics committees state both that ‘a research ethics committee (REC) need not reconsider the quality of the science’ and that ‘The committee has to be assured that any anticipated risks, burdens or intrusions will be minimised for the people taking part in the research, and are justified by the expected benefits for the participants or for science and society’.2 The research ethics guidelines of the Council for International Organizations of Medical Sciences are much clearer on this point, stating that ‘Scientific review and ethical review cannot be separated’.3
The situation is further complicated by the fact that a negative part 1 review body decision from one MS means that the trial cannot go ahead in any MS (itself an interesting point given that respondents to the CTR consultation stated that it is ‘very unusual not to receive divergent assessments’ from different MSs4), but a part 2 review body's (ie, an ethics committee's) concerns about part 1 issues would only prevent the trial going ahead in the MS housing that particular ethics committee. In essence, this means that a trial could go ahead in multiple MSs simply because the review body that found serious flaws in part 1 is an ethical rather than a scientific committee. The CTR’s artificial division between ethical and scientific review also conveys a misleading positivist message that science is universal, while ethics is merely a subjective local matter.
Furthermore, Article 28 states that ‘a clinical trial may be conducted only where…the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored’. Given that ethics committees are normally responsible for ongoing monitoring, this means that ethics committees (or whoever is reviewing part 2) are not just able, but actually obliged to review part 1 criteria in depth, meaning that there is very real room for disagreement between the two review bodies. (Indeed, respondents to the CTR consultation stated that ‘divergent assessments of Ethics Committees….was the main challenge today when rolling out a clinical trial’.5) The situation is further complicated by the relatively tight timelines for simultaneous part 1 and part 2 review and approval or rejection of applications (45 days). What if the ethics committee finds design flaws? The CTR appears to have little provision for communication between the two review bodies during this period, although presumably individual MSs could legislate for such contact.
Compatibility with other guidelines
The CTR also contradicts itself with regard to compatibility with other guidelines. Article 80 of the Regulation claims that it is compatible with the 2008 version of the Declaration of Helsinki and with the International Conference on Harmonisation's Good Clinical Practice Guidelines (ICH GCP): ‘this Regulation is in line with the major international guidance documents on clinical trials, such as the 2008 version of the World Medical Association's Declaration of Helsinki and good clinical practice, which has its origins in the Declaration of Helsinki’. This is curious, given that the 2008 revision of the DoH clearly contradicts ICH GCP on some key issues.6 However, Article 43 makes it clear that ICH GCP takes precedence:
When designing, conducting, recording and reporting clinical trials, detailed questions may arise as to the appropriate quality standard. In such a case, the ICH guidelines on good clinical practice should be taken appropriately into account for the application of the rules set out in this Regulation, provided that there is no other specific guidance issued by the Commission and that those guidelines are compatible with this Regulation.
This passage actually contradicts Article 80, as the latter claims that the CTR is compatible with ICH GCP while Article 43 casts some doubt on compatibility. Another tension generated by the CTRs reliance on ICH is that the GCP document places a great deal of responsibility for both ethical review and monitoring on ethics committees, which is problematic given that the CTR moves all consideration of risk, benefit, relevance and design to the part 1 review body. Simultaneously disempowering ethics committees while reaffirming adherence to a trials guidance document that places great responsibility upon ethics committees does not seem like a wise strategy.
We have highlighted in this paper how the CTR imposes an artificial distinction between ethical and scientific review, which in turn hamstrings ethics committees' abilities to properly review projects. It is essential that ethics committees are able to review all aspects of a project that could have ethical implications; contrary to what the drafters of the CTR seem to think, this is not confined to issues about consent, and also includes risk, design and statistical issues. It is somewhat disappointing that these issues persist in the CTR given that most of them were raised 6 years ago in the public consultation. For example, the summary of the consultation states that ‘Respondents raised several critical comments, for example as regards the role of ECs (who, in some MSs, assessed several aspects that were assessed by NCAs [national competent authorities—Part 1 review bodies] in other MSs)’. Similarly, it was ‘stressed that ECs had to take safety and scientific merit into account in their assessment, which inevitably led to a double assessment’—the very point about risk/benefit analysis and scientific design that continues to plague the CTR. Finally, the idea of having one body combine part 1 and 2 review functions was also raised 6 years ago. Had these points been addressed, the CTR would probably be more fit for purpose. As it stands, however, the CTR creates division and discord in what should be a unified and efficient regulatory process.
Correction notice This article has been corrected since it first published Online First. The title has been amended.
Contributors DS and DT conceived the article together and DS wrote the first draft. Both authors revised the intellectual content.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.