Unlicensed medicine prescribing in general practice

Case scenario

Howard is a 7-year-old with autism. He has seen your colleagues previously with his mother about sleep difficulties. A letter from his paediatrician suggests melatonin tablets, 4.5 mg once a day. On checking the British National Formulary, preparations currently available for a 28-day prescription (January 2022 tariff price in brackets) include Slenyto® 5-mg modified-release tablets (£103.00) (a licensed dose and preparation) or Circadin® 2-mg modified-release tablets (£15.39). Liquid preparation in the form of a 150 ml of melatonin 1-mg/ml oral solution (£130.00) is also available. On discussion with the pharmacist, you are informed Circadin® can be crushed, but such use would be unlicensed. Howard’s mother, after further discussion, decides to crush the Circadin® prescription. It is agreed that if there are no adverse therapeutic effects or associated problems affecting his swallowing of the crushed preparation, then this would be reviewed and could be continued. This discussion is documented in the patient's notes. Two weeks later you receive a letter from his mother reporting a so-far successful use of the medication and it is continued as a repeat prescription with a note to adjust the dose according to changes in weight.

History of licensing

Thalidomide was given to thousands of pregnant women between 1956 and 1961 as an anti-emetic, causing phocomelia in large numbers of newborn babies. This led to the creation of the Expert Committee on Drug Toxicity by the Association of the British Pharmaceutical Industry in 1962. The UK Government Standing Medical Advisory Committee established the Committee on the Safety of Drugs in 1963, to consider toxicity, clinical trials, therapeutic efficacy and adverse drug reactions (Bourns, 2017). Following this, the Medicines Act 1968 created the legal framework requiring all medicines to be reviewed and if appropriate, licensed with marketing authorisations in September 1971 (Bourns, 2017).

How do medications become licensed?

In the UK, before any medication can be prescribed it must be approved for use by the Medicines and Healthcare products Regulatory Agency (MHRA), a UK Government agency of the Department of Health, established in 2003 with the merger of the Medicines Control Agency and the Medical Devices Agency . The role of the MHRA is to ensure the safety and effectiveness of medicines and medical devices. The MHRA gives each medication a marketing authorization, which states the conditions under which it can be prescribed as well as its terms of use. This was previously known as a product licence, hence, the terminology licensed and unlicensed medicines.

The MHRA assesses each medication and reviews the research and clinical trial data available. It looks at all aspects of the medication, including assessing the safety of the medicines, logistical aspects such as the supply of the medication, and any legislation or regulations required. If the MHRA concludes that a medication can be licensed, authority to market the medication is granted. The grant of a license indicates that the medication meets required quality standards and is safe for use within its licensing conditions (NHS Greater Glasgow and Clyde, 2013). The licence will include information on the indications for use and how the medication can be stored, prescribed, and dispensed. This is the summary of product characteristics.

What are unlicensed medicines?

The term ‘unlicensed medicine’ can refer to three different aspects of use as described by Sutherland and Waldek (2015). First, it can refer to off-label use of medications. This means that a medication is being used outside the terms of the licensed indications. For example, the use of a medication for a different illness, at a different dose, or in a different age group to the licensing agreement (Sutherland and Waldek, 2015). A common example of medication use outside of the licence agreement is use of medication in children when licensed only for use in adults. Difficulties in developing formulations appropriate for different ages and in carrying out clinical trials for all age groups may explain this situation. The case scenario about melatonin prescriptions in paediatric patients is an example. Melatonin is licensed for treating sleep disorders in patients over 55 years in age, yet it is often used for insomnia in paediatric patients with learning disabilities and behaviour challenges. Such use is considered to be off-label use (British National Formulary, 2021). Crushing of medication often constitutes an off-label use, this is common in paediatric prescribing due to the very high cost of the preparatory oral solutions.

Second, medicines may be unlicensed and therefore have no licence for use or any marketing authorisation (Sutherland and Waldek, 2015). Medications may not have a licence because they are still undergoing testing in clinical trials or are waiting for a licence to be granted by the MHRA. The medicine may be licensed in another country and imported to the UK (Hull University Teaching Hospitals, 2020).

Finally, unlicensed medicines may be ‘specials medicines’. These are used when there is no available licensed medicine for a patient, so a medication is manufactured for the specific individual by the manufacturer. These medications are much rarer than off-label medications and are produced for the individual only (Sutherland and Waldek, 2015). Examples include special formulation of medication because of an intolerance or allergy to a particular constituent of the formulation or an inability to ingest solid oral dosage formulations (MHRA, 2014a).

The MHRA (2014a) states that each of the following conditions must be met when prescribing specials medicines:

The product is manufactured and assembled in accordance with the specification of a person who is a doctor, dentist, nurse independent prescriber, pharmacist, independent prescriber, or supplementary prescriber registered in the UK.

Guidance on prescribing unlicensed medicines

The 1968 Medicines Act allows prescription of unlicensed medicines without a licence if the prescriber accepts all responsibility for the prescription (MHRA, 2014b). As these medications do not have a marketing authority, the manufacturers are not liable for any adverse effects; rather the prescriber is responsible for this problem. Figure 1 shows a decision tree outlining the process of prescribing an unlicensed medicine, and the order in which different prescriptions should be considered.

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Figure 1.

A decision tree approach to prescribing unlicensed medicines.

The General Medical Council (GMC) also provides prescribing guidance for doctors, explaining how and when a doctor can prescribe these medications. Within their document ‘Good Practice in prescribing and managing medicines and devices’ (GMC, 2021), it states that the prescribing doctor should:

Be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy.

Risk of unlicensed medicines

Due to the limited detailed guidance available for the prescribing and dispensing of unlicensed medicines, there are risks associated with it. One guideline analysis (Donovan et al., 2018) revealed that prescribers often struggle with how to implement guidelines on unlicensed medicines. The study also described that instead of establishing evidence for the use of unlicensed medicines, it was using informal methods to measure benefit, such as whether the patient’s clinical condition seems to improve or whether the patient was more easily able to self-administer the medication (Donovan et al, 2018). Other concerns highlighted by the study included variation in terminology of what constitutes an ‘unlicensed medicine’, which is potentially misleading for both healthcare professionals and their patients. Some organisations place responsibility for the entire process of prescribing an unlicensed medicine on a single clinician, increasing the risk for patients, other guidelines recommended involvement of a multi-disciplinary team, a safer option that would be appropriate to adopt more widely (Donovan et al., 2018).

As described by Bourns (2017), the risks associated with prescribing unlicensed medicines can be split up into three different areas: clinical; product quality; and financial costs. There is a clinical risk because an unlicensed medicine has not been subject to clinical trials, meaning its use may carry additional risks, for example, if the medicine has a narrow therapeutic index, dose variation may be critical or risk-adverse drug reactions (Bourns, 2017).

An unlicensed product may not have the same product quality as one that is licensed; the licensing agreement ensures the medications to be of high and consistent quality, produced to a consistent formulation and standard. However, unlicensed medicines may be subjected to manufacturer change, meaning the product quality and consistency may also change (Bourns, 2017), further increasing risk due to product variation.

When a patient is discharged from hospital, they are discharged back to their GP. Often the expensive unlicensed medicines that are suggested or initiated in secondary care can carry a financial pressure and real risk to a Clinical Commissioning Group’s budget, deterring the GP from prescribing them (Bourns, 2017). If prescribing the medication, the GP takes all the clinical, professional, and legal responsibility of the drugs used, so if the unlicensed medicine is relatively sub-speciality and rare, and the GP does not have experience of it, the GP may refuse to prescribe (Bourns, 2017). As mentioned already, if this occurs, guidelines are needed to aid prescribing.

Adverse effects with use of unlicensed medicines

Having such rigid processes and guidelines for licensing of medicines means unlicensed medicines come with a higher risk. Studies have shown that there is an increased risk of adverse effects when using unlicensed medicines, particularly in paediatric patients (Bellis et al., 2014). Paediatric patients are more often prescribed unlicensed medicines than other patients in the NHS, because clinical trials in paediatric patients, necessary for licensing, pose additional challenges, including ethical ones. A large-scale study by Bellis et al., (2014) concluded that paediatric patients prescribed off-label and unlicensed medicines were more likely to experience adverse drug reactions (ADRs), than with licensed medicines. Patients prescribed an unlicensed medication were 67% more likely to experience ADRs (relative risk of 1.67, p = <0.001). Studies to assess the toxicity of unlicensed medicines in children are needed.

It is important that the MHRA are aware of the adverse effects of medications, so that they can review the marketing authority of a medication and prevent other patients being affected. To address this the MHRA created the Yellow Card Scheme in 1964 following the thalidomide scandal, for collecting and monitoring information on safety concerns such as suspected side effects, or adverse incidents involving medications and medical devices in the UK (MHRA, 2021). The scheme collects data through voluntary reporting by health professionals and the public, including patients, carers, and parents. They are particularly interested in receiving Yellow Card reports for adverse drug reactions in children (MHRA, 2021). Prescribers have a professional responsibility to report adverse events through this scheme.

Despite the increased risk of adverse effects, it is important that patients continue to receive these medications as often they offer the only therapeutic option. It is not clinically appropriate to prevent prescription of these medications because they can be more beneficial than licensed medicines, especially for paediatric patients. However, the onus is on the prescriber to ensure that these medications are offered in a safe manner and ensure that any side effects are properly communicated by the patient, and then reported to the MHRA.

Patient communication

In a 10-minute appointment it can be a challenge to convey complex information about unlicensed medicines to a patient. Unlicensed medicine use is common in paediatrics, where it is often the parent or guardian making the decisions. Lenk et al. (2009) looked at parental attitudes and their knowledge of off-label medications in paediatrics. They found there was a very limited understanding of these medications and their uses. Parents had poor knowledge of the practice of off-label drug use and were likely to refuse use in their children. In the group that included parents of ill children, 63% either did not know of their existence, or did not believe children received unlicensed medications (Lenk et al., 2009). This raises concerns about the validity of ‘informed consent’ given every day by parents.

In addition to prescribing risks, other studies have shown there are communication problems. A questionnaire study carried out by Chisholm (2012) found that clinicians had little knowledge of the GMC guidelines on the use of unlicensed medicines. This suggests poor communication with patients is likely to leave them poorly equipped to make informed decisions or to enable safe and appropriate use of medication (Chisholm, 2012).

To make consent valid and informed, it is important doctors make it clear to patients that the medication is unlicensed, and what this means. Patients must be told why the drug is being prescribed, the risks and the alternatives. Patients should have time to ask questions and have answers. The prescribing doctor should clearly record the discussion that ensues and document patients’ understanding of the risks of unlicensed medicines along with their willingness to accept these risks (Medical Defence Union, 2014). These steps should ensure that consent has been given with full information and appropriate documentation.

The Royal College of Paediatrics and Child Health have produced a leaflet in collaboration with the WellChild charity about unlicensed medicines. This leaflet gives clear and easy to understand information for parents about medications their child is being offered (Medicines for Children, 2020). The general Patient Information Leaflet approved by the Licensing Authority cautions against use, and this may undermine confidence in any additional balanced advice given by health professionals treating individual patients (Royal College of Paediatrics and Child Health, 2013).

The MHRA (2014b) states that best practice for communication involves:

Giving patients (or those authorising treatment on their behalf) sufficient information about the proposed treatment, including known serious or common adverse reactions, to enable them to make an informed decision.

Ethical concerns

Lack of information about unlicensed medicines for patients raises ethical concerns, because in making an informed choice, patients need to be fully informed about the risks and benefits, as well as other options. Their consent is only valid if all information about their medication and treatment options has been explained to them, making it important that every prescriber communicates this to the patient.

A survey done by Pavis and Wilcock (2001) found that fewer than 5% of practitioners either always obtained verbal consent for unlicensed medicine use, documented unlicensed use in the patient’s notes, or informed other professionals of it. The main reasons given were the impracticality of routinely obtaining written consent and causing anxiety for the patient or carer when discussing unlicensed medicine (Pavis and Wilcock, 2001). This is concerning for ethical reasons, as it prevents the patient from having full autonomy over their treatment decisions. They could be unaware of taking an unlicensed medicine, or of the potential risks.

It can be difficult to ensure patients have a full understanding of this complex topic in time-constrained GP consultations or in busy hospital settings. Therefore, literature should be offered to patients each time an unlicensed medicine is suggested to them. Clear concise literature explaining the topic and allowing patients to review this in their own time is helpful for patients. An example of this is the leaflet created by Hull University Teaching Hospitals (Hull University Teaching Hospitals, 2020). It is important that with such leaflets patients are given further opportunities to raise concerns or queries before giving their consent for the use of unlicensed medicines. The prescriber is responsible for these medications and it is therefore their duty to ensure that this process is followed.

Key points

The MHRA gives each medication a marketing authority which states the conditions under which it can be prescribed and its terms of use