Regulation of vaccines CEMDC-PharmaTrain Module 7. Zsuzsanna TÓTH 11 February, 2017

Sanofi Pasteur Heritage - Four Paths, One Destiny One goal – protecting people from infectious diseases 1887 - Institute Pasteur, France => 1973 - Pasteur Serums & Vaccines . 1897 - Institute Mérieux, France 1914 - Connaught Laboratories, Toronto, Canada 1897 - Pocono Biological Laboratories, Swiftwater, Pennsylvania Today Part of Sanofi Headquarters in Lyon with 15 production and R&D sites More than 1 billion doses of vaccines produced yearly to immunize more than 500 million people in the world Largest product range available, against 20 infectious diseases More than €1.5 billion euros invested in the last 5 years. Our credo: we believe in a world in which no one suffers or dies from a vaccine-preventable disease. Regulation of vaccines

Legal framework governing medicinal products for human use in the EU EUROPEAN COMMISSION/COUNCIL/ PARLIAMENT Regulations, directives, resolutions MEMBER STATES National law THE EUROPEAN PHARMACOPOEIA COMMISSION monographs, general chapters and other texts of European Pharmacopoeia Court of Justice of European Union decisions EU COMMISSION, EUROPEAN MEDICINES AGENCY, INTERNATIONAL COUNCIL FOR HARMONIZATION (ICH) Scientific guidelines European Centre for Disease Prevention and Control https://ec.europa.eu/health/human-use/legal-framework_en https://ec.europa.eu/health/documents/eudralex/vol-1_en https://www.ogyei.gov.hu/magyar_jogszabalyok/

European medicines regulatory network European Medicines Agency BENEFITS? Scientific Committees EMA Secreteriat Working Parties CHMP National Competent Authorities Hungary National Institute of Pharmacy and Nutrition National Centre of Epidemiology

Lifecycle of a vaccine (post-approval) Variations Registration Cessation/ Withdrawal Renewal Regulation of vaccines

Registration Regulation of vaccines

Marketing authorization of medicinal products Registration A medicinal product may only be placed on the market in the European Economic Area when a marketing authorisation has been issued by the competent authority of a Member State for its own territory (national authorization) or when an authorisation has been granted in accordance with Regulation (EC) No 726/2004 for the entire Union (an Union authorization). Authorities/Agencies evaluates if the tests and studies performed with the candidate medicinal product is in compliance with official and scientific regulations in terms of: Quality Safety Risk/benefit ratio Effectiveness Efficacy Regulation of vaccines

Types of applications (legal basis) Depends on the particulars and documents which must be accompanied of the application for marketing authorisation (how efficacy and safety proven) full application - Article 8(3) of Directive 2001/83/EC pharmaceutical (physico-chemical, biological or microbiological) tests, preclinical (toxicological and pharmacological) tests, clinical trials relevant published literature generic, hybrid or similar biological applications - Article 10 reference can be made to the dossier of a reference medicinal product for which a marketing authorisation has been granted in the Union well-established use application - Article 10a supported by bibliographic literature fixed combination application - Article 10b informed consent application- Article 10c Regulation of vaccines

EU Authorization/registration procedures Centralized Procedure (CP) application is assesses by European Medicines Agency, the authorization is issued by the European Commission valid for the entire EU market Products of major publich health interest (therapeutic innovations), biosimilars, National procedure strictly limited to medicinal products which are not to be authorized in more than one Member State Mutual Recognition procedure (MRP) the new product has been authorized at least in one European country in the time of submission of the application Decentralized procedure (DCP)  the new product has not been authorized in any European coutries in the time of the submission of the application Cyprus close (Article 126a of Directive 2001/83/EC) justified public health reason - in the absence of a marketing authorisation or of a pending application for authorisation for a medicinal product, which has already been authorised in another Member State, a Member State may for justified public health reasons authorise the placing on the market of that medicinal product Regulation of vaccines

Comparison of procedures Concerned member states ALL SELECTED ONE Type of procedure Centralized Procedure National Procedure MRP DCP Timelines 210 days + clock stop National phase: 210 d AR: 90 d MRP: 90 d 1st evaluation phase: 120 d Clock stop 90 d 2nd evaluation phase: 90 days 210 days Type of Marketing Authorization Centralized MA National MA Regulation of vaccines

Fees in HU Centralized Procedure National Procedure MRP/DCP (RMS) MRP/DCP (CMS) MA application From €278800 €4500 €10100 €7200 Renewal €2,100 €5100 €3600 Annual Fee €100000 €870 Type II variation €83700 €1100 €1500 Regulation of vaccines

Common Technical Documentation Beadvány Regulation of vaccines

Plasma Master File (PMF) Vaccine Antigen Master File (VAMF) certification system Optional certification procedure Centralised assessment of the PMF/VAMF application dossier submitted by the applicant or marketing authorisation holder => certificate of compliance to Union legislation, issued by the EMA, valid in European Union. The VAMF is a stand-alone part of the marketing authorisation application dossier for a vaccine. One given VAMF contains all relevant information of biological, pharmaceutical and chemical nature for one given vaccine antigen, which is common to several vaccines from the same applicant or marketing authorisation holder. The PMF is a stand-alone documentation, which is separate from the dossier for marketing authorisation. It provides all relevant detailed information on the characteristics of the entire human plasma used as a starting material and/or a raw material for the manufacture of sub/intermediate fractions, constituents of the excipient and active substance(s), which are part of medicinal products or medical devices incorporating stable derivatives of human blood or human plasma. Regulation of vaccines

1. Module 1: ADMINISTRATIVE INFORMATION 1.1 Table of contents. 1.2. Application form. 1.3. Summary of product characteristics, labelling and instructions for medical use: 1.3.1. Summary of product characteristics. 1.3.2. Labelling. – Braille excemption 1.3.3. Instructions for medical use. 1.3.4. Mock-ups and specimens. 1.3.5. Summary of product characteristics already approved in the manufacturer/applicant- country. 1.4. Information about the independent experts: 1.5 Specific requirements for different types of applications. 1.8 Information relating to Pharmacovigilance – Risk Management Plan 1.10 Information relating to Paediatrics Annex to Module 1. Environmental risk assessment Module 1 should contain region‑specific administrative and product information. Regulation of vaccines

Validity of MA Certificate Marketing authorisation (MA) is valid for five years from the date of notification Once renewed, the MA will be valid for an unlimited period Conditional MAs granted under Article 14(7) of Regulation (EC) No 726/2004 the benefit-risk balance of the product is positive; the benefit of immediate availability outweighs the risk of less comprehensive data than normally required it is likely that the applicant will be able to provide comprehensive data; unmet medical needs will be fulfilled; For example Avian influenza vaccine, March 2006 (prevention of an infectious disease) Ebola vaccine (rare disease, not enough patient – probability of favourable risk/benefit ration is high – data will be/was provided later) Valid for 1 year, can be extended for 1 more year Regulation of vaccines

Content of Marketing Authorization certificate Decision Name, registration number (OGYI-T-XXXXX/YY), pack sizes, MAH, batch release site, Confidential part Composition, shelf-life, information on storage, packaging, manufacturing sites (DP, DS), Summary of product charteristics Patient information leaflet Labelling Drug database available online: www.ogyei.gov.hu/ Regulation of vaccines

Specific release procedures for vaccine batches Vaccine batch manufactured Batch release by manufacturer Batch release by independent national laboratory (OCABR) Issue European Batch Release Certificate Delivery the vaccine batch to Hungary Local release by National Institute of Pharmacy and Nutrition Local release by National Centre for Epidemiology Release by distributor Market Regulation of vaccines

VARIAtion Regulation of vaccines

Variation A variation is a change to the terms of a marketing authorisation. Legal basis: COMMISSION REGULATION (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products  Type IA variations – minor variation Where no immediate notification is needed; where immediate notification is needed; Type II variations major variation that may have a significant impact on the quality, safety or efficacy of a medicinal product Extension – certain changes that fundamentally alter the terms of MA certain changes to the active substance; pl. different salts changes to the strength, pharmaceutical form and route of administration; Adacel vial – prefilled syringe Type IB variations; Murphy's law - Anything that can go wrong, will go wrong. Regulation of vaccines

Evaluation Type Duration of the validation period Duration of the procedure (assessment) Date of implementation IA – 30 days date stated by the applicant IA IN - date of submission IB 7 days 31. day of the procedure II 14 days 60 days 90 days with the date of issuing the decision Regulation of vaccines

Grouping of variations Group several Type IA and IAIN variations under a single notification to the same relevant authority Several IA or -IAIN affecting one medicinal product One IA or IAIN affecting several medicinal products from the same MAH Several IA or IAIN affecting several medicinal products from the same MAH, provided that these variations are the same for all medicinal products and are submitted to the same relevant authority http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000086.jsp&mid=WC0b01ac058013f56c Regulation of vaccines

Worksharing of variations Aim: to avoid duplication of work in the evaluation of variations Submit: the same Type IB or Type II variation, or the same group of variations affecting more than one marketing authorisation from the same MAH in one application. possible to include a group of type IA and IAIN variations  One authority is chosen amongst the competent authorities of the Member States and the Agency, will examine the variation on behalf of the other concerned authorities. Product Dultavax Tetraxim Pentaxim Hexacima Valences DT-IPV DTaP-IPV-HIB HepB Registr. National MRP CP http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000087.jsp&mid=WC0b01ac058013f56d Submit the same Type IB or Type II variation, or the same group of variations affecting more than one marketing authorisation from the same MAH in one application. it is possible to include a group of type-IA and -IAIN variations with a type-IB or a type-II variation, which is submitted for a worksharing procedure Changes to multiple generic marketing authorisations (MAs) containing the same active substance. Changes to the active-substance master file. Update of the Certificate of European Pharmacopeia. Revision of test method for the active substance. Regulation of vaccines

National scope variations Transfer of the marketing authorisation to a new holder („MAH transfer”) Change in the legal status of the product Combination of the registration numbers Include/exclude pack sizes in the Hungarian Marketing Authorisation within the values approved in MRP/DCP Evaluation: 21 days Implementation: with the date of issuing the decision Directive 2001/83 61(3) Notification a change to an aspect of the Labelling and/or Package Leaflet (PIL) text not connected with the Summary of Product Characteristics (SmPC). E.g. local representative, abbreviation of batch number, combined packaging Evaluation 90 days Implementation: 91. day of the procedure Regulation of vaccines

Annual update for human influenza vaccine strain(s) As the influenza virus is constantly changing, WHO reviews the recommendation twice a year and recommends vaccine composition since 1999.2 mid-February: for the following winter in the Northern hemisphere (November to April). September: for the following winter in the Southern hemisphere (May to October) Hány törzs van az influenza vakcinában? Mennyit ajánl a WHO/EMA How many stains are in the vaccine? How many strains does the WHO/EMA recommend? Summary of annual process of development, manufacturing and distribution of influenza vaccines in the northern hemisphere. 1 1.Hannoun C. Expert Rev Vaccines 2013; 12(9): 1085-1094 2.http://www.who.int/docstore/wer/pdf/1998/wer7340.pdf Regulation of vaccines

Annual update of human influenza vaccine strain(s) EU annual strain(s) and reassortant recommendations on the EMA website Type II#B.I.a.5 variation in ‘two step’ approach First step– Submission of the application Administrative information (SmPC) Chemical-pharmaceutical and biological information for chemical active substances and biological products no need to provide non- clinical/clinical data Second step– Submission of additional data (if requested) Regulation of vaccines

END OF LIFECYCLE Regulation of vaccines

Product is not available – potential reasons Cessation of marketing or placing on the market product, a pharmaceutical form or strength of a medicinal product in at least one Member State Withdrawal - initiated by MA holder Low sales Production problems Discovery of serious side effects Apprearance of modern vaccines Withdrawal initiated by HA – Sunset Close If an authorised product is not placed on the national market within three years of its granting OR not marketed for three consecurive year, the Medical Products Agency will decide that the authorisation shall cease to be valid.  Regulation of vaccines

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