Under the Human Medicines Regulations a company may only market, that is advertise and sell, their product in the United Kingdom if they hold a market- ing authorisation for that product. Furthermore the therapeutic or diagnostic purposes for which the product can be marketed are limited by the terms of the authorisation. Thus a product licensed only for the treatment of gastric ulcers may not be marketed for the treatment of indigestion.
However, this legislation does not affect the clinical freedom of doctors to prescribe what they believe is best for their patient. They may use or recom- mend medicines which do not have a licence (unlicensed) or use medicines in ways different to those specified in the marketing authorisation (off-label).
UNLICENSED PRODUCTS
Doctors may prescribe several categories of unlicensed products. Some sub- stances, for example raw chemicals may on occasions be prescribed as med- icines, although they are not normally thought of as medicines, and are not marketed as such. Other medicines may be available in another country but not licensed in the United Kingdom.
OFF-LABEL USE
‘Off-label’ medicine describes the use of licensed medicines in a dose, age group or by a route not in the product licence specification. The product can- not be marketed for any use outside the licence conditions, but doctors are free to prescribe outside those conditions. Such use is now generally referred to by the US term ‘off-label use’. Many medicines used in children are prescribed and used off-label. Clinical trials are rarely carried out on children, espe- cially very young children, so the licensed use is restricted to those groups of patients where clinical trials have been carried out.
REASONS FOR USING UNLICENSED PRODUCTS They may be used because:
● The medicine is prepared by the original manufacturer, but is not on sale in United Kingdom.
● It is the prescriber’s own formula for a specific patient.
● It is an unusual form, for example liquid preparation of a medicine nor- mally available only as capsules.
● It is an unusual strength.
● It is an unusual combination of active ingredients.
● It is an unusual formulation, for example no preservative eye drops, lactose free tablets.
● It is a discontinued product.
● The normal product is temporarily unavailable.
EXEMPTIONS FOR UNLICENSED MEDICINES
Most of the relevant legislation is to be found in the Human Medicines Regulations. These provide exemptions from the normal licensing requirements, so as to allow pharmacists to order Specials and to hold stock ready for dispensing.
OBTAINING UNLICENSED PRODUCTS Unlicensed medicines may be obtained in three ways:
(1) Prepared extemporaneously in the pharmacy (2) Obtained from a ‘Specials’ manufacturer (3) Imported from another country via a wholesaler.
EXTEMPORANEOUS PREPARATION IN THE PHARMACY
Pharmacists may carry out the preparation of an unlicensed medicine in the pharmacy.
The exemptions allow a pharmacist to:
● prepare or dispense a product against a prescription;
● prepare a stock in anticipation of dispensing;
● prepare or dispense a medicinal product against a specification given by the intended purchaser, where the product is to be administered to that pur- chaser or to someone under his care;
● prepare a product for counter-prescribing.
Dispensing Against a Prescription
A pharmacist can prepare a product or assemble a product against a prescrip- tion given by a prescriber.
PREPARATION OF STOCK
Regulations 17 and 46 of the Human Medicines Regulations prohibit the plac- ing on the market or the wholesale distribution of a relevant medicinal product unless it has a marketing authorisation. Products specially made for a particu- lar patient will not have a marketing authorisation.
A pharmacist can prepare a stock of medicinal products in a registered pharmacy:
● with a view to dispensing them in accordance with a prescription given by a practitioner OR
● with a view to dispensing them in accordance with a specification from a person who is going to administer them to himself or to someone under his care.
((s10)(4)(b) Medicines Act 1968) The product must be prepared under the supervision of a pharmacist, and in a pharmacy, hospital or a health centre.
Dispensing to a Formula
A pharmacist may prepare or dispense a medicinal product in a registered pharmacy:
● by or under the supervision of a pharmacist, and
● in accordance with a specification furnished by the person to whom the product is or is to be sold or supplied, and
● if the person is going to administer the product to himself or to someone under his care.
Counter-prescribing
A pharmacist may prepare or dispense a medicinal product in a registered pharmacy, if the following conditions are satisfied:
● the product is for administration to a person
● the pharmacist was requested by or on behalf of that person to exercise his judgement as to the treatment required
● the person was present in the pharmacy at the time of the request.
((s10)(4)(a) Medicines Act 1968)
Chemist’s Nostrums
The pharmacist may prepare a medicinal product (or a stock of such products) with a view to retail sale rather than to supply against an order. The sale must be from the registered pharmacy where the product was prepared. The product may not be advertised.
GUIDANCE ON THE EXEMPTION FOR PHARMACISTS
The Medicines and Healthcare products Regulatory Agency (MHRA) Guidance Note No.14 ‘The supply of unlicensed relevant medicinal prod- ucts for individual patients’ indicates how in practice MHRA will determine whether an activity is ‘preparation’ or ‘manufacture’. Criteria include location of the process, nature of the activity, and scale of the activity.
Following a case where a mixture was wrongly dispensed, resulting in the death of a child, the pharmacist and post-graduate trainee involved were both found guilty of a breach of Section 64 of the MA 1968.
At the time the Royal Pharmaceutical Society of Great Britain (RPSGB) issued guidance:
Pharmacists are advised to check carefully all calculations, paying particular attention to the decimal points, and to either carry out the preparation themselves or to delegate to suitably trained staff. In all cases the pharmacist should verify the formula used, the weightings or other measurements, and the calculations. Where possible an independent check is advisable. The pharmacist should always undertake a final review before the product is supplied to the patient.
The RPS issued a separate guidance document entitled ‘Dealing with Specials’ in June 2010.1
SPECIALS
The terms ‘named–patient medicine’ and ‘Specials’ are used interchangeably to refer to an unlicensed medicine specially ordered from a manufacturer. It is usually a medicine available ready-made from the manufacturer, not made up to a recipe supplied by the pharmacy or the doctor.
According to the Human Medicines Regulations, medicinal products which have no marketing authorisation may be marketed in the following circumstances:
● The company must hold a special manufacturers licence
● The manufacture must be under adequate conditions and supervision
● Records must be kept
● The product must be formulated in accordance with the specification of a prescriber
● The product is supplied for use by a prescriber, or by his individual patients, on his direct responsibility
● The supply must be to the prescriber or for use under the supervision of a pharmacist in a pharmacy, hospital or health centre
● The product must be distributed by a licensed wholesaler.
RECORD KEEPING
The ‘Specials’ manufacturer, the pharmacist and any practitioner who sells or supplies a ‘special’ must keep records for at least 5 years, which show:
● the source of the product
● the name of the person who obtained the product
● the date of the transaction
● the quantity of each sale or supply
● the batch number
● details of any adverse reaction to the product which he knows about.
Advertising of Specials
● Unlicensed medicines cannot be advertised to the public.
● Orders must be unsolicited – no advertisements are allowed. Catalogues and circular letters may only be sent to health care professionals on receipt of a bona fide unsolicited order.
● However, a Specials manufacturer, distributor or importer can issue a price list to health care professionals without first having received a bona fide unsolicited order. Regulation 7(3) excludes ‘trade catalogues’ and ‘price lists’ from the definition of ‘advertisement’.
The MHRA advise that any price list should consist only of a basic line listing providing the following information:
● reference number
● drug name (BAN or equivalent)
● dosage form
● strength
● pack size
● price
No product claims may be included.
IMPORTS
A further exemption allows importation of unlicensed products. Regulation 167 of the Human Medicines Regulations2 allows for the importation and sup- ply of unlicensed relevant medicinal products for the special needs of individ- ual patients, commonly, but incorrectly called ‘named patients’.
These regulations allow a licensed wholesaler to import an unlicensed product in response to a bona fide unsolicited order to fulfil special needs, for- mulated in accordance with the specification of a doctor or dentist and for use by his individual patients on his direct personal responsibility.
There are conditions laid down in the regulations:
(1) The importer must give written notice to the MHRA before importing and allow MHRA 28 days to object.
(2) The quantity imported must not exceed 25 single doses or 25 therapeutic courses (each not to exceed 3 months).
(3) The product must not be promoted.
(4) Records must be kept, and the MHRA notified of any adverse reactions.
EXEMPTION FOR DOCTORS
Doctors may prepare products themselves for use on patients. They may order the products from a registered pharmacy, which may make them without any further licensing. Doctors may order products themselves from licensed Specials manufacturers.
Regulation 3 of the Human Medicines Regulations 2012 states that the restrictions imposed by Regulations 17 and 46 (which generally require licenses) do not apply, where:
(1) a medicinal product is manufactured or assembled by a doctor or dentist;
and
(2) the medicinal product is supplied:
(a) to a patient in the course of the treatment of that patient; or
(b) to a patient of another doctor or dentist who is a member of the same medical or dental practice.
(3) the product is not manufactured or assembled:
(a) on a large scale; or (b) by an industrial process.
This allows a doctor to make or order an unlicensed product.
There are restrictions on the amount of stock held by a doctor – 5 l of fluid and 2.5 kg of solids.
Records must be kept for 5 years of the supplier, the recipient, the date of supply, batch details and details of any suspected reaction of which the sup- plier is aware.
Mixing of Medicines Prior to Administration
Until recently the view was that mixing of two medicines in a syringe prior to administration produced a new unlicensed medicine and was therefore an illegal act.
The matter has now been clarified by Regulation 20 of the Human Medicines Regulations.
(1) Regulation 17(1) (manufacturing of medicinal products) does not apply to the mixing of medicines by:
(a) a nurse independent prescriber;
(b) a pharmacist independent prescriber;
(c) a supplementary prescriber, if the mixing of medicines forms part of the clinical management plan for an individual patient;
(d) a person acting in accordance with the written directions of a:
(i) doctor, (ii) dentist,
(iii) nurse independent prescriber or (iv) pharmacist independent prescriber; or
(e) a person acting in accordance with the written directions of a supple- mentary prescriber, if the mixing of medicines forms part of the clini- cal management plan for an individual patient.
(2) In this regulation ‘mixing of medicines’ means the combining of two or more medicinal products together for the purposes of administering them to meet the needs of an individual patient.
Mixing of Controlled Drugs
Similarly the Misuse of Drugs (Amendment No. 2) (England, Wales and Scotland) Regulations 2012,3 which came into force on 23 April 2012, allows for the compounding or mixing of controlled drugs (CDs) for administration.
The regulations provide that:
a nurse independent prescriber acting in her capacity as such, or a supplementary prescriber acting under and in accordance with the terms of a clinical management plan, may compound any drug specified in Schedule 3 or 4 for the purposes of administration in accordance with regulation 7;
And similarly:
any person acting in accordance with the written directions of a doctor, a dentist, a nurse independent prescriber, a pharmacist independent prescriber, or a supplementary prescriber acting under and in accordance with the terms of a clinical management plan, may compound any drug specified in Schedule 3 or 4 for the purposes of administration in accordance with regulation 7.
Liability Issues with Use of Specials
Special consideration should be given to issues of liability when unlicensed products are used, or when products are used off-licence. The summary of product characteristics gives some information about the use of any particu- lar medicine, and prescribing within its limitations is unlikely to give rise to claims of negligence on the part of either doctor or pharmacist. Other informa- tion may be obtainable from specialist units.
The prescriber assumes legal liability when he or she prescribes unlicensed or off-label products. If a patient is harmed by the prescribing of an unlicensed
or off-label product, then it may be alleged that the prescriber and/or the pharmacist has been negligent. The test of whether a doctor or pharmacist is negligent is referred to as the ‘Bolam test’. This broadly states that a profes- sional person will not be negligent if what he does would be approved of by a responsible body of opinion in his profession. See Chapter 23.
The liability of the manufacturer for any harm caused by off-label use remains untested in court, although theoretically there could be liability under the Consumer Safety Act 1987.
Similarly there may be a possibility that the pharmacist might be liable in circumstances where he was aware of the use, where he knew about the pos- sibility of harm and where he could have taken action.
Advice Given to Doctors
The Medical Defence Union has advised doctors using off-label products for child patients that they must explain to those with parental responsibility that the drug is not appropriately licensed for paediatric use. Several studies recently have indicated that many doctors are unaware of the limitations for use set out in the data sheets for a product, and they may be grateful for a reminder.
Article 126a Authorisation
In order to increase the availability of some medicinal products, in particu- lar on smaller markets, Article 126a of Directive 2001/83/EC provides that, even in the absence of a marketing authorisation a medicinal product, which has already been authorised in another Member State, may be placed on the market.
In such cases, the competent authority of the Member State has to inform the marketing authorisation holder where the medicinal product concerned is authorised.
The Member State must ensure that the following requirements are com- plied with:
● the labelling and package leaflet
● the classification of the medicinal product
● advertising
● pharmacovigilance and
● supervision.
The publicly available register of the medicinal products authorised to be placed on the market under Article 126a is available at the Commission web site.4
Article 126a authorisations are dealt with by Regulation 156 of the Human Medicines Regulations:
(1) The licensing authority may grant an Article 126a authorisation for a medicinal product if the following conditions are met.
(2) Condition A is that no United Kingdom marketing authorisation, certif- icate of registration or traditional herbal registration is in force for the product.
(3) Condition B is that no application is pending in the United Kingdom for a marketing authorisation, certificate of registration or traditional herbal registration for the product.
(4) Condition C is that the licensing authority considers that the placing of the product on the market in the United Kingdom is justified for public health reasons.
(5) Condition D is that the product is imported from another Member State that has, in accordance with the 2001 Directive, authorised the placing on the market of the product in that Member State.
(6) Condition E is that the person to whom the authorisation is granted is established in the European Union.
(7) Before granting an Article 126a authorisation, the licensing authority must notify the authorisation holder in the Member State mentioned in paragraph (5) of the proposal to grant the Article 126a authorisation.
(8) Before granting an Article 126a authorisation, the licensing authority may request the competent authority in the Member State mentioned in paragraph (5) to provide in accordance with Article 126a(3)(b) of the 2001 Directive a copy of:
(a) the assessment report for that product as mentioned in Article 21(4) of the 2001 Directive; and
(b) the authorisation in force for that product.
(9) An Article 126a authorisation remains in force for the period specified in it unless revoked before the end of that period.
(10) That period may be specified by reference to the occurrence or non- occurrence of a particular event or events.
EXTRACTS FROM THE HUMAN MEDICINES REGULATIONS 2012
Special Provisions for Pharmacies, etc.
4.—(1) Regulations 17(1) (manufacturing of medicinal products: requirement for licence) and 46 (requirement for authorisation) do not apply where any provision of section 10 of the Medicines Act 1968(1) so provides.
(2) Chapter 1 of Part 13 (requirements for packaging and package leaflets relating to medicinal products) does not apply to a medicinal product that is sold or supplied in circumstances where paragraph (3) or (4) applies in relation to the product, except to the extent set out in paragraph (6), but the requirements of paragraph (5) shall apply.