Earlier this year the National Institute of Health and Care Research (NIHR) announced it had agreed to fund the PATHWAYS clinical trial of puberty blockers in children with gender incongruence. The trial has not yet received ethical approval. CAN-SG does not believe that it will be possible to conduct an ethical puberty blocker trial and has written to all those involved expressing our concerns. Read our letter here.
Ethical regulatory framework
Medical clinical trials within the UK are governed by national and international codes of ethical conduct, regulation and quality standards founded by the Nuremberg Code (1947), the International Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice (GCP). UK legislation, the Medicines for Human Use (Clinical Trials Regulations) (2004) governing the conduct of clinical trials is derived from and concordant with these international regulations.
UK Clinical Trial Regulations
The UK Medicines for Human Use Clinical Trials Regulations include the following requirements:
A trial should be initiated and continued only if the anticipated benefits justify the risks.
A trial should not be conducted where there is a preceding belief that death or disabling injury will occur.
Trials with human participants must conform to scientific principles.
The information sought must be unprocurable by other methods.
There are specific protections for vulnerable groups such as children. Trials involving children must be designed to minimise any foreseeable risk in relation to a child’s stage of development (Schedule 1 Part 4 Principle 14 of the Medicines for Human Use (Clinical Trials) Regulations 2004).
Why CAN-SG believes a trial will be unethical
See here for a detailed critique of the ethics of the proposed trial, but in summary:
- The benefits do not justify the risks: there are established substantive harms and risks of the intervention and the potential benefits are unclear, with no good evidence of benefit.
- There are reasons, based on previous research and outcomes of treatment to believe that disabling injury will occur including to fertility, brain and cognitive development, sexual function and bone metabolism.
- A puberty blocker trial cannot conform to scientific principles as there is insufficient understanding of the condition being treated, no rationale for the use of puberty blockers, no diagnostic criteria for selecting those likely to benefit from such an intervention and lack of clarity of the aims of the trial. A two year trial cannot measure the outcomes of concern, such as on long term mental and physical health, fertility and sexual function, and the proposed measures of “wellbeing” are not valid proxy measures for those long term outcomes.
- Information on how to support children and young people with gender related issues is procurable by other methods such as the data linkage study following up the 9000 children who have been through the GIDS gender clinic and research on psychosocial interventions.
- Foundational research on the nature of gender dysphoria/ incongruence and the reasons for the 5000% increase in referrals of teenage girls (aetiology and epidemiology) should be done before proposing an interventional trial for a poorly understood condition.
- Other research avenues that could be explored prior to considering an interventional trial of GnRHa on children with gender incongruence/dysphoria include systematic reviews of GnRHa in other health conditions and animal studies.
Research priorities are wrong
The Cass Review recommended a very different approach to the previous medical pathway to supporting children and young people with gender related problems, saying that the priority should be holistic psychosocial assessment and support. This has been taken forward in the draft NHS Children and Young Peoples Gender Service specification which stated that psychosocial interventions should be the primary intervention.
The primary intervention for children and young people who are assessed as suitable for The Service is biopsychosocial and psychological support and intervention; the main objective is to alleviate distress associated with gender incongruence and promote the individual’s global functioning and wellbeing.
The Cass Review said there was not enough research on what forms of psychological and psychosocial intervention would be most helpful. It is inexplicable that this area of research has not been prioritised over puberty blocker research, given its central importance to the new youth gender services.
Prioritising a puberty blocker trial over research into psycho-social treatments could undermine the implementation of the new approach to supporting this group of children and young people recommended in the Cass Review. It reinforces beliefs about the potential efficacy of puberty blockers and could disincentivise children and their families from participating in therapeutic work which they could see as a barrier to access to the desired puberty blockers.
Who provides ethical approval?
The trial will be assessed for ethical approval by a Research Ethics Committee (REC) appointed by the Health Research Authority (HRA) and the Medicines and Healthcare Products Regulatory Agency (MHRA). In addition the trial investigators, sponsors and funders share responsibility to ensure the proposed research is ethical. The following information was provided to us by the MHRA about the process.
The MHRA is the competent authority for authorising clinical trials in the UK. Therefore, before a clinical trial of an investigational medicinal product can begin, the MHRA needs to review and authorise it. The review of the MHRA is combined with the review of a Research Ethics Committee (REC), and approval from both bodies is required.
Clinical trials must be conducted in the UK following established standards to protect the rights, safety and well-being of the study participants, and it is the sponsor’s responsibility to warrant that these are in place. These standards include the International Council on Harmonization Good Clinical Practice (ICH-GCP E6) Guidelines. In the UK, it is a regulatory requirement to conduct clinical trials in accordance with the conditions and principles of good clinical practice.
The MHRA confirms compliance with these requirements while assessing any clinical trial authorisation (CTA) submission. This would include any trial to test puberty blockers. Approval should only be granted once a thorough assessment process is completed, and it is confirmed that the risk/benefit balance is considered positive for the study participant.
How confident can we be in the regulatory process?
Concerns were raised about research ethics governance of the previous UK trial of puberty blockers at the Tavistock GIDS, particularly as regards the regulatory oversight by the UK’s Health Research Authority. Given the serious ethical questions raised by the proposal to run another interventional trial on puberty blockers, and the inadequacy of past oversight and regulation, CAN-SG is very concerned to know that those responsible have learned from that and are paying due attention to the ethical issues now.
CAN-SG has written to all with ethical responsibilities
We have been informed that although the final decision on ethical approval will be taken by the MHRA and HRA (through one of the HRA appointed Research Ethics Committees), the trial investigators, funder and sponsors also have responsibilities to ensure that the proposal conforms to ethical principles and regulations.
CAN-SG has written to the Lead Investigators; Children and Young People’s Gender Research Oversight Board; trial sponsors (Kings College London and South London and Maudsley NHS Foundation Trust); funder National Institute of Health and Care Research (NIHR); regulators Health Research Authority (HRA), Commission on Human Medicines (CHM), MHRA; NHS England; Department of Health and Social Care; relevant government ministers and all the Research Ethics Committees that assess research in children about our concerns. Our aim was to ensure they are aware of the serious ethical issues involved in the proposed puberty blocker trial and take our concerns into consideration when making their decision on whether to ethically approve the proposed research. You can read our letter here.
Responses to our letters
Many of those we have written to have not responded. We have had some acknowledgements. None of them addressed our concerns directly but some said they would consider them.
The Children and Young People’s Gender Research Oversight Board sent the following response on 6 March:
Thank you for your recent letter in relation to the planned PATHWAY study, which Professor Sir Simon Wessely has read in full and with interest in his role as Chair of the national Children and Young People’s Gender Research Oversight Board.
In common with other publicly funded studies, the PATHWAYS study proposal has already been subject to independent peer review and NIHR funding committee consideration, and will now need to secure the usual research approvals, including research ethics committee approval, prior to the protocol being finalised and the study moving to set-up and recruitment.
These approval steps are clearly very important, and will ensure an appropriate and balanced consideration of the issues you raise in this complex area of healthcare. Yours sincerely, NHS England CYP Gender Programme Team
Professor Steve Turner who is President of the Royal College of Paediatrics and Child Health and who is on the Children and Young People’s Gender Research Oversight Board wrote:
Dear CAN-SG members, Many thanks for your letter dated 8th March 2025. The PATHWAYS trial was funded by the NIHR after a peer review process. The trial was designed to address the gap in our knowledge in the role of puberty blockers to manage distress related to gender dysphoria in children and young people. The gap is described in a series of literature reviews and highlighted by the Cass Review. The RCPCH accepts the recommendation made by the Cass review that a trial should take place, and we are supportive of the PATHWAYS trial moving forward. The RCPCH is not directly involved in the trial, and I suggest that directly approach the funder, sponsor or trial team with your concerns. Kind regards. Professor Steve Turner. President RCPCH
The funders, the National Institute of Health and Care Research (NIHR) directed us to the study’s sponsors, KCL
Please direct all correspondence to the study sponsor’s research governance office.
The MHRA informed us that the study’s sponsors have a responsibility to ensure that the research conforms to required ethical standards:
Clinical trials must be conducted in the UK following established standards to protect the rights, safety and well-being of the study participants, and it is the sponsor’s responsibility to warrant that these are in place.
The sponsors, Kings College London, did not address their role in the ethical assurance process but informed us the UK regulators and HRA would subject the research to rigorous regulatory and ethical approval.
Thank you for your email and letter of 6 April to Professor Shitij Kapur, sharing your concerns about the PATHWAYS trial. The PATHWAYS programme will be overseen by independent advisory groups and will be subject to rigorous regulatory and ethical approval by UK regulators and the Health Research Authority. For further information please see the research website https://www.kcl.ac.uk/research/pathways.
The Health Research Authority replied on 11 April to say it will file our letter as a “complaint” to be considered once they receive a research application for the trial.
Thank you for your letter dated 7 April 2025 on behalf of the Clinical Advisory Network on Sex and Gender (CAN-SG), in which you raise concerns about the proposed clinical trial of puberty blockers for children with gender dysphoria/incongruence. Your concerns have been forwarded to the Health Research Authority (HRA) complaints team and will be handled in accordance with our policy and procedure for managing complaints relating to third parties. Please find a letter attached in acknowledgement of your complaint which provides further information.
The HRA has not yet received a research application for the proposed clinical trial. However, we will keep your complaint open and when an application is submitted, your concerns will be reviewed in the context of that submission to determine whether any further action is required.
We will update this page with further responses as we receive them.