Cass Review – implications for Scotland: findings report

Annex C: Prescribing Regulations, Policy and Guidance

Regulation of medicines

The regulation for the licensing of medicines is reserved to the UK Government. The regulations involved are the Human Medicine Regulations 2012. Parts 3-5 cover the regulations relating to licensing. They outline the approach to the authorisation (licensing) of products; for the manufacture, import, distribution, sale and supply of those products; for their labelling and advertising; and for pharmacovigilance (the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problems associated with pharmaceutical products).

The Medicines and Healthcare products Regulatory Agency (MHRA) is the UK regulator for medicines and medical devices.

Before a medicine can be marketed, a pharmaceutical company must be able to demonstrate its safety, quality and efficacy. This is done through a series of rigorous clinical trials, consisting of four phases.

Pharmaceutical Clinical trials for drugs to achieve licencing requirements

Each phase of a clinical trial varies in size, character and focus:

Phase 1 primarily determines how a medicine works in humans and helps to predict the dosage range for the medicine, and involves healthy volunteers;

Phase 2 tests efficacy as well as safety among a small group of patients (100-300) with the condition for which the medicine has been developed;

Phase 3 involves a much larger group (1000-5000) of these patients which will help determine if the medicine can be considered both safe and effective; and

Phase 4 trials are conducted after a medicine has been granted a licence and involves real world evidence to develop new treatment uses for the medicine, compare with other treatments for the condition and determine the clinical effectiveness of the medicine in a much wider variety of patient types in conditions of “real life”. Safety is a major part of phase 4 trials, which often involve several thousand patients so that more rare side effects, if any, may be detected.

Applications to the MHRA for a marketing authorisation must include data demonstrating the quality, safety and efficacy of the medicine. After detailed assessment and providing the data is satisfactory, a marketing authorisation (sometimes called a licence) may be granted.

A marketing authorisation is granted to the manufacturer to market the medicine for a specific indication and not to the medicine itself.

All licensed medicines are required to have a Summary of Product Characteristics (SPC) and a Patient Information Leaflet (PIL). These contain information on what a medicine is used for, how it should be used and what risks may be associated with the medicine. The SPC is available to prescribers and the PIL is specifically written for patients.

The MHRA tries to ensure that all known side effects of licensed medicines are documented so that patients and clinicians are informed about them. However, it is not possible to predict which individuals may be at risk or when side effects may occur.

Pharmacovigilance – managing the risks and benefits of medicines

Despite the extensive research in clinical trials for a specific medicine, some adverse drug reactions (ADRs) may not be seen until a very large number of people have received the medicine. Therefore, it is vital that the safety of all medicines is monitored throughout their marketed life - this is known as pharmacovigilance.

Pharmacovigilance involves monitoring the use of medicines in everyday practice to identify previously unrecognised adverse effects or changes in the patterns of adverse effects, assessing the risks and benefits of medicines to determine what action, if any, is necessary to improve their safe use, providing information to healthcare professionals and patients to optimise safe and effective use of medicines, and monitoring the impact of any action taken.

For a medicine to be considered safe, its expected benefits should be greater than any associated risks of harmful reactions. All medicines can cause reactions; however, most people take medicines without suffering any serious side effects. Healthcare professionals should be able to discuss such information with patients, parents and carers, be vigilant in the detection of suspected ADRs and prompt in reporting them via an MHRA process called the Yellow Card Scheme.

Information from many sources is used for pharmacovigilance. These include spontaneous adverse drug reaction (ADR) reporting schemes, for example, the Yellow Card Scheme; clinical and epidemiological studies; worldwide published medical literature; pharmaceutical companies; worldwide regulatory authorities; and morbidity and mortality databases.

Prescribing of medicines

The decision to prescribe a medicine for a person, and which medicine to prescribe, is entirely for the clinician in charge of their care, having considered the person’s clinical condition and any relevant clinical guidance.

As part of the medical responsibility of doctors their primary imperative under General Medical Council (GMC) regulation and accountability is to ‘first do no harm’; in other words a doctor is accountable for the care they provide, or fail to provide, to the person they treat and to the regulator and to their own employers through clinical governance pathways and not to any other party.

Clinicians should usually prescribe licensed medicines in accordance with the terms of their marketing authorisation. However, they may prescribe unlicensed medicines or medicines ‘off-label’ (outside the UK marketing authorisation) where, based on an assessment of the individual person, they conclude, for medical reasons, that it is necessary to do so to meet the specific needs of that person.

Prescribing unlicensed medicines or medicines off-label may be necessary if, for example, there is no suitably licensed medicine to meet the person’s need (this is often the case with children where a medicine is licensed only for adult patients), a licensed medicine is not available because of a temporary shortage in supply, or the prescribing is part of research. Occasionally, clinicians may prescribe a medicine when the product licence does not cover the indication if they consider there would be significant clinical benefit to the patient and in line with local Health Board governance processes and protocols.

A clinician is professionally and clinically responsible for any medicine that they prescribe. The responsibility that falls on them, and on the dispenser of that medicine, when prescribing either a medicines off-label or an unlicensed product is greater than when prescribing a licensed medicine within its licence.

The GMC guidance on Good Practice when Prescribing and Managing Medicines and Devices advises that clinicians must, when prescribing in these circumstances: be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy; take responsibility for prescribing the medicine and for overseeing the person’s care, monitoring and any follow up treatment, or make sure that arrangements are in place for another suitable doctor to do so; and make a clear, accurate and legible record of the reasons for prescribing an unlicensed/off-label medicine.

Clinicians must give patients, or their parents or carers, sufficient information about the medicines they propose to prescribe, to allow them to make an informed decision. It is more difficult to capture pharmacovigilance data when medicines are prescribed off-label.

Off-label Prescribing of puberty-suppressing hormones Suppressors

There are no licensed medicines to supress the onset of puberty.

The National Institute for Health and Care Excellence (NICE) completed an evidence review on this subject in 2020 which included nine observational studies. The quality of evidence for the identified critical outcomes for decision making, gender dysphoria and mental health, was assessed at the time as very low certainty. There was no statistically significant difference in measurements compared with baseline. No evidence was found for quality of life. The quality of evidence reported for important outcomes was also assessed as very low certainty.

A re-run of the search was undertaken by NHS England (NHSE) in April 2023 to capture literature published after the NICE evidence review in 2020. Nine further studies were identified.

Subsequent trials in other contexts have shown that the use of puberty-suppressing hormones may be associated with significant harm in some, as well as benefit in others. The mounting evidence suggests that these medicines are certainly not harmless and are not as safe to use as had been initially thought.

In addition, this evidence base does not provide adequate data to address questions about the longer-term benefits or harms in relation to mental health, bone health, fertility or other yet unknown risks at a very critical stage in child growth and development.

NHSE concluded, in March 2024, that there was not enough evidence to support the safety or clinical effectiveness of puberty blocking medicines to make the treatment routinely available currently.

Off-label Prescribing of puberty-suppressing hormones – the Clinical Perspective

Based on the latest evidence, clinicians who are specialists in this field have developed a consensus that is that it is no longer safe to continue to prescribe these medicines without further evidence developed within the rigorous clinical trials that apply to all other medicines. It is their concern around the welfare and health of the children in their care that has brought clinicians to this decision.

In April 2024 NHS Greater Glasgow and Clyde (GGC) and NHS Lothian issued a joint statement highlighting that both Health Boards would pause any new prescribing of GnRH analogues via their Paediatric Endocrinology teams to children and young people under 18 years of age for the purpose of suppressing puberty. Existing children and young people who were receiving these medicines were not affected by the pause. An exercise was undertaken to ensure that all children and young people directly affected by this change were notified prior to the announcement.