All questions
The regulatory regime
i Classification
The MHRA has primary responsibility for determining whether borderline products are medicinal products or medical devices. The MHRA’s Medicines Borderline Section considers each product on its merits and any information that may have a bearing on the product’s status.
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.
ii Non-clinical studies
The Animals (Scientific Procedures) Act 19868 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 19999 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). 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.
Non-UK sponsors of clinical trials in the UK must designate a UK legal representative. All investigational medicinal products (IMPs) must have been manufactured or imported by the holder of a manufacturer’s authorisation in the UK, unless they are sourced from a jurisdiction on the ‘approved country for import list’. The list initially includes all EU and European Economic Area (EEA) countries. In such cases, a UK Manufacturing and Import Authorisation (MIA(IMP)) holder must put in place a system overseen by a Qualified Person (QP) to check these IMPs have been certified by a QP in a listed country, before release to trial sites.
Sponsors must submit reports of suspected unexpected serious adverse reactions relevant to a UK trial to the MHRA and the relevant research ethics committee. There is also a requirement to submit annual safety reports.
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.
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 medical device without a UK conformity assessment (UKCA) or CE mark.
There is a different process for performance evaluation of an in vitro diagnostic medical device (IVD) without a UKCA or CE mark. 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
The Medicines Regulations allow 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). 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.
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 good manufacturing practice (GMP).
Medical devices
The Medical Devices Regulations permit the supply of custom-made medical devices that meet the essential requirements but have not been CE-marked or UKCA 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
The Medicines Regulations 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 UK now has three forms of national marketing authorisations. UKMA(UK) is in force in the entire United Kingdom, UKMA(GB) is in force in Great Britain only and UKMA(NI) is in force in Northern Ireland only. UK marketing authorisations for Great Britain are granted by the MHRA under national procedures as they can no longer participate in EU mutual recognition procedures or decentralised procedures. Centralised marketing authorisations granted by the European Commission no longer apply in Great Britain but, unless the marketing authorisation holder opted out, all existing centralised marketing authorisations were converted into UKMA(GB)s on 1 January 2021.
However, at the time of writing, pursuant to the Northern Ireland Protocol, existing and future centralised marketing authorisations continue to apply in Northern Ireland. Also, Northern Ireland can continue to be included in EU mutual recognition procedures or decentralised procedures as a Concerned Member State.
Medical devices
The EU chapter summarises the conformity assessment and CE-marking procedures for medical devices. Because there is little regulatory pre-market review and approval of medical devices (with the exception of a medicines regulator’s review of devices incorporating medicinal products and blood products), the MHRA has no involvement in the process leading up to CE marking.
Following Brexit, the UK has decided not to implement either the EU Medical Devices Regulation or its IVD equivalent. In the short term at least, the UK will align its medical devices regime with the current EU devices directives (although as the time of writing the MHRA is reviewing responses to its consultation on proposed changes to the medical devices regulatory framework). Until 2023, it will allow CE-marked devices to be placed on the market in the UK but, from 2023, medical devices for the Great Britain market must bear the UKCA mark. Post-Brexit, all medical devices and IVDs placed on the market in the UK must be registered with the MHRA, although there are grace periods for manufacturers of those classes of devices that were not required to be registered under the previous regulations.
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).
The UK will continue to offer orphan exclusivity in accordance with EU standards, but applicants will submit applications to the MHRA and timing of exclusivity protection will be calculated from the product’s first approval in the UK. Similarly, companies must agree paediatric investigation plans (PIPs) with the MHRA post-Brexit and will benefit from rewards equivalent to those under EU law (although there is added complexity as the territorial scope of the supplementary patent certificate and marketing authorisations may vary).
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. 469/2009.10
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 1977.11 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 currently closely mirror the EU requirements. However, reports and notifications are exclusively to the MHRA, post-Brexit.
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 UK 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.
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 and import 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.
Post-Brexit, entities with a UK wholesale dealer’s licence can import medicines into Great Britain from a country on the ‘approved country for import’ list (which currently includes all EEA Member States) if the entity appoints a Responsible Person (import) and this person confirms (1) the required QP certification has taken place and, if applicable, (2) the required independent batch release certificate is available for biological products. Medicinal products imported from countries not on the approved country must be imported by the holder of a manufacturers import authorisation (MIA) and batch released for the Great Britain market by a UK QP. The UK has stated it will review its acceptance of batch testing done in EEA countries before 31 December 2022 and a two year notice period will be given in case of changes. However, at the time of writing, products entering Northern Ireland will need to be batch released by a manufacturer in the EEA. Therefore, entities that were previously a medicine retailer/wholesaler that obtains medicines from Great Britain would now need to be authorised as an importer (although the European Union did provide a limited transition period for products being imported into Northern Ireland from Great Britain).
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 underwent a major overhaul in 2021 and is now more closely aligned with the European Federation of Pharmaceutical Industries and Associations Code of Practice (the EFPIA Code).
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
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 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.
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 currently has no specific rules governing the distribution or wholesale of medical devices and the UK has indicated that it does not currently intend to implement the rules governing distributors and other economic operators in device supply chains under the EU Medical Devices Regulation (EU) 2017/745 and In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746. However, as these Regulations apply in Northern Ireland it should be noted that those acting as retailers/distributors in Northern Ireland and purchasing devices from Great Britain will now be considered as importers.
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 generally reflect those at EU level, although Brexit has made the rules somewhat more complex. Unless products are intended only for trans-shipment via the United Kingdom, they must be imported by the holder of a manufacturer’s authorisation or (as explained above), if importation is from an approved country into Great Britain, the holder of a wholesale dealer’s licence. Products may only be exported by authorised manufacturers or distributors.
xiii Controlled substances
The Misuse of Drugs Act 197112 and subordinate legislation, including the Misuse of Drugs Regulations 2001,13 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.
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. Additionally, if companies are ruled in breach of Clause 2 they must pay £4,000 towards the cost of advertising that fact in the relevant press. 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, with new powers to enforce civil sanctions under the Medicines and Medical Devices Act 2021.
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.
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