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Legal and ethical issues with the use of unlicensed medicines

In the current climate of austerity, the NHS is 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 considerably less expensive. Such medicines may well be unlicensed and not authorised for use in the same indications. It is this latter approach which may pose ethical and legal difficulties.

Licensing medicines ensures they have an acceptable balance of risk versus benefit based the toxicological, clinical safety and efficacy data and pharmaceutical quality data of the product. Under European law all medicinal products have to have marketing authorisation before being supplied and distributed. In the UK this is the responsibility of the MHRA.

The European Medicines Directive2001/83/EC sets out all the particulars and documents which must be submitted for marketing authorisation, including the results of pharmaceutical and pre-clinical tests and clinical trials.

Also the application dossier must contain a Summary of Product Characteristics (SmPC) which sets out the terms on which the product is authorised and this is 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. The Medicines Directive provides that the marketing authorisation shall be refused if the risk: benefit balance is not considered to be favourable or the product's therapeutic efficacy is insufficiently substantiated by the applicant.

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 prescribed 'off label' may be a product holding a marketing authorisation for a therapeutic indication(s) other than the one(s) listed in the SmPC. 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.

I now turn to the specific liabilities of all those involved in the supply, prescribing and dispensing of medicines which do not carry marketing authorisation or which are used outside their licensed indications.

There will liabilities both in common law (negligence and possibly contract), statutory obligations and liabilities under the Consumer Protection legislation and obligations under the appropriate professional codes of conduct (General Medical Council and Royal Pharmaceutical Society). The appropriate 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 patients 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

In addition to these legal and ethical professional duties, 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 such as a health authority/NHS trust 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.

Health authorities and/or NHS trusts may become liable under the consumer protection legislation

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 of a medicinal product without a product licence or wholesale dealing without a wholesale dealers licence; failure to inform employees and/or subcontractors of licence provisions relevant to their role in production of medicine.

Also 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

There may also he potential issues in Employment Law. For instance where the employer, for instance NHS Trust, explicitly orders an employee prescribing physician to prescribe an unlicensed medicine, for which the exemption from the need for marketing authorisation has not been satisfied, this will be effectively an unlawful order and the employer could be held criminally liable for conspiracy to commit a crime.

In conclusion policy decisions to substitute innovator branded medicinal products 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!