Don't prejudge a trial

It is too soon to say that an ethical trial of puberty blockers is impossible

Photo by Adrian Salazar on Unsplash

Pre-emptive opposition to the idea of any clinical trial of puberty blockers for gender dysphoria is mistaken because there may be ethical trial designs capable of answering a series of research questions about the effects of these drugs, according to an advocate for evidence-based medicine, Professor Susan Bewley.

“Many people think a clinical trial with random allocation of participants to treatment and control groups would be unethical,” Professor Bewley told GCN.

“There is a wide range of viewpoints. Some people believe it’s a human right to have certain medical interventions offered by autonomous clinicians for identity indications. Others believe this is bad medicine or maybe does not belong within the scope of medicine at all.

“The claim of being ‘unethical’ is made of two parts: the quality of the science (bad science is always unethical); and the information and risks participants undergo (protected by research integrity and law).

“When there are actual medical uncertainties, many of us believe it’s unethical not to do research which could be collaborative and worldwide.

“Other trials of more dangerous medications—for example, chemotherapy and radiotherapy for childhood cancers—have been ethical to test, even as they have lifelong impacts on children’s health and development.

“It’s surely wrong to take against all trials of puberty blockers or cross-sex hormones because each one is designed to answer a different initial question. We can’t make a blanket comment on the ethics as each research question is different.”

Professor Bewley, former chair of the UK charity now called HealthSense, which promotes fair testing, integrity and science in healthcare, said research questions could include—

feasibility testing on the acceptability and uptake of a trial;

whether the choice of diagnosis and classification system—between gender dysphoria requiring clinically significant distress and gender incongruence not requiring distress at all—would affect which children can be invited to take part;

whether there are differences with early-onset or adolescent-onset of gender distress;

the effect of starting the blockers-to-hormones pathway early or later in puberty;

differential impacts by sex, given that female puberty starts younger;

the effect of differences in dosage or duration of clinical assessment;

whether or when children can tell they have received blockers or a placebo;

the provable impacts in randomised cohorts of participants followed longer term.

Dr Bewley, emeritus professor of obstetrics and women’s health at King’s College London (KCL), was commenting on opposition to a puberty blocker trial emerging from a September 16 webinar organised by the UK and Irish Clinical Advisory Network on Sex & Gender (CAN-SG).

A news report in the British Medical Journal said the experts at the seminar believed the ethical and methodological problems were too serious for the trial proposed by England’s National Health Service (NHS) to proceed.

One of those experts, Dr Sinead Helyar, a nurse and researcher with experience in clinical trials, said the evidence base for puberty blocker use with gender-distressed children was too weak for there to be the “presumption of benefit” necessary for an ethical trial.

And although there was a lack of high-quality data on the side effects of blockers, Dr Helyar said “the known risks include blood clots, gallstones, weight gain, dyslipidaemia, elevated liver enzymes, polycythaemia, hair loss, and in some cases infertility”.

The proposed NHS puberty blocker trial under the leadership of KCL’s Professor Emily Simonoff is yet to receive ethical and regulatory clearance.

UK Health Secretary Wes Streeting said last month that he hoped the trial would begin as soon as possible. It is not yet clear what precise research questions this trial would seek to answer.

“As you can imagine, in an area of medicine like this, it’s really important the trial is robust, safe and effective,” Mr Streeting told the Press Association.

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Video: The challenges of researching puberty blockers, a webinar hosted by the Clinical Advisory Network on Sex & Gender

Data priorities

While Professor Bewley said the very possibility of an ethical and useful trial should not be rejected at this stage, the first step should be to revive the proposed follow-up of former child patients at the London-based Tavistock Gender Identity Development Service (GIDS).

“It can’t be right to even consider doing a trial—or to offer puberty blockers—until we know more about what happened to the 9,000 children who went through GIDS services,” she told GCN.

“The information that exists but has not been unearthed may already reveal the benefits and harms of gender-affirmation of children.

“Their experiences may be excellent, uncertain or terrible, and it’s wrong to design clinical trial research without that. In fact, I don’t see how they can even be designing good research without that information.”

This Tavistock follow-up, known as the Data Linkage Study, was planned as part of the 2020-24 Cass review, but fell into abeyance after six of NHS England’s seven adult gender clinics refused access to their patient records.

The retrospective study of the estimated 9,000 patients aged 18 or younger when referred to GIDS between 2009 and 2020 was to track outcomes such as surgical and medical interventions, detransition, mental health diagnoses and treatment, and co-occurring diagnoses of autism spectrum disorder. The study had ethical approval.

In her report, Dr Cass pointed out it would take 10-15 years for a prospective study to gather such follow-up data. Lack of long-term data is a troubling feature of paediatric medical transition.

Professor Bewley said the decision of the adult gender clinics not to co-operate with the Data Linkage Study was “unacceptable”.

“It might suggest the adult clinicians are not bothered about the outcomes for children, or that they are actually anxious about what might be revealed and the impact it might have on adult services and the trans community,” she said.

“If they were confident in the results, they’d surely be happy to collect better follow-up data.”

On the proposed puberty blocker trial, the BMJ’s September 29 news report quoted Dr Helyar as saying—

“Prescription of puberty blockers in the context of a trial would, in effect, introduce known harms and risk of systemic physical harm to a physically healthy child.

“There are strong grounds to believe puberty blockers will, in effect, impact on the child’s neuro- and physical development.

“To commence a trial with these known and potential harms and outcomes goes against clinical trial regulatory and ethical practice, which seeks to protect from harm.”

Another participant at the CAN-SG webinar, Dr Hannah Ryan, a registrar in clinical pharmacology and general medicine who has authored Cochrane evidence reviews, said—

“For a good trial, you need to have a good research question, and really the design of your trial flows from your research question.

“You also need a clear and coherent hypothesis about a condition and an intervention, and how that intervention helps that condition.

“But we don’t really know with any clarity what this condition is, if it indeed is one coherent condition; we don’t really have a clear hypothesis as to how the intervention works and over what time period; and we don’t know how to measure any kind of benefit.”

Dr Ryan said she believed the results of the trial would probably be skewed by strong placebo effects in the puberty blocker group of participants and nocebo (negative) effects in the control group denied the sought-after puberty suppression.

Professor Bewley said placebo and nocebo effects existed for all interventions, “but in this case we haven’t even tested for them and measured their sizes and duration of effect”.

She said that, depending on the choice of research questions, the design might offer an open choice of puberty blocker drugs, just one group given the drugs, or a double-blind placebo randomised controlled trial. (Blockers may be given as an implant or by injection, which can be mimicked by placebo injection.)

In a double-blind trial, she said that children would not know whether they were allocated to the treatment or placebo group, and “even if they work it out later, this advances knowledge about the impacts of the drugs separate from the effects of expectation and just growing a bit older”.

Professor Bewley said the magnitude of the likely risks and benefits was unclear amid polarised disagreement between critics of puberty blockers and their advocates.

“We might be able to get some agreement if everyone sat in a room together and compared evidence,” she said.

“The main problem seems to be a collective refusal to accept that there is uncertainty—or even to discuss and pin down the likely range of sizes of benefits and harms.

“As with other medical or life-changing situations, accurate information derived from robust research is the power that child and adolescent patients, their parents, doctors and policymakers need to weigh up options and trade-offs.”

Dr Cass remains in favour of a trial and last month she told the BMJ—

“There is insufficient evidence in either direction on the efficacy and outcomes of use of puberty blockers—hence the need to build the evidence base.

“NHS England acted on that recommendation and in partnership with NIHR [the National Institute for Health and Care Research] consulted as advised and determined that a trial should be developed within a wider research programme.

“Clearly, the trial will not go ahead unless it achieves the normal approvals from a research ethics committee.”

The BMJ reported that a decision on the proposed trial was expected from the Medicines and Healthcare Products Regulatory Agency and the Research Ethics Committee by the end of September. It appears that delays in the process continue. The proposal was submitted for ethics approval on August 21.

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