An Introduction to EU Pharmaceutical Regulatory Affairs

AN INTRODUCTION TO EU/UK PHARMACEUTICAL REGULATORY AFFAIRS Clare Rosser MChem (Hons), PhD Samantha Knight BSc (Hons) Mandy Tyler-Mahon, MChem (Hons), PhD, MTOPRA Jay Gandecha*, BSc (Hons), MRSC, MTOPRA April 2023 *Main author of the presentation Objectives • An interactive session to share an overview of regulatory • • • • affairs in UK and EU such that you have a basic understanding of this topic at the end of the session See how patients experience the output of regulatory affairs Give you an idea of what it is like to work within regulatory affairs in a large pharmaceutical company Provide you with contacts in the pharma regulatory affairs industry Answer any questions you may have Presenters • Clare Rosser, Director, Small Molecules Development Projects, CMC Regulatory Affairs • Samantha Knight, Director, Vaccines Mature Products, CMC Regulatory Affairs • Mandy Tyler-Mahon, Director, Portfolio Management, Established Products Regulatory Affairs Contents • Why we need to regulate medicines • History of medicines regulation in the UK • Formation of Regulatory Bodies in the UK • Regulatory agencies across Europe • Marketing Authorisation Process • The Dossier – Common Technical Document • Break • Quality Standards • Post approval changes • Brexit Why do we need to regulate medicines? Why do we need to regulate medicines? • Drugs are not ordinary consumers’ products. In most instances, consumers are not in a position to make decisions about when to use drugs, which drugs to use, how to use them and to weigh potential benefits against risks as no medicine is completely safe. • Professional advice from either prescribers or dispensers are needed in making these decisions. However, even healthcare professionals nowadays are not in capacity to take informed decisions about all aspects of medicines without special training and access to necessary information. • The production of medicines, their distribution and dispensing also requires special knowledge and expertise Brief history of UK medicines regulation • Before the middle of the nineteenth century there were no effective controls over the sale of medicines, and only limited progress was made in ensuring their safety and efficacy • A number of sudden deaths were reported following the introduction of chloroform as an anaesthetic, as a result of which a British Medical Association (BMA) working party suggested in 1880 the setting up of an independent body to assess drug safety. • Before the Medicines Act of 1968 medicines were classified as poisons. • A new category of dangerous drug introduced in 1920 and therapeutic substances in 1925. Some legislation to control the quality, sale and promotion of medicines existed before then, but its impact was very limited. Brief history of UK medicines regulation • The first edition of the British Pharmacopoeia (BP) appeared in 1864, and this laid down standards for the manufacture of common established drugs. • The Therapeutic Substances Act 1925 introduced regulations concerning the manufacture of biological substances; it was strengthened in 1956. • Legislation did not keep pace with the enormous progress that was made in the middle of the twentieth century in the discovery of new medicines, and it had little relevance to the therapeutic revolution that was taking place. The thalidomide disaster • The thalidomide disaster in 1961 was the major watershed that transformed medicines regulation in the UK. Thalidomide first went on sale in 1956 as a sedative and hypnotic. • It was widely prescribed during the late 1950s and early 1960s for insomnia, because it was seen to be vastly safer than barbiturates • following anecdotal reports of benefits in the treatment of vomiting in early pregnancy, it was heavily promoted for the relief of morning sickness in the first few months of pregnancy. The thalidomide disaster • But in 1959 reports started to appear of babies being born with malformed limbs and other associated internal malformations. • November 1961 a possible link between these serious birth defects and thalidomide was highlighted, as a result of which the drug was withdrawn. Within nine months or so the epidemic of malformations returned to background levels. The thalidomide disaster • In a bid to prevent a similar occurrence, the Committee on Safety of Drugs (CSD) was set up in 1963. It had no legal powers but worked effectively with the pharmaceutical industry to advise on clinical trials and the marketing of new medicines. This committee also set up a system of adverse drug reaction reporting for drugs by means of reply-paid yellow cards; this became known as the “Yellow Card Scheme” • A White Paper in 1967 recommended legislation rather than a voluntary system to control medicines and the Medicines Act received Royal Assent in October 1968. This Act established the requirement that, from 1 September 1971, all medicines, for both human and animal use, already on the UK market had to be reviewed, whilst any new products had to be first approved and licensed before being allowed onto the UK market. Regulatory bodies • Responsibility for this role initially lay with the Medicines Division of the Department of Health for human medicines. Rising demands and delays in licensing led to the creation of the Medicines Control Agency (MCA) in 1989 • MCA then merged with the Medical Device Agency to become the Medicines and Healthcare products Regulatory Agency (MHRA) in 2003 Regulatory bodies • National Competent Authorities e.g. MHRA (UK) • The MHRA is responsible for regulating all medicines and medical devices in the UK by ensuring they work and are acceptably safe. • The MHRA also regulate Blood • It is the responsibility of the MHRA and the expert advisory bodies set up by the Medicines Act to ensure that the sometimes difficult balance between safety and effectiveness is achieved. • MHRA experts assess all applications for new medicines to ensure they meet the required standards. This is followed up by a system of inspection and testing which continues throughout the lifetime of the medicine. • Safety monitoring is also continuous and the MHRA also ensures that doctors and patients receive up-to-date and accurate information about their medicines. This is achieved by ensuring that product labels, leaflets, prescribing information and advertising meets the required standards laid down by the Regulations. Regulatory Agencies • EMA: European Medicines Agency: • The European Medicines Agency is a decentralised agency of the European Union, located in Amsterdam. The Agency is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. It began operating in 1995. • The European Medicines Agency's (EMA) main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. • The Agency is responsible for the scientific evaluation of applications for European Union (EU) marketing authorisations for human and veterinary medicines in the centralised procedure. • The EMA is responsible for coordinating the EU's safety-monitoring or 'pharmacovigilance' system for medicines. It constantly monitors the safety of medicines through the EU network and can take action if information indicates that the benefit-risk balance of a medicine has changed since it was authorised. The EMA has a Pharmacovigilance Risk Assessment Committee (PRAC), which provides recommendations on the safety of human medicines. Regulatory Agencies • The HMA: Head of Medicines Agencies • The Heads of Medicines Agencies (HMA) is a network of the heads of the National Competent Authorities (NCA) whose organisations are responsible for the regulation of medicinal products for human and veterinary use in the European Economic Area. • The HMA co-operates with the European Medicines Agency (EMA) and the European Commission in the operation of the European medicines regulatory network and it is a unique model for cooperation on statutory as well as voluntary regulatory activities. • The HMA: • addresses key strategic issues for the network, such as the exchange of information, IT developments and sharing of best practices • focuses on the development, co-ordination and consistency of the European medicines regulatory system • ensures the most effective and efficient use of resources across the network. This includes developing and overseeing arrangements for work-sharing • co-ordinates the mutual recognition (MRP) and decentralised procedures (DCP). EU Member states What do regulatory authorities do? Principle responsibilities of regulatory authorities • Licensing of the manufacture, import, export, distribution, • • • • • • promotion and advertising of medicines Assessing the safety, efficacy and quality of medicines, and issuing marketing authorisation for individual products Inspecting and surveillance of manufacturers, importers, wholesalers and dispensers of medicines Controlling and monitoring the quality of medicines on the market Controlling promotion and advertising of medicines Monitoring safety of marketed medicines including collecting and analysing adverse reaction reports Providing independent information on medicines to professionals and the public The story so far… Medicines regulation Regulatory Agencies National Agencies Pharmaceutical Companies EU Legislation • The three main types of EU Legislation are: • Regulations • are addressed to all member states and are applied in full. They are directly applicable without the need for national legislation. • Directives • are addressed to all member states. National authorities must draw up legislation in order to conform with the directive. • Decisions • are issued by the Council or Commission; these are not of general application. They may be addressed to particular member states, individuals or companies and they are binding on those to whom they are addressed EU Legislation applicable to pharmaceutical product lifecycle REGULATION (EC) No 1901/2006 (Medicines for children) Regulation (EC) 141/2000 (Orphan medicines) EU Clinical Trial Regulation 536/2014 Commission Regulation (EC) No 1234/2008 (Variations) Directive 2001/83/EC; Regulation (EC) No 726/2004 (Community procedures for authorisation, supervision and Pharmacovigilance) Regulation (EC) No 1394/2007 (Advanced therapy medicinal products) EU Pharmaceutical legislation • Directive 2001/83/EC • Applies to all medicinal products for human use, except for: • medicinal products prepared in a pharmacy in accordance with a • • • • • • medical prescription; medicinal products prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia; medicinal products intended for research and development trials; intermediate products intended for further processing; radionuclides in the form of sealed sources; whole blood, plasma or blood cells of human origin; innovative therapeutic medicinal products prepared on an as-needed basis, under the professional responsibility of a doctor, to carry out a given medical prescription. EU Pharmaceutical legislation • Marketing authorisation procedure • No medicinal product (with the exception, under certain conditions, of radiopharmaceuticals prepared at the time of use) may be placed on the market of a Member State unless an authorisation has been issued by the competent authorities of that Member State or by the European Medicines Agency. • Only applicants established in the Community (EU) may be granted a marketing authorisation – Marketing Authorisation Holder (MAH) • The medicinal product must be released (Manufacturer) in the Community (EU) Marketing Authorisation Procedure • Certain particulars and documents must be included with the authorisation request (registration dossier), namely: • the name and constituents of the medicinal product; • the manufacturing method; • a description of control tests employed by the manufacturer; • expected shelf-life, precautionary and safety measures during storage • • • • • • • and administration of the medicinal product; therapeutic indications, contra-indications and side-effects; posology, method and route of administration; disposal of waste; the risk to the environment; the results of pharmaceutical, pre-clinical and clinical tests; a summary describing the applicant’s system of pharmacovigilance; a copy of any marketing authorisation obtained in another Member State or non-member country. The Dossier – CTD triangle The Dossier – CTD – Module 1 • Module 1 is for administrative information and product information (SmPC, PIL), and should contain documents that are specific to each region; for example, application forms or the proposed label (artworks) for use in the region. The Dossier – CTD – Module 2 • Module 2 contains the CTD summaries and should begin with a general introduction to the drug, including its pharmacological class, mode of action and proposed clinical use. • Module 2 should also provide the overall summary of the ‘quality’ information provided, the non-clinical overview and the clinical overview, as well as the non-clinical written summaries and the tabulated summaries, and the clinical summary. The Dossier – CTD – Module 3 • Module 3 contains detailed information on quality topics. • Divided into S (substance) and P (product). • Often called the “CMC section” of the dossier (Chemistry, Manufacturing and control). • http://www.ema.europa.eu/docs/en_GB/document_library/Scientific _guideline/2009/09/WC500002725.pdf The Dossier – CTD – Modules 4 & 5 • Module 4 contains the nonclinical study reports • http://www.ema.europa.eu/docs/en_GB/document_library/Scientific _guideline/2009/09/WC500002727.pdf • Module 5 contains the clinical study reports: • clinical study report (CSR) on a clinical trial is a detailed document about the methods and results of a clinical trial. • A CSR is a scientific document addressing efficacy and safety PIL and SmPC • How patients and health care professions see/experience the CTD triangle is as the Patient Information Leaflet (PIL) and the Summary of Product Characteristics (SmPC) • Home - electronic medicines compendium (emc) Reg Affairs in Pharma Companies • Significant sized department • Global nature – likely to have Reg Affairs in each region • Employees from many backgrounds, eg: • Chemistry • Biology • Pharmacy • Analytical • Quality • Manufacturing • R&D • Wide interactions across the company, eg: • Medical • Clinical • R&D • Supply chain/manufacturing • Commercial • Quality • Legal Marketing Authorisation Procedure • Once the authorisation has been approved, the competent national authority may impose an obligation on the holder to perform a post-authorisation safety or efficacy study. • The authorisation is valid for five years and is renewable. Following issue of the authorisation the holder must take account of scientific and technical progress and ensure that the medicinal product is manufactured and checked by means of generally accepted scientific methods. The competent authority must approve any changes to the product. Once the marketing authorisation has been renewed, it is valid for an unlimited period (with occasional exceptions). Marketing Authorisation Procedure • The marketing authorisation application will be rejected if it appears that: • the risk-benefit ratio is not seen as favourable; • its therapeutic effect is insufficiently substantiated; • its qualitative and quantitative composition is not as declared; • the particulars and documents which accompany the application are inconsistent with the provisions of the Directive. • The duration of the procedure for granting an authorisation to place a medicinal product on the market may not exceed 210 days. Types of Applications CP • Centralised Applications: • The Centralised Procedure (CP) essentially allows applicants to obtain a Marketing Authorisation that is valid throughout the EU. This involves submitting an application directly to the European Medicines Agency (EMA) where it is assessed by the Committee for Medicinal Products for Human Use (CHMP). • Mandatory scope of CP: • Orphan drugs (rare diseases) • All biotech products • Monoclonal antibodies • Gene therapy products Types of Applications • Centralised Applications: • Also: • Certain therapeutic areas: • Cancer, aids, neurodegenerative disorders, diabetes, autoimmune diseases & viral diseases. • For any other type of products going down the CP route, the applicant must prove eligibility e.g. if the product is of significant scientific / therapeutic innovation etc. CP EMA Marketing https://www.ema.europa.eu/en/documents/presentation/marketing-authorisationevaluation-process-dr-evdokia-korakianiti_en.pdf CP Types of Applications NP • National Procedure: • A National Marketing Authorisation (MA) is a licence to market a product in an individual EU member state. Due to the advent of procedures such as the Decentralised and Centralised Procedures, which allow registration across the community, the number of national submissions has declined over the years. Types of Applications MRP • Mutual Recognition Procedure (MRP): • Once a national application has been approved in a Member State, to gain approval in other member states the Mutual Recognition Procedure (MRP) must be used. MRP is a 90 day procedure (no ‘clock stops’ are allowed) during which the recipients of the applications are asked to ‘recognise’ the positive opinion of the member state that granted the first (National) MA. This procedure results in a series of national MAs. CMS 1 RMS CMS 2 CMS 3 Types of Applications DCP • Decentralised Procedure (DCP): • The Decentralised Procedure is a means of obtaining Marketing Authorisations in two or more EU member states simultaneously. • In order to be eligible for the Decentralised Procedure, the applicant must not hold a licence for the product in question in any EU member state. If such a licence already exists, the Mutual Recognition Procedure can be used to achieve the desired market presence in further countries. • The Decentralised Procedure follows tight timelines and is characterised by close coordination between the Health Authorities of the participating Member States. It is the principle route to market for generic products RMS CMS 1 CMS 2 CMS 3 Types of Applications MRP DCP HMA Head of Medicines Agencies MHRA (NI only) HPRA (IE) SUKL (CZ) Infarmed (PT) Total of about 34 national competent authorities NP CP EMA European Medicines Agencies Fees • MHRA (National) and incoming MRP & DCP (NI) fees: • https://www.gov.uk/government/publications/mhra-fees/currentmhra-fees#licence-applications-marketing-authorisations-includingextension-applications-fees • Centralised licence fees: The story so far… R&D Clinical Trials Dissolution studies Formulation, Manufacturing, Quality Control Pharmacovigilance activities Regulatory Affairs strategy Dossier (CTD) CP NP MRP DCP Quality Standards • Good manufacturing practices (GMP) are the practices required in order to conform to guidelines recommended by agencies that control authorisation and licensing for the manufacture and sale of drug products, and active pharmaceutical products. • These guidelines provide minimum requirements that a pharmaceutical product manufacturer must meet to assure that the products are of high quality and do not pose any risk to the consumer or public. • Good manufacturing practices, along with good laboratory practices and good clinical practices, are overseen by regulatory agencies in the United States, Canada, Europe, China, and other countries. Quality Standards • Good manufacturing practice guidelines provide guidance for manufacturing, testing, and quality assurance in order to ensure that a drug product is safe for human consumption. • Within the European Union, GMP inspections are performed by National Regulatory Agencies. Quality Standards • In the EU, the GMP requirements are covered by Eudralex Volume 4: • https://ec.europa.eu/health/medicinalproducts/eudralex/eudralex-volume-4_en Quality Standards • In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide", which is named so because of the colour of its cover; it is officially known as “Rules and Guidance for Pharmaceutical Manufacturers and Distributors”. Quality Standards • Other good-practice systems (GxP), along the same lines as GMP, exist: • Good Laboratory Practice (GLP), for laboratories conducting non• • • • clinical studies (toxicology and pharmacology studies in animals); Good Clinical Practice (GCP), for hospitals and clinicians conducting clinical studies on new drugs in humans; Good Regulatory Practice (GRP), for the management of regulatory commitments, procedures and documentation. Good Distribution Practice (GDP) deals with the guidelines for the proper distribution of medicinal products for human use Good Transportation Practice (GTP) deals with the guidelines for the proper domestic and international transportation of medicinal products for human use Quality standards Audit & Inspection fees in the UK • https://www.gov.uk/government/publications/mhra- fees/current-mhra-fees#inspection-fees The story so far… R&D Clinical Trials Dissolution studies Formulation, Manufacturing, Quality Control GLP, GCP, GxP GMP, GDP, GTP, GcP CP NP MRP DCP Regulatory Agencies Pharmacovigilance activities Medicines regulation Disasters Post approval changes • Once a marketing authorisation has been granted, quite often, changes to aspects of the dossier are required, for example: • moving manufacturing sites to a different location, • changes in the manufacturing process, • changes to the QC methods of analysis, • changes to the Patient Information such as the SmPC, PIL or Labelling, • Inclusion of new safety information in the SmPC or PIL • Etc. • All of the changes involve a revision of the registration dossier. Variations • Changes to a marketing authorisation are typically managed by 'Variations' to the product licence. • Guidance on variations is published by the European Commission. • Commission Regulation (EC) No 1234/2008 (Variations) • The Annex to this Guideline consists of four chapters classifying variations related to: • A) Administrative changes; • B) Quality changes; • C) Safety, Efficacy and Pharmacovigilance changes • D) Specific changes to Plasma Master Files and Vaccine Antigen Master Files. Variation classification • Variations are classified as: • Type IA – minor changes • Type IAIN – minor changes that need immediate notification • Type IB – minor changes • Type II – major changes Type IA and IAIN • Type IA variations are also known as "do and tell" variations. • These variations can only be submitted AFTER the change has been made. • These variations are only for minor changes to the product licence and must be submitted within one year from implementation of the change. • Type IAIN variations or "immediate notification" variations must be submitted within two weeks of implementation of a change. Type IB • Type IB variations are still minor, but must be submitted and approved BEFORE the change is implemented. • Typically, competent authority approval is required before implementation of the change, although if they don’t respond within 30 days, the change may be implemented! Type II • Commission Regulation (EC) No 1234/2008 defines a type II variation as a major variation that may have a significant impact on the quality, safety or efficacy of a medicinal product. Variation classification guideline • https://eur-lex.europa.eu/legal- content/EN/TXT/PDF/?uri=CELEX:52013XC0802(04)&fro m=EN Applicability • These types of changes apply to all MAAs, regardless of whether they were obtained via the CP, National, MRP or DCP routes. Fees for variations • UK Fees (National, MRP/DCP as CMS): • https://www.gov.uk/government/publications/mhra-fees/currentmhra-fees#variations-licence-variations-application-fees • EU Centralised licence fees (example) Summary Post-approval changes R&D Clinical Trials Dissolution studies Formulation, Manufacturing, Quality Control GLP, GCP, GxP GMP, GDP, GTP, GcP Pharmacovigilance activities Post-approval changes CP NP MRP DCP Regulatory Agencies Medicines regulation Disasters THE IMPACT OF BREXIT Brexit Background • In 2016, a referendum resulted in 52% of people voting for the • • • • • UK to leave the European Union. From the date of 29th March 2017, when Article 50 was triggered, the UK had 2 years to negotiate a withdrawal. However, with no deal being agreed between the EU and UK by 29th March 2019, the exit was postponed. On the 31st January 2020, the UK officially left the EU and entered the transition period enabling the same trading terms in this duration while an exit deal was negotiated. On 24th December 2020, a deal was signed by both parties and the transitional period ended on 31st December 2020. On the 1st January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) became UK’s standalone medicines and medical devices regulator. Northern Ireland Protocol • The Northern Ireland Protocol was agreed as part of the Withdrawal • • • • Agreement In October 2019. Establishes a single regulatory zone on the island of Ireland (UK(NI) and IE) Northern Ireland remains as part of the EU single market and they are required to align with EU rules. MHRA continue to act as the overseeing Regulatory Authority for the whole of the UK. NI business have “unfettered access” to move goods to the GB market. Grandfathering of Centrally Authorised Products • All existing centrally approved MAs were converted automatically to GB • • • • licenses (“grandfathered”) unless the MA holders informed MHRA that they wished to opt-out. New licences were issued by MHRA and were valid from 1st January 2021 – although note that renewals etc are calculated from the original EU approval. There was no fee associated with the conversion from a CAP to a Great Britain MA. MHRA required that eCTD baselines were submitted before any lifecycle submission or by 1st January 2022 (whichever was soonest). Requirement to update labels to include UK specific requirements by 1st January 2023 with new artwork on the market by 1st January 2024. Managing existing MRP/DCP • When the transition period ended, the UK were no longer considered a CMS within the procedure. However, UK(NI) were considered a CMS • MA Holders have a number of options: a) Maintain a UK-wide MA ​within MR/DCP -​ UK(NI) retained as a CMS and UK(GB) is aligned with, but not part of, MR/DCP.* b) Withdraw UK(NI) as CMS from MR/DCP – Results in a UK wide national MA completely outside the MR/DCP. c) Request separate MAs for NI and GB - Results in two MAs with UK(NI) as CMS and UK(GB) completely separate.​ * This is the default situation and MHRA applies the RMS decision to the whole licence. If MHRA do not accept the RMS decision they would notify the MAH within 30 days and separate MAs for GB and NI would need to be issued. Creating new MRP/DCPs • Procedures may be used to introduce UK(NI) authorisation into an EU MRP/DCP procedures in consultation with the EU RMS. However, UK wide authorisations may not be introduced. • As the MHRA can’t act as RMS, they cannot initiate an MRP based on the MA in UK(NI). Therefore, if the MAH wishes to obtain a MA in the EU for a product only authorised in the UK(NI), an RMS in the EU should be chosen, and the application submitted via DCP including UK(NI) as CMS Summary of Impact to Licences Licence Options Prior to 31Dec20 UK National Licences (PL) UK National Licences (PL) Centralised Procedure Licence UK Wide MR/DC Procedure Applicable for all EU markets Licence Options from 2021 UK National Licences (PL) Automatically implemented on 01Jan21 MR/DC Procedure (Only NI considered CMS) (Depends on route of initial approval) MA Holder’s Choice UK National Licences (PL) UK Wide NI Licences (PL(NI)) Northern Ireland Only GB Licences (PL(GB)) England, Scotland, Wales Centralised Procedure Licence Applicable in EU and NI Only UK New Licence Application Routes Project Orbis is a is a programme coordinated by the US Food and Drug Administration (FDA) to review and approve promising cancer treatments. • Each country remains fully independent on their final regulatory decision. • Applications submitted to the MHRA within a Project Orbis procedure are national (Great Britain only) marketing authorisation applications and variations. • Provides a framework for concurrent submission and review of oncology products among international partners. It aims to deliver faster patient access to innovative cancer treatments with potential benefits over existing therapies across the globe. Access Consortium this is a medium-sized collation of regulatory authorities that that work together to promote greater regulatory collaboration and alignment of regulatory requirements, reduce duplication and increase each agency’s capacity to ensure patients have timely access to high quality, safe and effective medicines. • The original consortium, formed in 2007 and known as ‘ACSS’, comprised the national regulatory authorities of Australia, Canada, Singapore and Switzerland. • MHRA joined in October 2020 and the group’s name was changed to ‘Access’. UK New Licence Application Routes • The EC Decision Reliance Procedure (ECDRP) - is available to MAs approved via the centralised procedure. • The intended operation of the ECDRP is submission of the Marketing Authorisation Application (MAA) to the MHRA immediately on receipt of a positive Committee for Medicinal Products for Human Use (CHMP) opinion, although applications can be submitted any time after the approval of a European Union Marketing Authorisation. • The MHRA aims to determine the Great Britain MA as soon as possible after EC approval. A delay in submission may affect the delivery of a decision within the 67-day timeline. • A similar reliance route is available for licences granted in the EU via MRP or DCP, known as the MRDCRP Any Questions? Further Reading / References: Regulatory Affairs • EU Legislation • Eudralex: http://ec.europa.eu/health/documents/eudralex/index_en.htm • ICH (international Conference on Harmonisation • http://www.ich.org/home.html • Heads of medicines agencies: http://www.hma.eu/ • European medicines agency: http://www.ema.europa.eu/ema/ • MHRA: https://www.gov.uk/government/organisations/medicinesand-healthcare-products-regulatory-agency Further reading/references: Brexit • HMA (CMDh): http://www.hma.eu/535.html • EMA: http://www.ema.europa.eu/ema/index.jsp?curl=pages/new s_and_events/general/general_content_001707.jsp&mid= WC0b01ac0580a809a7 • MHRA - New guidance and information for industry from the MHRA - GOV.UK (www.gov.uk) • Good article covering the history of EU leglislation: https://www.pharmavibes.co.uk/2021/02/20/a-walkthrough-eu-medicines-legislation/