Off-label and off-licence prescribing

In the UK, the terms “off-label” and “off-licence” prescribing are often used interchangeably, but they refer to slightly different concepts. The General Medical Council wisely unified both concepts to the term ‘unlicenced prescribing’ . It does not mean ‘illegal prescribing’. Most unlicenced prescribing in the practice of medicine happens in psychiatry. Why is unlicenced prescribing a big deal? In a nutshell, it is because when a medication is used outside of it tested development parameters special precautions ought to be taken. Patients need to be informed as part of consent procedures. For those who are not of capacity the burden of care and caution is heavily on the prescriber.

Table of Contents

• Off-label prescribing:
  • Off-licence prescribing:
  • ‘Unlicenced prescribing’
• Typical but fictional scenario
  • Analysis:
  • Key points
  • SPC (or SmPC)
  • Relevance of approval of medications
  • Symptomatic treatment
• Capacity/Consent
• Relevance to prescribing in psychiatry
• Prescribing in personality disorder
• Prescribing in intellectual disability
• Conclusion
  • Supplemental References

Off-label prescribing:

This occurs when a medication is prescribed for a purpose, dosage, or patient group that is not included in the approved product label or Summary of Product Characteristics (SPC). The SPC is the official document that provides information about the approved uses, doses, and safety precautions for a medication. Off-label prescribing is based on the prescriber’s professional judgment and is often supported by clinical evidence, despite not being officially approved for that particular use.

The Mental Health Services Group (2021) in Scotland has given sound guidance on the matter. They correctly point out five domains where off-label prescribing can happen (and I quote):

1. Demographic: The age of the patient may lie out with the recommended range e.g. the use of sertraline for depression in a 16 year old.
2. Disorder: Prescribing for a condition which is out with the marketing authorisation e.g. the use of hyoscine hydrobromide for clozapine-related hypersalivation.
3. Dosage: Prescribing at a dose that is higher than recommended e.g. olanzapine prescribed at 30mg daily.
4. Duration: Prescribing for a longer period of time than is recommended e.g. a benzodiazepine prescribed for longer than 4 weeks.
5. Domain: Where a drug is licensed for a particular indication in one country and not another e.g. in some EU member states, valproate salts have a licence for prevention of migraine.

They make one significant error in quoting CR210 when they state, “There is no legal requirement to disclose the off-label use of a drug to a patient but such disclosure is advocated strongly.” The error arises because CR210 quotes Frank (2008)   Sadly all authors are wrong, because the law says they are wrong. How? I could easily veer off into what a ‘legal requirement’ means, but I’ll keep it simple and tight. In the context of prescribing, the legal requirements based on duties of care, arise from several UK Statutes and reams of case law. There are serious legal consequences for not disclosing to a patient the licensed use of medications prescribed (save minor exceptions in mental health law, and rare exceptions in emergency care). Therefore any doctor who cannot find a valid legal exception for non-disclosure of off-label (or unlicenced) prescribing to patients, is courting dire legal consequences and GMC attention. Do you feel lucky?

The terms off-label and off-licence describe situations where a medication is prescribed in a manner that is not explicitly approved by the regulations or regulatory authorities. However, the specific circumstances for each term are as follows:

Off-licence prescribing:

This term refers to the prescription of a medication that is not licensed for any use in the UK. This might occur if a medication has been licensed in another country but not in the UK, or if a medication has been withdrawn from the market for reasons unrelated to safety or efficacy. In these cases, the prescribing clinician must take full responsibility for the decision to use the medication, as it is not supported by a UK marketing authorisation.

Despite the differences between off-label and off-licence prescribing, both practices can be legal and clinically justified in certain circumstances. Healthcare professionals must weigh the potential benefits and risks for individual patients and base their decisions on available evidence and professional judgment.

Off-licence prescribing is not typically defined by a single authoritative body, as it is a term used to describe a practice that arises in certain clinical situations. However, various organisations and governmental bodies provide guidance and recommendations related to off-licence prescribing. In the UK, the General Medical Council (GMC), the Medicines and Healthcare products Regulatory Agency (MHRA), and the National Institute for Health and Care Excellence (NICE) all offer guidance on prescribing, which includes discussions of off-licence and off-label prescribing.

‘Unlicenced prescribing’

The General Medical Council (GMC) at para 103 of Good Prescribing Guidance, considers the term to “[..]describe medicines, which are used outside the terms of their UK licence or that have no licence for use in the UK.” In other words, the GMC has fused the concepts of off-label and off-licence on grounds of the duties of care involved.

The Royal College of Psychiatrists issued guidance in CR210 (2017) on the use of unlicenced medications. This will not be summarised here. It needs to be read by, and implemented by all psychiatrists.

Very informative is the Mental Health Services Prescribing Management Group (Glasgow) [2021] https://bit.ly/MHS-PMG-guidance.

[Note that the GMC has merged off-label and off-licence prescribing into ‘unlicenced prescribing’.]

Typical but fictional scenario

Choice and medication (NHS leaflet) https://bit.ly/factsheet-ul-medication

Key points

1. Off-label prescribing occurs when medication use falls outside the scope of the marketing authorisation with respect to one of five key domains:
   1. Demographic: The age of the patient may lie out with the recommended range e.g. the use of sertraline for depression in a 16 year old.
   2. Disorder: Prescribing for a condition which is out with the marketing authorisation e.g. the use of hyoscine hydrobromide for clozapine-related hypersalivation.
   3. Dosage: Prescribing at a dose that is higher than recommended e.g. olanzapine prescribed at 30mg daily.
   4. Duration: Prescribing for a longer period of time than is recommended e.g. a benzodiazepine prescribed for longer than 4 weeks.
   5. Domain. Where a drug is licensed for a particular indication in one country and not another e.g. in some EU member states, valproate salts have a licence for prevention of migraine.
2. Consent:
   1. Prescribers must now ensure that patients (or their carers if the patient lacks legal capacity) are aware of any ‘material risks’ involved in a proposed treatment, and of reasonable alternatives, following the judgment in the Montgomery case (Montgomery v Lanarkshire Health Board 2015). ‘The test of materiality is whether, in the circumstances of the particular case, a reasonable person in the patient’s position would be likely to attach significance to the risk, or the doctor is or should reasonably be aware that the particular patient would be likely to attach significance to it.’ (page 4)
3. Robust record-keeping and documentation is fundamental to all prescribing practice. When commencing new treatments, patients should be provided with sufficient information to allow them to make an informed decision.
   1. Remember to RECoRD……
      1. Rationale
      2. Evidence-base
      3. Consent
      4. Review
      5. Document

From MHRA https://bit.ly/unlicenced-meds-mhra-guidance

“The responsibility that falls on healthcare professionals when prescribing an unlicensed medicine or a medicine off-label may be greater than when prescribing a licensed medicine within the terms of its licence. Prescribers should pay particular attention to the risks associated with using unlicensed medicines or using a licensed medicine off-label. These risks may include: adverse reactions; product quality; or discrepant product information or labelling (eg, absence of information for some unlicensed medicines, information in a foreign language for unlicensed imports, and potential confusion for patients or carers when the Patient Information Leaflet is inconsistent with a medicine’s off-label use).”

SPC (or SmPC)

While the BNF is an excellent resource for healthcare professionals, it does not contain the complete Summary of Product Characteristics (SPC) for each medication. The BNF is designed to provide a more concise overview of key information, while the SPC offers comprehensive information on a medication, as it is prepared by the pharmaceutical company and approved by the regulatory authorities.

To access the full SPC for a medication, you can visit the website of the European Medicines Agency (EMA) or the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Additionally, the Electronic Medicines Compendium (eMC) is a useful online resource that provides access to the SPCs for thousands of medicines approved for use in the UK. The eMC is available at https://www.medicines.org.uk/emc/.

Relevance of approval of medications

Before a medication can be approved for use and marketed to the general public, it must undergo a series of clinical trials to evaluate its safety, efficacy, and optimal dosing. The clinical trial process typically consists of several distinct stages, known as phases:

1. Preclinical trials: Before a drug enters human trials, it goes through preclinical testing in the laboratory and in animal models. This stage aims to evaluate the drug’s safety, pharmacology, and potential efficacy. If the results are promising, the drug’s developer will submit an Investigational New Drug (IND) application to the appropriate regulatory authority (e.g., the U.S. Food and Drug Administration or the European Medicines Agency) to begin clinical trials in humans.
2. Phase 1 trials: This phase primarily focuses on evaluating the safety and tolerability of the medication in humans. A small group of healthy volunteers (typically 20-100 individuals) receives the drug to assess its pharmacokinetics, pharmacodynamics, and to determine the appropriate dosage range. Researchers also monitor for any adverse effects.
3. Phase 2 trials: involve a larger group of participants (usually 100-300), who have the condition the medication is intended to treat. This phase aims to assess the drug’s efficacy and further evaluate its safety. Researchers use a variety of outcome measures to determine if the drug has a therapeutic effect and to identify the optimal dosing regimen.
4. Phase 3 trials: In this phase, the medication is tested on an even larger group of participants (typically 1,000-3,000) to confirm its efficacy, monitor side effects, and compare it to commonly used treatments. Phase 3 trials are usually multicentre, randomised, and controlled, often with a double-blind design to minimise bias. If the results are positive, the drug developer will submit a New Drug Application (NDA) or Marketing Authorisation Application (MAA) to the regulatory authorities for approval.
5. Phase 4 trials (post-marketing surveillance): After the medication is approved and marketed, phase 4 trials, also known as post-marketing surveillance, continue to monitor the drug’s safety, efficacy, and optimal use in real-world settings. These trials may uncover rare side effects or long-term consequences that were not detected in earlier phases. Regulatory authorities may require additional studies or impose restrictions based on the findings of these trials.

The entire process of drug development, from preclinical research to market approval, can take several years to more than a decade. This rigorous process helps ensure that new medications are safe, effective, and provide a benefit to patients before they are widely available. In the above medications are tested for efficacy on recognised and diagnosed medical conditions. There are isolated exceptions to the above in emergency situations – most notably in the development of COVID-19 vaccines.

Whilst symptoms and signs constitute medical conditions, the above process will not have included single symptoms or groups of symptoms that are not part of diagnosis. The reason for this should be obvious i.e. masking of a symptom is not treatment. In other words – it is the reason why heroine is not approved for treatment of every condition where pain is part of the syndrome or condition.

Symptomatic treatment

The term is culturally entrenched in psychiatry and other parts of medical practice. At its core it means, ‘If the diagnosis is not known or cannot be made, treat the symptoms‘. That’s probably a reasonable thing to do in non-specific headache or the odd backpain. In more complex scenarios it is often stated, “I treat paitents not diagnoses!” – as a way of justifying prescribing. Treating symptoms leads to symptom relief which is a strong reinforcer a) for the patient that they are receiving the right treatment and b) for the doctor – in that if the patient is improved, that’s what matters. By extension, of that logic – cocaine could be a symptomatic treatment for most ailments, steroids for lots of ailments, and analgesics of various types for any condition where pain is a symptom. The author asserts that that is not the scientific basis of medical practice.

Prescribing a medication for a symptom that is not part of a diagnosed nosological condition, could be considered off-label prescribing if the medication is being used for a purpose, dosage, or patient group that is not included in the approved product label or Summary of Product Characteristics (SmPC). In such cases, the prescriber is using their professional judgment to manage the patient’s symptoms, even though the specific use may not be approved by the regulatory authorities.

Almost every medication that becomes approved by regulatory bodies will have been tested on recognised medical conditions.

Off-label prescribing can be clinically justified and is sometimes necessary when there are no approved treatments for a specific symptom or condition, or when existing treatments are ineffective or have unacceptable side effects. However, it is important for healthcare professionals to carefully weigh the potential benefits and risks for each patient and to base their decisions on the best available evidence and their professional judgment. No psychotropic medication requiring a prescription, has ever been licensed for treatment of a single symptom without an underlying diagnosed medical condition. [Paracetamol and other OTC medications do not require prescription.]

Capacity/Consent

Informed consent (and there is no such thing as uninformed consent) involves providing patients with sufficient information about the proposed treatment, including its potential benefits, risks, and alternatives. There are currently six criteria for capacity in the UK. When prescribing off-label, healthcare professionals should explain to the patient that the medication is being used outside its approved indications and discuss the reasons for this choice. The patient should also be informed about any potential side effects or risks associated with the off-label use, as well as any available alternative treatments. The most recent criterion of ‘material risk’ arising from Montgomery 2015, becomes particularly important in off-label/off-licence prescribing.

In the UK, the General Medical Council (GMC) provides guidance on obtaining informed consent for off-label prescribing. According to the GMC’s “Good practice in prescribing and managing medicines and devices,” healthcare professionals should involve patients in decisions about their treatment, including the use of off-label or unlicensed medications, and inform them about the potential risks and benefits. Particular attention should be paid to paragraphs 103-109.

Ultimately, obtaining informed consent is a vital aspect of ethical medical practice and patient-centred care, especially when prescribing medications off-label or outside of their approved indications.

Relevance to prescribing in psychiatry

From my experience, I have seen too many situations where patients are prescribed large cocktails of medications. This is called inappropriate polypharmacy where there is no clear clinical rationale for such prescribing that is rooted in widely accepted standards of practice.

The situation often visited is when a patient has been seen by several psychiatrists over the years.

1. The patient may have been on one medication at the outset. The diagnosis is not to be found. Instead the rationale for an antidepressant may have been documented as ‘treatment of low mood’. This is off-label prescribing because
   1. low mood is not a recognised medical condition and
   2. no antidepressant is approved for treatment of a single symptom (that could arise from several mental disorders).
2. Another psychiatrist comes along months or years later and finds ‘mood instability’ and decides to start lithium. Mood instability is not a diagnosis and can occur across several mental disorders. Lithium is not licenced to treat ‘mood instability’.  By this stage the patient is on two unlicenced medications according to the GMC.
3. Neither of the above psychiatrists will have documented any true rationale that is GMC compliant for use of unlicenced medications.
4. A third psychiatrist comes along and decides to augment the antidepressant and lithium with an antipsychotic. The antipsychotic is not licenced for augmentation.
5. Now the patient is on three unlicenced medications after 5 years – and no better off.

All of the above happens right under the inspections of the CQC. Notably the GMC is not an inspectorate nor does it actively monitor standards of medical practice. It will not know of the above unless some serious event brings a doctor to their attention.

Prescribing in personality disorder

NICE (2009) states, “Using sedative or antipsychotic medication for short‑term crisis management means using it cautiously in a crisis as part of the overall treatment plan for people with borderline or antisocial personality disorder. The duration of treatment should be agreed with the person, but should be no longer than 1 week.” Notably NICE also stated, “The guideline also covers the treatment and management of people diagnosed with emotionally unstable personality disorder based on ICD-10 criteria.” This means that the guidance applies to diagnoses of borderline PD (F60.3) and the impulsive type (F60.31) of EUPD – and therefore all of EUPD.

The following infographic of a real patient (with nothing that makes the patient identifiable) is not uncommon in forensic psychiatry.

It is the sort of case where one might find five (5) psychotropic medications prescribed by accumulation over many years, and no one will be able to decipher which medication is for which condition. So one may find lithium and valproate prescribed for ‘mood instability‘, along with clozapine and other medications. Similar situations arise in Intellectual Disability services. This is not just polypharmacy, it is polypharmacy in the context of poor medical practice and unlicensed prescribing. [I cannot get into specifics of the case].

My experience on the last 15 years informs me that there is widespread – and to some extent reckless prescribing of medications to people suffering with personality disorder. I can say that because in only one instance over that time I found a robust documented rationale for such prescribing. The vast majority of psychiatric prescribing is about managing symptoms, absent of rational or valid exceptions to NICE guidance.

Prescribing in intellectual disability

The situation is worse among patients with an intellectual disability, from my experience – which at 2023 concurs with the following:

“In 2019-20 the percentage of patients with a learning disability who had been prescribed antipsychotics was significantly higher (15.2%) than in patients without a learning disability (0.9%). the percentage of patients with a learning disability who had who had been prescribed benzodiazepines was significantly higher (7.2%) than in patients without a learning disability (2.1%). the percentage of patients with a learning disability who been treated with antidepressants without an active diagnosis of depression was significantly higher (11.6%) than in patients without a learning disability (4.4%). the percentage of patients with a learning disability who been treated with epilepsy drugs without an active diagnosis of epilepsy was significantly higher (5.6%) than in patients without a learning disability (2.4%).” according to NHS Digital (2019-2020).  See tabulated summary:

Medication class	Learning disability	Without learning disability	Ratio
Antipsychotics	15.2%	0.9%	17
Benzodiazepines	7.2%	2.1%	2
Antidepressants (with no diagnosis of depression)	11.6%	4.4%	4
Antiepileptics	5.6%	2.4%	2

The figures are shocking, considering that the Government’s STOMP agenda has been in place from 2016, and ‘everybody’ is signed up to it.

However, NICE 2015 states that “Antipsychotics are the most frequently used drugs for people with a learning disability and behaviour that challenges, often in the absence of a diagnosis of a mental health problem. The use of antipsychotics should be limited, and regular review should ensure that there is an appropriate rationale for prescribing. A full multidisciplinary review will also help to reduce prolonged use of antipsychotics and thereby potential side effects.” Some may have overlooked the words ‘in the absence of a diagnosis of a mental health problem‘.  This must clearly mean there is a lot of unlicenced antipsychotics being prescribed. t this time, 2023-05-07 12:57PM, I am not aware that anyone has objectively assessed the scale of unlicenced prescribing among people with learning disabilities (aka disorders of intellectually development as per ICD-11).

NICE 2015 further requires that, “Evidence of local arrangements and written protocols to ensure that people with a learning disability and behaviour that challenges have a multidisciplinary review of their antipsychotic medication 12 weeks after starting treatment and then at least every 6 months.“

Conclusion

The seriousness of unlicenced prescribing has not been nationally recognised as yet in the UK.

Supplemental References

1. Off-label or unlicensed use of medicines: prescribers’ responsibilities (Medicines and healthcare products Regulatory Agency 2015 UK Gov).
2. Medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes – NICE (2015 NG5)
3. Mental health problems in people with learning disabilities: prevention, assessment and management – NICE Guideline 2016 (NG54)
4. Learning disability: behaviour that challenges – NICE Guideline 2019 (QS101)
5. Co-prescribing of unlicensed medication – The MDU.