On 2 December CAN-SG send the following letter to the Health Research Authority (HRA), the Medicines and Healthcare Regulatory Authority (MHRA), the PATHWAYS trial sponsors Kings College London (KCL) and South London and Maudsley NHS Trust (SLAM), the trial funders National Institute for Health and Care Research (NIHR), the Government Chief Scientific Officer and Wes Streeting, Secretary of State for Health and Social Care (DHSC). We’ve had a reply from the HRA, appended at the end.
Letter to PB trial regulators and Government bodies
2 December 2025
We are writing to you with regards to the PATHWAYS study of puberty suppression for gender incongruence in children and adolescents, particularly with regards to PATHWAYS Trial.
Following the trial launch on 21st November 2025, there has already been substantial scientific disquiet (and media coverage) of the controversies surrounding the trial. Given the high stakes involved, and the extraordinary context of the current ban on prescribing GnRHa for this indication outwith a trial, we are making an Appeal against the approval you gave the Trial. At the very least, we are calling on you to pause the recruitment process so that post-publication peer review of the trial protocol is facilitated and made publicly available. We believe this is critical, to ensure the conduct of good research, and promote trust and transparency in research in the United Kingdom on this controversial topic.
Currently it looks as if the HRA accepts that the only issue in the halting of normal pubertal development of children is a 12-month timing difference in starting, rather than questioning the benefits and risks of the whole pathway itself. Thanks to the government via the NIHR making funding available for a limited question, it is quite plausible that the ‘many eyes of science’ based on the current best available evidence have not been applied properly.
We would be pleased to present a detailed critique of the protocol. Briefly, our top line concerns are as follows:
- There is no clear research question that is grounded in a hypothesis about how the mechanism of action of the drug might confer benefit in children with gender incongruence.
- GnRHa is not an isolated drug treatment that ‘works’ on its own; it is planned to be used with the later cross-sex hormones. Proponents of this approach have made this point repeatedly with regards to the equivocal or negative results of observational studies. It simply cannot be tested on its own.
- Given it is the whole pathway that is planned to be given to children, it is the whole pathway that needs testing. Given the high likelihood of harm to fertility, bone development, and possibly neurocognition, it would seem that to comply with clinical trials regulation other approaches to the management of paediatric gender incongruence should be studied first.
- There is no randomised control group that will not receive GnRHa, and thus provide a reliable comparison, and no justification is offered for not doing this.
- The primary endpoint is a quality-of-life metric measured at 24 months post randomisation, when both arms have been established on GnRHa, and the study has been powered to detect a 5-point difference on this score. It is unclear how even a statistically-significant difference between groups would yield a clinically meaningful result that could guide patients, families, clinicians and policy makers to either accept or reject GnRHa as efficacious.
- The inclusion criteria stipulate that children must have gender incongruence as defined by the ICD 11 criteria, but this diagnosis has no positive predictive value for who will benefit from medical transition, and relies on a set of highly subjective preferences, largely based on sex-role stereotypes. There is no exploration of why the children experience these feelings, or acknowledgement that the aetiology and natural history of gender-related distress in childhood is poorly understood.
- As the Cass Review acknowledges, there is currently no reliable way to predict which children will continue to experience gender-related distress into adulthood and which will experience spontaneous resolution. This means that PATHWAYS Trial will inevitably subject many children to puberty suppression who would otherwise have simply stopped experiencing gender-related distress.
- Children from Tanner stage 2 to Tanner stage 5 will be included, but there is no acknowledgement that the use of GnRHa at these extremes of pubertal development constitutes a radically different intervention, with different potential benefits and a very different risk profile. The trial will inevitably be under-powered to detect effects in subgroups, and similarly differential effects between the groups will likely not reach statistical significance.
- No explanation is given as to why the trial is being advanced prior to completion of important safety studies such as the Data Linkage Study, or animal studies exploring the neurocognitive, metabolic and cardiovascular effects. While the Data Linkage Study could not provide a reliable efficacy estimate, it is probable that it will provide some important safety information about the use of GnRHa, and subsequent cross-sex hormones, in childhood gender incongruence. Given the very serious risks related to the expected effects of the drug (including loss of sexual function and fertility, reduced bone mineralisation, and possibly impaired cognitive development), and in the context of the wider prescribing ban, it would seem critical to have this information in advance of initiating a new trial. Also, these data could provide important hypothesis-generating information that would inform a more robust future trial.
Given the above issues, and others, we believe that the PATHWAYS Trial falls short of the standards set out in the UK Policy Framework for Health and Social Care Research, and may fall short of the legal requirements in the Medicines for Human Use (Clinical Trials) Regulations 2004, because:
- The safety and well-being of individual participants will not be prioritised.
- The trial is not scientifically sound.
- There has been insufficient transparency in the development of the study.
- The expected benefits do not outweigh the expected risks.
- Foreseeable risks to child development are not minimized.
Dr Hilary Cass told the Sunday Times that, “Some people feel that these treatments should be freely available because they believe them to be so beneficial to children and young people, and others feel that enough risk has been demonstrated that the trial shouldn’t be allowed on ethical grounds, so you’ve got polarised views on this.”
For research to have an effective role in settling clinical controversy, and for it to be ethical, it must provide reliable and meaningful data that will allow us to accept or reject this treatment approach.
PATHWAYS Trial is not capable of delivering on this point.
We await your response with interest. We will publish this letter in one week.
Health Research Authority response
December 3 2025
Thank you for your letter of 2 December 2025 to Matt Westmore [HRA CEO]. He has reviewed your email and letter and has delegated it to me to respond.
The information you have provided will first be considered in line with our Standard Operating Procedures (SOPs), with reference to the application and its review, to establish whether it is new relevant information, not originally considered by the Research Ethics Committee (REC) related to the scientific value; scientific design and conduct of the study and risks to the safety or physical or mental integrity of participants. We will let you know more information on our review of your concerns, including circumstances whereby the REC reviews its opinion.
We will send you a response following our deliberations, including any further advice sought, and whether there are any next steps in line with the SOPs.
Kind regards,
Information Governance and Complaints Manager Health Research Authority