Doubts over evidence for using drugs on the young by Prof Carl Heneghan in The Times 08.04.19

The original article is here.

You would think, when it comes to children, the testing and evaluation of medicines would be robust — ensuring the utmost safety. Well, you’d be wrong. The mess we have gotten ourselves into with the treatment of gender dysphoria in children and adolescents highlights all that is concerning with the present use and evaluation of powerful medicines in this age group.

Most evidence for drug use is based on information in adults; evidence in children is scarce, and the majority of drugs in use are frequently supported by low-quality evidence about their use beyond the usual age for puberty, or in many cases no evidence at all.

Drugs in children, therefore, often require off-label use, meaning their use is outside of what the drug was approved for and detailed in the Summary of Product Characteristics, including using a drug to avoid, not just delay, puberty and following it with cross-sex hormone treatment.

As an example, in transgender females, oestrogen therapy alone is often insufficient to produce the desired feminising effects. Spironolactone, commonly used in the treatment of heart failure, is used off label owing to its oestrogenic effects. It blocks testosterone, and the oestrogen-like effects cause menstrual disturbances, breast enlargement and breast tenderness in females, and gynaecomastia (swelling of the breast tissue in boys or men) and impotence in males, often leading to its discontinuation.

The GIDS does not use spironolactone, but it has been used to treat adolescents with gender dysphoria in the US. All clinics use different drugs and different doses and that in itself is concerning.

Children are not small adults; their changing body composition requires careful dosing; their physiology creates unique challenges that increase risks, and off-label use may lead to serious and life-threatening consequences. In my view, given the paucity of evidence, the off-label use of drugs that occurs in gender dysphoria largely means an unregulated live experiment on children.

Treatments for gender dysphoria in children and adolescents include suppressing puberty and the use of gender-affirming hormones before decisions about gender-affirming surgery. The collection and evaluation of evidence, particularly when it comes to ensuring their safety, should therefore be a priority. It is not.

The available evidence comes from small studies, is retrospective rather than prospective, and has lost considerable numbers of children in the follow-up. Studies also lack control groups (making it difficult to tell anything about the intended effects), there are no randomised trials and the presence of subjective outcomes along with the lack of blinding mean all together the current evidence does not support informed decision-making. The dearth of evidence in gender dysphoria doesn’t surprise me. What does surprise me is that we have devolved responsibility for making life-changing decisions to one clinic, to a few doctors, with no national guidelines in place. And that we have accepted that individuals facing distressing life-changing situations are ill informed.

The Department of Health told the BBC’s Panorama programme that it was “committed to ensuring thorough accountability and oversight. . . and will review any arrangements when appropriate”. Its response is pitiful — “review any arrangements when appropriate”, what does that mean?

The BBC investigation I participated in highlights the considerable uncertainties that require addressing to inform safe care for gender dysphoria. If in doubt, ask for the evidence.

Carl Heneghan is a professor of evidence-based medicine at the University of Oxford

GIDS response
GIDS has explained it uses licensed precocious puberty drugs whose long-term effects are known. It said “There is growing evidence internationally on the outcomes of pubertal suppression and sex hormones in adolescents with gender dysphoria. Thus far there is little reported evidence of harm” It added that it “responds to emerging evidence in an appropriate and considered way.” and is carrying out its own research and uses “the preliminary data from this work to inform clinical care”. It added that the service is safe and an independent review “did not identify any immediate issues in relation to patient safety or failings in the overall approach taken by the service.