This was the central question that experts debated at a special CAN-SG webinar earlier this week (16th Sept) and their answer was a resounding ‘no’.
They agreed that the government’s plan to run a clinical trial on children with gender distress to determine whether puberty blockers (PBs) are safe raises too many ethical and methodological problems for it to be justified.
Instead, they said other non-pharmaceutical methods of research must be explored as a priority.
What trial is proposed?
Already commissioned by NHS England, the ‘Pathways’ puberty suppression and transitional care study has the backing of more than £10 million in public funding from the National Institute for Health and Care Research (NIHR). The proposed research programme, which includes a clinical trial of PBs for children referred to youth gender clinics, is to be led by a team at King’s College London and the South London and Maudsley NHS Foundation Trust.
This clinical trial, known as the Pathways trial, was originally expected to begin recruiting patients in the Spring (2025) but it has only recently been submitted for ethical approval.
However, panellists of the webinar, which was chaired by retired consultant psychiatrist and former staff governor of the Tavistock and Portman NHS Foundation Trust Dr David Bell, agreed the concept of the trial was deeply flawed and it should therefore not be granted ethical approval.
Ethical objections: protecting vulnerable children
Dr Sinead Helyar, a registered nurse and clinical researcher with expertise in clinical trials, outlined the major ethical concerns around conducting such a clinical study.
First, she said it would breach core regulatory and ethical requirements designed to protect vulnerable participants. She explained that all medical clinical trials in the UK must adhere to national and international ethical codes, that prioritised the rights, safety, and well-being of the individual participants. UK trials must minimise foreseeable risks in relation to a child’s development and prohibits studies where there is a clear risk of disabling injury.
In contrast to those requirements, she said the proposed trial intended to prescribe PBs to physically healthy children to prevent normal pubertal development, thereby aiming to interfere with child development. This would create “an unacceptable level of risk” to participants.
Second, she said any drug-related clinical trial for children requires a ‘presumption of benefit’ supported by scientific rationale. However, evidence to support the use of PBs for gender incongruence had been assessed as being of “very low or low quality”.
Known and potential harms
Common justifications for use of PBs such as they prevented suicide or provided a helpful pause for children to think about their identities while delaying puberty had been undermined by evidence.
But Dr Helyar listed multiple health harms associated with their use, including reduced bone density and early onset osteoporosis, brain swelling and concerns around impairment of future sexual functioning and ability to form emotional relationships. And if PBs were administered at Tanner Stage 2 and followed by cross-sex hormones, she said they can also leave children sterile.
“To commence a trial with these known and potential harms and outcomes, goes against clinical trial regulatory and ethical practice, which seeks to protect from harm,’ she said.
“The first duty of any clinician in a clinical trial is to ensure safety. In contrast, any research proposal to medicate selected children who present with gender dysphoria with PBs as part of a clinical trial goes against the ethical demands and normal regulatory practice of such trials. There is evidence that it will cause harm to the children that such research is actually supposed to protect.”
Methodological concerns: a flawed design
Dr Hannah Ryan, a registrar in Clinical Pharmacology and General Medicine who has authored Cochrane evidence reviews, told the meeting she initially believed a clinical trial might be helpful. However, she ruled that out after learning more about the condition and the state of the field (that there is not true clinical equipoise).
She said the design for such a study would fail on every essential element, and she went on to detail them.
Unclear research question and hypothesis
“For a good clinical trial, you need to have a good research question, and the design of your trial flows from your research question,” she said. “You need to have a clear and coherent hypothesis about a condition and an intervention, and how that intervention helps that condition, and how you might measure how that intervention helps the condition.
“But we don’t really know with any clarity what this condition is, if it indeed is one coherent condition; we don’t really have a clear hypothesis as to how the intervention works and over what time period; and we don’t know how to measure any kind of benefit. We don’t know what measures reflect medium or long term benefit.”
Heterogeneous and unrepresentative population
She said recruiting patients to such a PB trial would also be problematic, since the patient group was “complex and heterogeneous”. (There has been a notable increase in incidence of comorbidities, including autism spectrum disorders, psychological issues, and adverse childhood events but excluding patients with comorbidities would result in a trial population that was unrepresentative of the cohort currently presenting for care.)
Other problems
The experts pointed out several other problems including:
- Timespan – the proposed two to three year window would not provide sufficient time to assess the crucial, long-term outcomes, such as psychosocial functioning in adulthood, or the need for subsequent surgical interventions.
- Unreliable results – since only highly motivated participants would enrol the intervention group (receiving PBs) would likely experience significant placebo effects. Conversely, the control group, denied their desired intervention, may experience disappointment, leading to nocebo effects. These factors would make it extremely difficult to attribute any differences between the groups solely to PBs.
- Problematic consent – children aged under 16 would need parental consent but this is highly complex as parents or legal guardians will be required to consent to the known and potential harms and potential sterility of their own physically healthy children.
- Coercion – the government’s ban on prescribing PBs outside of clinical trials creates a “form of research coercion,” as families desperate to access the medication may feel pressured to participate, thereby undermining true informed consent and potentially skewing trial results.
Some children change their mind if not treated
Dr Bell, a whistleblower of the Gender Identity Service for Children and Adolescents (GIDS) at the Tavistock before it closed last year, warned the trial could do more harm than good since it would treat children who would naturally change their mind if they were not started on a medical pathway.
“There are children, of course, who present, say, 14, with gender distress, and when they’re 23, 24, 25 they still want to transition. That’s true. But the evidence suggests this is a very small number. If there are two groups of children, and the children who will persist are Group A, and the children who will desist or change their minds are Group B. Group B is much larger than Group A, especially if there’s proper, supportive psychological, psychotherapeutic intervention. But, given there’s no way of knowing if any child is in group A or group B, a blanket prescription of puberty blockers is going to do very much more harm.”
What should happen instead?
The panel postulated as to why the trial had been recommended in the first place, given the multiple ethical and methodological flaws.
“It beggars belief how this can be seriously thought about,” said Dr Bell. Dr Ryan agreed, adding: “I think there are political motivations for conducting a trial. And I also think there are lots of well-meaning people who maybe just haven’t thought through the some of these ontological issues.”
Irrespective of why, the panel agreed that non-pharmaceutical methods of research must be explored as a priority, instead. These included the long-term follow-up studies of children who have already received PB medication or qualitative studies on the experiences of transitioning individuals. Psychotherapeutic interventions and juvenile animal studies were other options.
“I think what we’ve got there is the cart before the horse and there are all sorts of things that we should be doing before we do a clinical trial, including completing the data linkage (follow-up) study,” said Dr Ryan.
“I would have thought that the very least we could do is wait for the outcome of that study and look at that data before we embark on a new piece of research giving PBs to children.”
The Call to Action
Louise Irvine, a GP and co-chair of CAN-SG, told the meeting, which attracted more than 100 participants, the clinical trial was meant to start recruiting in Spring 2025, and the delay suggested the organisers were “really struggling” with the process.
“And even if the trial receives Research Ethics Committee approval, it will still require agreement from the MHRA, the sponsors’ ethics committees and the individual hospitals involved in recruitment.”
CAN-SG, alongside others, has already made representations to regulators the MHRA and the HRA, as well as the trial leads and researchers, the research oversight committee, the funder, sponsors (KCL and SLAM), NHS England and the Department of Health and Social Care. See below for suggestions on who to contact to voice concerns.
Listen to webinar as a podcast here.
References
References and Resources on puberty suppression for gender-related distress in children and adolescents
Ethics and Regulations
Nuremberg Code
World Medical Association (2022) WMA Declaration of Helsinki – Ethical principles for medical research involving human subjects. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects – WMA – The World Medical Association.
Health Research Authority (2020). Good Clinical Practice. Good Clinical Practice – Health Research Authority (hra.nhs.uk).
Government of the United Kingdom (2004). The Medicines for Human Use (Clinical Trials) Regulations. The Medicines for Human Use (Clinical Trials) Regulations 2004 (legislation.gov.uk).
Health Research Authority. (2021). Research involving children. Research involving children – Health Research Authority (hra.nhs.uk). Accessed 28th January 2024.
Co – Morbidities
Separation and trauma
Matthews, T., Holt, V., Sahin, S., Taylor, A., & Griksaitis, D. (2019). Gender Dysphoria in looked-after and adopted young people in a gender identity development service. Clinical Child Psychiatry and Psychology., 24, 1–128.
https://doi.org/10.1177/1359104518791657
Psychological presentations
Koslowska, K., McClure, G., Chudleigh, C., Maguire, A. M., Gessler, D., Scher, S., & Ambler, G. R. (2021). Australian children and adolescents with gender dysphoria: Clinical presentations and challenges experienced by a multidisciplinary team and gender service. Human Systems: Therapy, Culture and Attachments
http://dx.doi.org/10.1177/26344041211010777
Other countries thinking of clinical trials
Society for Evidence Based Gender Medicine (2021) Sweden’s Karolinska Ends All Use of Puberty Blockers and Cross-Sex Hormones for Minors Outside of Clinical Studies. Sweden’s Karolinska Ends All Use of Puberty Blockers and Cross-Sex Hormones for Minors Outside of Clinical Studies | SEGM Accessed 27th February 2024
Suicidality
Ruuska, S-M., Tuisku, K., Holttinen, T., Kaltiala, R. (2024) All-cause and suicide mortalities among adolescents and young adults who contacted specialised gender identity services in Finland in 1996–2019: a register study. BMJ Mental Health. All-cause and suicide mortalities among adolescents and young adults who contacted specialised gender identity services in Finland in 1996–2019: a register study | BMJ Mental Health
Prof Louis Appleby’s report on suicide following the puberty blocker ban: https://www.gov.uk/government/publications/review-of-suicides-and-gender-dysphoria-at-the-tavistock-and-portman-nhs-foundation-trust/review-of-suicides-and-gender-dysphoria-at-the-tavistock-and-portman-nhs-foundation-trust-independent-report
Prof Michael Biggs’ analysis of suicidality amongst clinic-referred adolescents: https://link.springer.com/article/10.1007/s10508-022-02287-7
Society for Evidence-based Gender Medicine (SEGM) analysis of Denmark health register study on suicidality amongst transgender people: https://www.segm.org/transgender_suicide_mortailty_Denmark
Impact on psychosexual development
Shirazi, T., N. Self, H., Dawood, K., Cárdenas, R., Welling, L., M., Rosenfield, M., A. Ortiz, T. L., Carré, J. M., Balasubramanian, R., Delaney, A., Crowley, W., Breedlove, S. M., Putsa,D. A. (2020) Pubertal Timing Predicts Adult Psychosexuality. Psychoneuroendocrinology. 119. https://www.ncbi.nlm.nih.gov/pmc/articles/
Impacts on brain development
Baxendale, S. (2024) The impact of suppressing puberty on neuropsychological function: A review. Acta Paediatrica. https://doi.org/10.1111/apa.17150.
Existing research on the use of puberty blockers for gender distress in children and adolescents:
Study mentioned by Hannah, lead author delayed publication as no positive effect of puberty suppression:
Olson-Kennedy, J., Durazo-Arvizu, R., Wang, L., Wong, C. F., Chen, D., Ehrensaft, D., Hidalgo, Marco A., Chan, Y.-M., Garofalo, R., Radix, A. E., & Rosenthal, S. M. (2025). Mental and Emotional Health of Youth after 24 months of Gender-Affirming Medical Care Initiated with Pubertal Suppression. https://doi.org/10.1101/2025.05.14.25327614
Key Systematic Reviews:
National Institute for Health and Care Excellence (NICE). (2020). Evidence review: gonadotrophin releasing hormone analogues for children and adolescents with gender dysphoria. NICE. https://cass.independent-review.uk/wp-content/uploads/2022/09/20220726_Evidence-review_GnRH-analogues_For-upload_Final.pdf
Taylor, J., Mitchell, A., Hall, R., Heathcote, C., Langton, T., Fraser, L., & Hewitt, C. E. (2024). Interventions to suppress puberty in adolescents experiencing gender dysphoria or incongruence: a systematic review. Archives of Disease in Childhood. https://doi.org/10.1136/archdischild-2023-326669
Miroshnychenko A, Roldan Y, Ibrahim S, Kulatunga-Moruzi C, Montante S, Couban R, Guyatt G, Brignardello-Petersen R. Puberty blockers for gender dysphoria in youth: A systematic review and meta-analysis. Arch Dis Child. 2025 May 16;110(6):429-436. doi: 10.1136/archdischild-2024-327909.
Important recent commentaries on research in the field of gender medicine
McDeavitt, K., Cohn, J. & Kulatunga-Moruzi, C. Pediatric Gender Affirming Care is Not Evidence-based. Curr Sex Health Rep 17, 12 (2025). https://doi.org/10.1007/s11930-025-00404-w
https://link.springer.com/article/10.1007/s11930-025-00404-w
Kozlowska, K., Hunter, P., Clayton, A., Kaliebe, K., & Scher, S. (2025). Obstacles to progress in paediatric gender medicine. European Journal of Developmental Psychology, 1–31. https://doi.org/10.1080/17405629.2025.2546574
https://www.tandfonline.com/doi/epdf/10.1080/17405629.2025.2546574?needAccess=true
Other information:
SEGM has a repository of significant papers on topics related to paediatric gender medicines with commentaries here: https://www.segm.org/studies
The Cass Review final report can be found here: https://webarchive.nationalarchives.gov.uk/ukgwa/20250310143933/https://cass.independent-review.uk/home/publications/final-report/
Information about the PATHWAYS study here: https://www.kcl.ac.uk/research/pathways
NIHR funding award notice here: https://fundingawards.nihr.ac.uk/award/NIHR167530
What you can do
Several people asked in the Q+A session what they can do to raise concerns about the puberty blocker trial. We suggest writing to the various bodies involved in the ethical approval and trial regulations.
The process of ethical approval has several stages: first it is approved by a Research Ethics Committee appointed by the Health Research Authority – once the HRA receives a proposal from the REC it will consider any letters of concern at that point:
“Should the HRA receive an application for the proposed clinical trial, your concerns will be ….considered alongside the research application, with input from the HRA Complaints Group and analysis from Approvals management. This review will determine whether any further action is required under the Research Ethics Service Standard Operating Procedures.” (HRA correspondence)
The proposal then has to be approved by the MHRA.
“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.” (MHRA correspondence)
In addition any clinical trial will have to be approved by the ethical committees of the trial sponsors, KCL and SLAM, and by the ethical committees of any institution recruiting children to participate in the trial, likely to be the new youth gender hubs.
The MHRA informed us of the responsibility of the trial sponsors:
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. (MHRA correspondence)
Furthermore, the trial will have to be approved by the ethics committees of all the institutions recruiting children for the trial. These are likely to be recruited via the new child and adolescent gender hubs. So far these include the NHS Children and Young People’s Gender Service (London), The NHS Children and Young People’s Gender Service (South West) and the NHS Children and Young People’s Gender Service (North West).
Each of these organisations bears individual responsibility for assuring themselves of the ethics and safety of the trial and should not avoid that responsibility by saying that some other body has approved it.
It may be worth writing now to express concerns about the ethics of a trial, and then also if/when the protocol is published one when the precise details of what is proposed will be known. But as we have argued, regardless of the trial design, we don’t think the trial will be ethical, based on fundamental ethical and scientific principles.
Who to write to
Health Research Authority
Professor Matt Westmore CEO, HRA: matt.westmore@hra.nhs.uk
Dr Neelam Patel, Chair, HRA: neelam.patel@hra.nhs.uk
Medicines and Healthcare Products Regulatory Authority
Mr Laurence Tallon CEO MHRA: laurence.tallon@mhra.gov.uk also Executive.Office@mhra.gov.uk
Commission on Human Medicines
Professor Munir Pirmohamed, Chair, CHM: munirp@liverpool.ac.uk
Children and Young People’s Gender Research Oversight board
Professor Simon Wessely, Chair: simon.wessely@kcl.ac.uk; england.cypgenderdysphoria@nhs.net
Lead researcher
Professor Emily Simenoff: emily.simonoff@kcl.ac.uk
Trial sponsors
Kings College London
Professor Shitij Kapur VC and President Kings College London: shitij.kapur@kcl.ac.uk
Professor Bashir M Al-Hashimi Vice President (Research & Innovation): bashir.al-hashimi@kcl.ac.uk
Kings Research Governance office: rgo@kcl.ac.uk
Kings Research Ethics Office rec@kcl.ac.uk
South London and Maudsley NHS Trust
Mr David Bradley, CEO: david.bradley@slam.nhs.uk
NHS England
Professor James Palmer, National Medical Director (Specialised Services), NHS England (also a member of the research oversight board): jamespalmer1@nhs.net
Department of Health and Social Care and NIHR (trial funder)
Professor Lucy Chappell is DHSC Chief Scientific Adviser. Her responsibilities include overall responsibility for the Department of Health and Social Care’s (DHSC) research policies and budget, including being head of the National Institute for Health and Care Research (NIHR)
Unfortunately we were not able to find an official email for Prof Chappell in her role at the DHSC or NIHR, and DHSC did not pass our letter to her (at least we assume not as we did not get a reply) but her KCL email is lucy.chappell@kcl.ac.uk
Secretary of State for Health and Social Care, Rt Hon Wes Streeting MP
Email: wes.streeting.mp@parliament.uk and dhsc.publicenquiries@dhsc.gov.uk
Further reading
Article by Dr David Bell and Dr Sinead Helyar outlining the ethical concerns about a puberty blocker trial, citing international and national clinical trial regulations.
Read our letter to regulators, sponsors etc.
and their responses