In the current climate of austerity, healthcare providers may be seeking ways to contain costs of treatment. A particularly effective way is the substitution of expensive medicines with either generic formulations when available in the market place or other sometimes older pharmacologically similar products which may be considerable less expensive. Such medicines may well be unlicensed and not authorised for use in the same indications. As Dr Peter Feldschreiber explains in this article, policy decisions to make such substitutions can be fraught with legal and professional conduct difficulties including regulatory, consumer protection and potentially criminal sanctions as well as financial remedies. They should be taken with great care!
The system of licensing medicines ensures they have an acceptable balance of risk versus benefit based on the toxicological, clinical safety and efficacy data and pharmaceutical quality data of the product. Under European law (the European Medicines Directive 2001/83/EC) all medicinal products have to have marketing authorisation before being supplied and distributed. In the UK this is the responsibility of the MHRA, who are required to refuse marketing authorisation if the risk: benefit balance is not considered to be favourable or the product's therapeutic efficacy is insufficiently substantiated by the applicant.
The application dossier for marketing authorisation will include the results of pharmaceutical and pre-clinical tests and clinical trials, as well as a Summary of Product Characteristics (SmPC) which sets out the terms on which the product is authorised and which will form the basis for the package leaflet.
Changes to the products must have variations to the marketing authorisation - for example the addition of new therapeutic indications or changes in the manufacturing process. More extensive changes, such as a new strength or new pharmaceutical form require new marketing authorisation.
What then is an 'unlicensed medicine'? If an application dossier for marketing authorisation has not been submitted to the Regulatory Authority it cannot be granted marketing authorisation and the product, or the unapproved indication and/or pharmaceutical formulation is unlicensed. The product cannot be placed on the market, and it cannot be supplied for therapeutic use.
This classification of 'unlicensed medicinal product' infers that either the data and general information on the product does not confer an appropriate risk: benefit profile because the regulator is not confident that the product can safely be placed on the market or that the producer has failed to investigate the quality safety and efficacy of the product. Either way, the prescriber and producer of an unlicensed product must comply with the specific provisions for the production and use of medicinal products under the exemption provisions for marketing authorisation.
The statutory exemptions from the need for a Marketing Authorisation apply if the product is needed to fill a special need in response to a bona fide unsolicited order, formulated in accordance with the specification of a clinician.
Similarly a medicine used 'off label' may be a product prescribed for a therapeutic indication other than the one(s) for which it holds a marketing authorisation. The authorised indications will be comprehensively described together with appropriate dosing instructions, warnings and contraindications.. Thus the therapeutic use of a product not specifically authorised for a particular indication is in effect operating outside its marketing authorisation and may well not comply with the risk: benefit profile originally endorsed by the regulatory authority for safe and effective use. It becomes essentially an unlicensed medicine.
Obligations and Potential Liabilities
The supply, prescription and dispensing of unlicensed medicines can give rise to obligations and liabilities under professional codes of conduct, common law (negligence and possibly contract) and statute.
Professional Codes of Conduct
The applicable professional guidance for medical staff is outlined in the supplementary guidance issued by the General Medical Council, Good Practice in Prescribing Medicines, 2008. Doctors may prescribe medicines for unlicensed indications provided that that it would better serve the patient's need than an appropriately licensed alternative; there is sufficient evidence or experience on its safe and effective use and they take sole clinical responsibility for prescribing; and they must explain to the patient the reasons for prescribing a medicine where there may be little research or other evidence to support its use.
The Royal Pharmaceutical Society Code of Conduct on Dispensing Unlicensed Medicines mirrors these provisions in that the pharmacist may dispense an unlicensed medicine in response to a request from a medical practitioner. However it is a professional requirement 'that where a product is ordered on prescription, a pharmacist must supply such a product with a marketing authorisation, where such a product exists and is available, in preference to an unlicensed product or food supplement'. In the situation where an off label use of a medicine is requested 'Reasonable steps should be taken to ensure that the prescribing doctor knows he has prescribed a product outside its marketing authorisation and the possible consequences of this. Pharmacists should liaise with the prescriber and in the light of the available data make a decision as to whether or not to make a supply....' Furthermore the pharmacist 'must consider and act in the best interests of individual patients and the public'.
The legislation and the professional codes of conduct for the GMC and the Royal Pharmaceutical Society are complementary in that both demand compliance with the principles of consent and alerting the patient to the use of an unauthorised medicinal product.
The liabilities of all those involved in the supply and distribution and prescribing of unlicensed medicines are articulated in the European Product Liability Directive and Part 1 Consumer Protection Act 1987 in the UK.
Under this legislation a hospital pharmacy reformulating the raw material ingredient of a licensed medicine into a formulation for use in an unauthorised indication would be potentially liable as a producer for the purposes of an action claiming a defective product. Similarly the employing body may incur liability as a producer where the product has to be prepared in some way before final use. The Product Liability Directive provides that a product is defective when it does not provide the safety to which a person is 'entitled to expect' In the absence of a robust regulatory evaluation of risk: benefit from data on clinical safety and efficacy and lacking a platform of basic pre-clinical and toxicological evidence, an unlicensed medicine risks being classified as defective when serious adverse reactions occur. The potential defectiveness of a medicine in its unlicensed indication may have reputational consequences for the mainstream approved product.
There are also situations where regulatory infractions regarding the manufacture, supply and use of unlicensed medicinal products can give rise to criminal liability.
Specific offences in Part II of the Medicines Act 1968 include sale or supply of a medicinal product without a product licence (other than by a doctor..); manufacturing or assembling a medicinal product without a product licence or wholesale dealing without a wholesale dealers licence; and failure to inform employees and/or subcontractors of licence provisions relevant to their role in production of medicine.
Selling, supplying, or possessing a medicinal product in the course of a business which does not comply with those regulations or which does not include the information required by the European regulations is an offence as is supplying or possessing a leaflet to go with a medicinal product that is false or misleading. The maximum penalty is a fine not exceeding £5000 in the Magistrates Court or two years imprisonment and/or an unlimited fine in the Crown Court.
Peter Feldschreiber is dually qualified as a barrister and physician. He practices from 4 New Square Chambers and can be contacted there or through Bircham Dyson Bell to advise on any of the issues raised by this article.
Peter specialises and advises in all aspects of medical and healthcare law including healthcare products liability, pharmaceutical and medical devices regulatory law, clinical negligence, personal injury and medically related employment litigation. He is General Editor of the Law and Regulation of Medicines, Oxford University Press 2008.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.