Is RCT of puberty blockers possible?

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bladibla
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Is RCT of puberty blockers possible?

Post by bladibla » Wed Dec 16, 2020 2:41 am

Hi

I would like to know if it is impossible to design an RCT that tests the efficacy of puberty blockers in kids with symptoms of gender dysphoria.

I have seen (after recent High Court judgement) that lots of people are saying that it is impossible and unethical to test this drug treatment with an RCT.

The main criticisms I saw are that 1) it is impossible to blind this treatment as kids would be aware that they are entering puberty if they are not in the treatment group. 2) It is unethical to not provide a treatment to kids that believe they need the drug.

With regards to objection 1, I can see that blinding would be impossible, but not all RCTs are blinded. WRT objection 2, surely this is the case in all RCTs, for example at least one person in the COVID vaccine trial died. This didn't meant that the RCT was invalid as the data gained helped a lot people. Kids with gender dysphoria don't die of any kind of pathological cause, however they may be at a heightened risk of suicidal ideation, although the Tavistock says that suicide in kids with gender dysphoria is a rare occurrence.

I'd be interested in any thoughts about whether it is possible/ethical to scientifically study this type of treatment. The treatment only recently became available in the UK. Presumably before that there weren't a rash of suicidal kids with gender dysphoria, so why not subject it to scientific analysis?

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Martin_B
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Re: Is RCT of puberty blockers possible?

Post by Martin_B » Wed Dec 16, 2020 3:21 am

It's not my area, but as you say, people with gender dysphoria may (I think do) have a heightened risk of suicidal thoughts, and also mental health issues, self-harm, etc.

Also, the term "rare occurrence" is subjective (rare compared to the common cold or rare compared to being being trampled to death by a unicorn?) but as suicidal thoughts are a known problem for people with gender dysphoria, they shouldn't be discounted or even taken lightly.

Any suicide is a tragedy and a trial which may increase the risk of anybody committing suicide would fail any ethical panel (or at least any ethical panel which I would be allowed to sit on.)
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Fishnut
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Re: Is RCT of puberty blockers possible?

Post by Fishnut » Wed Dec 16, 2020 10:35 am

bladibla wrote:
Wed Dec 16, 2020 2:41 am
Hi

I would like to know if it is impossible to design an RCT that tests the efficacy of puberty blockers in kids with symptoms of gender dysphoria.

I have seen (after recent High Court judgement) that lots of people are saying that it is impossible and unethical to test this drug treatment with an RCT.

The main criticisms I saw are that 1) it is impossible to blind this treatment as kids would be aware that they are entering puberty if they are not in the treatment group. 2) It is unethical to not provide a treatment to kids that believe they need the drug.

With regards to objection 1, I can see that blinding would be impossible, but not all RCTs are blinded. WRT objection 2, surely this is the case in all RCTs, for example at least one person in the COVID vaccine trial died. This didn't meant that the RCT was invalid as the data gained helped a lot people. Kids with gender dysphoria don't die of any kind of pathological cause, however they may be at a heightened risk of suicidal ideation, although the Tavistock says that suicide in kids with gender dysphoria is a rare occurrence.

I'd be interested in any thoughts about whether it is possible/ethical to scientifically study this type of treatment. The treatment only recently became available in the UK. Presumably before that there weren't a rash of suicidal kids with gender dysphoria, so why not subject it to scientific analysis?
Objection 2 seems to misunderstand how trials work. These days when testing new interventions you don't normally have your placebo arm as "do nothing". Yes, there are circumstances where you do - the covid vaccine is a great example of that - but that is because we're trying to create something entirely new, not improve on existing treatments. When you're developing, say, cancer treatments, you don't have your new drug in one arm of the trial and a placebo on the other, that would be massively unethical. You use the drug that is currently being used to treat that cancer because you want to know if your new drug is better than it. Puberty blockers are being used as a treatment for gender dysphoria. So the RCT would be between the normal treatment now (presumably specialist counselling) and puberty blockers to determine which gives better outcomes for patients with gender dysphoria.

While not an RCT, an observational study published at the beginning of this year found that puberty blockers are associated with better mental health outcomes. I've seen plenty of other data showing similar results but I don't have the time to find them all right now.

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lpm
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Re: Is RCT of puberty blockers possible?

Post by lpm » Wed Dec 16, 2020 11:45 am

Do a trial on animals. Should be able to get a lot of info on physical impacts, e.g. bone density, brain development, plus get some indications of emotional impacts, e.g. aggression levels.
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dyqik
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Re: Is RCT of puberty blockers possible?

Post by dyqik » Wed Dec 16, 2020 12:08 pm

Isn't objection 1) the point of the trial?

Again taking the CoVID vaccine as an example; people in both the placebo arm and the intervention arm were fully aware if they got CoVID while in the trial. Testing was done regularly, and those who tested positive had to quarantine etc.

What's blinded is likelihood of getting CoVID and reporting of potential side effects. Neither arm knows if they have had the vaccine or not, and so takes the same precautions as the rest of the population. If they do get CoVID, neither arm knows if that's despite having had the vaccine, or because they are in the placebo group. And neither arm knows if the symptoms they are reporting are side effects from the real vaccine, coincidence, or psychosomatic effects from being told about the potential side effects.
Last edited by dyqik on Wed Dec 16, 2020 12:16 pm, edited 1 time in total.

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Re: Is RCT of puberty blockers possible?

Post by dyqik » Wed Dec 16, 2020 12:14 pm

Martin_B wrote:
Wed Dec 16, 2020 3:21 am
Any suicide is a tragedy and a trial which may increase the risk of anybody committing suicide would fail any ethical panel (or at least any ethical panel which I would be allowed to sit on.)
All trials carry that risk, as any drug may do that, or interact with other medication that is usually taken to treat conditions that raise the risk of suicide. You can also replace suicide with heart attack, stroke or any other likely fatal medical incident in this objection.

How trials get past this ethical objection is a) to gradually step up the size of each phase of the trials, from very small numbers in very carefully screened groups that are selected for low risk, to larger numbers in wider groups; and b) to provide significantly more monitoring and/or controlled environments than is the case for non-trial participants, so that the chances of untreated incidents is not significantly higher than in the general population.

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Fishnut
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Re: Is RCT of puberty blockers possible?

Post by Fishnut » Wed Dec 16, 2020 3:30 pm

I had a long post that you'll be pleased to hear I've deleted. Instead I'd just urge people to read this excellent editorial from the International Journal of Transgender Health published earlier this year. It methodically goes through all the objections to using puberty blockers for gender dysphoria and demolishes them. There is a detailed discussion on RCTs that is far too long to quote in full but answers all the questions raised by bladibla and more.

For those averse to clicking on links the key points are:
patients who approach clinics for help because of distress caused by the first signs of puberty will be unlikely to accept to be a part of a RCT. Medications are needed within a relatively short period of time, at pain of treatment being less effective or ineffective. Recruitment would thus be hard if not impossible.
a RCT of puberty delay could not maintain blinding. Because GnRHa are effective in delaying puberty it would soon become evident to participants, researchers and outcome assessors who was in the active treatment arm and who was not. This breakdown of blinding would mean that there would be potential bias in the outcome assessments, both in relation to biological and psychological outcomes. It would also mean that participants allocated to the non-treatment arm of the study would be likely to either withdraw from the study at a much higher rate than in the treatment arm introducing potential bias, and/or be more likely not to adhere to the trial but seek puberty delaying treatment outside of the trial thereby adding a confounder. It is also not clear that a RCT would provide answers to the questions that are still outstanding in relation to puberty delay with GnRHa in the relevant group of patients.
The questions that still need answering are about the medium- and long-term effects of puberty delay. We can divide these in two categories, that is questions about 1) negative side-effects, e.g., in relation to bone density or other long term biological risks, and; 2) effects on gender dysphoria and gender transition... it is important to note two things. First, that both types of questions require long-term follow up that extends well into adulthood and much longer than in a typical RCT. Second, that in those patients who eventually continue transition with cross sex hormones4 and in some cases surgery or other gender affirming medical interventions, the effects of puberty delay will become entangled with the effects of later treatments and will become difficult to assess because of confounding. The absence of RCT evidence, which could in reality not be obtained, does not make the prescription of GnRHa for puberty delay in adolescents with gender dysphoria experimental.
A couple of other points the piece makes are worth noting.

Firstly, it points out that puberty blockers have been the standard recommendation for at least two decades, both in the UK and internationally. The Royal College of Psychiatrists was recommending the use of puberty blockers all the way back in 1998 for
...delaying puberty in young adolescents who experienced strong and persistent “cross-sex identification” and distress around the physical body that intensifies with the onset of puberty" [quote from the paper, rather than the RCP].
Another common objection is that puberty blockers for treatment of gender dysphoria is 'off-label' and therefore accused of being experimental or potentially even dangerous. The editorial makes this point,
Off label prescription is both common and necessary in pediatrics, because many drugs have only been tested on adults as part of the development process leading to licensing and are therefore only licensed for use in an adult population (Balan et al., 2018; Cuzzolin et al., 2003; Magalhães et al., 2015). Off-label prescribing in pediatrics is endorsed in general by the Royal College of Pediatrics and Child Health (RCPCH), and even for a sensitive area such as pediatric psychiatry by the British Association for Psychopharmacology (Sharma et al., 2016)

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