Chapter 28 Pharmaceutical acquis (human and veterinary medicinal products) Screening meeting with Serbia 5 December 2014 DG SANTE D5: Medicinal products - authorisations, EMA; D6: Medicinal products - Quality, Safety and Efficacy Directorate General for
HUMAN MEDICINES
Principles of EU pharmaceutical legislation Objectives Protection of public health Free movement of medicinal products within the EU
EU Pharmaceutical legislation Directive 2001/83/EC The core legislation governing the regulation of medicines in EU: placing on the market, production, labelling, classification, distribution and advertising of medicinal products for human use. Regulation (EC) No 726/2004 Sets the procedures for the authorisation and supervision of medicinal products at EU level and establishes the European Medicines Agency
Human Medicinal Products Orphans Reg. 141/2000 Herbals Dir. 2004/24/EC Clinical Trials Reg. 536/2014 Dir.2005/28/EC Paediatrics Reg.1901/2006 Medicinal Products Community Code Dir. 2001/83/EC Generics Dir. 2004/27/EC Variations Reg. 1234/2008 Regulation (EU) No 712/2012 Medicinal Products Centralised procedure Reg. 726/2004 Pharmacovigilance Dir. 2010/84/EC 2012/26/EC Reg 2012/1027 Good Manufacturing Practices Dir. 2003/94/EC Advanced Therapy Reg.1394/2007 Falsified medicines DIRECTIVE 2011/62/EU
Pricing and reimbursement Transparency Directive National authorities Council Directive 89/105/EEC Common procedural framework Aims to ensure that national pricing and reimbursement decisions are made in a transparent manner and do not disrupt the operation of the Internal Market Organise their own social security systems Free to set the prices of medicinal products and to designate the treatments that they wish to reimburse under their social security system Each country uses different schemes and policies, adapted to its own economic and health needs. Article 168 TFEU: "Union action shall respect the responsibilities of the Member States for the definition of their health policy and for the organisation and delivery of health services and medical care"
Autorisation procedures
Marketing authorisation for medicinal products in the EU A medicinal product may only be placed on the market in the European Union when a marketing authorisation has been issued: by the competent authority of a Member State (national authorisations) or when an authorisation has been granted for the whole EU (union authorisation). Authorisations are granted on the basis of the criteria of QUALITY, SAFETY and EFFICACY 9
Marketing authorisation application Admin & Prescribing Inf Authorisation of medicines in the EU reflects the internationally agreed standards Quality overall summary Non- Clinical Overview Non- Clinical Overview Clinical Overview Clinical study EU CTD (Common Technical Document) presentation is applicable irrespective of the type of procedure (centralised, mutual recognition or national). Module 3 Module 4 Module 5 Quality Non Clinical Study Reports Clinical Study Reports Companies need to submit data of tests and trials, demonstrating the Efficacy, Safety and Quality of the medicinal product.
Procedures for granting MA Approval in one Member State National Authorisation Approval in n or all Member States Centralised Procedure (CP) Mutual Recognition Procedure (MRP) Decentralised Procedure (DCP) Route? Choice? Depend on: Type of product Authorisation history in EU Regulatory & marketing strategy Company preferences etc
Procedures for granting MA Mutual recognition procedure Decentralised procedure Principle of recognition of an already existing national marketing authorisation by one or more Member States Application for the marketing authorisation submitted simultaneously in several Member States, one chosen as the Reference Member State national marketing authorisations are granted in the Reference and in the Concerned Member States Centralised procedure Compulsory for: products derived from biotechnology, orphan medicinal products, treatment of AIDS, cancer, neurodegenerative disorders or diabetes, for veterinary medicinal products to promote growth or to increase yields from treated animals. Scientific assessment made by the EMA and authorisation granted by the European Commission Such a marketing authorisation is valid throughout the Union 12
Mutual Recognition Procedure (MRP) Authorisation in one Member State, the Reference Member State (RMS) (210 days) Submission to chosen Concerned Member States (CMS) for recognition of Authorisation (90 days) Authorisation in CMS (within 30 days) In case of disagreement referral to CMD(h)/CHMP (60+ 60 days) Serious risk to public health Referral to CMD(h)
Decentralised Procedure (DCP) No MA existing in EEA Application to RMS & CMS Initial assessment by RMS and comments by CMS (120 days) Second phase of assessment and position by Member States (90 days) Authorisation in CMS (within 30 days) In case of disagreement referral to CMD(h)/CHMP (60+ 60 days) Serious risk to public health Referral to CMD(h)
Mandatory Biotech, AIDS, Diabetes, Cancer, Orphan, Neurodegenerative Centralised procedure Application dossier sent to EMA Optional Significant therapeutic, scientific or technical innovation EMA validation (14 days) CHMP starts evaluation (Day 0) List of questions sent to applicant (Day 120) Checks application meets criteria Reviews by rapporteur and corapporteur Review clock starts Review clock stops (up to 3 months) Ap pprox 12-14 months Potential for further questions and clock stops for responses or oral explanation 3-4 months Company Appeal Second Opinion Responses submitted by applicant (Day 121) CHMP Opinion (Day 210) Review clock restarts Review ends Within 30 days, EMA transmit: Opinion Assessment report Summary of Product Characteristics Labelling and Package sent to: European Commission, Member States and Applicant 67 days Draft Commission Decision Standing Committee (Member States) Approval Commission Decision Publication in the Official Journal of the EU European Public Assessment Report (EPAR)
Number of Commission Decisions per year 1600 1400 1200 1000 800 Referrals and other Orphans 600 400 Centralized 200 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Herbal medicinal products 1. Marketing authorisation, in particular WEU 2. Simplified registration for traditional herbal medicinal products Lighter procedure to facilitate market access Relies on primarily bibliographical data for safety and efficacy
Traditional herbal medicinal product 30 years of medicinal use, including at least 15 years in the Union required Indication without supervision of medical practitioner Product proves not to be harmful in the specified conditions of use Registration without results of pre-clinical test and clinical trials Bibliographical review of safety data together with an expert report Possibly additional data required to assess the safety of the medicinal product 18
Homeopathic medicinal products Marketing authorisation National rules on preclinical tests and clinical trials Simplified registration for homeopathic medicinal products Oral external administration Without indications Sufficient degree of dilution to ensure safety
Pharmacovigilance
Pharmacovigilance legislation - Commission implementing measures Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional monitoring Delegated Regulation (EU) No. 357/2014 of 7 February 2014 specifying situations in which a post-authorisation efficacy study may be required
Pharmacovigilance Pharmacovigilance is the process and science of monitoring the safety of medicines and taking action to reduce the risks and increase the benefits of medicines Related activities Collecting and managing data on the safety of medicines (RMP, PSURs) Evaluating the data to detect 'signals' (any new or changing safety issue) Acting to protect public health (including regulatory action) Communicating with and informing stakeholders and the public Stakeholders Users of medicines (reporting ADRs) Health care professionals working with medicines Regulatory authorities, including the European Medicines Agency (EMA) and those in the Member States responsible for monitoring the safety of medicines Pharmaceutical companies and companies importing or distributing medicines
Functioning of the system Triggers of the decision making procedure Actions based on pharmacovigilance concerns Monitoring ADRs Signal of a new AE, ADR Periodic safety update reports Oversight of postauthorisation obligations Specific procedure: referrals Change of MA Suspension Withdrawal Revocation Non-renewal
Manufacturing
Manufacturing of medicinal products Manufacturing authorisation required Application by manufacturer Inspection Granted by National competent authority GMP certificate issued Import requires manufacturing authorisation Medicinal products for export
Obligations of manufacturing authorisation holder Suitable and sufficient premises Technical equipment and control facilities Staff, including a qualified person Dispose of products according to EU legislation Comply with Good Manufacturing Practice Use only active substances complying with GMD and GDP for API
Good Manufacturing Practice (1) Directives setting out high-level principles EU GMP Guide (EudraLex, Vol 4): Part I: GMP principles for manufacture of medicinal products Part II: GMP for API used as starting materials Part III: GMP related documents clarifying regulatory expectations
Good Manufacturing Practice (2) References: Directive 2003/94/EC + Directive 91/412/EEC EudraLex Volume 4 http://ec.europa.eu/health/documents/eudralex /vol-4/index_en.htm
Good Distribution Practices
Wholesale distribution of medicinal products An important activity in integrated supply chain management. Includes all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Complex network and involves many players (e.g. manufacturers or their depositories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public). The quality and the integrity of medicinal products can be affected by a lack of adequate control.
What is Good Distribution Practice? GDP is the collection of actions which ensures that the level of quality of a medicinal product determined by GMP during its manufacture is maintained throughout the distribution network To ensure that authorised medicines are distributed to other wholesalers, retail pharmacists and to others authorised to sell medicines to the general public without any alteration of their properties. For the wholesale operation - requirement of distribution authorisation Holders of manufacturing authorisation can distribute the products covered by this authorisation
Holder of distribution authorisation Can purchase the products only from manufacturers or holders of distribution authorisation Can sale the products only to holders of distribution authorisation or to entities authorised/entitled by the MS to sale the products to the public Retail of medicinal products national law of the MS
The guidelines on Good Distribution Practice (GDP), 2013/C 343/01 Outline appropriate tools: to assist wholesale distributors in conducting their activities with an assurance of product quality maintenance and to prevent falsified medicines from entering the legal supply chain. They outline all-encompassing principles taking into account the various operations of wholesale dealers to ensure GDP
Advertising
Advertising Banned in the EU Package leaflet Answer to a specific question Factual, informative announce- ments and reference material
Falsified medicines directive new measures
Falsified Medicines Directive (Directive 2011/62/EC amending Directive 2001/83/EC) Specific measures to keep the falsified medicines outside the supply chain, among others: - safety features (GMP) - not yet implemented; - new rules on import of API (GMP); - common EU logo for online sale of medicinal products not yet in application.
Clinical trials
A. Directive 2001/20/EC currently applicable legal framework B. Regulation (EU) 536/2001
A. The Clinical Trials Directive (2001/20/EC) Aims: Ethical soundness Reliability and robustness of data Exhaustive harmonisation In force since 2004 Covers inter alia Protection of participants/informed consent covered Manufacturing of IMP (Directive 2003/94/EC) GCP (Directive 2005/28/EC) Information on clinical trials - including database (EudraCT) Authorisation of CT decision by ethics committee + competent national authority Applies to Interventional clinical trials with human medicinal products All phases of clinical trials Criticized revision in 2014
B. Clinical trials regulation ((EU) 536/2014) Adopted on 16 of April 2014 (OJ of 27 May, L 158, p.1) Entry into force on the 20 day following the day of the publication; Application: minimum two years, 6 months after the Commission publish in the OJ that the EU Clinical Trials portal and database is operational Transitory period: Directive 2001/20/EC will be repealed on the day of entry into application of Regulation EU 536/2014. It will however still apply three years from that day to: CT applications submitted after the entry into force of the Regulation and before the entry into application; CT applications submitted within one year after the entry into application if the sponsor opted for old system
New EU Clinical Trials Portal and Database Bone of the system To be developed and managed by EMA Application of Regulation linked to the full functionality of portal and database (not before 2y. from publication) Single entry point for sponsor EU database in principle publically accessible, except for: Personal data CCI Communications between MS Ensure supervision of CT
Authorisation procedure One single entry point for sponsor (EU portal) Two parts; join assessment (the Reporting Member State selected from all Member States concerned leads the process); national part; Strictly defined timelines: 45 days (+ max 31 days if questions to sponsor, + max 50 if expert consultation needed on ATMP); One decision by the Member State (internal assessment process, including the involvement of the ethics committees, determined by national rules) Tacit approval if the Member State fails to comply with deadline
Application dossier Harmonised application dossier throughout the EU (mandatory information to be provided defined in Annex I to the Regulation); If reference to other CT these have to be registered in a public register which is a primary or partner register, or data provider to the WHO ICTRP or published.
Publication of CT Results Summary of results and layperson summary 1 year after the end of the trial in all MS concerned (details in Annexes); CSR (no raw data) 30 days after MS granted, decision making process completed, withdrawal of application; Raw data on voluntary basis
Other provisions In principle a common regime on the protection of subjects (few changes comparing to the Directive 2001/20/EC, e.g. emergency clinical trials); CT master file to be archived for at least 25 years; Inspections reports, including the third country inspection reports, submitted to the EU database; For the sponsors outside the EU an obligation to provide, in principle, a legal representative, or, in case of agreement of all MSc, a contact person in the EU Damage compensation according to the system in the MS concerned
VETERINARY MEDICINES
Current legislation on veterinary medicinal products Directive 2001/82/EC of the European Parliament and of the Council on the Community code relating to veterinary medicinal products under review Regulation (EC) 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products Regulation (EC) 470/2009 of the European Parliament and of the Council laying down Community procedures for the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin Commission Regulation (EU) 37/2010 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin DG SANCO
Granting of a marketing authorisation basic principles A veterinary medicinal product may only be placed on the market in the European Union when a marketing authorisation has been issued by the competent authority of a Member State for its own territory (a national authorisation) or when an authorisation has been granted for the entire Community (a Community authorisation) Authorisations are granted on the basis of the criteria of QUALITY, SAFETY and EFFICACY For food producing species - Maximum Residue Limit must be established for the relevant tissues
Data requirements Companies need to submit data demonstrating the quality, safety and efficacy of the product Results of clinical trials Requirements detailed in legislation (Annex I to Directive 2001/82/EC) and supported by guidelines DG SANCO
Manufacturing Manufacturing site needs a valid GMP certificate issued by a Competent Authority Inspection of the site by a Competent Authority Marketing authorisation application includes a description of the manufacturing method: technique and equipment used, quality control method
Pharmacovigilance Member States and marketing authorisation holders - pharmacovigilance system for the collection and evaluation of adverse events of veterinary medicines Inspection of marketing authorisation holder to check compliance with pharmacovigilance requirements Application for a marketing authorisation requires detailed description of the pharmacovigilance system Marketing authorisation holder has an obligation to send an evaluation of pharmacovigilance data regularly to Competent Authority (PSURs)
Revision of the veterinary medicines legislation DEVELOPED WITH NEEDS AND CHARACTERISTICS OF THE VETERINARY SECTOR IN MIND Rules are diverging from the pharmaceutical legislation for medicinal products for human use Bringing together all rules for veterinary medicines in one Regulation 53
Objectives Increase the availability of veterinary medicinal products Reduce administrative burden Stimulate competitiveness and innovation Improve the functioning of the internal market Address the public health risk of antimicrobial resistance While safeguarding public and animal health and protection of the environment 54
Revision of the veterinary medicines legislation REGULATORY NETWORK no major changes regulatory network structure unchanged 4 procedures for granting a marketing authorisation: national centralised mutual recognition decentralised EC CMDv Member States EMA 55
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