The regulatory regimei Classification
The MHRA has primary responsibility for determining whether borderline products are medicinal products or medical devices. It does so case by case, having regard to the legal definition of a medicinal product and a medical device set out in EU law and implemented in the United Kingdom.
The MHRA's Borderline Section considers each product on its merits and any information that may have a bearing on the product's status; for example, its mode of action, pharmacological properties of the product's ingredients, the claims made for the product, whether there are any similar regulated products on the market, and how the product is presented through labelling, packaging, promotional literature and advertisements.
The Borderline Section provides informal, written advice on classification in response to specific enquiries about potential borderline issues. However, it will also exercise its enforcement powers following complaints about a particular product or based on its review of a product. In the latter scenario, the Borderline Section has a range of powers available to it to require removal of the product from the market (e.g., because it is an unlicensed medicine or a medical device that does not conform to the Medical Devices Regulations). However, the MHRA's usual approach is to serve a provisional determination notice advising that the MHRA considers the product a medicinal product or a medical device. A provisional determination must set out the reasons for the Agency's position and the options available to the person served with the notice should that person disagree with the determination. The options include the right to request an independent (advisory) review panel to review the determination and associated documentation. After considering the panel's advice, the MHRA makes a final determination. There is no right of appeal against a final determination, other than via the courts and judicial review. It is a criminal offence not to comply with the conditions of a final determination.ii Non-clinical studies
The Animals (Scientific Procedures) Act 1986 implemented Directive 2010/63/EU into UK law from 1 January 2013. It permits research involving animals only in premises licensed by the Home Office, by appropriately qualified staff and in accordance with procedures designed to minimise animal pain and suffering.
The Good Laboratory Practice Regulations 1999 transpose Directive 2004/10/EC into UK law. They require that all animal studies be conducted in accordance with sound standards of good laboratory practice. These standards reflect the Organisation for Economic Co-operation and Development requirements.iii Clinical trialsMedicines
Clinical trials of medicines for human use are regulated under the Medicines for Human Use (Clinical Trials) Regulations 2004 (the Clinical Trial Regulations), which implement Clinical Trials Directives 2001/20/EC and 2005/28/EC into UK law. Clinical trials of medicinal products in humans are generally only permitted if the MHRA has granted a clinical trial authorisation (CTA) and an ethics committee has issued a favourable opinion. A CTA is not required for 'non-interventional' trials, but the definition of a non-interventional trial is very narrow. It covers only trials involving approved medicines used on-label where there are no changes to routine medical care, including prescribing decisions or additional monitoring or information-gathering procedures.CTA approval process
Applicants for a CTA must first have obtained a EudraCT number and must then submit the relevant application form, the investigational medicinal product dossier (IMPD) and supporting documentation to the MHRA. The MHRA aims to assess applications within 30 days from receipt of a valid application, but there are accelerated review times for certain studies. The Agency aims to review applications for Phase I trials in healthy volunteers within 14 days and there is also a 14-day notification scheme for clinical trials that involve an authorised medicinal product and meet certain conditions.
Applications for a positive ethics committee opinion are usually considered in parallel with applications for a CTA and are made via the National Research Ethics Service, which is part of the Health Research Authority. Following the adoption of the new Clinical Trials Regulation (EU) No. 536/2014, the United Kingdom is currently working towards the establishment of a system for the granting of a single approval for a clinical trial, encompassing both MHRA and ethics committee review.
All investigational medicinal products must have been manufactured or imported by the holder of a manufacturer's authorisation in the European Economic Area (EEA). The manufacturer or importer must ensure that a qualified person has performed batch release of the products for clinical-trial use, which is only possible if the product is manufactured in accordance with an appropriate standard of good manufacturing practice (GMP) and if the product conforms with the specifications in the IMPD.
Sponsors must submit reports of suspected unexpected serious adverse reactions (both United Kingdom and non-United Kingdom) relevant to a UK trial to the MHRA and the relevant research ethics committee. There is also a requirement to submit annual safety reports. They must provide investigators with information on safety issues relevant to whether they enrol patients or allow them to continue with the study.
The Clinical Trial Regulations require sponsors to provide adequate insurance or indemnity to cover liabilities that may arise in relation to the clinical trial. The MHRA expects that a sponsor's insurance policy or indemnity will reflect the form recommended by the Association of the British Pharmaceutical Industry (ABPI) Clinical Trial Compensation Guidelines. The ABPI has also published specific insurance and compensation guidelines for Phase I clinical trials.Assessment process
The MHRA will assess the application within 30 days of receipt of a valid submission unless the applicant indicates that the study is eligible for the shorter 14-day assessment time.Medical devices
Clinical investigations of medical devices are governed by the Medical Devices Regulations. In addition to obtaining research ethics committee approval, the manufacturer must notify the MHRA prior to the conduct of a clinical investigation involving a non-CE-marked medical device. The MHRA assesses notifications within 60 days of receipt of a complete notification.
There is a different process for performance evaluation of a non-CE-marked in vitro diagnostic medical device (IVD). Manufacturers must draw up a declaration and follow the procedure set out in Annex VIII of the IVD Directive 98/79/EC and must also register details of the IVD for performance evaluation with the MHRA.
Manufacturers must report serious adverse events involving a device under clinical investigation to the MHRA. The MHRA requires manufacturers to provide insurance for subjects in clinical investigations of medical devices.iv Named-patient and compassionate-use proceduresMedicines
Regulation 167 of the Medicines Regulations implements the named-patient exemption under Directive 2001/83/EC into UK law. It allows the supply of unlicensed medicines in response to a bona fide unsolicited request by a healthcare professional to meet the unmet clinical needs of an individual patient. Medicinal products supplied under the named-patient exemption are known as 'specials'. A special may not be advertised (although price lists may be made available) and they should not be supplied if an equivalent authorised product is available. The responsibility for patient safety remains with the prescribing clinician.
If a special is manufactured in the United Kingdom, the manufacturer must hold a manufacturer's (specials) licence granted by the MHRA. Importers of specials must hold the appropriate wholesale dealer's or manufacturer's authorisation. In addition, importers must notify the MHRA 28 days prior to importing a special.
There are record-keeping requirements and serious adverse drug reactions must be reported to the MHRA.
The compassionate use exemption under Article 83 of Regulation (EC) No. 726/2004 applies directly in the United Kingdom.
The MHRA's Early Access to Medicines Scheme (EAMS) provides another exemption to the requirement for a medicinal product to have a marketing authorisation prior to being placed on the market. The EAMS has been adopted to enable patients with 'life-threatening or seriously debilitating conditions' to have early access to medicines that have yet to receive a marketing authorisation. The process for joining the scheme involves a two-stage evaluation by the MHRA: step I is the promising innovative medicine (PIM) designation, and step II is the EAMS scientific opinion. For medicines to qualify for the EAMS, they must meet the following criteria:
- the product is needed to treat a life-threatening or seriously debilitating condition, and there is a high unmet need;
- the medicinal product is likely to offer significant advantages over methods currently used in the United Kingdom;
- the potential benefits of the medicinal product outweigh the adverse effects; and
- the applicant is able to supply the product and to manufacture it to a consistent quality standard of GMP.
The Medical Devices Regulations permit the supply of custom-made medical devices that meet the essential requirements but have not been CE-marked, and also devices that do not meet the essential requirements, provided that the MHRA authorises their use.
The use of an individual non-complying medical device, for a single named patient, is permitted only in exceptional circumstances; for example, where no alternative CE-marked devices are available or where it has been demonstrated that the morbidity or mortality of patients is significantly reduced with the use of the device in question as compared to those using alternative available treatment. The MHRA requires that an application be made for each patient, which includes information from the manufacturer and relevant clinician.v Pre-market clearanceMedicines
Regulation 46 of the Medicines Regulations implements Article 6(1) of Directive 2001/83/EC, which requires that a medicinal product has a marketing authorisation prior to being placed on the market. It is an offence for any person to sell or supply, or offer to sell or supply, an unauthorised medicinal product or a medicinal product otherwise than in accordance with the terms of a marketing authorisation.
The MHRA is the UK national competent authority for review of marketing authorisation applications under the national, mutual recognition and decentralised procedures, although the relevant ministers acting through the licensing authority grant the authorisations.Medical devices
The EU chapter summarises the conformity assessment and CE-marking procedures for medical devices. Since there is little regulatory pre-market review and approval of medical devices (with the exception of European Medicines Agency review of devices incorporating medicinal products and blood products), the MHRA has no involvement in the process leading up to CE marking.
However, the Medical Device Regulations require that manufacturers and authorised representatives based in the United Kingdom that are placing Class I or custom-made devices on the market to register details of themselves and the medical devices with the MHRA. Manufacturers or authorised representatives for IVDs must register themselves and their IVDs via the EU database, Eudamed.vi Regulatory incentivesMedicines
The Medicine Regulations implement the EU periods of eight years' regulatory data exclusivity (during which generic applicants cannot file) followed by two years' market exclusivity (during which regulators may review generic applications, but generic manufacturers cannot launch) under Directive 2001/83/EC for products for which qualifying national applications were submitted after 30 October 2005. For complete free-standing applications submitted on or before that date, UK marketing authorisation holders would benefit from 10 years of data exclusivity protection, during which generic applicants cannot file. These regulatory exclusivity periods begin when the product is first approved anywhere in the EEA, not necessarily in the United Kingdom.
The additional data exclusivity provisions for 'orphan medicinal products' and for products with paediatric indications developed in accordance with an approved paediatric investigation plan under Regulation (EC) No. 141/2000 and Regulation (EC) No. 1901/2006, respectively, apply directly.
In the United Kingdom, the Intellectual Property Office is responsible for granting supplementary patent certificates for medicinal products that meet the criteria under Regulation (EC) No. 469/2009.Medical devices
UK legislation does not provide specific regulatory exclusivity periods for medical devices. A device may be protected by a UK patent if it satisfies the requirements for patentability under the Patents Act 1977. A UK patent is granted initially for four years and is renewable annually thereafter up to a maximum of 20 years from the filing date of the patent application.vii Post-approval controls
The United Kingdom's post-approval controls over marketing authorisation holders for medicines and manufacturers of medical devices closely mirror the EU requirements.Transfer of marketing authorisations for medicines
Marketing authorisation holders may apply to the MHRA to 'transfer' ownership of their marketing authorisations to third parties. If satisfied that the recipient is suitable to hold the approval, the MHRA will grant the transferee a new marketing authorisation. It will usually also allow the original authorisation to remain in force for a transitional period. This avoids interruptions in supply by allowing a product in the name of the original authorisation holder to be placed on the market until the new product is widely available.Revocation, suspension or variation of marketing authorisations
The licensing authority, acting through the MHRA, has the power to revoke, suspend or vary a marketing authorisation. Companies that are unhappy with the proposal have the right to appeal to the appropriate committee, then to an independent review panel in accordance with Schedule 5 of the Medicines Regulations. However, these procedures do not apply when the product is centrally approved or has been subject to either the mutual recognition procedure, the decentralised procedure or an EU referral. Under those circumstances, the relevant procedures are governed by EU law.viii Manufacturing controls
The substantive requirements governing the manufacture of medicinal products, including the need for a manufacturing or import authorisation, a qualified person and compliance with GMP, are discussed in the European Union chapter.
The MHRA regulates pharmaceutical manufacturing operations within the United Kingdom, although the licensing authority actually grants, suspends and revokes manufacturing authorisations. The MHRA will conduct inspections of manufacturing facilities before authorisation and periodically thereafter.
Changes to UK manufacturing and wholesale distribution authorisations require variations to be submitted to the MHRA. A change of name of the licence holder, if it remains the same legal entity, requires a simple administrative notification to the MHRA. Transfers of authorisations from one legal entity to another require submission of a change of ownership application signed by both the transferor and the transferee. The MHRA will only accept such change of ownership applications if there is no substantive change to premises, operations or personnel. If there are any substantive changes, the MHRA will treat the application as an application for a new licence.ix Advertising and promotionMedicines
The Medicines Regulations implement the EU advertising rules into UK law. These include the general requirements that advertisements should not be misleading, that they should be substantiated and that they should be accompanied by appropriate prescribing information. There is also a prohibition on pre-approval or off-label promotion of medicines, advertisements of prescription-only medicines to the general public, and illegal inducements to prescribe. Guidance from the MHRA, called the Blue Guide on Advertising and Promotion of Medicines in the UK (the Blue Guide), supplements the Regulations and is intended to provide additional clarification on the interpretation and application of the law. The MHRA is the statutory enforcement body for these rules and requires pre-vetting of advertising material in some circumstances, for example, new active substances granted marketing authorisations.
The statutory scheme is supported by a long-standing system of self-regulation based on the ABPI Code of Practice for the Pharmaceutical Industry (the ABPI Code). The ABPI Code is enforced by a self-regulatory body called the Prescription Medicines Code of Practice Authority (PMCPA), which adjudicates complaints by competitor companies and individuals, but can also bring proceedings itself.
The ABPI Code governs the advertising of prescription-only medicines to health professionals, relevant administrative staff and to the general public. It only applies to companies that are members of the ABPI or that have formally agreed to abide by the ABPI Code. The success of this self-regulatory scheme has meant that the MHRA has not needed to exercise its statutory enforcement powers against legitimate pharmaceutical companies for nearly 30 years.
The provisions of the ABPI Code are consistent with the Medicines Regulations and in some instances more stringent. For example, under the ABPI Code, promotional material must not be issued unless its final form has been certified on behalf of the company by a person that is a registered medical practitioner or a UK-registered pharmacist. It also significantly limits companies' ability to provide promotional aids and seeks to regulate certain company interactions with the National Health Service (NHS).Medical devices
The United Kingdom has no specific device advertising legislation. Medical device advertising is subject to general advertising rules, requiring that advertisements be substantiated, factual, balanced and not misleading.
The Association of British Healthcare Industries (ABHI) has incorporated advertising guidelines into its Code of Business Practice (the ABHI Code). The provisions of the ABHI Code only apply to ABHI members and companies that have formally agreed to abide by the ABHI Code. There is a complaints procedure, but at the time of going to press, the Complaints Adjudication Panel has yet to hear a complaint.x Distributors and wholesalersMedicines
As under EU law, distributors of medicinal products must hold a wholesale dealer's licence, and must operate appropriate facilities and staff under the supervision of an appropriately qualified responsible person. They must comply with good distribution practices (GDP) and maintain appropriate batch records.
The Medicines Regulations define wholesale dealing as 'selling or supplying it, or procuring or holding it or exporting it for the purposes of sale or supply' to a person who receives it for the purposes of selling or supplying it, or administering it or causing it to be administered to a human being, in each case in the course of a business carried on by that person. Thus, the sale of a medicine without physically handling the product constitutes wholesale dealing, for which a distributor's authorisation is required.
The licensing authority, acting through the MHRA, is responsible for issuing, suspending and revoking wholesale dealers' licences in the United Kingdom. The MHRA will conduct inspections prior to the grant of such a licence and then periodically thereafter.
Consistent with EU law, the Medicines Regulations also regulate 'brokers', meaning persons who engage in activities in relation to the sale or purchase of medicinal products, except for wholesale distribution, that do not include physical handling and that consist of negotiating independently and on behalf of another legal or natural person. UK-based brokers must comply with GDP and must be registered with the MHRA.Medical devices
The United Kingdom has no specific rules governing the distribution or wholesale of medical devices.xi Classification of productsMedicines
The Medicines Regulations presuppose that new medicinal products are generally restricted to use under medical supervision and made available only on prescription. There is also scope for imposing additional restrictions, such as requiring that certain products are prescribed only by specialists, or in hospitals. Non-prescription status is appropriate only for products with an appropriate level of safety and where self-diagnosis and treatment is appropriate without a healthcare professional's intervention or supervision.
There are two classes of non-prescription or over-the-counter drugs in the United Kingdom. Consumers must obtain pharmacy supply products bearing the designation 'P' from pharmacies, where they are dispensed under the supervision of a registered pharmacist. General sale list products may be sold through general retail channels, such as supermarkets, convenience stores, petrol stations and the like. These products bear the designation 'GSL'.Medical devices
There are no UK rules governing the classification of medical devices that restrict their sale to the public.xii Imports and exports
The United Kingdom's regulations governing the import and export of medicinal products reflect those at EU level. Unless products are intended only for trans-shipment via the United Kingdom, they must be imported by the holder of a manufacturer's authorisation. Products may only be exported by authorised manufacturers or distributors.xiii Controlled substances
The Misuse of Drugs Act 1971 and subordinate legislation, including the Misuse of Drugs Regulations 2001, implement the UN Single Convention on Narcotic Drugs 1961 and the UN Convention on Psychotropic Substances 1971 into UK law. A 'domestic licence' is required to produce, possess, supply or offer to supply any controlled substance. Any person that intends to import or export a controlled substance must also obtain an import or export licence for the particular consignment, as applicable. The Home Office is responsible for issuing controlled substances licences in England and Wales. A domestic licence holder may only supply controlled substances to persons authorised to possess such substances; for example, registered pharmacists.xiv EnforcementMedicines
A breach of the Medicines Regulations is in most cases a criminal offence, and the MHRA has an Enforcement Division that considers and manages prosecutions. When the MHRA identifies a potential breach of the legislation, a letter is sent to the individual outlining the Agency's provisional view. The letter will generally list the potential breach or breaches and any public health risk identified where appropriate, along with any action the MHRA requests the company to take. The process to resolve these issues tends to be informal, with individuals agreeing to take voluntary action, so prosecutions are rare. Offences under the Medicines Regulations are usually triable either way (i.e., in summary proceedings before magistrates or on indictment before a crown court judge and jury, depending on the seriousness of the breach). They usually carry a penalty of a fine on summary conviction, or an unlimited fine and the possibility of up to two years in jail on indictment. The historic limit of £5,000 for fines on summary conviction was removed for offences committed after March 2015.
When the PMCPA Panel rules there is a breach of the ABPI Code under the self-regulatory scheme, the company concerned must give an undertaking not to repeat the offending advertisement or activity. The company, whether a member of the ABPI or not, must also pay an administrative charge of £3,500 per matter (or £4,500 per matter for non-members) where it accepts the Panel's decision that it breached the Code. The charge increases to £12,000 per matter (or £13,000 per matter for non-members) where the company appeals the Panel's decision and is unsuccessful. At the conclusion of a case, the PMCPA will also publish a detailed case report in its Code of Practice review and on its website.Medical devices
The MHRA is responsible for ensuring compliance with the Medical Devices Regulations. For enforcement purposes, an offence under these Regulations is often treated as a breach of a safety regulation under the Consumer Protection Act 1987. A person who contravenes the Medical Devices Regulations is liable for a penalty of six months' imprisonment or a fine per breach.
The main sanction under the ABHI Code for non-compliance is negative publicity. An administrative charge is also payable. However, there have been no complaints procedures under the Code and the level of the administrative charges payable has not yet been determined.