CAN-SG letter to PATHWAYS puberty blocker trial investigators, oversight board and regulators

CAN-SG wrote in March and April 2025 with our concerns about the ethics of the proposed PATHWAYS puberty blocker trial to the Lead Investigators, Children and Young People’s Gender Dysphoria Research Oversight Board, the trial sponsors (Kings College London and South London and Maudsley NHS Foundation Trust), Great Ormond St Hospital, Health Research Authority, National Institute for Health and Care Research (NIHR), Commission on Human Medicines, MHRA, NHS England, Department of Health and Social Care and relevant government ministers about our concerns. We also wrote to all the Research Ethics Committees who approve clinical research in children.

All the above individuals and bodies have a role and responsibility in assuring that a proposed trial complies with ethical regulations. This includes the researchers, sponsors, funders, participant recruitment sites and oversight and regulatory authorities.

Here is our letter in full, which was slightly adapted to individual recipients in recognition of their particular responsibilities to ensure that a proposed trial conforms to ethical clinical trial principles and regulations.

CAN-SG Letter

We are writing on behalf of the Clinical Advisory Network on Sex and Gender. CAN-SG is an established network of over 100 health professionals committed to open discussion and proper consideration of evidence in the field of gender medicine, and with a principle of “first do no harm”.

We respectfully request that you consider our very serious ethical and scientific concerns about the PATHWAYS trial [1] ofgonadotrophin-releasing hormone agonists (GnRHa), or ‘puberty blockers’ for children with gender incongruence when you assess the trial submission.  

We believe that the trial will not comply with the ethical and regulatory requirements of clinical trials on children, including the Medicines for Human Use (Clinical Trials) Regulations (2004) and the Declaration of Helsinki, ICH) Good Clinical Practice. It could also breach the European Convention on Human Rights.

UK law mandates that clinical trials in children must be designed to minimise any foreseeable risk to a child’s stage of development (Schedule 1 Part 4 Principle 14 of the Medicines for Human Use (Clinical Trials) Regulations 2004). [2]  GnRHa use in children with gender dysphoria/incongruence has  documented risks of serious injurious adverse effects that impact children’s development and health for life. Given that puberty blockers by definition disrupt a crucial phase of human development, the anticipated benefits must be tangible and significant to justify the risks to children. The Systematic Review commissioned by the Cass Review did not identify any good quality evidence of benefit of puberty blockers. [3]. There is thus no clinical equipoise and to proceed counters international standards of clinical trial ethics, regulation, and legislation.  

Furthermore, we do not think a trial could conform to scientific principles: there is a lack of knowledge regarding fundamental aspects of gender dysphoria/incongruence that would inform intervention research, including  aetiology, epidemiology and diagnosis.                       

There is no cogent rationale for how puberty blockers might benefit children with gender dysphoria/incongruence. The available data suggest that the majority of children who do not have medical intervention experience resolution of gender dysphoria/incongruence through puberty, and currently it is not possible to discern clinically which children will have persistent gender dysphoria/incongruence into adulthood and which will not.  

The evidence also suggests that the majority of children who receive puberty blockers go on to take cross-sex hormones. Therefore, it is arguable that puberty blockers should not be viewed as a discrete intervention, but rather a precursor to cross-sex hormones. This is the implication of the Commission on Human Medicines recommendation that GnRHa should continue to be offered after a child leaves the trial until they are 16 and able to start cross sex hormones. 

We argue that data already exist to evaluate questions about how best to help children and young people with gender incongruence, and that other interventions, such as counselling and psychosocial interventions, are likely to be effective with no risk of medical adverse effects: investment and effort in conducting trials on these interventions would be more worthwhile. 

In summary, this trial is unethical as 

a) it contravenes UK and international clinical trial regulations

b) the intervention with GnRHa will interfere with the child’s development, by definition; 

c) there are established substantive harms and risks of the intervention; 

d) the benefits are contested, both in terms of lack of evidence and lack of a plausible rationale; 

e) information about the safety and effects of puberty blockers is procurable by other methods; 

f) it is not possible to select children who will have persistent gender dysphoria/incongruence as adults, and therefore a trial will inevitably expose many children to harm who would otherwise have experienced symptom resolution with no treatment.  

Annex    

UK legislation governing the conduct of clinical trials (Medicines for Human Use – Clinical Trials Regulations 2004)[6] is concordant with the Declaration of Helsinki and (ICH) Good Clinical Practice. UK regulations specify the following:

  1. A trial should be initiated and continued only if the anticipated benefits justify the risks and should not be conducted where there is a preceding belief that death or disabling injury will occur.
  2. Trials with human participants must conform to scientific principles.
  3. The information sought must be unprocurable by other methods.
  4. A trial 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) [2].

It should be noted that according to UK law a child or a minor is anyone under the age of 18 (Children Act 1989), so where the research funding agreement repeatedly refers to “young people” instead of “children” it risks obscuring the fact that this research proposal is about children and therefore all laws protecting children in research must apply to all participants in the proposed research. (As this is an interventional trial of a medicinal product the rules around CTIMP trials should apply.)

It is important to note that the effect of puberty blockers followed by cross sex hormones is sterilising and that gamete retrieval to preserve fertility is not possible at the stage when puberty blockers are given (Tanner stage 2) as neither sperm nor ova have matured. The technology does not currently exist to remove ova and mature them in vitro. Sterilising children is likely to breach Article 8 (the Right to Privacy and Family Life) and Article 12 (the Right to Marry and Found a Family) of the European Convention on Human Rights.

Our concerns can be summarised as follows:

Anticipated benefits do not justify the risks

GnRHa as prescribed for gender dysphoria/incongruence cause harm to bone development[7] , and concerns have been raised about impaired development of cognitive function[8], inadequate development of the sex organs, infertility[9,10] and lack of sexual function[11]. In accordance with the Declaration of Helsinki the anticipated benefit must be tangible and significant to outweigh these risks [12], but observational studies have failed to demonstrate benefit to mental or physical health or well-being from use of GnRHa in gender dysphoria/incongruence.  

No trial design could conform to scientific principles

Ethical trials need to conform to scientific principles. Given the lack of consensus around the diagnosis and prognosis for gender dysphoria/incongruence in children (Cass, 14.9) [4] clinical equipoise lies at the point of enquiry regarding the aetiology, natural history, and causes of the dramatic changes in epidemiology [13] seen in recent decades. It is premature to consider a drug trial when these questions have not been addressed. 

Scientific rationale is flawed 

  • There is no plausible scientific rationale for the mechanism by which puberty suppression alleviates gender dysphoria/incongruence in childhood and adolescence; rather, it was hypothesized as a way to enhance cosmetic outcomes in transgender adults and, therefore, improve adult psychosocial functioning [14]. Historical cohorts demonstrate that the majority of children with gender dysphoria will have spontaneous resolution of their symptoms during puberty [15]. Conversely, the majority of children treated with puberty blockers in published cohorts progress to cross-sex hormones [16,17]. It is therefore plausible that puberty suppression could actually exacerbate rather than remediate gender dysphoria/incongruence. 
  • We note that the PATHWAYS trial proposes interventions for “gender incongruence” not “gender dysphoria”. (The Cass Review referred to both gender dysphoria and gender incongruence, and most of the published research is on gender dysphoria). ICD11 makes clear that “gender incongruence” is not a disorder, but a “condition of sexual health”. No rationale for medicalising “gender incongruence” has been provided. 
  • The ICD11 definition of gender incongruence does not include references to dysphoria or dysfunction.      It is even more outwith the bounds of ethical research to medicalise the non-disorder of gender incongruence in children than it would be to medicalise gender dysphoria (classified as a mental disorder in DSM V).
  • No studies have demonstrated diagnostic criteria that reliably discriminate between children who will persist with gender dysphoria/incongruence into adulthood and those who will experience spontaneous resolution [4]. A prospective trial will inevitably involve giving GnRHa to a significant number of children who would have simply desisted, as there is no proven way of excluding these children at screening. 
  • GnRHa is one step in a pathway of interventions for gender dysphoria/incongruence that goes on to include cross-sex “gender-affirming” hormone therapy and various surgical procedures.. Originally it was hypothesised that GnRHa would facilitate better “passing” in adulthood, as well as reducing the need for “gender-affirming” surgeries to modify secondary sexual characteristics, and thus GnRHa would promote better mental health and social functioning in adulthood post transition GIDS Early Intervention Study Protocol [18]. The outcomes we have seen for the PATHWAYs trial include measures of physical, social and emotional wellbeing at two years. As there are no published data of adult outcomes for children treated with GnRHa, there are no evidence-based endpoints for a trial of GnRHa in children that can act as reliable proxies for adult outcomes. For example, we have no idea whether improved social functioning after two years on GnRHa correlates at all with improved social functioning in adulthood. Thus, all proposed outcome metrics for a trial are entirely speculative and may be grossly misleading with regards to long-term benefits. 
  • The Cass Review Report set out the very complex events that take place in the adolescent brain during puberty and said that blocking the release of these sex hormones could have a range of unintended and as yet unidentified consequences on brain development. The Review expressed concern that brain maturation may be temporarily or permanently disrupted, as well as having possible longer- term neuropsychological consequences. Animal trials have demonstrated permanent adverse impact on the adolescent brain and cognitive function [8]. We do not feel assured that “pen and paper” tests and MRIs at two years will address these concerns. Risking permanent adverse effects on brain and cognitive function for little tangible benefit is one of several reasons we believe this trial to be unethical.
  • The PATHWAYS trial will not study how puberty blockers are actually used in real world conditions where they are a step in the gender affirming pathway and lead, in the vast majority of cases, to cross sex hormones. It does not make scientific sense to propose a study that does not look at the full consequences of the intervention. For example it is known that the combination of puberty blockers and cross sex hormones is sterilising.  This is a serious outcome and ethical concern as detailed above. 

Foundational research still has not been done

The Cass Review (page 40 para 131 said: “The gaps in the evidence base regarding all aspects of gender care for children and young people have been highlighted, from epidemiology through to assessment, diagnosis and intervention.” If these are the gaps then why not start with the fundamentals of building an evidence base for how best to support children and young people presenting to gender services? We still have little understanding of aetiology of gender incongruence/dysphoria, no good understanding of the reasons for the changed epidemiology and no useful diagnostic criteria that can predict who will persist with these feelings into adulthood.  

Data already available     

Observational data from the cohorts of children treated by the Gender Identity Disorders Service (GIDS) at the Tavistock and Portman NHS Foundation Trust will likely provide important safety information that should inform decisions around a prospective trial. The retrieval and analysis of this data, including adult outcomes, is still in progress, and given the paucity of long-term outcome data for this intervention and the gravity of the potential risks, we must wait for this information prior to recruiting healthy children to a trial. Any other approach would be to disregard the primacy of participant safety. 

Research alternatives

Other less risky interventions including psychosocial support, psychotherapy and “watchful waiting” are also lacking in evidence, and these interventions, as well as, for example, a systematic review of the safety of GnRHa in other clinical populations, e.g. prostate cancer and precocious puberty, as well as juvenile animal studies, should be prioritised for research over GnRHa for gender dysphoria/incongruence. 

Research into psycho-social interventions should be prioritised

Dr Cass said it was important that there be a full programme of research including into psycho-social interventions. It is noteworthy that this is not being proposed as part of the PATHWAYs research and we are concerned that a GnRHa trial will hamper the development of psycho-social interventions, which the Cass Review recommended as first line treatment for all children and young people presenting to services with gender related distress. 

As Dr Cass said (Cass Review p. 179 para 14.54) “The focus on puberty blockers and beliefs about their efficacy has arguably meant that other treatments (and medications) have not been studied/developed to support this group, doing the children and young people a further disservice.” Prioritising a GnRHa trial over research into psycho-social treatments reinforces these beliefs and could disincentivise children and their families from participating in therapeutic work. This could undermine the implementation of the Cass Review recommendation for a fundamental shift in approach to care for this group of children and young people.

References

  1. PATHWAYS funding award https://fundingawards.nihr.ac.uk/award/NIHR167530
  2. Government of the United Kingdom (2004). Schedule 1, Part 4 -Conditions and principles which apply in relation to a minor. Principles – 14. The Medicines for Human Use (Clinical Trials) Regulations 2004
  3. Taylor J, Mitchell A, Hall R, et al Interventions to suppress puberty in adolescents experiencing gender dysphoria or incongruence: a systematic review Archives of Disease in Childhood 2024;109:s33-s47. 
  4. The Cass Review (2024). Independent review of gender identity services for children and young people: Final Report. Final Report – Cass Review
  5. Commission on Human Medicine report on proposed changes to the availability of puberty blockers https://assets.publishing.service.gov.uk/media/678e6994ea48a571517acf98/chm-advice-to-sos-on-gnrh-agonists-for_pubertal-suppression.pdf  (Para 79)
  1. 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)
  2. Sebastian E E Schagen, S, E. E., Wouters, F., M. Cohen-Kettenis, P. T., Gooren, L. G., Hannema. S. E. (2020) Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones. The Journal of Clinical Endocrinology & Metabolism, 105 (12) e4252–e4263. https://doi.org/10.1210/clinem/dgaa604  
  3. Baxendale, S. (2024) The impact of suppressing puberty on neuropsychological function: A review. Acta Paediatrica.https://doi.org/10.1111/apa.17150.
  4. Murugesh V, Ritting M, Salem S, Aalam SMM, Garcia J, Chattha AJ, Zhao Y, Knapp DJ, Kalthur G, Granberg CF, Kannan N. Puberty Blocker and Aging Impact on Testicular Cell States and Function. bioRxiv [Preprint]. 2024 Mar 27:2024.03.23.586441. doi: 10.1101/2024.03.23.586441. PMID: 38585884; PMCID: PMC10996503. 
  5. Cheng PJ, Pastuszak AW, Myers JB, Goodwin IA, Hotaling JM. Fertility concerns of the transgender patient. Transl Androl Urol. 2019 Jun;8(3):209-218. doi: 10.21037/tau.2019.05.09. PMID: 31380227; PMCID: PMC6626312. 
  6. Biggs, M. (2022). The Dutch Protocol for Juvenile Transsexuals: Origins and Evidence. Journal of Sex & Marital Therapy, 49(4), 348–368. https://doi.org/10.1080/0092623X.2022.2121238
  7. 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 Participants – WMA – The World Medical Association
  8. Griffin, L., Clyde, K., Byng, R., & Bewley, S. (2021). Sex, gender and gender identity: a re-evaluation of the evidence. British Journal of Psychotherapy Bulletin, 45(5), 291–299. https://doi.org/10.1192/bjb.2020.73
  9. Delemarre-van de Waal, H. A., & Cohen-Kettenis, P. T. (2006). Clinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects. European Journal of Endocrinology, 155(suppl 1), S131-S137
  10. Ristori, J., & Steensma, T. D. (2016). Gender dysphoria in childhood. International review of psychiatry (Abingdon, England), 28(1), 13-20. https://doi.org/10.3109/09540261.2015.1115754
  11. Carmichael, P., Butler, G., Masic, U., Cole, T. J., De Stavola, B. L., Davidson, S., Skageberg, E. L., Khadr, S., & Viner, R. M. (2021). Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK. PLoS One, 16(2), e0243894. https://doi.org/10.1371/journal.pone.0243894
  12. Wiepjes, C. M., Nota, N. M., de Blok, C. J. M., Klaver, M., de Vries, A. L. C., Wensing-Kruger, S. A., …den Heijer, M. (2018). The Amsterdam cohort of gender dysphoria study (1972–2015): Trends in prevalence, treatment, and regrets. Journal of Sexual Medicine, 15, 582–590. doi:10.1016/j.jsxm.2018.01.016
  13. Tavistock and Portman NHS Foundation Trust. (2019) Freedom of Information Act 2000 disclosure log entry. Reference 19-20011. https://tavistockandportman.nhs.uk/wp-content/uploads/2023/10/FOI_19-20011_GIDS_Research_Information_with_attachments.pdf