Off licence

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Off licence, out of licence, off license, out of license, off-label are all terms that may be used when a drug or preparation is used for a condition or indication which is not mentioned in the licence obtained by the manufacturers and distributors from the regulatory authority for medicines in the jurisdiction concerned.

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Use outside the indications of the MHRA or EMEA marketing authorisation as detailed in the current SPC for a medicine. Strictly this is unlicensed use in UK law. The responsibility for such use lies with an ill-defined mix of the prescribers and the manufacturers. However the responsibility to prescribe a licensed preparation if available for an indication before considering prescribing unlicensed preparations (which may be even compounds of the same active ingredient) is greater in UK and EU law than that of some other jurisdictions. Indeed as recently as March 2015 the view that a licensed medication takes precedence even when an unlicensed one is equivalent in clinical outcome but cheaper has been reaffirmed as government policy[1]. This is in the context that the MHRA will not authorise the import of an unlicensed medicine where a licensed one is available, unless there is a “special need” which means that the unlicensed treatment is better suited to the clinical need of an individual patient. As technically out of license use is unlicensed use of a preparation the prescriber could take on most of the medico-legal responsibility. Also technically in the UK, only doctors may prescribe unlicensed medications for compounding by a pharmacist, and indeed often are the only prescribers who can order the preparation an unlicensed medication from two licensed medications. The situation is only resolved with regard to compounding under organisational policy as may apply for example where medications are mixed in a palliative care syringe and is likely to remain so for the vast majority of mixtures used in clinical practice. Problematically many doctors do not read the SPC and so if they prescribe in a situation with a clear contraindication in the SPC, even where the indication is as in the SPC, they are theoretically entirely liable for any injury.

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See off-label and link to commentary on one aspect of such use.

Fraught, but very very common and if a reasonable extrapolation of the evidence base has probably no more responsibility and liability attached than use for a strict indication.

Contents

Guidance

  1. The first problem for a prescriber is that of identifying off-licence use that is well supported by evidence and when it is not.
  2. The second problem is that relevant laws for each jurisdiction are different. UK law is now very similar to EU law, which is different to former British Commonwealth law, and different to US law.

Strong evidence for use

In cases where there is good evidence the issues of consent are no more difficult than for a licensed product. The main issue for a prescriber is to ensure they are familiar with the contents of any patient information leaflet that comes with a dispensed licensed medication because they might want to prevent queries by explaining why the leaflet does not mention the patients actual diagnosis as an indication.

Identifying poor evidence situations

Positive answers to these 5 questions should generate a warning that the use of the drug will need a bit more thought[2]. Is the drug?

  1. for a novel indication
    • A common pitfall is to not regard chronic use in a drug as a new indication when the drug is only licensed for a short course
      • A good proportion of recent restrictions of drugs by the licensing authorities have resulted from chronic exposure experience
    • Any totally new indication is really a research topic and use implies same ethical considerations
      • Example is the use of anti-psychotic agents in dementia - not subject to good research for years and lack of evidence not understood by most
  2. known to have serious adverse effects
    • These have a nasty habit in being more common in off licence use
  3. new to market
    • Very rarely will such a drug have a good evidence base for any out of license use and in any case the safety issues will be much less defined. Risk benefit data that can be extrapolated to a new use will take over 3 years to gather.
  4. high-cost
    • Because off licence use rarely has the benefit/risk ratio of in-licence use the cost benefit ratio for patient will also be higher. For a drug whose resource benefit is marginal when used according to license this translates into a much higher likelihood of resources being wasted
  5. Does a situation exist where the patent holder may assert their rights.
    • An example in 2015 was with pregabalin where the patent holder as part of an injunction in the UK was able to instruct NHS England to communicate to all GPs[3]

To obtain evidence to support your prescribing decision you will rarely have the ability to evaluate the full evidence base yourself. Clinical guidelines written by a group of experts, independent of industry, relating to the indication are always a good place to start. Once you have the support of the body of medical opinion a recommended next step is to look at the manufacturers licensed prescribing information. If you find your patient is in a caution group you might have to initiate inquiries as to why. But otherwise the degree of consent involved is basically the same as for a drug whose out of license use is backed by sound evidence. You might start thinking of written consent when risks could be serious, and indeed you might well be advised to treat consent issues exactly as for an unlicensed drug.

If you, or another subset of the profession are extrapolating from the literature because of analogy, explanation and consent will be more time consuming and complete. At an extreme you should be treating the issue as for research because you do not really know if the drug will work.

References