How puberty blockers slipped through the dangerous loophole in Britain’s drug regulation
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“Shaky foundations”. That’s how Dr Hilary Cass characterised the ground that gender medicine was built on in this country. In a health system where clinicians are typically cautious, where emerging areas are treated carefully and medicines well-regulated, the Cass Review into the gender identity clinic at the Tavistock Centre, in London, determined “quite the reverse” had been true when it came to gender care for children.
Of the myriad holes Cass exposed – from the lack of evidence underpinning the guidelines for managing gender dysphoria, to the insufficient studies supporting the use of hormone treatment – perhaps the most striking were her findings on puberty blockers. The use of the drugs (historically prescribed to pause symptoms in very young children experiencing precocious puberty) was informed by a single, Dutch medical study, which, Cass said, suggested puberty blockers “may improve psychological wellbeing for a narrowly defined group of children with gender incongruence”.
“Some practitioners abandoned normal clinical approaches to holistic assessment which has meant that this group of young people have been exceptionalised compared to other young people with similarly complex presentations.”
She added: “They deserve very much better.”
Puberty blockers were meant to simply buy children time to think. In fact, Cass showed the vast majority of children who were prescribed them then went on to do hormone treatment. Of the 50 papers on the effects of puberty blockers in adolescents that researchers at the University of York identified for the report, only one was deemed to be of high quality.
In the wake of Cass’s findings, published last week, it’s tempting to look forward – to focus on her recommendations and train your eyes on what happens next. But to do that, you have to understand how it happened in the first place. For many, the fact that it was possible for clinicians to prescribe an under-researched drug freely to children exposes a gaping hole in the drug regulation system in this country.
At Gids, puberty blockers were prescribed off-label. Put simply, if a drug is being used off-label then it will have been originally licensed by the government’s regulator – the Medicines and Healthcare products Regulatory Agency (MHRA) – but is now being used in a different way (for a different condition, a different group of patients or at a different dosage).
It’s common practice (particularly in paediatrics, as drugs aren’t generally trialled on children), but National Institute for Health and Care Excellence (Nice) guidelines state healthcare professionals must “[give] information about the treatment and [discuss] the possible benefits and harms so that the person has enough information to decide whether or not to have the treatment. This is called giving informed consent.”
“The key thing the GMC [General Medical Council] would say,” says Prof Anthony Cox, an expert in clinical pharmacy and drug safety at the University of Birmingham, “is that you have to be satisfied there is sufficient evidence or experience of using the medicine to demonstrate safety and efficacy, and I think that wasn’t met by Tavistock [when] prescribing puberty blockers.”
How did they get around it? “They would argue there was evidence,” says Cox. “And [that] they’d developed a practice over years. But by the late 2010s it was quite clear that there were concerns about the lack of evidence.”
Those concerns, he says, were being shared by people “who raised their voices and were knocked down, and whistleblowers”.
For many, it speaks to a “loophole” in the system which allowed medical professionals prescribing these drugs to fall back on the fact that it had been licensed for use and had even been used on children before, just for a different purpose.
There was a sense of “What’s the problem?”, says Prof Carl Heneghan, director of the Centre for Evidence-Based Medicine at the University of Oxford. Using off-label drugs is common practice, he says, “and that’s the loophole that’s been used [here]”.
“We need a much more robust, evidence-based approach for how we licence children’s medicines. That’s why we said we need a new regulator that looks into this.”
Heneghan says the fact that the drug had already been prescribed to children legitimised its use in young people experiencing gender dysphoria. “That’s the loophole – you say we’re doing it over here, but actually we’re using it in precocious puberty, and therefore it’s alright to be using it in children for transgender or gender dysphoria.”
It should have been particularly important to interrogate the way the drugs were being prescribed given the “irreversibility” of the intervention, he says. “That should create a more stringent approach to the regulation.”
For Heneghan, the whole system of off-label drug regulation requires examination. The current one “puts the onus on individual doctors to take the responsibility”.
“I think, given what’s happened with gender dysphoria, there needs to be a real look at the situation. Certainly, a general practitioner can’t have the evidence and experience to say ‘I can prescribe off-label in children’ where the harms are quite significant and the use is limited.
“A regulator, if they were in place, might say, ‘Yes actually this drug, if it’s to be used off-label, can only be prescribed in the context of secondary care where the person is known to a, b and c.’ And that would bring in another level of safety that is missing at this moment in time.”
There needs to be a “tightening of the regulations”, he says, in order to “prevent this happening again”. Meanwhile the MHRA, he says, “should say ‘It is our responsibility to keep children safe and ultimately we will take the can for when it goes wrong’”.
The MHRA is clear it has not licensed “any medicines” for the treatment of gender dysphoria. Dr Alison Cave, MHRA chief safety officer, says: “Clinicians, under their professional responsibility, may decide to prescribe a medicine ‘off-label’. The use of medicines ‘off-label’ is a matter of clinical practice and is not regulated by the MHRA.”
Patient safety, she adds, is their “top priority”.
Maria Caulfield, the health minister, says: “There are no circumstances where a child under the age of 18 should be prescribed puberty blockers off-label for gender dysphoria under the recommendations of the Cass Review.
“We are working to implement all of Dr Cass’s recommendations, including closing any loopholes to prevent these treatments from being given to children.”
Sallie Baxendale, a professor of clinical neuropsychology at UCL, says that, though doctors have a right to prescribe off-label, puberty blockers “escaped out into the wild”.
“Now they’re bringing it right the way back to ‘OK, if you want to use this drug, it’s got to be part of research. If it’s going to be part of research it will have to go through an ethics committee, so you will have to present to the ethics committee the reasons why you want to use it, why you think it’s going to work, who you’re going to give it to, why you’re going to give it to them.’ All of that will have to be set out and that’s going to be a challenge on the back of Cass.”
Baxendale points to the dysfunctional prescription process at the Gender Identity Development Service (Gids) at the Tavistock, as laid out in the book Time to Think by journalist Hannah Barnes. “She described how psychologists, who do not have prescribing rights, were making the recommendations for the drugs. Endocrinologists were then prescribing the drugs, on the recommendation of the psychologists.
“Barnes reports that it became a process whereby no one really took responsibility for the treatment. The psychologists were not responsible because they weren’t actually prescribing. The endocrinologists were only going on what the psychologists said. That’s why Cass insists on a medically-led service now, as part of a multidisciplinary team.
“It’s extraordinary that such a model developed with an experimental, off-label treatment.”
Ashley Grossman, a consultant endocrinologist and professor of endocrinology at Oxford, says if he was prescribing a drug off-label he would first run it past a multidisciplinary group or a pharmacology committee in his hospital and “get other people’s views”. “Almost certainly that didn’t happen at all [at Gids] and that was the problem,” he says.
“I think people came from a viewpoint that any child that says, ‘I’m in the wrong sex’ had to be believed automatically and had to transition. It was an affirmation of a change without any counselling, any discussion, any consideration of other possibilities. It was a mindset that was pointed in one direction and one direction alone.”
The result, he says, was children “being treated with essentially a completely new and experimental drug – experimental in the sense that it had never been used in this situation”. Campaigners have long insisted that puberty blockers are “just one possible part of a young person’s gender journey”.
Grossman points out that people who raised doubts about the drugs “were shut down”. “On social media, a lot of us who were concerned were frightened to put our heads above the parapet because of the trolling and nastiness that went around.”
A “custom of practice, and perhaps ideology” led clinicians at Gids to “believe they were doing the right thing,” says Cox, “when actually I don’t think they had the evidence to say that it was safe and effective, what they were trying to do”.
The “normal mechanisms” that might have hindered the widespread use of a controversial drug in another NHS trust weren’t present at Gids, he says. “I suppose if your whole organisation has a sort of groupthink going on then the normal mechanisms you might have in place within an NHS trust to oversee such things like prescribing possibly would start to fail.”
It didn’t help that the Tavistock was seen as an expert hub. “If you’re considered to be a national centre of excellence in whatever condition you’re dealing with then there is a certain expectation that there would be a level of professionalism that would mean that you wouldn’t get this sort of behaviour,” says Cox.
“You would have thought a national centre would be the type of place that would be on top of the evidence.”
He wonders if, in the wake of Cass, there should be a “review of professional bodies”, though he warns against overcorrecting. “It’s dangerous to start tying the hands of clinicians too much because you will end up having a perverse outcome in that you will cause harm to patients by creating a system where you can’t actually use medicines that there is evidence for.”
What’s clear, he says, is that in the case of puberty blockers, it was too “simplistic” a defence to argue that off-label prescribing was common practice in paediatrics.
“[Off-label drugs] are used with due regard to safety and efficacy. And if that isn’t happening then there’s a failure.
“And if you’ve got people telling you there’s a potential issue and you’re not taking that seriously, and you develop a groupthink that ‘We are right’ and have an almost ideological stance towards the use of a drug, then I think you’ve gone down a really dangerous dead end.”
Many hope that dead end has come to its final conclusion with Cass – that the loophole will finally be closed.
