MHRA Consultation on Proposals for Legislative Changes to Clinical Trials
Introduction
Akrivia Health works with a network of 16 mental healthcare organisations (the Akrivia Network) providing them with a service. The service involves de-identification of electronic health record (EHR) data, utilising natural language processing (NLP) to structure free-text information to make it accessible for authorised researchers, without compromising the privacy and confidentiality of patients. This enables researchers to use otherwise inaccessible information to accelerate the trajectory of research in mental health.
Akrivia held roundtable discussions with members of the Akrivia Network including research leads, and with our Public & Patient Involvement (PPI) Group, to discuss the proposed changes and bring together professional and lived experience of health care and clinical trials. These discussions were held independently from one another, with only two members of the Akrivia Health Team party to each roundtable, so that neither the research leads, nor PPI Group were aware of the other’s views.
Patient & Public Involvement
Q: Do you agree that the legislation should include a requirement for the involvement of people with relevant lived experience in the design, management, conduct and dissemination of a trial?
Response: Yes (emphatic!)
The feedback from both our PPI Group and Akrivia Network partners was enthusiastic about the inclusion of PPI throughout the clinical trial process. Research leads felt that there was a value in involving PPI as early as possible in the trial process, including protocol development and fundraising. Both the research leads and the PPI Group agreed that PPI inclusion in the clinical trial process brough significant value, and that it had to be done well. In particular, the PPI Group expressed the necessity for PPI input to be actively valued by researchers and noted the danger that the legislative change requiring PPI activity could result in a tick-box exercise. PPI Group members were positive about the research that they themselves had been involved with and stated that they had felt valued and included by clinicians and researchers.
Both groups independently shared the view that PPI was at its best when PPI members were embedded within research and within trial management groups. Both groups felt this would require a level of training to enable the PPI members to be as actively involved as possible. The PPI Group astutely observed that there was a danger of ‘professionalising’ PPI members, which may risk diminishing the degree to which they were authentically and truly representative of the public and patients.
Akrivia strongly believes that patient and public involvement is a crucial part of healthcare, including clinical trials and research into new treatments. This activity needs to be authentic and honest rather than tokenistic to realise its fullest value. Good PPI involvement strengthens the clinical trial process and builds public trust.
Research Transparency
Q: Do you agree that the legislation should include a requirement to register a trial? Yes/No Please provide any further detail to your answer.
Response: Yes.
The Akrivia Network partners were vocally supportive of the requirement to register a trial, noting that it lends strength to the integrity of the scientific process, commenting that registering of the trial and the expected outcome would reduce the likelihood of outcome switching during the course of the trial. The group also observed that it is frequently a requirement or expectation from external research ethics committees (RECs), and that it is a very small step to making that a legal requirement.
Akrivia’s PPI Group agreed in principle and noted that there is a balance to be struck between ensuring that the clinical trial process is scientifically robust and maintaining protections for the commercial interests of clinical trials sponsors, in particular in relation to intellectual property.
Akrivia feels that registration of clinical trials is important for transparency and puts longstanding ethical expectation[*] onto a statutory footing, whilst ensuring that trial sponsors’ commercial interests are taken into consideration.
Q: Do you agree that the legislation should include a requirement to publish a summary of results within 12 months of the end of the trial unless a deferral has been agreed? Yes/No Please provide any further detail to your answer.
Response: No.
The PPI Group disagreed that there should be a requirement to publish a summary of results within 12 months of the end of the trial, depending on the extent of the results required for publishing. Some in the group voiced concerns over the quality of the peer-review process and that the principle of this requirement could be undermined.
The Akrivia Network partners agreed in the spirit of the proposed change, in particular that it provided a potential safeguard against trials being repeatedly extended. The group suggested that instead of a requirement to publish, legislation should require researchers to submit results for publication with the 12-month period after the end of the trial, which would safeguard against delays in the peer-review process which are not within the researcher’s control.
Akrivia Health agrees with the spirit of the proposal but suggests that a requirement to submit the results for publishing is a fairer requirement.
Q: Do you agree that the legislation should include a requirement to share trial findings with participants? (Or explain why this is not appropriate) Yes/No Please provide any further detail to your answer.
Response: Yes.
Both groups were sympathetic to the proposal in its aim to be as transparent as possible with the individuals participating in trials, and upon whom researchers are dependent, but noted that the implementation would benefit from a more nuanced approach than simply providing a lay summary of findings.
The PPI Group noted that participants in trials may suffer from adverse reactions, including reactions to medication, and that they may wish to hear nothing further about the trial, especially if the reaction was sufficiently adverse as to be traumatic.
Akrivia Network partners noted that this places a burden on the trial’s sponsor, depending on the medium by which trial findings are distributed. While researchers are often enthusiastic about engaging with participants and taking the time to answer questions, it is easy to conceive of a scenario where inboxes are overrun with questions.
Akrivia Health broadly agrees with the proposed change to legislation and suggests that rather than a requirement to share trial findings, that the proposed change should require trial findings to be offered to participants. The MHRA could provide guidance on mediums by which these findings could be distributed, including lay summaries, webinars, and Q&A sessions, which allow participants to engage as much or as little as they like.
Research Ethics Reviews
Q: Do you have any views about the membership or constitution of Research Ethics Committees?
Neither the PPI Group nor the Akrivia Network partners had any particularly strong views about the membership or constitution of research ethics committees (RECs). The PPI Group noted that there is an incredibly steep learning curve for individuals entering onto an REC, particularly but not exclusively, for individuals joining as lay members.
Both groups touched lightly on the distinction between ‘expert’ and ‘lay’ members and whether this is a useful distinction. The legal definition of ‘expert’ is incredibly narrow[1] and this may dissuade other specialists with relevant expertise from volunteering their time, including specialists in ethics, data protection, human rights, and philosophy, whose expertise is arguably important in the REC’s mission to “protect the rights, safety, dignity and wellbeing of research participants.[2]”
The Network partners noted that there was a need to increase the diversity of individuals forming the RECs, and active encouragement and action to ensure representation from under-represented groups.
Akrivia believes wholeheartedly that the RECs play a vital role in ensuring that trials and conducted in ways which reduce the risk to infringements to individuals’ rights, freedoms, and dignity, and applauds the MHRA’s openness to reviewing the REC membership and constitution and would be eager to engage further.
Q: Should we introduce legislative requirements to support diversity in clinical trial populations? Yes/No Please provide any further detail to your answer If yes, what legislative requirements could be introduced to better support increased diversity in trial populations?
Response: No.
Both the PPI Group and Akrivia Network partners thought that increasing and supporting diversity in clinical trial populations was an incredibly important goal but noted that this was an enormous issue which requires deft handling. Neither group had any particular views on legislative changes that could be made to facilitate this and did query whether legislation was the right solution to this problem. Blunt instruments like quotas or mandated population proportions may have positive results where there are large pools of patients but may reduce the opportunities for research on conditions and treatments for small populations. Any legislation would need to be cognisant of this.
Safety Reporting
Q: Do you agree to remove the requirement for individual SUSARs to be reported to all investigators? They will still be informed via Investigator’s Brochure updates. Yes/No Please provide any further detail to your answer.
Response: No.
Both the Akrivia Network partners and PPI Group felt that safety reporting requirements should not be diluted. Network partners noted that, depending on the study, notification via Investigator Brochure updates could result in unnecessarily delayed communications. Research leads felt that generally the burden of this reporting requirement is minimal due to relatively small numbers of SUSARs, and that if there are a sufficiently large number of SUSARs as to make the process burdensome, that is likely evidence of itself that they need to be reported as soon as possible.
Q: Do you agree that, where justified and approved by the regulatory authority, SUSARs can be reported in an aggregate manner? Yes/No Please provide any further detail to your answer.
Response: No.
The Akrivia Network partners did not feel that there was any clear benefit to this change, and that any process for approval and justification by the regulatory authority may result in a net zero gain in terms of reducing the reporting burden.
Q: Do you agree with the proposal to remove the requirement to include listings of serious adverse events and serious adverse reactions in annual safety reports and instead include an appropriate discussion of signals/risks associated with the use of the medicinal product as well as proposed mitigation actions? Yes/No Please provide any further detail to your answer.
Response: No.
Network Partners were concerned that this proposed change could downplay the risk to patient safety and/or detract the human element from serious events and adverse reactions. There was a lack of information from the MHRA justifying or explaining the rationale behind this proposal. Akrivia Health does not disagree with the proposal of a discussion of risks associated with the use of medicinal products, but that this should be a complementary part of the safety reporting.
Akrivia appreciates the necessity for supporting trial sponsors and reducing the cost and burden of clinical trials where possible, whilst also noting that reductions in clinical safety reporting could easily to undermine public trust, as well as create an unnecessary risk to patient safety.
Conclusion
Akrivia Health is glad for the opportunity to respond to the MHRA consultation and hopes that we have been able to provide a multi-faceted view bringing together professional and lived experience. Akrivia believes that the clinical trial process can be strengthened by drawing upon public expertise both in the form of public and patient involvement, and in other expert areas for RECs. We feel that changes to reporting requirements need to be made in balance to the necessity to maintain patient safety which was a frequently linked relationship with public trust in how data is used. We would be delighted to work further with the MHRA on this matter.
References
[*]Paragraph 35 of The Declaration of Helsinki lays out expectations that “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.”
[1] The Medicines for Human Use (Clinical Trials) Regulations 2004, schedule 2, paragraph 1.
[2] HRA Website, Research Ethics Service and Research Ethics Committees; https://www.hra.nhs.uk/about-us/committees-and-services/res-and-recs/ accessed 09/03/2022.
