In March 2020, the World Health Organisation acknowledged that no pharmaceutical products had, at that point, been shown to be safe and effective for the treatment of COVID-19. However, a number of medicines were being suggested as potential investigational therapies, and in due course many were studied in formal clinical trials. Some of the drugs trialled on Covid-19 patients included those normally used to treat HIV, pneumonia and Lyme disease, and drugs used for malaria prevention and rheumatoid arthritis.
However, in the interim in many countries, doctors were and still are giving COVID-19 patients medicines that have not been approved for this disease. The use of licensed medicines for indications that have not been approved by a national medicines regulatory authority is considered “off-label” use and is subject to local law and Codes of Conduct.
In the UK, recently concluded litigation about the off-label or possibly unlicensed use of Avastin (Bevacizumab) helped to shed light on some of the associated issues of such prescribing and the intentional preparation of medications for off-label use. In November 2020, the Supreme Court refused permission for the pharmaceutical company Bayer to pursue an appeal against 12 NHS Clinical Commissioning Groups ("CCG's") based in the North East of England. In light of the ongoing Covid-19 pandemic and the need for medication to be available at an unprecedented pace to tackle the virus, this article considers off-label prescribing generally, the impact of the Avastin case on the pharmaceutical industry and the use of off-label drugs to tackle the Covid-19 virus.
The Avastin case
The rejection of the appeal to the Supreme Court in the Avastin case in November 2020 confirms the Court of Appeal decision which was handed down on 25 March 2020. The Court of Appeal decision allowed the 12 NHS CCGs to lawfully issue a policy which encourages clinicians at NHS Trusts to prescribe the drug Avastin to treat an eye condition known as 'wet age related macular degeneration' ("wet AMD"). The decision is important because Avastin had been produced and licenced to treat a range of cancers, and, though it was known that it could treat wet AMD, it has never been licenced for such use (and still remains unlicensed for this use). Thus, any use of Avastin to treat wet AMD by the NHS Trusts will represent 'off-label' use of the drug. The case explored whether and how such off-label prescribing could happen, particularly at scale.
What is off-label prescribing?
Before a medicine can be used in the UK, it must have a product licence or authorisation. Off-label prescribing occurs when a drug is prescribed for an illness or condition that was not its intended use and was not described, or supported with clinical trial data, in the licence obtained for that drug. In most cases, this will occur when a prescriber has found that a medicine works well for an illness or condition which is outside of the terms of the licence, and wishes to prescribe the medicine 'off-label' to treat it. This is a common practice in certain areas of medicine, and although the Medicines and Healthcare Products Regulatory Agency ("MHRA") and the professional regulatory bodies do not encourage off-label use of products, and expect that if a licensed product can meet a clinical need then it should usually be preferred and prescribed.
What is the difference between off-label and unlicensed prescribing?
In the UK, an unlicensed medicine is one which has no recognised product licence for any indication. Unlicensed medicinal products should not generally be supplied as they will be outside the usual regulatory protections, but again there are exemptions where prescribers consider they meet the 'special needs' of a patient. In relation to the Avastin case, it had been accepted by the MHRA that certain ways of using Avastin to treat wet AMD (which required dividing a vial intended for cancer into smaller doses to be administered to the eye) did not mean that such "compounded bevacizumab" constituted a distinct, unlicensed medicine, and within the case it was determined that the preparation and supply of Avastin in certain circumstances did not mean that the medicine was unlicensed.
Why would a medicine be prescribed off-label?
Off-label prescribing places heightened expectations on a prescriber to have considered the evidence to justify such use and to obtain appropriately informed consent. In the Avastin litigation, one motivation for it being prescribed off-label as opposed to a prescriber opting to use the alternative licenced products, was said to be that there could be a substantial cost savings to prescribing the off-label drug.
The key conclusions of the Avastin litigation
In addition to concluding that the compounding of bevacizumab did not result in a new unlicensed medication, the case re-iterated that each preparation of Avastin for the treatment of wAMD had to be on the instruction of a prescriber for an identified patient. These principles had already been considered in a very similar German case ("Apozyt").
The final issue was whether there was a "placing onto the market" of the compounded bevacizumab particularly if commercial pharmacies (not those in NHS hospitals) became involved in the bulk preparation or compounding of the drug. Although not fully resolved, the suggestion was that it would not be, as long as the requirement for individual prescriptions was adhered to.
The impact of using off-label drugs
The Court of Appeal's decision in Avastin clarifies the questions to be asked to distinguish between off-label and unlicensed, modified medicines. It re-states the personal responsibility that a prescriber must take if opting to prescribe off-label and confirms that such an approach always needs a personal prescription. However, having set out the legal framework it is a helpful case to enable NHS bodies to know where the boundaries lie and to consider innovative treatments in these unprecedented times.
The off-label use of drugs does present other considerations, and any off-label product may be being used without the usual safety and effectiveness data, which comes from a licenced medicinal product. For this reason many of the experimental off-label treatments from the beginning of the Covid-19 pandemic have been folded into well-respected clinical trials and may well become authorised treatments (on-licence) in due course.
This article was originally published by The Pharma Letter.
 Novartis Pharma GmbH v Apozyt GmbH C-535/11, ECLI:EU:C:2013:226
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