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EU- Fees & Payment arrangements
-Complex, Cumbersome but Important aspect-
1. Dossier Submission Fees – Varies as per selected
Procedure (DCP/National),
RMS/CMS,
Article of EC directive,
API (DMF/CEP),
Number of strengths involved
2. Annual Maintenance Fees (After approval)
3. Variation Fees (Based on type of variation Type IA/IB/II)
4. Renewal Fees (After 4 years & 3 months after getting
EOP)
5. Sunset Clause exemption Fees [Italy & UK (invoice)]
6. Price Dossier Fees (Italy- at the time of national MA grant)
7. FMD - Portal access & maintenance fees
8. Pharmacovigilance Fees from EMA based on EVMPD
data upload
9. Regulatory / Scientific Advice Fees (if needed)
Types of regulatory Fees – (not limited to)](https://image.slidesharecdn.com/euregqualityenvironment-abhishekr-190902043702/85/Eu-Regulatory-Quality-Environment-Abhishek-Raval-29-320.jpg)
Eu Regulatory & Quality Environment- Abhishek Raval
- 1. 1 Presented By- Abhishek Raval (M.Pharm; MBA(Pharma), C.I.M.) Regulatory Affairs-Regulated Markets Feasibility Planning Submissio n Developm ent Submissio n Address MOH Queries Product Approval Identification and Mitigation of Risks
- 2. 2 Evolution of the European Regulatory Environment since 1993… 1995 2000 2003 2004 2005 2006 2007 EMEA Centralised Procedure Mutual Recognition Procedure Orphan Drugs Regulation Annex I (to Directive 2001/83/EC) (CTD) New Legisl. Title IV of Reg. 726/04 immediate New Legisl. fully into force Paediatric Regulation Legisl. on Advanced Therapy Enlargement (to 15 MS) Enlargement to 25 MS (CY, CZ, EE, HU, LT, LV, MT, PL, SI, SK) Enlargement to 27 MS (BG & RO) 2008 Enlarged Scope of CP 2010 New Variation Regulation New Pharmacovi gilance legislation 2013… Accession of Croatia 2012 Implem. of New PV Legisl. PRAC (July 2012)
- 3. Confidential-For Internal Use only 3
- 4. 4 EU – 28 Countries EEA-EFTA – 3 Countries Austria, Belgium, Bulgaria, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden and the UK. Iceland, Liechtenstein and Norway Countries involved in Europe Baltic region Nordic region Benelux Lithuania Estonia Latvia Sweden, Finland Norway, Denmark Belgium, Netherlands Luxembourg Geological Clustures Europe – Allied Nations Serbia, Moldova, Montenegro, Bosnia-Herzegovina, Macedonia Switzerland & Turkey Regulation, Directive & Decision- What is the difference?
- 5. 5 Registration in Europe Post Nov 2005 : Three European Systems Centralised Procedure (via EMA) Mutual Recognition procedure Decentralised Procedure 5
- 6. Overview of the Centralized Procedure Legal Basis: Regul. (EC) No 726/2004 (also establishing “EMA” European Medicines Agency) Principle: single application / evaluation single authorization direct access to all EU(28 MSs) + Norway, Iceland and Liechtenstein Scope: ◦ Compulsory for: Biotech (recombinant DNA, gene expressed proteins, hybridoma & monoclonal antibodies) New Active Substances in Specific Therapy Areas: AIDS, Cancer, Neuro-degenerative disorder, Diabetes, Auto-immune disease, other immune deficiencies, Viral diseases Orphan Drugs pursuant to EC Regulation no. 141/2000. ◦ Optional for: Any Other New Active Substance Significant innovation (therapeutic, scientific or technical) In the interests of patients at community level Generic of Centralised reference prod. (may use CP or MRP/DCP) 6
- 7. 7 Data and Market Protection for Reference Product & Generic Product Entry
- 8. Generic Medicine Registration For Human Medicines – Article 10 of the Human Medicine Directive 2001/83/EC Article 10 - Subcategory: ◦ 10a - well-established medicinal use (OTC drugs) ◦ 10b – Fixed Dose Combinations ◦ 10c – Informed Consent ◦ 10.1- Generic application ◦ 10.3 – Hybrid Application ◦ 10.4 - Biosimilar application For Veterinary Medicines – Article 13 of the Human Medicine Directive 8
- 9. Mutual Recognition Procedures Mutual Recognition Procedure ◦ Art. 28 para. 2 of Dir. 2001/83/EC ◦ For products with an existing MA Decentralised Procedure ◦ Art. 28 para. 3 of Dir. 2001/83/EC ◦ Only possible, if no authorisation has already been granted ◦ Most significant difference with MRP = consultation between MS‘s before 1st MA issued : 9
- 10. MRP & DCP: Key authority stakeholders CMDh ("Coordination group for mutual recognition and decentralised procedure for human medicinal products"): ◦ Mixed responsibilities: procedural, regulatory and scientific ◦ One representative from each MS, appointed for 3 years (renewable) + observer from EMA and Commission ◦ CMD(h) Chair appointed for 3 years + Vice-chair representative of MS that has presidency of Council RMS ("Reference Member State") ◦ Selected by the applicant ◦ Has to prepare the assessment report (AR) ◦ Acts as central point between MS and MAH CMS ("Concerned Member State(s)") ◦ All other MS‘s where the Company has submitted the dossier 10
- 11. Confidential-For Internal Use only 11 MRP – Flow Chart
- 12. Confidential-For Internal Use only 12 DCP – Flow Chart
- 13. Overview of the MRP Application to Reference Member State (RMS) RMS Approval (Day 210) Submit MR application to Member States National Submission 210 days Mutual Recognition 90 days Closure of procedure (AR, SPC, labelling, PIL) Arbitration by CHMP (Art.32, 33, 34) 60 days (CHMP opinion) + 30 days (Commission decision) National licences granted within MSs Approval Arbitration By CMDh (60 days) CMDh National Step (30 days) Serious objections Referral to CMDh Approval 13
- 14. Overview of the DCP Submission of dossier to Reference Member State (RMS) and Concerned Member States (CMSs) RMS starts evaluation, and issues preliminary Assessment Report (AR) for comments by CMSs RMS sends consolidated list of questions to Applicant RMS prepares draft AR, draft SPC and draft labelling/package leaflet Submit MR application to Member States Closure of procedure (AR, SPC, labelling, PIL) Arbitration by CHMP (Art.32, 33, 34) 60 days (CHMP opinion) + 30 days (Commission decision) National licences granted within MSs Approval DCP Step1 120 days DCP Step 2 90 days Arbitration By CMDh (60 days) CMDh Clock stop National Step (30 days) Serious objections Referral to CMDh Approval (recommended 3 mths) 14
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- 16. The “Pharmacovigilance and Risk Assessment Committee” (PRAC) Mandate: Risk detection, Benefit-Risk Assessment, Communication of risk and benefit/risk, Risk Minimisation and Analysis Impact, Design and Evaluation of PASS CHMP & CMDh to “rely upon” recommendations from PRAC but retain responsibility for benefit-risk assessments PRAC started in July 2012 Membership: ◦ 1 member (& 1 alternate) from each MS ◦ Chair Person ◦ Vice-Chair: Person Interaction between PRAC & CHMP: ◦ About 30% of CHMP agenda would go to PRAC ◦ Aiming that PRAC Rapporteur could come from same MS as CHMP Rapporteur ◦ Challenge with timing of PRAC opinions: i.e. trying to fit the PRAC 60 day review timeframe into overall timelines and still allow CHMP time to consider PRAC input before adopting their opinion 16
- 17. National Phase Submission After EOP, Within 5 (working) days for UK, IE, SE, DE, etc. High quality national translations for SmPC/PL/Label are submitted by help of local associates/ agreed translation service partners. Corrections / Acceptance Price dossier in country like Italy Final MA Grant Same follows for labeling variations & renewal approvals 17
- 18. Requirements for the Marketing Authorisation Application (MAA) Pharmacovigilance System Master File (PSMF) MAH must prepare and maintain “Pharmacovigilance system master file” (PSMF): replaces former “Detailed Description of Pharmacovigilance System” (DDPS), and must be held at MAH site Summary of the Pharmacovigilance System must be included in the MAA dossier Full PSMF to be provided within 7 days of request from a competent authority Risk Management Plan (RMP) Detailed description of risk management system RMPs to be included in MAAs for all new products N.B.- Authorities can impose need for Risk Management System on already authorised products if concerns about Benefit/Risk balance Format and content of RMPs addressed in Commission’s implementing measures 18
- 19. Post Approval Activities Renewal Renewal date – 5 years from date of EOP To be submitted 9 months before renewal date. Outcome - Approval for indefinite time or call for one additional renewal cycle. 19 Variations Types –based on impact on product quality Cost & approval time increases towards higher category ◦ Type IA - To be submitted within 12 months of implementation of change case ◦ Type IAIN – To be submitted within 15 days of implementation of change case ◦ Type IB- Submit- Hold - Implement ◦ Type II - Prior approval ◦ Z category – To be submitted as Type IBz-for non-categorized changes ◦ Article 61(3) variations ◦ Batch Specific Variation- (mostly type-II & Submitted by QP)
- 20. Sunset Clause In the context of the sunset clause provision, the MA of a medicinal product will cease to be valid if: - 1. the medicinal product is not placed on the market within 3 years of the authorisation being granted or, 2. where a medicinal product previously placed on the market is no longer actually present on the market for three consecutive years SSC Exemption application - European Commission(for CP) & NCA (for NP) may grant exemptions on public health grounds and in exceptional circumstances if duly justified. 20 Post Approval Activities
- 21. GMP Supervision Of Manufacturers & Inspection Any of the EU member state can audit and update EudraGMDP database The system is based on 2 main pillars: 1. The authorization of operators in supply chain (Mfg, BR & BT sites) & 2. Inspection of those operators ◦ To ensure compliance with - Legal requirement GMP Requirements in the MA /CTA 3. Re-audit frequency –based on risk based model 21
- 22. For API Manufactures- ◦ If API gets imported to EU FP site- WC (introduced in July-2013 by Dir. 2011/62/EU) is needed for each batch and can be waived if EU-GMP or any MRA - GMP is available. ◦ For any non-compliance issue, exporting country will inform to EMA as per WC. ◦ The EU legislation places the responsibility for using API mfd in compliance with GMP, by direct /contractual audit, on – 1) FP Manufacturer 2) Importer at EU ◦ EU agency /EDQM team from Council of Europe (under EDQM inspection program) may audit API site/s following risk-based approach or suspicion of 22 GMP Supervision Of Manufacturers & Inspection
- 23. 23 EDQM - The European Directorate for the Quality of Medicines & HealthCare, HQ: Strasbourg, France Members Observers Signatory to the Convention on the Elaboration of a Ph. Eur. 1. Participate in the scientific work of the European Pharmacopoeia Commission 2.Benefit from the European experience in this area 3.Gain access to the work on the quality control of medicines and the methods of analysis used. Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Republic of Moldova, Romania, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, the Republic of North Macedonia, Turkey, Ukraine, United Kingdom, and the European Union. Last membership: Republic of Moldova (2017), Ukraine (2013) Albania, Algeria, Argentina, Armenia, Australia, Azerbaijan, Belarus, Brazil, Canada, China, Georgia, Guinea, India, Israel, Japan, Kazakhstan, Republic of Korea, Madagascar, Malaysia, Morocco, Russian Federation, Senegal, Singapore, South Africa, Syria, Tunisia, the United States of America, Uzbekistan, the Taiwan Food and Drug Administration (TFDA) and the World Health Organization (WHO). Last observerships: Uzbekistan (2018), Japan (2016), India (2016), Republic of Korea (2015), Azerbaijan (2014), The Taiwan Food and Drug Administration (TFDA) of the Ministry of Health and Welfare and South Africa (2013).
- 24. Functions of EDQM Develops & Maintains Pharmeuropa & European Pharmacopoeia ◦ Pharmacopeial reference standards ◦ Fixed Calendar of publication of monographs Issues CoS – which can replace most of the data expected for DS part of the product dossier. Evaluating quality in the manufacture of substances for pharmaceutical use and the related inspections programme OMCL Network: Quality control of medicines on the market Pharmaceutical care and combating counterfeit medicines Classification of medicines authorised in Europe into OTC and POMs EDQM Standard Terms 24
- 25. For API Manufactures- Every application for MA/Site addition must include a confirmation that the MAH has verified GMP compliance of the API manufacturer (or any intermediate/micronisation sites, if any) as per EU-GMP principles with date of audit. This is called – QP declaration signed by QP of all involved BRS. Guideline on QP declaration and requirements has been percolated on many occasion- Any queries ? 25 GMP Supervision Of Manufacturers & Inspection
- 26. Qualified Person (QP) ◦ Must have nationality of EU member state. ◦ All imported batches undergo a full retest in EU (at BTS) against MA approved release specification. ◦ Every single batch only be released after certified by QP for its regulatory compliance at BRS. ◦ Testing is waived if MRA in place between EU & exporting country ◦ NCA is empowered to take administrative & disciplinary measures against QP, if QP failed to fulfil his/their obligation/s. ◦ Batch Specific Variation (BSV) by QP (Majorly, Type –II). 26 GMP Supervision Of Manufacturers & Inspection
- 27. The GMP/GDP Inspectors Working Group (GMDP IWG) Forum for harmonization & discussion of common issues by inspectors taken back to NCA for implementation. Any new/amended text of EU GMP guide is developed by this group, with the EC responsible for the adoption. The GMDP IWG also maintains the CoUP(Compilation of EU procedures on Inspections & Exchange of Information) and overseas on behalf of HMAs the Joint Audit Programme They Meet at EMA 4 times/year Representatives from EC, EDQM accession countries, MRA partners and from other int’l authorities on case basis. Organises training for EEA inspectors & accession countries to raise technical capability of the inspectors Thus ensures common understanding for GMP issues & harmonization. EMA also has signed partnership agreement with PIC/S on training for GMP inspectors , to avoid duplication of efforts. 27
- 28. 28 Drug Import & Release arrangements to be confirmed at the time of dossier compilation BRS/ Manufacturer – EU GMP approved (within EEA) & Qualified Person (European nationality). Now for QP declaration- Every 3 years On-site audit by FP manufacturer/MAH is mandatory including the all the production sites/ KSM Mfg site / Intermediate sites. BTS - EU GMP approved (within EEA) & AMT arrangements from ADL/QC to BTS (can be done after MA approval). BRS & BTS has to be separately authorized to import the Narcotic / Hypnotic drugs from EU- NCA. Separate In house coding for Narcotic drugs to ease / control commercial activities precisely . DHCP Letter distribution with Product samples (case basis)
- 29. 29 EU- Fees & Payment arrangements -Complex, Cumbersome but Important aspect- 1. Dossier Submission Fees – Varies as per selected Procedure (DCP/National), RMS/CMS, Article of EC directive, API (DMF/CEP), Number of strengths involved 2. Annual Maintenance Fees (After approval) 3. Variation Fees (Based on type of variation Type IA/IB/II) 4. Renewal Fees (After 4 years & 3 months after getting EOP) 5. Sunset Clause exemption Fees [Italy & UK (invoice)] 6. Price Dossier Fees (Italy- at the time of national MA grant) 7. FMD - Portal access & maintenance fees 8. Pharmacovigilance Fees from EMA based on EVMPD data upload 9. Regulatory / Scientific Advice Fees (if needed) Types of regulatory Fees – (not limited to)
- 30. 30 MAH- Obligations Vs CDMO-CMO Business Model - Establishment Registration in EU /EEA - BRS –EU GMP approved - BTS - EU GMP approved - QP per BRS - CESP Access - NCA Fees & Regulatory Portals - FMD Registration & Access to EMVS - All types of Fees payments - Importer’s obligations and compliances Pharmacovigilance: - PSUR/PSUSA Submission - Appoint QPPV - xEVMPD / IDMP submissions - ADE reporting portal creation - EURD (EU reference dates) Tracking - PRAC/ Paediatric / RMP labeling updates
- 31. Confidential-For Internal Use only 31