NICE Evidence Review for Use of Puberty Blockers for GD - Now Released

[IDontOnlyLikeJazzFunk]

now released. NC. The full link is below, this is the summary. It's not looking good.

Discussion
A key limitation to identifying the effectiveness and safety of GnRH analogues for children and adolescents with gender dysphoria is the lack of reliable comparative studies. The lack of clear, expected outcomes from treatment with a GnRH analogue (the purpose of which is to suppress secondary sexual characteristics which may cause distress from unwanted pubertal changes) also makes interpreting the evidence difficult.

The studies included in this evidence review are all small, uncontrolled observational studies, which are subject to bias and confounding, and all the results are of very low certainty using modified GRADE. They all reported physical and mental health comorbidities and concomitant treatments very poorly. All the studies are from a limited number of, mainly European, care facilities. They are described as either tertiary referral or expert services but the low number of services providing such care and publishing evidence may bias the results towards the outcomes in these services only and limit extrapolation.

Many of the studies did not report statistical significance or confidence intervals. Changes in outcome scores for clinical effectiveness and bone density were assessed with regards to statistical significance. However, there is relatively little interpretation of whether the changes in outcomes are clinically meaningful.
In the observational, retrospective studies providing evidence on bone density, participants acted as their own controls and change in bone density was determined between starting GnRH analogues and follow up. Observational studies such as these can only show an association with GnRH analogues and bone density; they cannot show that GnRH analogues caused any differences in bone density seen. Because there was no comparator group and participants acted as their own controls, it is not known whether the findings are associated with GnRH analogues or due to changes over time.

Conclusion
The results of the studies that reported impact on the critical outcomes of gender dysphoria and mental health (depression, anger and anxiety), and the important outcomes of body image and psychosocial impact (global and psychosocial functioning), in children and adolescents with gender dysphoria are of very low certainty using modified GRADE. They suggest little change with GnRH analogues from baseline to follow-up.

Studies that found differences in outcomes could represent changes that are either of questionable clinical value, or the studies themselves are not reliable and changes could be due to confounding, bias or chance. It is plausible, however, that a lack of difference in scores from baseline to follow-up is the effect of GnRH analogues in children and adolescents with gender dysphoria, in whom the development of secondary sexual characteristics might be expected to be associated with an increased impact on gender dysphoria, depression, anxiety, anger and distress over time without treatment. The study by de Vries et al. 2011 reported statistically significant reductions in the Child Behaviour Checklist (CBCL) and Youth Self-Report (YSR) scores from baseline to follow up, which include measures of distress. As the aim of GnRH analogues is to reduce distress caused by the development of secondary sexual characteristics, this may be an important finding.

However, as the studies all lack appropriate controls who were not receiving GnRH analogues, any positive changes could be a regression to mean.

The results of the studies that reported bone density outcomes suggest that GnRH analogues may reduce the expected increase in bone density (which is expected during puberty). However, as the studies themselves are not reliable, the results could be due to confounding, bias or chance. While controlled trials may not be possible, comparative studies are needed to understand this association and whether the effects of GnRH analogues on bone density are seen after they are stopped. All the studies that reported safety outcomes provided very low certainty evidence.

No cost-effectiveness evidence was found to determine whether or not GnRH analogues are cost-effective for children and adolescents with gender dysphoria.

The results of the studies that reported outcomes for subgroups of children and adolescents with gender dysphoria, suggest there may be differences between sex assigned at birth males (transfemales) and sex assigned at birth females (transmales).

arms.nice.org.uk/resources/hub/1070905/attachment

The words unreliable, questionable, poor reporting. So I wonder why this ever took off, any ideas?

The report is too long for me to go through in full, especially as I don't have any expertise, so I looked at conclusions and have skipped some area. Thanks op for your good analysis

So the studies are not good enough to draw conclusions?

We couldn't do a Cochrane Review because the quality of data is so poor?

So, this is amateur science? Making life long patients of young people?

So....public enquiry into why we have this remarkable spike in prevalence of young people with gender related distress?

It would be quite shocking if any clinician carried on prescribing them with that analysis of the available evidence.

There is a similarly damning report on the use of 'Gender Affirming' hormones - the conclusion is much the same - extremely poor quality studies that provide inadequate data on which to draw conclusions. What information there is certainly doesn't demonstrate positive outcomes, in fact in most instance it demonstrates a very negative outcome, for instance cholesterol, blood pressure and BMI increased in ftm patients and bone density didn't increase as it should for their age.

Total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels significantly worsened in transmales, but mean levels were within the UK reference range at the end of treatment.
• Diastolic blood pressure was statistically significantly increased in transfemales and transmales. Systolic blood pressure was also statistically significantly increased in transmales, but not in transfemales. The absolute increases in blood pressure were small.
• Body mass index was statistically significantly increased in transfemales and transmales, although most participants were within the healthy weight range (18.5 to 24.9 kg/m).

arms.nice.org.uk/resources/hub/1070871/attachment

I have just posted this link onto the Good Law Project thread. I wonder when sense will prevail and what is happening to our teen children starts to be looked at without all the emotion and with a real sense of what might be best. It's time these big Pharma companies took note

[quote IDontOnlyLikeJazzFunk]now released. NC. The full link is below, this is the summary. It's not looking good.

Discussion
A key limitation to identifying the effectiveness and safety of GnRH analogues for children and adolescents with gender dysphoria is the lack of reliable comparative studies. The lack of clear, expected outcomes from treatment with a GnRH analogue (the purpose of which is to suppress secondary sexual characteristics which may cause distress from unwanted pubertal changes) also makes interpreting the evidence difficult.

The studies included in this evidence review are all small, uncontrolled observational studies, which are subject to bias and confounding, and all the results are of very low certainty using modified GRADE. They all reported physical and mental health comorbidities and concomitant treatments very poorly. All the studies are from a limited number of, mainly European, care facilities. They are described as either tertiary referral or expert services but the low number of services providing such care and publishing evidence may bias the results towards the outcomes in these services only and limit extrapolation.

Many of the studies did not report statistical significance or confidence intervals. Changes in outcome scores for clinical effectiveness and bone density were assessed with regards to statistical significance. However, there is relatively little interpretation of whether the changes in outcomes are clinically meaningful.
In the observational, retrospective studies providing evidence on bone density, participants acted as their own controls and change in bone density was determined between starting GnRH analogues and follow up. Observational studies such as these can only show an association with GnRH analogues and bone density; they cannot show that GnRH analogues caused any differences in bone density seen. Because there was no comparator group and participants acted as their own controls, it is not known whether the findings are associated with GnRH analogues or due to changes over time.

Conclusion
The results of the studies that reported impact on the critical outcomes of gender dysphoria and mental health (depression, anger and anxiety), and the important outcomes of body image and psychosocial impact (global and psychosocial functioning), in children and adolescents with gender dysphoria are of very low certainty using modified GRADE. They suggest little change with GnRH analogues from baseline to follow-up.

Studies that found differences in outcomes could represent changes that are either of questionable clinical value, or the studies themselves are not reliable and changes could be due to confounding, bias or chance. It is plausible, however, that a lack of difference in scores from baseline to follow-up is the effect of GnRH analogues in children and adolescents with gender dysphoria, in whom the development of secondary sexual characteristics might be expected to be associated with an increased impact on gender dysphoria, depression, anxiety, anger and distress over time without treatment. The study by de Vries et al. 2011 reported statistically significant reductions in the Child Behaviour Checklist (CBCL) and Youth Self-Report (YSR) scores from baseline to follow up, which include measures of distress. As the aim of GnRH analogues is to reduce distress caused by the development of secondary sexual characteristics, this may be an important finding.

However, as the studies all lack appropriate controls who were not receiving GnRH analogues, any positive changes could be a regression to mean.

The results of the studies that reported bone density outcomes suggest that GnRH analogues may reduce the expected increase in bone density (which is expected during puberty). However, as the studies themselves are not reliable, the results could be due to confounding, bias or chance. While controlled trials may not be possible, comparative studies are needed to understand this association and whether the effects of GnRH analogues on bone density are seen after they are stopped. All the studies that reported safety outcomes provided very low certainty evidence.

No cost-effectiveness evidence was found to determine whether or not GnRH analogues are cost-effective for children and adolescents with gender dysphoria.

The results of the studies that reported outcomes for subgroups of children and adolescents with gender dysphoria, suggest there may be differences between sex assigned at birth males (transfemales) and sex assigned at birth females (transmales).

arms.nice.org.uk/resources/hub/1070905/attachment[/quote]
Is it awful that one of my first thoughts is fear for the authors of this NICE review; that they'll get attacked for doing their jobs?

In February 2019 Professor Carl Heneghan was interviewed on BBC Panorama about the conclusions of his study of the evidence base informing the prescription of hormone therapies to children identified as transgender. The conclusion of his analysis was that 'informed consent is not possible'

BMJ EBM Spotlight paper:
'Gender-affirming hormone in children and adolescents – Evidence review'
Posted on 25th February 2019

(extract)
"Gender dysphoria occurs when a person experiences discomfort or distress because of a mismatch between their biological sex and gender identity. Gender dysphoria can arise in childhood and adolescent which raises many questions about how best to handle the condition. This post sets out the current evidence for gender-affirming hormones in adolescents and children to aid decision making. (continues)

"Conclusions

There are significant problems with how the evidence for Gender-affirming cross-sex hormone has been collected and analysed that prevents definitive conclusions to be drawn. Similar to puberty blockers, the evidence is limited by small sample sizes; retrospective methods, loss of considerable numbers of patients in follow-up. The majority of studies also lack a control group (only two studies used controls). Interventions have heterogeneous treatment regimes complicating comparisons between studies. Also adherence to the interventions are either not reported or at best inconsistent. Subjective outcomes, which are highly prevalent in the studies, are also prone to bias due to lack of blinding, and many effects can be explained by regression to the mean.

The development of these interventions should, therefore, occur in the context of research. Treatments for under 18 gender dysphoric children and adolescents remain largely experimental. There are a large number of unanswered questions that include the age at start, reversibility; adverse events, long term effects on mental health, quality of life, bone mineral density, osteoporosis in later life and cognition. We wonder whether off label use is appropriate and justified for drugs such as spironolactone which can cause substantial harms, including death. We are also ignorant of the long-term safety profiles of the different GAH regimens. The current evidence base does not support informed decision making and safe practice."
blogs.bmj.com/bmjebmspotlight/2019/02/25/gender-affirming-hormone-in-children-and-adolescents-evidence-review/

thread: www.mumsnet.com/Talk/womens_rights/3518188-BMJ-Prof-Carl-Heneghan-Evidence-Based-Medicine-Oxford-Panorama-Trans-Kids-Gender-affirming-hormone-in-children-and-adolescents-Evidence-review-concludes-There-are-significant-problems

BBC 'Trans Kids: Why Medicine Matters'
More young people than ever are exploring their gender identity. Last year, two and a half thousand under-eighteens were referred to NHS England's gender identity clinics for support. Some are hoping to get access to potentially irreversible treatments as soon as they can. Doctors are divided about the best way to help.

Dr Faye Kirkland investigates how much we understand about the care being offered to transgender children."
www.bbc.co.uk/programmes/m0002tw1

thread
www.mumsnet.com/Talk/womens_rights/3517453-Panorama-25-Feb-20-30hrs-Trans-Kids-Why-Medicine-Matters-Thread-title-edited-by-MNHQ

BBC News coverage:
www.bbc.co.uk/news/health-47456938

"Young transgender people are being let down by the "terrible" quality of evidence underpinning their treatment and care, a leading researcher warns.

Prof Carl Heneghan, from Oxford University, said there was an "urgent" need for a new regulator in the field.

He said much more "rigorous" and "robust" research was needed into the effects of drugs given to young transgender people.

But the Department of Health says it has no plans to create a new regulator.

Prof Heneghan, director of the Centre of Evidence Based Medicine at Oxford University, along with Prof Tom Jefferson, who is also a clinical epidemiologist carried out an independent analysis of the most recent international research on medical interventions for the BBC's Panorama programme.

Prof Heneghan said "One of the key issues is to be able to say to parents and children in making a decision... 'Here's an informed decision based on the evidence.'

"The quality of evidence in this area is terrible."

Thank you OP

It would be quite shocking if any clinician carried on prescribing them with that analysis of the available evidence.

Quite

I am looking forward to reading what Drs McCartney and Professor Bewley have to say about this.

@highame

I have just posted this link onto the Good Law Project thread. I wonder when sense will prevail and what is happening to our teen children starts to be looked at without all the emotion and with a real sense of what might be best. It's time these big Pharma companies took note

The report is not in the least bit positive and I find the result in the Good Law Project case in light of this report very, very worrying.

I can't envisage how the two situations will work together.

The problem is that "the internet" and media has decided they're "a good thing" and fully normalised pbs.

People find ways to get drugs illegally.

Will this make any difference? I'd like to hope it will, but it just seems that every time damning evidence comes to light, everyone who should sit up and listen just doubles the fuck down.

Three high court judges called the 'treatment' experimental. Instead of a collective ''oh fuck, what have we been doing?!'', we had cries of ''wah, you're all just meanies,'' ''this is discrimination'', ''the judges are 'cis', 'transphobic', and therefore whatever they say is irrelevant''.

We had an organisation trying to find loopholes to keep giving PB's to kids when there's no evidence of benefit and they know they can't consent to it.

And of course, the service doing this to children decided to appeal a safeguarding decision. They were told this is experimental, that children can't possibly understand how this decision will affect them later on, y'know 'cause they're just CHILDREN, and instead of having a good look at themselves, they chose to APPEAL

What's it going to take to open their eyes, seriously?

I fear it's going to take deaths, Winterfire

Until we have heaps of young people dying from coronary heart disease that they should not have had before they were at least 60 ( if they'd had the protective qualities of oestrogen), then no one will listen.

And, even then, trans men are female, so, you know, way down the pecking order.

I am deeply cynical about the pharmaceuticals and who they are funding

I am so glad this has been through Nice. I work in another field of medicine and I know just how high the standards are for efficacy and value for money to get any treatment approved.

It has been staggering to me that anyone has been allowed to prescribe children experimental drugs, with known, severe and permanent side effects outside of a well defined randomised clinical trial.

If this went through the usual approval routes as a clinical trial, I am not sure how it would get past an ethics committee.

It is yet another example of how usual practices, that are there to safeguard people, have been trampled over in the name of transgender rights. It is so so damaging.

Does this happen with other drugs where there is a poor outcome of evidence to support their efficacy?
I fear it's going to take deaths, - or an awful lot of people sueing the pharmaceutical companies and the medics when the results dont turn out as hoped or worse, have serious adverse effects.

The pharmaceutical companies definitely have an unhealthy interest in all this. I think they just see these kids as lifelong money farms 🤑🤑🤑

Could Keira sue based on this lack of evidence?

Is it awful that one of my first thoughts is fear for the authors of this NICE review; that they'll get attacked for doing their jobs?

Mumofgirls - it is awful in the fact that at the current time it is a reasonable concern for you to have.

They did do their best - they adopted all the 'correct' language, they carefully used 'assigned sex at birth' etc but I guess you can't make a silk purse out of a sows ear.

I do detect a slight note of exasperation in some of the conclusions.

I think there are big questions around why the UK’s supposed centres of excellence like the Tavistock have been unable to conduct rigorous research. Why is that?

@flyingfoxkins

Does this happen with other drugs where there is a poor outcome of evidence to support their efficacy? I fear it's going to take deaths, - or an awful lot of people sueing the pharmaceutical companies and the medics when the results dont turn out as hoped or worse, have serious adverse effects.

Nice can look at new treatments or those already in use in the NHS. In my field a new drug would not be allowed to be prescribed outside a clinical trial until it had approval from Nice. I don't know how puberty blockers were approved for proscribing. Normally commissioners would want the nod from Nice before paying for them.

The Nice review has a pretty set structure and very clear definitions for what constitutes strong evidence (large scale meta analysis of several large high quality studies) versus weak evidence (pretty much everything highlighted above). They apply the same criteria across all their reviews. It is a tried and tested methodology.

Whilst there will always be room for interpretation, especially when it comes to value for money, it would be nigh on impossible to subvert the entire process. It simply is not possible to look at a poorly designed, small study in a badly defined patient group and conclude anything other than it has no real value in clinical decision making.

This is more sunlight, cold, hard, sunlight that leaves no wiggle room. One this evidence, where the the potential for harm remains and the benefits are so uncertain, they should not be prescribed. No other drugs would be.

Patient groups can be very powerful in insisting on experimental/off-label use of drugs. Sometimes, more power to them but also sometimes when you look at who's funding the patient groups ( Big Pharma ) they look a lot less grass-roots.

In this case, when you kick up a massive stink any time anyone suggests research into your condition (gender dysphoria) then don't be surprised when there's no good quality evidence to back up your assertions.

Why are these studies so poorly conducted?

Blimey.

Does this happen with other drugs where there is a poor outcome of evidence to support their efficacy?

The simple answer is no.