The process for licensing a product in Europe is well defined and has evolved to allow two potential routes within the European Union (EU): a centralised system encompassing marketing approval in all EU States, or a decentralised system involving individual state assessment and recommendation for approval (e.g. via the MHRA in the UK) to other member states.
If there is a special patient need that cannot be met with a licensed medicine, a physician may decide to prescribe an unlicensed alternative. Article 5.1 of Directive 2001/83/EC allows each EU member state to establish its own national arrangements for regulating the provision of unlicensed medicines. Medicines may be unlicensed for several reasons.
In the UK, the Committee for Medicinal Products for Human Use Regulations SI 1994/3144, the Medicines Act (1968) and MHRA Guidance Note 14 all have a role to play in the regulation of unlicensed medicines.
The MHRA is currently reviewing the guidelines associated with the supply and distribution of unlicensed medicines with a view to continuing to protect patient safety and minimise risk. At present the perceived hierarchy of risk from licensed to specials is presented below:
Challenges for the pharmacist
Principle one of the pharmacist Code of Ethics states:
‘The care, well-being and safety of patients are at the centre of everyday professional practice. They must be your primary and continuing concern when practising.’
The law allows a pharmacist to prepare or dispense a product which does not have a MA, or to dispense a medicinal product outside the terms of its MA, in response to a prescription from a medical practitioner. However, the challenge is to be able to dispense the product with the confidence that it has been sourced and provided in a way that will consistently ensure patient safety.
The supplying pharmacist may assume some liability with the prescribing doctor. The extent of this liability, however, depends on the facts of every case.
MHRA Guidance Note 14 provides conditions that the pharmacist should check before sourcing and dispensing an unlicensed medicine. The key conditions are summarised:
- Confirm with the supplier that the product is for an individual patient. The pharmacist does not have to supply the patient name to the supplier primarily because of patient confidentiality issues, but the pharmacist should keep a record.
- All within the supply chain should be aware that the product is unlicensed. The pharmacist should liaise with the prescriber and ensure that they are aware of the unlicensed status. The MHRA review of unlicensed medicines may make it necessary for product packs to display clearly the unlicensed status.
- Check that the manufacturer and supplier have the required licences for the provision of unlicensed medicines. Manufacturers of unlicensed medicines must hold a ‘Specials’ licence. Importers must hold a Wholesale Dealer’s Licence which states clearly an ability to hold and manage unlicensed medicines (for import within the EU/EEA) and a Manufacturer’s Specials Licence (for import from outside the EU/EEA). These companies will also be inspected and audited regularly by the MHRA.
- Imported products should be notified to the MHRA. If the product is imported, the supplier must notify the MHRA at least 28 days in advance of each importation and allowed the MHRA to carry out safety checks before approval. The quantity on each ‘notification’ must not exceed 25 single administrations or 25 courses of treatment (a maximum three month course). Again, this stipulation is currently being reviewed.
- ‘Special’ products must comply with Good Manufacturing Practice. If a product is manufactured as a ‘special’ in the UK, a qualified person will ensure that it complies with GMP standards and the GMP Inspector will check stability, labelling and expiry information.
- Licensed manufacturers and distributors must have satisfactory pharmacovigilance support. Providers need to maintain batch records and traceability to facilitate batch recall if required. They also must have processes for reporting adverse events which will allow effective communication between the manufacturer and MHRA, and ensure appropriate action is taken in the interests of patients. These records should be kept for a minimum of five years.
- MHRA must be notified of supply interruptions. If there are stock shortages of a licensed product, or manufacturing problems, there may be a need to import an unlicensed alternative. However, all manufacturers have a legal obligation to notify the MHRA of any potential supply difficulties.
Recent examples and potential issues
Co-proxamol was withdrawn by the MHRA in December 2007 due to concerns over drug related fatalities. The medicine was subsequently allowed to be provided on an unlicensed, named patient basis. The supplier worked with the MHRA to agree the principles of communication and supply to over 12,000 pharmacists. Communication was instigated with key professional and patient organisations. The supplier also worked closely with the Department of Health on pricing amendments and re-imbursement issues and co-proxamol is now listed by the DH in category C of the Drug Tariff.
This has enabled appropriate patients to remain on their required therapy and improve their health outcome. It has also been suggested that the number of fatalities relating to co-proxamol use has reduced significantly.
Residual licensed packs that were manufactured prior to the withdrawal of the MA accounted for a significant level of the product supply in 2008, one year after the MA withdrawal. This led to some confusion with pharmacists as to whether the unlicensed or licensed pack should be dispensed (the MHRA had asked for a voluntary recall of all licensed packs). This may have led to the subsequent manufacture and supply of some packs that were considered illegal in the UK with intervention required by the MHRA enforcement officers
PCTs took different steps in advising GPs on the availability of co-proxamol. Therefore prescribing has been in line with MHRA intention in some areas, while in others a patient who needs the product may have been denied unfairly, due a different interpretation and communication to prescribing GPs. This is almost a ‘postcode’ lottery of availability.
Two years on from the licence withdrawal and most pharmacists are able to provide a consistent and quality supply to patients who need the product.
Nabilone is a synthetic canabinoid that was withdrawn in the 1980s. Nabilone 1mg is licensed and indicated for the control of nausea and vomiting caused by chemotherapeutic agents in patients who have failed to respond adequately to conventional antiemetic treatments. However, nabilone is unlicensed in the 250mcg form and needs to be provided on a named-patient basis. Both forms are used ‘off-label’ in 90 per cent of cases for pain relief in fibrous myalgia.
Potential complexities for the pharmacist include:
- Unlicensed and licensed forms of the same product;
- ‘Off-label’ usage.
In these circumstances the pharmacist may be forgiven for wondering where the boundaries of liability lie, and what should be communicated to the patient at the point of dispensing. Certainly they will take some comfort from knowing that their supplier has the right licenses, knowledge and expertise in supplying the product.
Virazole (ribavirin) has antiviral inhibitory activity in vitro against respiratory syncytial virus, influenza virus and herpes simplex virus. The injectable form of the product is unlicensed as an acute treatment for patients with vulnerable immune systems which can be life threatening, and has been supplied in the past on a named patient basis.
Virazole inhaler is licensed for the treatment of severe respiratory syncytial virus (RSV) bronchiolitis in infants and children, and may need to be supplied in this formulation together with the necessary equipment for nebulisation.
Virazole injection is expensive (at over £3500 per pack), unlicensed and rarely used, but it is life-saving product often used for children undergoing transplant operations. In this case it is important for the pharmacist to be confident that the supplier can provide the product quickly and efficiently even in emergency and ‘out-of-hours’ situations.
Scott Smith, Commercial Director of Clinigen