“10. The PATHWAYS Trial underwent a thorough and rigorous funding application and approval process, involving multiple internal and external reviews. That process was as follows: a. In September 2023, there was an initial workshop to discuss the initial design of the trial, attended by two NIHR Programme Directors, the Chair (Consultant Advisor), and individuals with a broad range of clinical experiences (including those with expertise in Child and Adolescent Psychiatry, Paediatrics, Epidemiology, Safeguarding, Adolescent Services, Paediatric Endocrinology and, Growth and Puberty). It was also attended by a Representative of the Cass Review, Clinical Trials Unit representatives with methodological and statistical expertise, NHS England, and observers from the Department for Health and Social Care (“DHSC”) and devolved administrations. b. We then received a draft trial protocol and held a further workshop to consider that draft proposal in March 2024. There were a range of individuals in attendance, including a Consultant Advisor (who was a physician that works within the NIHR coordinating centre, with lots of trial methodology experience). It was also attended by the funding committee, who are independent experts in their fields covering expertise in Paediatric Endocrinology, mental health and wellbeing, transgender, psychology and statistics and methodology. The applicant team were also in attendance. c. In April 2024, there was a formal funding committee meeting, where the applicant team were not present. Following this we provided feedback to the applicant team to be considered when submitting the full application. The full funding application was submitted in July 2024. d. In August 2024, in addition to undergoing an independent review by the funding committee, the funding application was also sent out for external peer review. The application went through eight reviews in total, undertaken by: the NHS England Specialised Commissioning Clinical Team, two Endocrinologists, a specialist General Paediatrics and Safeguarding, a specialist in Child and Adolescent Psychiatry, a Clinical Psychologist and Gender Specialist, and a Psychologist. There was also additional input via NHS England separately. It is unusual for a funding application to undergo eight peer reviews. Typically, the level of review would link to the size of funding but would usually be between four to six reviews for a trial in the range of£2m -£6m . In this instance, it was necessary to have eight reviews because of the importance of the subject area of the clinical trial and the scale of the funding sought. e. In September 2024, the peer review comments were shared with the applicant team so that they could respond to any issues raised. A final workshop then took place that same month, to discuss any outstanding questions. This workshop was attended by the Programme Director and Chair, two Consultant Advisors, and experts in Paediatric Endocrinology, Psychology, Medical Statistics and Trials Methodology, Endocrinology and a member of the public. We would not usually meet with the application team this much. Typically, when an application goes to the funding committee, they will provide their feedback, the applicant team will respond, and then we make a decision which is either ‘fund’ or ‘no fund’. However, with this particular application, we wanted to maximise the chances of getting the best scientific quality from the clinical trial. We cannot do this for every trial, as it is highly labour intensive and simply would not be possible. However, in this instance, it was considered to be the most efficient and effective way of ensuring that all information was obtained and scrutinised to enable the funding decision to be made. f. In September 2024, a formal funding committee meeting took place which was again attended by the Programme Director and Chair, two Consultant Advisors, and experts in Paediatric Endocrinology, Psychology, Medical Statistics and Trials Methodology, Endocrinology and a member of the public. The decision made was ‘fund with changes’. This means that funding was subject to the applicant team responding to some additional points that arose at the final review. Those additional points were addressed, and a final funding decision was made by NIHR and passed to NHS England and DHSC in November 2024.” a. In September 2023, there was an initial workshop to discuss the initial design of the trial, attended by two NIHR Programme Directors, the Chair (Consultant Advisor), and individuals with a broad range of clinical experiences (including those with expertise in Child and Adolescent Psychiatry, Paediatrics, Epidemiology, Safeguarding, Adolescent Services, Paediatric Endocrinology and, Growth and Puberty). It was also attended by a Representative of the Cass Review, Clinical Trials Unit representatives with methodological and statistical expertise, NHS England, and observers from the Department for Health and Social Care (“DHSC”) and devolved administrations. b. We then received a draft trial protocol and held a further workshop to consider that draft proposal in March 2024. There were a range of individuals in attendance, including a Consultant Advisor (who was a physician that works within the NIHR coordinating centre, with lots of trial methodology experience). It was also attended by the funding committee, who are independent experts in their fields covering expertise in Paediatric Endocrinology, mental health and wellbeing, transgender, psychology and statistics and methodology. The applicant team were also in attendance. c. In April 2024, there was a formal funding committee meeting, where the applicant team were not present. Following this we provided feedback to the applicant team to be considered when submitting the full application. The full funding application was submitted in July 2024. d. In August 2024, in addition to undergoing an independent review by the funding committee, the funding application was also sent out for external peer review. The application went through eight reviews in total, undertaken by: the NHS England Specialised Commissioning Clinical Team, two Endocrinologists, a specialist General Paediatrics and Safeguarding, a specialist in Child and Adolescent Psychiatry, a Clinical Psychologist and Gender Specialist, and a Psychologist. There was also additional input via NHS England separately. It is unusual for a funding application to undergo eight peer reviews. Typically, the level of review would link to the size of funding but would usually be between four to six reviews for a trial in the range of£2m -£6m . In this instance, it was necessary to have eight reviews because of the importance of the subject area of the clinical trial and the scale of the funding sought. e. In September 2024, the peer review comments were shared with the applicant team so that they could respond to any issues raised. A final workshop then took place that same month, to discuss any outstanding questions. This workshop was attended by the Programme Director and Chair, two Consultant Advisors, and experts in Paediatric Endocrinology, Psychology, Medical Statistics and Trials Methodology, Endocrinology and a member of the public. We would not usually meet with the application team this much. Typically, when an application goes to the funding committee, they will provide their feedback, the applicant team will respond, and then we make a decision which is either ‘fund’ or ‘no fund’. However, with this particular application, we wanted to maximise the chances of getting the best scientific quality from the clinical trial. We cannot do this for every trial, as it is highly labour intensive and simply would not be possible. However, in this instance, it was considered to be the most efficient and effective way of ensuring that all information was obtained and scrutinised to enable the funding decision to be made. f. In September 2024, a formal funding committee meeting took place which was again attended by the Programme Director and Chair, two Consultant Advisors, and experts in Paediatric Endocrinology, Psychology, Medical Statistics and Trials Methodology, Endocrinology and a member of the public. The decision made was ‘fund with changes’. This means that funding was subject to the applicant team responding to some additional points that arose at the final review. Those additional points were addressed, and a final funding decision was made by NIHR and passed to NHS England and DHSC in November 2024.”
“19. Between December 2024 and August 2025, significant work went into preparing the application for regulatory approval for submission to the [HRA] and the [MHRA]. We appointed advisory boards with lived experience, i.e. young adults with non-binary gender and parents/carers of young people with experience of gender incongruence. Final aspects of the study design, including confirmation of study measures and development of participant-facing information were completed with our lived experience advisory boards. Final costings for all aspects of the PATHWAYS Trial were completed. This included the full range of safety checks including blood and urine tests, measures of bone health and cognition (learning and memory) and brain development. We established final details on how the study PSH would be administered and how any adverse effects would lead to modification in administration. The latter involved working with a very experienced group of clinicians who have delivered this intervention to many young people in the past, but where their practice has not required them to follow a strict trial protocol for all patients. Hence, we needed to ensure that good clinical practice was captured in a treatment protocol that would ensure that all participants at every trial site would receive the same treatment and care. 20. A further piece of work between the PATHWAYS research team and the clinicians in the NHS Gender Services was to describe the detailed clinical eligibility process and the steps that are needed to determine a young person’s potential eligibility for the trial. This work was undertaken between February and June 2025. It involved a series of joint meetings to agree the principles underpinning different eligibility criteria (the different characteristics that need to be present for a young person to be considered eligible to take part in the Trial), how these would be measured objectively, and how the information would be recorded for the [NMDT]. A distinctive feature of the PATHWAYS trial is that the young person must themselves want the intervention. That is necessary but not sufficient. They must also pass through the clinical eligibility pathway, NMDT review, consent/assent process and baseline safety checks.”
“a. On6 September 2024 KCL (on behalf of the NHSE Specialised Services Clinical Team) submitted a request to MHRA for expert advice regarding [PSH] for children and young people with gender incongruence. The request for advice stated that the ‘aim is to establish whether the planned trial of puberty suppression in youth with gender incongruence will supply sufficient evidence to support a future licence variation application’. That reflected the fact that once the PATHWAYS programme was complete, NHS England planned to consider whether a change in clinical policy and clinical practice was indicated in terms of routine NHS access to [PSH]. The ‘licence variation’ to which KCL’s request refers would be a variation to the licenced [PSH] products to include an indication for gender incongruence. The request was accompanied by a list of specific questions for MHRA scientific advice. b. On27 November 2024 MHRA met with NHSE Specialised Services Clinical Team and KCL to discuss the pre-application request for scientific advice. In advance of that meeting NHSE and KCL produced a briefing document. As a result of that meeting a list of actions were recorded for the trial team. c. Following the meeting on27 November 2024 MHRA provided its final scientific advice in response to the6 September 2024 request from KCL and NHSE on23 December 2024 . The MHRA’s advice was based on the questions and documentation submitted to the MHRA by NHS England at the time. It does not, and cannot, account for the future changes and developments in scientific knowledge or regulatory requirements developed since then. Aspects of the discussion of note for the purposes of this claim include: i. The MHRA suggested that the trial team might wish to consider more robust eligibility criteria - for example, that participants had ‘exhausted non-endocrine interventions for clinicians to consider puberty suppression, as judged by their clinician and the [NMDT]’. ii. The MHRA recommended consideration of setting a minimum age for trial participation, rather than sole reliance on Tanner stage 2 criteria for admission to the Trial. ‘Tanner stages’ are a standardised S-point scale used by healthcare providers to track physical development during puberty. The scale measures secondary sexual characteristics (such as breast and genital development). Tanner stage 1 is prepubertal, and Tanner stage 5 represents adult sexual maturity. iii. The MHRA acknowledged the inherent difficulty in making such a trial ‘blind’ because the knowledge of puberty suppression was a major component of the intervention. It further acknowledged that there was a risk of comparator participants taking [PSH] out-of-protocol, or comparators not being directly comparable to Trial participants due to being ineligible for [PSH] for preference or clinical reasons. iv. The MHRA accepted the use of the KIDSCREEN-10 tool to measure health-related quality of life in Trial participants as a primary outcome. v. As to longer-term follow up to assess benefits and risks beyond the initial Trial period, the MHRA emphasised ‘it would be important to follow up for as long as possible and ensure joined up services as children and young people transition into adult services. Concerns include long term benefits, future fertility, bone health, future genital surgery, sexual function and cognitive development/maturation and long term follow up could be required for a period of up to 20 years.’…” i. The MHRA suggested that the trial team might wish to consider more robust eligibility criteria - for example, that participants had ‘exhausted non-endocrine interventions for clinicians to consider puberty suppression, as judged by their clinician and the [NMDT]’. ii. The MHRA recommended consideration of setting a minimum age for trial participation, rather than sole reliance on Tanner stage 2 criteria for admission to the Trial. ‘Tanner stages’ are a standardised S-point scale used by healthcare providers to track physical development during puberty. The scale measures secondary sexual characteristics (such as breast and genital development). Tanner stage 1 is prepubertal, and Tanner stage 5 represents adult sexual maturity. iii. The MHRA acknowledged the inherent difficulty in making such a trial ‘blind’ because the knowledge of puberty suppression was a major component of the intervention. It further acknowledged that there was a risk of comparator participants taking [PSH] out-of-protocol, or comparators not being directly comparable to Trial participants due to being ineligible for [PSH] for preference or clinical reasons. iv. The MHRA accepted the use of the KIDSCREEN-10 tool to measure health-related quality of life in Trial participants as a primary outcome. v. As to longer-term follow up to assess benefits and risks beyond the initial Trial period, the MHRA emphasised ‘it would be important to follow up for as long as possible and ensure joined up services as children and young people transition into adult services. Concerns include long term benefits, future fertility, bone health, future genital surgery, sexual function and cognitive development/maturation and long term follow up could be required for a period of up to 20 years.’…”
“56. The Trial entailed providing 226 participants under the age of 16 with [PSH]. Participants were to be randomly assigned either to start treatment immediately, or after a one-year delay. The two groups would be compared over two years to assess 'how the timing of treatment affected quality of life, mental health, gender identity/dysphoria and body satisfaction impact on cognition and brain development, and physical effects including bone density. The primary objective of the Trial was to measure the short and medium-term benefits and risks/harms of [PSH], and (by comparing the two groups) to determine whether early intervention improves outcomes. 57. Alongside the PATHWAYS Trial, the application included a participant group known as PATHWAYS HORIZON INTENSIVE, made up of 300 patients not wishing to take, or not eligible for, [PSH]. The intention was to broadly match patients in PATHWAYS HORIZON INTENSIVE to those in the Trial, and to provide the same physical and cognitive measures to that group, thus providing information on the developmental trajectories of those characteristics among young people with gender incongruence who do not receive endocrine interventions. The study also involved PATHWAYS CONNECT, a study of brain development using MRI, which involved examining a subset of 150 participants in the Trial and 100 participants in PATHWAYS HORIZON INTENSIVE. 58. It was explained that all the participants in the study were already under the care of [NHS England’s] specialist gender services and would undergo a clinical eligibility process before being approached for research, which involved assessment for eligibility by both their local clinical team and the [NMDT]. A detailed consent and capacity checklist would need to be completed by clinicians over multiple sessions, including 1:1 sessions with the child or young person (‘CYP’) and their parent(s), and at least one person with parental responsibility would need to provide consent. Participants must have had persistent gender incongruence for a minimum of 2 years and must have a strong desire to ‘transition’ and live as the experienced gender; and their request for puberty suppression must persist after receiving other care prior to the initiation of [PSH].”
“The clinician in the [children and young people’s gender services] leading on care for that [child or young person] believes ‘the [child or young person], with persistent gender incongruence despite other appropriate care, is likely to’ benefit from [PSH]. This benefit ‘is expected to’ be achieved in relation to quality-of-life parameters (e.g., confidence in peer and family relations, participation in school and/or leisure activities, improved sense of well-being), mental or physical health.”
“The clinician in the [children and young people’s gender services] leading on care for that [child or young person] considers that [PSH] for that [child or young person] for puberty suppression offers a reasonable prospect of benefit. That benefit might be achieved in relation to quality-of-life parameters (e.g. confidence in peer and family relations, participation in school and/or leisure activities, improved sense of well-being), mental or physical health.”
“The CIT was satisfied that KCL’s proposed wording on benefit at paragraph 80.b above [and as set out at para. 20 of this judgment] was also sufficient. KCL pointed out in discussions that it would be impossible for an individual clinician to predict the outcome of treatment in relation to an individual child; they could only assess that the child had a reasonable prospect of benefit. Whether such benefit was in fact established was (as with all clinical trials) what the Trial was designed to assess. The CIT was satisfied with that explanation, which it considered sufficiently addressed the benefit/risk balance, in light of the tests which a Trial participant would satisfy, before taking part in the Trial (i.e., persistent gender incongruence, assessment as suitable by the NMDT and local Clinician, and several rounds of consent process).”
“3.4.1 Each REC is made up of a range of people with individual expertise and experience, including registered health and social care professionals, research professionals, and a wide range of people with much broader experience, including members of the public who have experience using health and social care services and no professional knowledge of research or health and social care. 3.4.2 REC members are appointed to provide a broad range of perspectives on the committees, which scrutinise the rationale, aims and objectives of the proposed research to reconcile this effectively with protecting the dignity, rights, safety and well-being of the people who are likely to take part. 3.4.3 REC members are appointed independently of their employing organisation and are expected to reflect their own experience and ethical judgement on an individual basis, bringing sound judgement and personal experience to undertake the REC review, underpinned and supported by relevant training and REC SOPs.”
“the HRA is one of several bodies that hold key responsibilities and accountability for different aspects of a clinical trial application and approval process. This is important because it is a consequence of the way in which the HRA approaches its health and social care research that it, and the REC, when they perform their roles, must take ‘assurances’ from others that they have performed their respective roles…”
“70. We were aware that the role of the national MDT was central to ensuring the right patient cohort was identified, and we asked for reassurance on how it would work. We were told by the sponsors that the national MDT would be composed of experienced expert members who understood both the science and the potential ramifications if the Trial went wrong. From our discussion, the REC were reassured that the national MDT and the applicants would not let anyone into the Trial unless they had been identified as having the most potential to benefit by their local clinical team and met very strict criteria (which I address below). 71. We, as a REC, felt that the local specialist gender services would have a good idea of how likely their patients would be to benefit from the Trial, and would have a very good idea of who they considered had that greatest potential to benefit. Once they had been recommended, the participants were then considered by a national MDT, with both organisations applying the eligibility criteria the applicants had proposed. We felt that the MDT was there to ensure the local teams were applying the eligibility criteria properly, and not picking participants inappropriately. They were therefore an extra safeguard and safety net to ensure only those who truly met the criteria were admitted. As in most drug trials, the question of who is suitable is normally made by the trial’s investigator alone in conjunction with the patient, this three stage process was significantly more than a usual trial application.”
“97… I recall we found the response to Question 1 of the October RFI helpful and detailed. What we had been looking for was for the applicants to articulate in writing, and more extensively, why they considered that the Trial was needed and what purpose it was achieving. We were satisfied after reviewing these responses that they had done so. Their clear and detailed explanations of the Trial in the context of the Cass Report and the CHM report (including the recommendation that a trial be undertaken) were important factors in our decision, as both were both significant reports in the field and had gone into lots of detail about the specific issues it involved. If applicants were making specific recommendations about what sector specialists feel is required based on such reports, that information is both helpful for us to know and can be a factor guiding our decision. 98. We also noted that the applicants, a professional clinical organisation, still wished to undertake the Trial, that they had reasonable reasons for wishing to do so and clarity on the ‘hoped for’ outcomes – the question in our minds was whether this was reasonable. We were aware of the previous banning order and the CHM report obtained for that. The fact of the ban itself did not cause us to consider the Trial must necessarily be unethical. Instead, as Baroness Cass identified, it was banned as the wider public did not know those long term outcomes, those answers needed to be found out, and this would require a Trial. We were conscious that the Cass report had not categorically set out how a trial should be run, so we had to consider the Trial as it had been presented to us. Following our review of the information, we considered that how the Trial would be run was articulated here very clearly, and the applicants were very clear on risks and how they were to be mitigated. We took the applicants – as we must take all applicants, who are the masters of the science, and indeed Cass and other sector experts – at their word that there was an insufficiency of evidence. From what we had been presented with, it seemed reasonable for the applicants to have concluded that there was. Overall, we were satisfied that there was justification for implementing the Trial (as opposed to investigating other options without the Trial), and that it would be appropriate. 99. …Taking the previous information, and additional clarification from the applicants, we concluded we were satisfied by their responses and felt we could reach an overall ‘favourable’ view… 100. Throughout our consideration of the study, my colleagues on the REC and I were aware that the risks were to some extent known, but were to some extent unknown (especially the long term risks). We do not know what long term effects of [PSH] are once children have gone down the road, what their development in their late teens and early 20s would be. For the REC, we looked to establish the likely risks and what they could be (e.g. brain development, bone and mineral and fertility in particular), and asked whether those risks were acceptable, whether they were likely to be reversible, whether the participants could make an informed choice (which we already knew would be difficult as the potential participants are all under 18) and whether the information they were being provided with was sufficient so they fully understand what was going on. We were conscious that for some members of the public, they may say ‘these are physically healthy children, so surely it must be unethical to do anything that might damage them physically’, and we asked that question and how the risks were being mitigated. Ultimately, the applicants satisfied us with their responses. 101. We had considered the real-world context of the Trial, which we and the applicants’ research team knew would be closely scrutinised. I found the applicants in our discussions to be taking the Trial, the risks and risk management very seriously. The REC and I considered that in having the brain scans, other checks, and offering options for fertility, that the applicants had done as much as they could to mitigate the risks. As we were considering a trial about young people who are very severely impacted by their condition, we formed the view that the benefits outweighed the risks from an ethical perspective.”
“119. This point was critical to the MHRA, because it recognised that for many participants in the Trial, the benefit of taking [PSH] from their point of view would be to allow them the possibility to transition their gender through access to MAF hormones, without having developed the secondary sexual characteristics of their birth sex. So, the potential pathway for accessing MAF hormones was a critical component of assessing the safety of trial participants: not least, because the MHRA wished to assure itself that a Trial participant who might have started in the Trial at an age as young as 11 (for a birth-registered female) would not need to take [puberty supressing hormones] for 7 years before being eligible for MAF hormones. 120. The MHRA position was that it was necessary to consider the long-term safety i.e. beyond the 2-year study period of the trial, for participants in its review of the Trial protocol. It also indicated to KCL that it would be necessary to ensure that for those children who wished to continue to take [PSH] after the end of the trial, an amendment should be submitted no later than Month 19 following the start of the Trial (i.e. Month 19 post-randomisation), to extend interventional access to [PSH] within the research context of the Trial.”
“The sponsor confirms that MAF hormones remain outside the scope of the PATHWAYS Trial protocol. KCL is not currently aware of any sponsor-specific impediment to participating in or supporting the development of a future, separate research study of MAF hormones, should such a study be considered appropriate by the relevant bodies. However, KCL cannot provide assurance that any such study will be available, approved, opened, funded or suitable for individual PATHWAYS participants, as those matters are outside the scope of the current trial and would depend on future commissioning, protocol development and regulatory/ethical approvals.”
“We took assurance from the CHM minutes and the MHRA review process that led to the modification being submitted, that those aspects of the modification which the MHRA had asked to be made seemed, now they had been made, likely to be approved by the MHRA. We therefore felt that should we be satisfied that the ethical aspects of the modification were in order, then it looked likely the MHRA would also approve the modification, all things being equal.”
“113. In considering the modification, we also considered the purpose of the Trial and clarified that it was not to allow or aimed at facilitating transition to the other gender, and that issues of potential future access to MAF hormones did not form part of the Trial itself. The applicants had previously explained, and reiterated, that any consideration of a young person for MAF would not be automatic after they had been on the Trial, but would only be considered following a thorough evaluation by local gender services and the national MDT (above) who would separately be considering whether this was indicated. We noted that extensive clarification that there should be no presumed or automatic link between the Trial, and GNRHa, and moving to MAF hormones had been provided in the covering letter, protocol and the participant information. That being said, we were also conscious from previous discussions and the original application, that in reality some participants in the Trial may go on to MAF hormones so we were aware we were reaching a judgment on the level of risk posed. 114. We were aware from the CHM minutes that MAF hormones had been ‘paused’ from being provided as a part of the NHS standard of care, and that there was some uncertainty in whether that standard of care would be resumed or not. We considered this but in our view, this was not a sufficient reason for the Trial not to proceed. One significant reason was that we considered that the Trial had independent value, distinct from whether participants went on to take MAF hormones, as its purpose was to identify the short, medium and long term effects of GnRHa itself where the evidential picture was not clear. However, we also had in mind that the Trial itself was intended to be a two year programme, and should any participants go on to consider MAF there would be a significant amount of time spent on the Trial before this decision was reached. I felt it was reasonable to expect that the question of access to MAF hormones to be resolved by this stage (i.e. by the end of the two year period), whether it progressed through a separate trial or as a part of a resumed NHS standard of care. There was also a possibility that the progress and outcomes from the Trial may themselves also impact on guiding those arrangements that may be made in relation to access to MAF hormones in the future. We were also assured that the CHM reached the same view (that the lack of clarity should not prevent the Trial from proceeding), for the reasons it gave.”
“119.1 The consent arrangements for young people and their parents continued to be appropriate. 119.2 The way in which the Trial compared to the current standard of care available to potential participants (in relation to [PSH] – MAF being addressed above) had not changed. 119.3 The measures for minimising risks, burdens and intrusions to participants, and the anticipated risks and benefits (to individual participants and the group) were acceptable, subject to confirmation as to the [open label extension]. 119.4 We considered that there remained the potential for some direct benefit for the group of patients involved in the Trial, who had not changed since the original application. 119.5 We agreed that the anticipated benefits outweighed the risks, having regard to a range of factors including the current standard of care, arrangements of consent, wider interests, and that this was so for individual participants (again, subject to confirmation as to the [open label extension]). 119.6 We also remained satisfied that the Trial was only such that it could be conducted with children and young people, and that it looked to be conducted in accordance with the GCP and Declaration of Helsinki principles.”
“(a) the relevance of the clinical trial and its design; (b) whether the evaluation of the anticipated benefits and risks as required under paragraph 10 of Part 2 of Schedule 1 is satisfactory and whether the conclusions are justified; (c) the protocol; (d) the suitability of the investigator and supporting staff; (e) the investigator’s brochure or, where the investigational medicinal product has marketing authorization and the product is to be used in accordance with the terms of that authorization, the summary of product characteristics, or equivalent document, relating to that product; (f) the quality of the facilities for the trial; (g) the adequacy and completeness of the written information to be given, and the procedure to be followed, for the purpose of obtaining informed consent to the subjects' participation in the trial; (h) if the subjects are to include minors or persons incapable of giving informed consent, whether the research is justified having regard to the conditions and principles specified in Part 4 or Part 5 respectively of Schedule 1; (i) provision for indemnity or compensation in the event of injury or death attributable to the clinical trial; (j) any insurance or indemnity to cover the liability of the investigator or sponsor; (k) the amounts, and, where appropriate, the arrangements, for rewarding or compensating investigators and subjects; (l) the terms of any agreement between the sponsor and the owner or occupier of the trial site which are relevant to the arrangements referred to in sub-paragraph (k); and (m) the arrangements for the recruitment of subjects.”
“1. Clinical trials must be conducted in accordance with the principles of good clinical practice set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, as amended from time to time. 2. Except where it would be a contravention of these Regulations, clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki.”
“21. Medical research involving human participants must have a scientifically sound and rigorous design and execution that are likely to produce reliable, valid, and valuable knowledge and avoid research waste. The research must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation… … 28. In medical research involving human participants incapable of giving free and informed consent, the physician or other qualified individual must seek informed consent from the legally authorized representative, considering preferences and values expressed by the potential participant. Those persons incapable of giving free and informed consent are in situations of particular vulnerability and are entitled to the corresponding safeguards. In addition to receiving the protections for the particularly vulnerable, those incapable of giving consent must only be included if the research is likely to either personally benefit them or if it entails only minimal risk and minimal burden.”
“(1) The validity of a decision of the licensing authority under Parts 3 (manufacturing and wholesale dealing), 5 (UK marketing authorisations), 6 (certification of homoeopathic medicinal products), 7 (traditional herbal medicinal products) or 8 (Article 126a authorisations) is not to be questioned in any legal proceedings. (2) The validity of a licence, authorisation, certificate or registration granted or issued, or other thing done, in pursuance of a decision of a kind mentioned in paragraph (1) is not to be questioned in any legal proceedings. (3) Paragraphs (1) and (2) are subject to the following provisions of this regulation. (4) A person to whom notice of the decision is given may make an application to the High Court to challenge the validity of the decision on the grounds that— (a) the decision is not within the powers conferred on the licensing authority; or (b) a requirement of these Regulations in connection with the matter to which the decision relates has not been complied with.” (a) the decision is not within the powers conferred on the licensing authority; or (b) a requirement of these Regulations in connection with the matter to which the decision relates has not been complied with.”
“Those words mean, and can only mean, in relation to this particular licence, Beechams. Nobody else, in my view, is in a position to make an application in respect of the licences which relate to them. Organon were not in a position to do so. This application… therefore in my view must be dismissed. There is an alternative application for judicial review. But judicial review falls fairly and squarely within subsection (1) of section 107 which provides (as I have already read in the earlier judgment): ‘Except as provided by the following provisions of this section the validity of the licensing authority's decision shall not be challenged in any legal proceedings’. That is an ouster clause, a perfectly effective ouster clause, since the right to challenge, which the statutory provision provides in subsection (2) to the licensee, is virtually co-extensive with judicial review the courts would not strain to say they can get round it somehow or other by way of judicial review.”
“A reviewing court should be very slow to conclude that the expert and experienced decision-maker assigned the task by statute has reached a perverse scientific conclusion.”
“where the decision maker is taking a decision in the health field with the objective of improving patient care; where the decision adopted is prospective and precautionary (i.e. based upon a prediction of future benefit and where there is perceived to be a benefit in acting sooner rather than later notwithstanding uncertainties); where the decision maker has indicated a willingness and intention to review the policy as it unfolds to ensure that it is in fact working adequately and to review and modify it to address emerging problems.”
“In my experience, the different types of members will pick up on and identify different issues. Expert members tend to have more background knowledge about the existing standard of care (or know where that information can be found) and tend to know more about e.g. the possible side effects of medication, possible risks, and whether a trial is necessary within a set of treatment options. The lay members are very good at analysing the participant information, looking at the burdens and impact of a trial on patients, and are generally better at asking those questions which would be important to real-world patients. This range of views is also why RECs benefit from having a range of people with different qualifications, backgrounds and experience.”
“234. In relation to the June decision, both the REC and MHRA failed to take account of mandatory considerations in relation to the destination therapy issue (see §§215-230), by focussing on whether there was sufficient assurance around the OLE study, and by proceeding on the basis of an assumption that MAF would be available to trial participants in due course through a separate research study if needed, rather than stepping back and considering the relevant regulatory questions and in particular the overall benefit-risk balance again in light of this issue. As set out at §§201-202, the REC (despite being asked to consider the point) left it to the MHRA. The MHRA de facto delegated consideration of the point to the CHM – see §§227. 235. What is more, this was not compatible with reg. 22C(6) of the 2004 Regulations, which should have had the effect that if there were any concerns about the response to an RFI the MHRA had no choice but to reject the modified Trial protocol. The CHM response was that they still had concerns, and on that basis (although the CHM still thought the Trial should go ahead) the MHRA were bound to reject it. However, the MHRA approved the modified Trial.”
“157. The MHRA was acutely aware that many Trial participants would likely wish to continue to take [PSH] after the end of the Trial and/or eventually to progress to taking MAF hormones, if their gender incongruence had not resolved. As I have explained above, the MHRA specifically took that fact into account when considering whether to give approval for the Trial protocol; and it and the CHM specifically considered in that regard the implications of a possible change in NHS prescribing conditions for MAF hormones (i.e., that they would not be available before the age of 18)…. The MHRA made no assumption that there would inevitably be an OLES, or a clinical trial of MAF hormones at the age of 16, in which Trial participants could take part, where that was desired and clinically appropriate. However, through the course of the assessment, DHSC has guaranteed funding for an OLES; and the Trial protocol requires any application for an OLES to be lodged by the Trial sponsor no later than Month 15 of the Trial (to give certainty for Trial participants). 158. While it is not possible for the MHRA to know with certainty how many [children and young people] may appropriately access MAF hormones after the Trial (if at all), the MHRA sought assurances, to the greatest extent possible, that there was no impediment to a MAF hormones clinical trial, as referred to in RFI4 of version 3 of the Protocol. Those assurances were then matters which fed into the MHRA’s overall assessment that the benefit/risk balance of the Trial for participants was positive.”
“the MHRA noted that given the change in NHSE’s policy on the prescribing of MAF hormones could potentially impact considerations around the long-term safety or well-being concerns of the participants, or to the risk-benefit profile of the trial (for example if trial participants will need to transition to taking MAF hormones after taking part in the trial), then that policy (and the evidence in support of it), which may only become relevant after the trial period, should be taken into account in reaching a decision on the trial.”
“…MHRA has been considering the position of participants at the conclusion of the 2-year trial period, including the potential future availability of masculinising and feminising (‘MAF’) hormones where clinically appropriate. This is currently uncertain because on9 March 2026 NHS England paused new prescriptions of MAF hormones to 16 and 17 year olds, while it consults on a revised policy under which MAF hormones would not be available as a routine commissioning option through the NHS Children and Young People's Gender Service. As you will know, this consultation is open for 90 days, until7th June 2026 and its outcome is therefore not yet known. Against this context, we would be grateful for clarification as to whether any outcome of the ongoing consultation could, of itself, as a matter of policy affect or impede access for PATHWAYS trial participants to MAF hormones at 16 years of age, where such access were proposed within a separately approved research study. For the avoidance of doubt, this request is not intended to seek any commitment or make any assumption regarding the future commissioning, funding, authorisation or undertaking of a trial, nor to pre-empt the outcome of the ongoing consultation process. Rather, we seek only confirmation as to whether the consultation and/or its outcomes would affect or impede consideration of such access in a future research context.”
“To take an unrelated example, say that a potential trial sponsor wanted to test GLP-1 weight loss drugs in children, to see whether the benefits outweighed the risks. The MHRA and HRA would need to be convinced that (a) the evidence indicated there would be some direct benefit for the group taking part in the as a whole; and (b) that for each individual trial subject the benefits justified the risks. It will usually not be possible to say with certainty whether the benefit will outweigh the burden for any individual trial child subject, but there must be sufficient evidence to believe that it will. That would be fulfilled, in the ordinary course of events, by there being previous research which tended to show this drug was effective in achieving weight loss and that there were no major side-effects or other risks which meant the anticipated benefits were not justified (the Declaration of Helsinki principles requiring that for children and others unable to give informed consent there must be minimal risk or burden).” (Emphasis in original.)
“In relation to the November and June decisions the REC failed to consider the following matters which were statutorily required, properly or at all: a. The requirement under reg 15(5)(h) and Sch 1, Part 4 condition 10 for ‘some direct benefit for the group of patients involved in the trial’, as set out at §§102-114 above. b. The inability, on the trial sponsors’ own evidence, for the statutory risk/benefit balance requirement for individual trial subjects under reg 15(5)(b) and Sch 1, Part 2 condition 10 (also as read with condition 16) to be satisfied: see §§102-114 above. c. The requirement to validate data that had been obtained by other means, under Sch 1, Part 4 condition 11; including consideration of (i) animal studies and (ii) follow-up of individuals who had previous been prescribed puberty blockers for gender incongruence or dysphoria: see §§117-123 above. d. Compliance with EMA scientific guidelines; in particular as to risk mitigation and trials involving children: see §§67-68 above. e. Failure to consider the trial protocol design, as required by reg 15(5)(a), and in particular failure to ask any or any adequate questions about its underlying scientific rationale and ability to yield clinically meaningful data: see §§124-131 above.”
“5.6 Transparency 5.6.1 RECs should publish a summary of the research they have reviewed, together with their opinion, whether favourable or otherwise.”
“240. Both the HRA/REC and the MRHA irrationally approved a trial protocol that lacked the essential components for a clinical trial; in particular (a) a clearly articulated scientific rationale; and (b) the ability to yield clinically meaningful data: see §§124-131 above. The ongoing confusion about the rationale is apparent even by the time of the June decision, when the REC accepted the primary benefit of GnRHa was ‘time to think’ whereas the MHRA accepted the primary benefit preserving the opportunity to initiate MAF before the development of secondary sexual characteristics. Both cannot be correct. 241. In relation to the June decision, both the REC and MHRA acted irrationally by failing to consider the risks and concerns raised by the destination therapy issue through the correct lens or ‘spectacles’ of the regulations and structure of the regulatory regime. In particular, as set out at §§201, 225-227 and 230, they did not ask themselves the questions set out in the 2004 Regulations and their Schedules (incorporating the ICH GCP and Declaration of Helsinki) or the EMA Guidelines, especially those relating to the balance of risk and benefit for children, but rather sought to reassure themselves that the sponsors’ responses (and those from the NIHR and NHS England in relation to the OLE study) were sufficient.”
“The weight to be accorded to this public interest will vary from context to context, but may be considerable. In many cases, the claimant would need to point to something very compelling to outweigh it. In deciding whether a claimant has done so, the court will consider both the prima facie strength of the claim and the gravity of the consequences that would follow if interim relief were not granted. It is not possible, and would not be desirable, to lay down anything more prescriptive than that.”
“The consideration of the balance of convenience involves balancing the harm to the claimant that would be caused if interim relief is not granted and the claim later succeeds against the harm to the defendant, any third parties and the public interest that would be caused if interim relief is granted and the claim later fails.” (Emphasis added.)