The launch of a clinical trial is usually met with a reaction somewhere between polite indifference and deafening silence.
The new Pathways study, however, is not that kind of trial. Last month, NHS-funded scientists announced they were seeking ethical approval to test banned puberty blockers on children with gender incongruence. If they receive the go-ahead from regulators — a decision expected in coming weeks — the £10.7 million trial will start by the end of the year.
The backlash has been immediate. On one side, some campaigners argue that trialling such risky drugs is unethical, tantamount to treating children as guinea pigs and little more than a loophole for the continued use of outlawed treatments.
On the other side, equally vocal campaigners argue that the ban — introduced in May by the Conservative health secretary Victoria Atkins and made indefinite in December by her Labour successor, Wes Streeting — unfairly denies puberty blockers to children struggling with their identity, and risks a surge in suicides among young trans people. Research is all very well, they argue, but not at the cost of routine access to what they claim are safe and proven drugs.
Between the two sides, struggling to make their voices heard above the din, are doctors who point out that puberty blockers were banned for routine use precisely because further research is needed. A trial, they argue, is how we find out more.
Cass review recommendation
Baroness Cass is the paediatrician whose highly critical review into gender identity services led to the withdrawal of the routine use of blockers and the closure of the controversial Gender Identity Development Service (Gids) at the Tavistock Centre in north London. Her 388-page report, published in April last year, was seen as a vindication for those who felt that the use of puberty blockers was leading to potentially catastrophic outcomes for young children.
But Cass’s review also recommended a trial, and she is sticking to her guns. It is the gulf between the two sides of the debate, she says, together with the dearth of robust evidence about the benefits and harms of the drugs, which means a clinical trial is essential.
“In the absence of this evidence, people draw their own conclusions,” Cass says, in her first public comments since the trial was announced. “There are very strongly held but polarised views on the use of these medications, with some people thinking they should be stopped entirely for young people with gender dysphoria, and others arguing they should be much more freely available.
“Both these positions have some cogent arguments, but the two positions are incompatible. From a clinical research perspective, this is called equipoise. We do need further research to fill some of the evidence gaps, to remove uncertainty for the young people, their families and clinicians.”
The atmosphere around this issue is so febrile that the government has already had to see off a judicial review against the puberty blockers ban, brought last year by the campaign group TransActual UK and the Good Law Project, led by the activist lawyer Jolyon Maugham.
Now it is being threatened with another. Lawyers for a group of campaigners on the other side of the argument, led by a “detransitioned” patient, Keira Bell, and psychotherapist James Esses, have threatened a judicial review against the Health Research Authority if it gives ethical approval for the Pathways trial.
How do puberty blockers work and where did they come from?
Puberty blockers are a class of drugs called gonadotropin-releasing hormone (GnRH) analogues, which suppress the release of sex hormones such as testosterone and oestrogen. Similar drugs are used to lower hormone levels in breast cancer and prostate cancer patients, and for those with heavy periods or endometriosis. Among boys, they decrease the growth of facial and body hair, prevent voice deepening and limit the growth of genitalia. In girls, treatment limits or stops breast development and stops menstruation.
They were initially used in children to temporarily stop puberty among those who started it prematurely, usually before the age of eight. But the drugs started to be used for gender dysphoria in the UK in 2011, based on the “Dutch protocol” developed by Peggy Cohen-Kettenis, a psychologist from Utrecht.
According to this protocol, blockers were useful for two key reasons. First, they provided a “pause” to the changes that come with puberty, allowing children identifying as transgender “time to think” before making a decision about their future. Second, they were thought to improve the ability of those born as one sex to “pass” as the other sex in later life. The Cass review found this was “particularly important” for boys who become transgender women, “who were able to access puberty blockers before developing facial hair and dropping their voice”.
But it also found little evidence these drugs worked to reduce the psychological distress of gender dysphoria. The Tavistock’s own initial study, on 44 children given puberty blockers between 2011 and 2014, found no statistically significant improvement in psychological wellbeing. Indeed, some children saw an increase in suffering. An independent review also found there was no evidence of a rise in suicides since puberty-blocking drugs were restricted at the Tavistock.
Instead of reporting these negative findings publicly, the study was buried by clinical staff until 2020. In the meantime, use of the drugs had become routine, as increasing numbers of children were referred to the service. As many as 2,000 children are thought to have been given blockers in total — as Anna Hutchinson, a senior clinical psychologist at Gids, later told the journalist Hannah Barnes: “There were no referral criteria … We were accepting everyone.”
The fundamental problem, according to Sir Jonathan Montgomery, professor of healthcare law at University College London and former chairman of the Health Research Authority, is that “these treatments had moved from use in a research context to business-as-usual usage at the Tavistock, without proper evaluation of the research data”.
Beneficial for small group
But rather than recommending an outright ban on the drugs, Cass became persuaded during her investigation that a small group of patients might possibly benefit from puberty blockers. A re-analysis of the early Tavistock data found that 9 to 29 per cent of those given the drugs saw a reliable improvement in distress levels, 15 to 34 per cent saw a deterioration and 37 to 70 per cent saw no change.
Determining whether some children might benefit, and identifying which children fell into that category, was Cass’s main argument for carrying out a trial. Without this certainty, some families with children convinced of their gender dysphoria would continue to seek out the drugs from overseas or on the black market.
The researchers at King’s College London, who will lead the trial among patients at new NHS gender dysphoria services in London, Bristol and Liverpool, and possibly another three centres that have yet to open, have decided not to release the study design before it has received final ethical approval. They are also not responding to inquiries.
The question at the heart of this debate is whether it is possible for doctors, amid all the politicisation and pressure provoked by this issue, with all the baggage of social media contagion, image problems, overdiagnosis and culture warfare that comes with it, to reliably distinguish between the minority of children who might actually benefit from puberty blockers and those for whom they could do lasting harm.
Dr Hannah Ryan, a specialist registrar in clinical pharmacology at Royal Liverpool University Hospital, is sceptical that it would even be possible to design a good study on the question.
“We have no way of predicting which children will persist with gender dysphoria into adulthood and who will simply desist,” says Ryan, a member of the Clinical Advisory Network on Sex and Gender (CAN-SG), an increasingly influential group of doctors campaigning against the trial. “Historically, around three quarters will desist without any intervention at all. You could not design inclusion criteria for a trial that would exclude those kids who will just simply grow out of this and not become transgender adults.”
Alternatives to new trial
Before carrying out a trial, Ryan argues, the NHS should track down the 2,000 or so children treated with puberty blockers at the Tavistock and assess the effects upon them. Cass called for such a review of existing patients but it has proved difficult to get access to medical records.
“Before taking risks with children’s health and wellbeing, we are obliged to look at that data,” Ryan says.
Sallie Baxendale, professor of clinical neuropsychology at University College London, agrees. Although pausing puberty is temporary, there may be lasting effects. “We currently don’t know what the long-term effects of [interrupting puberty] will be, or whether the brain ever catches up on that period of suspended development,” she says. “A clinical trial looking at the impacts in the short term won’t give us these answers.”
But Dominic Wilkinson, a paediatrician and professor of medical ethics at Oxford University, argues that a lack of evidence only strengthens the case for a clinical trial. “One of the things that, as paediatricians, we’re very conscious of, is that many of the drugs that we use have not been properly evaluated in children,” he says.
“That’s because people have avoided doing the research trials that we need to be able to inform the decisions that we make. When there is genuine uncertainty, the way to address it is by doing carefully designed and conducted trials. We need to tackle it head-on.”
