Human Medicines Regulations 2012 Licensing System - Part 1 PDF

WEEK 16 Human Medicines Regulations 2012 The Licensing System – Part 1 John Sherwood MRPharmS 13th November 2024 Slide 1 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16...

WEEK 16 Human Medicines Regulations 2012 The Licensing System – Part 1 John Sherwood MRPharmS 13th November 2024 Slide 1 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Learning outcomes Briefly explain the licensing system and the licenses which form part of the system Explain what a marketing authorisation and SmPC are Explain the role of the MHRA in the granting of licenses, in particular the criteria required for the granting of a marketing authorisation Understand manufacturer’s and wholesale dealer’s licenses Explain what biosimilar medicines are and understand why they are not generic equivalents of the originator product Explain how herbal medicines are licensed Define ‘pharmacovigilance’ and explain its importance in the safety of medicines Explain what the early access to medicines scheme is and what orphan drugs are Slide 2 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 The licensing system The licensing system was the main novel feature of the Medicines Act 1968 (now controlled by the Human Medicines Regulations 2012) Three types of licence: Marketing Authorisation (MA) Manufacturer’s Licence (ML) Wholesale Dealer’s Licence (WDL) Two types of certificate: Clinical Trials Certificate (CTC) Clinical Trials Exemption Certificate (CTX) Licences and certificates permit a person or company to engage in specific, controlled activities. Companies may, therefore, need more than one licence to carry out a process It is an offence to perform any of these activities without the appropriate licence or certificate unless an exemption exists Each licence or certificate is used at a definite stage in the life of a medicinal product Slide 3 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 The licensing process Clinical trials in patients with the disease CTC/CTX granted MA Compile data about drug properties/formulation etc Submission MA granted Plan to produce product in large batches, ML assemble and pack it for sale Submission ML granted WDL Plan to store and distribute product by wholesale Submission WDL granted Marketing and distribution Slide 4 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Key criteria in licensing a new medicine Safety Quality Efficacy Cost? Slide 5 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Marketing authorisations (1) Formerly known as a ‘product licence’ (PL) A marketing authorisation (MA) is the regulatory approval of a specific medicinal product, thus enabling it to be marketed The approving authority in the UK is the Medicines and Healthcare Products Regulatory Agency (MHRA) It is unlawful to sell, supply or offer to sell or supply a medicinal product unless that product has a UK MA (NB there are some exceptions to this for pharmacists – see Licensing, Part 2) All commercially available medicinal products must have a MA MA are issued for a period (usually 5 years or less) and may have certain restrictions attached After this period the MA holder must re-apply to renew the licence MHRA has power to withdraw, amend or suspend a MA at any time Slide 6 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Marketing authorisations (2) To obtain a MA for a medicinal product, information on the product must be submitted to the MHRA If it is a new product, full information about manufacturing and testing, including clinical trial results, must be made available to the MHRA The MHRA also operates a ‘fast track’ international recognition route if a product has already been licensed in an EEA country and some other countries (i.e. Japan, Singapore, Canada, US, Switzerland, Australia) When granted, a MA authorises the holder to: Sell, supply or export a medicinal product Procure its sale, supply or exportation Procure its manufacture or assembly A Summary of Product Characteristics (SmPC) (formerly known as a ‘data sheet’) for the product must be submitted as part of the licensing process for approval by the MHRA Slide 7 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Summary of Product Characteristics (SmPC) Prepared by the holder of the MA Part of the licensing application and is the only part of the application which is made ‘public’ Regulations list what information the SmPC should contain SmPC describes the medicinal product’s properties and the conditions attached to its use SmPC is laid out in a standard format and it is an important source of information for healthcare professionals It is non-promotional and the content has been assessed and approved by the MHRA SmPCs are also the basis for the preparation of patient information leaflets (PILs) It is a requirement that SmPCs are updated as necessary for the lifespan of the product as new safety data emerges SmPCs and PILs are available online at www.medicines.org.uk Slide 8 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 What information does a SmPC contain? (1) 1. NAME OF THE MEDICINAL PRODUCT 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 3. PHARMACEUTICAL FORM 4. CLINICAL PARTICULARS 4.1 Therapeutic indications 4.2 Posology and method of administration 4.3 Contraindications 4.4 Special warnings and precautions for use 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose Slide 9 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 What information does a SmPC contain? (2) 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties 5.2 Pharmacokinetic properties 5.3 Preclinical safety data 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling 7. MARKETING AUTHORISATION HOLDER 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Slide 10 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Marketing authorisations (3) Generics A product is defined as a generic medicinal product if: It has the same qualitative and quantitative composition in active substances as the reference medicinal product (RMP) and It has the same pharmaceutical form as the RMP and Bioequivalence with the RMP has been demonstrated Safety and efficacy data can be used from the RMP after a ‘data exclusivity period’ has elapsed The data exclusivity period is 8 years Then an ‘abridged’ application can be made using the data from the RMP Note that the data exclusivity period is different to the patent protection period – the two periods run consecutively Slide 11 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 BIOLOGICS AND BIOSIMILARS Slide 12 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Marketing authorisations (4) Biologics and biosimilars (1) A biologic is a medicine made from a variety of natural sources that may be human, animal or microorganism in origin, resulting in a medicine which is a biological molecule Most biologics in current clinical use contain active substances made of proteins that differ in size and structural complexity, from simple proteins (such as insulin) to more complex proteins (such as monoclonal antibodies) Examples include insulin glargine, infliximab, epoetin alfa The first or original biologic on the market is termed the originator or reference product A biosimilar is a biologic medicine that is like an already licensed biologic medicine in terms of safety, quality and efficacy A biosimilar is specifically developed and licensed to treat the same disease(s) as the original biologic A biosimilar can only be marketed after the patent of the originator has expired Slide 13 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Marketing authorisations (5) Biologics and biosimilars (2) Due to the complexity of structure and greater size of biologics it is not possible to make an identical copy of the originator biologic (unlike making a generic medicine) The manufacturing process of a biologic is highly complicated compared to that of a small molecule medicine Biosimilars may differ to the originator in terms of dimensions (molecular weight), method of synthesis, purification, stability and immunogenicity Manufacturers of biosimilars must submit ‘comparability data’ as part of the licensing application Biosimilars, unlike generic medicines, will have a unique brand name The MHRA advises that all biologics and biosimilars should be prescribed by brand name Adverse events to biosimilars should be reported to the MHRA and reports should include the brand name and batch number Like generics, biosimilars are much less expensive than the originator biologic, and thus offer cost saving potential to the NHS Any decision to change a patient from a biologic to a biosimilar should be made by the prescriber after discussion and agreement with the patient Slide 14 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Early access to medicines scheme Aim of this scheme is to enable patients to access medicines which have not yet obtained a MA This scheme is only used for medicines which are to treat life-threatening or seriously debilitating conditions and where no suitable alternative is available This is a voluntary scheme and it consists of 2 parts 1) Early clinical data is made available to the MHRA several years prior to a MA being formally applied for 2) Scientific advisers consider the benefit/risk profile of the medicine An opinion is given which supports the use of the medicine before the medicine receives a MA Slide 15 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Orphan drugs These are drugs used to treat conditions that occur so infrequently that the cost of developing and bringing a medicinal product to the market would not be recovered by the expected sales The disease should be ‘life threatening or chronically debilitating’ and the incidence should be less than 5 in 10,000 persons Only conditions for which they are no current treatments will be considered or, if medicines are available, the new treatment must offer a significant benefit over these Orphan medicinal products benefit from up to 10 years of market exclusivity. Orphan drugs for paediatric indications are eligible for an additional 2 years of market exclusivity Products are listed in the GB Orphan Register Slide 16 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Manufacturer’s licence Authorises the holder to manufacture or assemble a medicinal product No person can manufacture a medicine unless they possess a manufacturer’s licence (unless an exemption applies) Manufacture does not include dissolving, diluting or mixing with some other substance used as a vehicle for administration Assemble means enclosing a product in a container which is labelled before the product is sold or supplied, or simply re-labelling a product The manufacturer’s licence describes the premises, equipment, people, records and qualifications of people involved Manufacturer must comply with principles and guidelines for Good Manufacturing Practice (GMP) At least one ‘qualified person’ (QP) must be nominated who is responsible for the quality control requirements of GMP MHRA inspectors visit the premises as part of the application and regularly thereafter The MHRA may grant, refuse, review, suspend, revoke or vary a ML This type of licence is needed before a company can apply for a MA for a medicinal product Slide 17 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Wholesale dealer’s licence Required by any person who sells a medicinal product by way of wholesale dealing No person can sell a medicine by wholesale dealing unless they possess a wholesale dealer’s licence (unless an exemption applies) Authorises the holder to sell to anyone other than the end user of the medicine (i.e. the patient) Describes premises where products are stored, distribution facilities, records and security Records are required for medicines received and dispatched Must have an emergency plan for the recall of medicines A ‘responsible person’ must be named in the application MHRA inspectors visit to inspect premises MA holder does not require a wholesale dealer’s licence – sales made by a manufacturer are excluded from the definition of wholesale dealing Slide 18 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Pharmacovigilance Pharmacovigilance is the name given to the post-marketing surveillance of the safety of medicines Holders of a MA must operate a pharmacovigilance system. This is especially focused on ‘black triangle’ medicines (see next slide) Completing a ‘yellow card’ (online or paper) is one way to report suspected adverse drug reactions MHRA constantly re-assesses the risk/benefit of medicines based on yellow card data and consider Clinical and epidemiological studies Worldwide published medical literature Information from pharmaceutical companies Information from other regulatory bodies elsewhere MHRA may restrict a drugs use, change dose, introduce specific warnings in the SmPC or PIL in response to reports received. In severe cases, may withdraw the product’s MA (i.e. remove the product from the market) Slide 19 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Medicines subject to ‘additional monitoring’ A black triangle is used to indicate that the medicine is subject to additional monitoring ‘Black triangles’ appear in the BNF, SmPC, and PIL A black triangle is always assigned to a medicine if: It contains a new active substance It is a biological medicine, such as a vaccine or a medicine derived from plasma (blood) It has been given a conditional approval (where the company that markets the medicine must provide more data about it) It has been approved under exceptional circumstances (where there are specific reasons why the company cannot provide a comprehensive set of data) The company that markets the medicine is required to carry out additional studies: for instance, to provide more data on long-term use of the medicine, or on a rare side effect seen during clinical trials. The information that appears in the PIL is shown below: Slide 20 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Slide 21 of 24 WEEK 16 Herbal medicines Definition: a medicinal product whose only active ingredients are herbal substances (plant or part of a plant) or herbal preparations (or both) Herbal medicines which are for sale to the public must have a licence Licensed as a medicine (i.e., have a MA) or Registered under the Traditional Herbal Registration (THR) scheme This does not apply to Chinese medicine practitioners, herbalists compounding a medicine for an individual (‘herbal practitioners’) This does not apply to herbal products marketed as foods THR Scheme Quality, safety and regulated manufacturing standards assured No data required on efficacy – use is based on ‘traditional use’ Must provide the patient with a PIL (including details on side effects, contraindications, use in children/pregnancy etc) THR logo (optional) and THR number (mandatory) on packaging Slide 22 of 24 OSPAP MPHM15 The Licensing System - Part 1 WEEK 16 Homeopathic medicines The licensing of homeopathic medicines is not covered in this lecture (information is available in Dale and Applebe’s Pharmacy and Medicines Law, 12th edn) The sale and supply of homeopathic products from pharmacies is controversial The RPS does not endorse homeopathy as a form of treatment because there is no scientific basis for it and there is no evidence of clinical efficacy beyond that of a placebo In 2017, NHS England recommended that GPs and other prescribers should stop prescribing homeopathic medicines for NHS patients due to ‘no clear or robust evidence to support it’ Be sure that you know the difference between a herbal medicine and a homeopathic medicine (it confuses the public!) The MEP (online) has some further information on herbal and homeopathic medicines and a link to a useful RPS information sheet Slide 23 of 24 WEEK 16 E-cigarettes E-cigarettes and e-liquids which are not medicinal products must be notified to the MHRA before they can be sold There are minimum standards for the safety and quality of all e-cigarettes and refill containers Side effects and concerns can be reported to the MHRA via the yellow card scheme E-cigarettes that are marketed for cutting down, quitting and reducing the harms of smoking must be licensed as medicinal products (i.e., have a MA) These medicinal products can be a higher strength and/or volume than those which are not medicinal products Slide 24 of 24 OSPAP MPHM15 The Licensing System - Part 1