Unlicensed and off-label drugs: What do we know?

Doctor writing a prescription

Following the death of a cancer patient after they were given an unlicensed drug, Diana Spencer unpacks the practice of prescribing unlicensed and off-label medicines.

This month, a cancer patient died and three others were hospitalised in the UK after they were administered an unlicensed version of the chemotherapy drug cabazitaxel. In a statement, the company at fault claimed the problem was caused by an issue at its medicines manufacturing unit.

In response to the incident, this article will examine the rules regarding the use of medicines that are unlicensed or off-label, and take a look at some high profile examples.

The rules and regulations

Unlicensed drugs are drugs that have not yet been assessed by a regulator, while off-label use is when an approved medication is prescribed outside of the terms of its license, e.g., for a different disease or in a different patient group.

In general, regulatory bodies place the responsibility for using unlicensed drugs and using drugs off-label with healthcare professionals. While sticking to licensed medicines is usually the best and safest option, there are clinical situations when the use of unlicensed medicines or use of medicines ‘off-label’ may be judged by the prescriber to be in the best interest of the patient.

The UK’s Medicines and Healthcare products Regulatory Agency says on its website “Healthcare professionals may have more responsibility to accurately prescribe an unlicensed medicine or an off-label medicine than when they prescribe a medicine within the terms of its licence.”

According to the Food and Drug Administration (FDA) in the US, once a medicine is approved, healthcare providers generally may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient.

When it is ‘medically appropriate’?

The practice of prescribing drugs ‘off-label’ is particularly common in certain areas of medicine: for instance, in paediatrics where difficulties in the development of age-appropriate formulations means that many medicines used in children are used off-label or are unlicensed.

Provision of unlicensed medicines for unmet medical needs in various places and circumstances may be referred to as single patient use, named patient use, compassionate use, expanded access, special access, managed access, importation of unlicensed medicine, or other names. This can be particularly important in Low- or Middle-Income Countries (LMICs) where access to medicines or supply is limited.

There are various schemes in force that allow patients access to unlicensed medicines that are in the late stages of clinical development (i.e., Phases II-III) that address unmet medical needs, usually called expanded access programmes (EAPs), compassionate use programmes (CUPs), or managed access programmes.

The MHRA Early Access to Medicines Scheme (EAMS) was launched in 2014 and aims to give people access to promising new drugs that are not yet licensed for life threatening or severely debilitating conditions when no other treatment is available.

The FDA says that it permits some unapproved drugs to be marketed if they are relied on by healthcare professionals to treat serious medical conditions when there is no FDA-approved drug to treat the condition or there is insufficient supply of FDA-approved drugs.

Off-label use could be used to contribute to real-world evidence in favour of licensing a product for that use and repurposing the drug.

What are the risks?

Placing the onus on the individual medical professional means that there can be risks involved in using unlicensed or off-label medicines.

Where there is no specific guidance available, one issue is inconsistency. A study into off-label use in the EU published in Rare Disease and Orphan Drugs Journal concludes: “The prevalence of off-label prescription is reported as being extremely variable…A common understanding of the concept and more alignment in off-label prescription practices and their regulation at member state (MS) level may contribute to further regulatory discussions.”

Schemes to allow expanded access to unlicensed therapies can also be open to abuse. In March 2022, the International Society for Cell & Gene Therapy (ISCT) established a task force to address practical, ethical, and regulatory issues that arise from the use, and potential misuse, of expanded access within the cell and gene therapy (CGT) sector. The ‘ISCT Expanded Access Working Group’ was created in response to growing concerns in the field that expanded access is being utilised in ways that fall outside its intended purpose.

Patricia Zettler, Chair of ISCT Expanded Access Working Group, comments: “Inappropriate use of expanded access could harm the entire CGT sector, undermine research efforts, and ultimately delay approval of products critical for many patients. Expanded access is an important mechanism for providing access to unproven, but promising, interventions for seriously and terminally ill patients who lack approved treatment options. However, at the same time, expanded access should not be understood as a mechanism for commercialising unproven, unlicensed interventions.”

The risk of off-label use of drugs was particularly highlighted during Covid-19 pandemic, when the urgency to prevent infections and save lives led to a number of drugs being used at unsafe doses. The most high profile examples were cases of the use of chloroquine and hydroxychloroquine, which led to a high mortality rates.

Bevacizumab for wet AMD

Cancer drug bevacizumab (Avastin) has long been prescribed off-label to treat wet age-related macular degeneration (AMD), despite the availability of ranibizumab (Lucentis), which is also made by Genentech (part of the Roche group) and approved by regulators as a wet AMD treatment. The reason is the relative cost of the two drugs, which in 2019 was reported as $40 per injection for Avastin and $2,000 per injection for Lucentis.

Genentech retains commercial rights to Lucentis in the US and Novartis has exclusive commercial rights for the rest of the world. Despite widespread calls for Avastin to be pursued as a licensed treatment for wet AMD or for a trial comparing the two drugs, the companies were reluctant to follow this up as Lucentis was already clinically proven. In 2010, the US National Eye Institute launched the Comparison of AMD Treatments Trials (CATT), a two-year clinical trial, comparing the two drugs head-to-head for the first time. At two years, the trial concluded that visual acuity with monthly treatment was slightly better than with as-needed dosing, regardless of the drug.

The use of Avastin was later challenged in court in the UK by Bayer, manufacturer of wet AMD treatment aflibercept (Eylea). The court, and then the Court of Appeal, ruled that the cancer drug Avastin (bevacizumab) can be used off-label to treat wet AMD to save costs to the NHS.

Following the court case, the MHRA released the following statement: “MHRA considers that a distinction needs to be drawn between the functions regulated in the European scheme of medicines regulation, and the clinical use of products within that marketplace. The medicines regulatory regime legislates for the placing on the market of industrially produced medicinal products. The regime does not legislate how medicines are to be prescribed and used by healthcare professionals once they have been placed on the market.”

GLP-1 receptor agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide and liraglutide are regulator approved to treat type 2 diabetes. Eli Lilly’s tirzepatide was most recently added to this class of medicines. Both GLP-1 receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, another type 2 diabetes treatment, have been found to dramatically increase weight loss and so are being increasingly used to help obese or overweight patients.

Recognising the commercial potential, the manufacturers of the drugs conducted studies into the safety and efficacy of the medicines for weight loss. As a result, both Wegovy (semaglutide) and Saxenda (liraglutide) have been approved in this indication, representing a successful off-label use that has resulted in repurposing of the drug. In a recent Phase III trial patients using tirzepatide saw a weight loss effect of up to 22.5% of their body weight, indicating that Lilly’s product will soon follow suit.

None of the SGLT2 inhibitors, including Invokana (canagliflozin), Farixga (dapagliflozin) and Jardiance (empagliflozin) have been investigated or approved for weight loss, though continue to be used off-label.

Both these classes of drugs are also being used as treatments for type 1 diabetes, despite there being no clinical evidence to support this and no intention on the part of the manufacturers to conduct trials in this indication.

To explore this, researchers at UT Southwestern Medical Center in Dallas conducted a real-world study into glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) for type 1 diabetes. They searched medical records for type 1 diabetes patients who had used any GLP-1RAs and/or SGLT2is for at least 90 days.

While the study results showed that both drugs can benefit patients with type 1 diabetes, some risks were also highlighted. “These findings, from our real clinic experience, show both benefits and some risk to patients with type 1 diabetes who take these medications in addition to insulin treatment,” concludes study leader Dr Ildiko Lingvay, Professor of Internal Medicine at UT Southwestern. “When viewed holistically at the person level, all of these small changes can add up to substantial overall clinical benefits, especially considering that improving glycaemic control in patients with long-standing [type 1 diabetes] can be challenging.”

Even for drugs that have been approved by regulators and are widely used, it is important that any risks to patient safety are continually monitored and carefully reviewed. The European Medicines Agency (EMA) safety committee, the Pharmacovigilance Risk Assessment Committee (PRAC), is currently reviewing data on the risk of suicidal thoughts and thoughts of self-harm related to GLP-1 receptor agonists. However, it is not yet clear whether the reported cases are linked to the medicines themselves or to the patients’ underlying conditions or other factors.


Use of unlicensed and off-label drugs is widespread and unregulated. Placing the responsibility with the individual healthcare professional can result in inconsistent access to medicines and some safety issues. However, in many cases the benefits to patients are deemed to be sufficient to outweigh the risks and these off-label uses can sometimes result in drug repurposing and new commercial opportunities for the manufacturers.

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