Dr Chalmers

Regulatory Approval Procedures: 

Regulatory Approval Procedures Dr Alan A. Chalmers

Cycle Romand en Sciences Biologiques: University of Fribourg: 

Cycle Romand en Sciences Biologiques: University of Fribourg Presentation on Regulatory Approval Procedures Friday 20 April 2007 Dr Alan A. Chalmers Pharma International Innovation Centre 4123 Allschwil BL

Regulatory Approval Procedures: 

Regulatory Approval Procedures General Introduction Regulatory Authorities EU Regulatory Procedures Recent changes Generic Products Parallel Importing Developing trends Discussion topics

General Introduction: 

General Introduction Drug development Patents Nomenclature Trade names REGULATORY APPROVAL

Pharmaceuticals: 

Pharmaceuticals The pharmaceutical industry is highly regulated and controlled. QUALITY SAFETY EFFICACY Drug development takes a long time ( e.g. 10 years from discovery to marketing approval ) It is very costly

Development in stages: 

Development in stages Discovery and selection Chemical and analytical development Pilot stage manufacture of active ingredient Dosage form development Non-clinical studies Clinical studies Marketing authorisation

Non-Clinical Studies: 

Non-Clinical Studies Pharmacological and toxicological Adsorption, metabolism, distribution and metabolism Acute and chronic toxicity testing studies Mutagenicity and carcinogenicity studies Pharmacokinetic studies Special studies

Clinical Studies: 

Clinical Studies Single dose studies, short term use Phase 1 Dosage finding studies Phase 2 Safety and Efficacy Studies Phase 3 Longer term, large pateint numbers SAFETY AND EFFICACY

Technical documentation: 

Technical documentation Chemistry,Manufacturing and Control (CMC) Active Pharmaceutical Ingredient(s) Excipients Final dosage Form Stability, Packaging , Labelling QUALITY

Regulatory Practices & Controls: 

Regulatory Practices & Controls R+D Good Laboratory Practice (GLP) Manufacturing controls –Good Manufacturing Practice (GMP) Clincial Trial conduct – Good Clincial Practice (GCP) Good Regulatory Practice (GRP)

Regulatory Procedures: 

Regulatory Procedures Clincial Trial Approvals USA : Investigational New Drug Applciation(IND) EU and Switzerland : Clinical Trial Approval (European Clinical Trials Directive CTD) Ethical Committes Approval

Regulatory Procedures: 

Regulatory Procedures New Drug Applciation ( NDA) in the USA Marketing Authorisation Applciation ( MAA) in the European Union Similar in Switzerland Japan Australia, Canada, South Africa Middle East, Africa, Asia, Latin America

Regulatory Authorities: 

Regulatory Authorities Switzerland : Swissmedic European Union: EMEA and national USA : Food and Drug Asministration (FDA) Japan : Ministry of Health & Welfare

European Union: 

European Union As from 01 May 2004 the 15 Member States : Austria, Belgium , Denmark , Finland ,France, Germany, Greece, Ireland, Italy ,Luxembourg ,Netherlands , Portugal, Spain, Sweden and United Kingdom have been joined by….. 10 new Member States ; Cyprus, Czech Republic, Estonia, Hungary ,Latvia, Lithuania, Malta, Poland, Slovenia, Slovakia…. In 2007 Bulgaria, Romania have also joined Currently 27 Member States………………. and other countries waiting Turkey approaching Links to Switzerland

EU Legislation-legally binding: 

EU Legislation-legally binding Directives: Binding legislation on member States/Objectives to be achieved. Require national implementation Regulations : Binding legislation- take precedence over any national law Decisions: Binding legislation on individual Member States, companies or persons

EU Legislation: Non-legally binding: 

EU Legislation: Non-legally binding Recommendations Opinions Communications Guidelines* *Examples: ICH, CHMP Guidelines

International links: 

International links International Conference on Harmonisation(ICH) European Union – Japan-- United States Regulators EMEA- MOHW-FDA Industry EFPIA- JMPA - PhRMA

Regional links: 

Regional links Gulf Cooperation Council (GCC) Association of South East Asian Nations (ASEAN) Latin America—Mercosur Bilateral agreements ( Switzerland and EU, Australia, Canada, USA)

Regultory Documentation: 

Regultory Documentation ICH developed CTD: Common Technical Document or standarised regualtory dossier Valid for EU, Japan, USA and some others Switzerland accepts CTD format as EU but some Swiss differences Similar trends in other regions eg ASEAN

Core EU Legislation: 

Core EU Legislation Council Directive 65/65/EEC and amendments Public health Marketing Authorisation (MA) necessary , documentation required Criteria of Quality, Safety, Efficacy Definition of a medicinal product Contents of SmPC Marketing Authorisation Holder (MAH )resident in the Community Requirements for renewing MAs every 5 years Variations Concept of data exclusivity and essential similarity Conditions for MA suspension or revoking

Core EU Legislation: 

Core EU Legislation Council Directive 75/318/EC and amendments Outlines data requirements for MAs Defines role of experts-pivotal in EU licensing process Defines role of Competent Authorities Established the Committee on Pharmaceutical Medicinal Products ( CPMP)-replaced in 2004 by CHMP Describes a procedure for mutual recognition of MAs Manufacturing Authorisations / Qualified Persons GMP requirements and inspections Pharmacovigilance

Core EU Legislation: 

Core EU Legislation Codified Directive 2001/83/EEC comprising 65/65EEC, 75/318/EEC, 75/319/EEC and 8 later Council Directives Incorporates immunological, radioactive and blood products Labelling and leaflets Legal status Wholesale distribution Advertising Specifically EXCLUDES Pricing and Reimbursement

EU Legislation EudraLex: 

EU Legislation EudraLex The Rules Governing medicinal Products in the European Union Vol. 1 : Pharmaceutical legislation-Medicinal products for human use Vol. 2A: Notice to Applicants-Procedures for Marketing Authorisation Vol. 2B: Notice to Applicants-Presentation and Content of the dossier Vol. 2C: Notice to Applicants- Regulatory Guidelines Volume 3A: Guidelines- Quality and bioavailability Volume 3B: Guidelines- Safety, environment and information Volume 3C: Guidelines-Efficacy http://dg3.eudra.org/F2/eudralex/index.htm

Eudralex Vol.2 : Notice to Applicants: 

Eudralex Vol.2 : Notice to Applicants Vol. 2A Procedures for Marketing Authorisation Chapter 1 Marketing Authorisation Chapter 2 Mutual Recognition Chapter 3 Community Referral Chapter 4 Centralised Procedure Chapter 5 Variations Chapter 6 Community Marketing Authorisation Chapter 7 General Information

Eudralex Vol 2. : Notice to Applicants: 

Eudralex Vol 2. : Notice to Applicants Volume 2B Presentation and Content of the Dossier 1A User guide for application form 1B Product Characteristics IC Expert Reports Part III Toxico-Pharmacological Documentation Part IV Clinical Documentation Index Annex

Eudralex Vol.2: Notice to Applicants: 

Eudralex Vol.2: Notice to Applicants 2B Presentation and content of dossier CTD 2001 edition incorporating Common Technical Document Module 1.2 Application form User guide for the application form Questions and Answers Electronic Common Technical Document ( eCTD)

EU Legislation changes: 

EU Legislation changes New Legislation entered force 20 May 2004 and more followed as from 20 November, 2005 ( based on EMEA/12332/04) New responsibilities New administrative structure New agency

EU Regulatory Authority: 

EU Regulatory Authority The European Agency for the Evaluation of Medicinal Products (EMEA) was established by Council Regulation EEC 2309/93 in 1995 New name since May 2004 is European Medicines Agency EC Regulation 726/2004 Remains known as EMEA Executive Director Thomas Lonngren http://www.emea.europa.eu.

EU Recent Changes: 

EU Recent Changes

EU Recent Changes: 

EU Recent Changes Reinforced role for the EMEA in providing scientific advice to companies Stronger role in provision of information to patients and the public ( database of all medicines approved in EU ‘Europharm’ Administrative and scientific support Opinions on compassionate use of unapproved medicinal products Opinions for the use of medicines outside the EU

EU Recent Changes: 

EU Recent Changes Committee for Medicinal Products for Human Use (CHMP) replaces the Committee for Proprietary Medicinal Products (CPMP) Instead of two now one member per Member State thus new 27 plus one each from Iceland and Norway New Committee for Herbal Medicinal Products (HMPC)

EU Recent Changes: 

EU Recent Changes Committee for Medicinal Products for Veterinary Use replaces Veterinary Medicinal Products Committee..still CVMP Committee for Orphan Medicinal Products (COMP) remains unchanged

EMEA Management Board: 

EMEA Management Board Changes from two to one member per Member State plus one each from European Parliament and European Commission; one representative each of doctors’ and veterinarians’ organisations New Board met for first time 24 May 2004 Composition of CHMP and CVMP

CHMP Members: 

CHMP Members Chairman Daniel Brasseur Belgium Vice-Chairman Eric Abadie France Members and alternates are appointed for a 3 year term by Member States and approved by EMEA Management Board

EU Regulatory Procedures: 

EU Regulatory Procedures The Centralised Procedure – single application with EU wide approval The Mutual Recognition Procedure- applications to individual member states Decentralsied Procedure National approvals

The Centralised Procedure: 

The Centralised Procedure One application centrally to the EMEA – involves the CHMP ( or CVMP) and leads to EU wide approval in all 27 Member States Obligatory for Biotech products such as recombinant DNA products, gene expressed products, hybridoma and monoclonal antibody products Veterinary performance enhancers

The Centralised Procedure: 

The Centralised Procedure Optional for:- Innovative delivery systems Significant entirely new indications Significant radioisotope products Human blood or plasma products Significant advanced manufacturing process New active substances ( changing)

Outline of Procedure: 

Outline of Procedure Application to EMEA Review CHMP( Rapporteur /Co-Rapporteur) Questions Response Review CHMP Opinion Hearing European Commission Decision

Pre-Application Activities: 

Pre-Application Activities Orphan Medicinal Product status Scientific Advice Selection of Rapporteur/Co-rapporteur Notification to EMEA of intention to submit ( by seven months in advance)

Centralised Procedure: 

Centralised Procedure Dedicated team needed to manage the procedure including documentation to all member states, response to questions from experts, translations, Clear communication lines internally and externally

Review Times A: 

Review Times A Submission, Validation, Preliminary assessment report CHMP Day 70 List of questions to applicant Day 120 Clock stop / start Responses to CHMP Final assessment report Day 150

Review Times B: 

Review Times B Oral explanation of outstanding issues - if required Day 180 CHMP Opinion Day 210 ( Appeal if needed 60 days) EC Decision

Review Times C: 

Review Times C Finalise translations 30 days Commission draft decision 30 days Standing Committee 30 days Commission final decision 30 days TOTAL TIME 300 days ( + response time to questions , possibly also appeal time)

Centralised Procedure: 

Centralised Procedure Single authorisation for all Member States One SmPC (Previously 13 now in 22 EU languages) Single trademark ( usually) Common labelling 10 years data protection

MA Maintenance: 

MA Maintenance Renewals to EMEA every 5 years Variations submitted to EMEA Type IA ( minor) Acknowledged in 14 days Type IB ( minor) EMEA Opinion in 30 days, 30 days for Questions Type II ( major) Assessed by CHMP, Opinion in 60 days ( or 90 days ) + clock stop for responses

Centralised Procedure- trends: 

Centralised Procedure- trends Help for small companies with limited market Compulsory for new active substances Shorter post-opinion decision making process Product to be marketed within 3 years of authorisation Renewal of MA after 5 years then unlimited

Centralised Procedure Summary: 

Centralised Procedure Summary Obligatory for Biotech and new innovative Single application to EMEA May not be assessed by rapporteur of choice Decision binding on Member States Single MA to maintain Quick but all or none risk

Mutual Recognition Procedure: 

Mutual Recognition Procedure Mutual Recognition Procedure (MRP) may be used for:-all standard applications but not biotech, abridged applications, bibliographical applications and variations to MRP approvals. MRP may be used repeatedly for same medicinal product

Mutual Recognition Procedure: 

Mutual Recognition Procedure Approval first in one member state the Reference Member State Assessment Report Concerned Member States which will be asked for mutual recognition of initial approval Can be selected or all the Member States

Mutual Recognition Procedure: 

Mutual Recognition Procedure In preparatory stage the Reference Member State must be informed of the applicant s intention to submit and request MRP Discussion on content of dossier with the Reference Member State

Reference Member State: 

Reference Member State Performs initial review and grants first regulatory approval Agrees Summary of Product Characteristics-model text for the other EU countries Is the first country where product can be marketed Liaison between applicant and concerned member states

Concerned Member States: 

Concerned Member States Asked to recognise the Assessment Report of the Reference Member State and accept the SmPC , grant local licence Can challenge the validity of initial approval in Reference Member State

MRP Timeframes Step 1: 

MRP Timeframes Step 1 Select Reference Member State and organise a meeting with competent authority Submit dossier to RMS and notify EMEA and all Concerned Member States Day -5/10 Validation and clock start for review Day 0 Questions and Answers with RMS 210 days with clock stop if issues raised by RMS require response from applicant

MRP Timeframes Step 2: 

MRP Timeframes Step 2 Preparation of Assessment Report by RMS maximum 90 days Updated dossier to be prepared and provided to all the Concerned Member States Applicant must give assurance that dossier and SmPC is identical to RMS and submission in all CMSs Inform EMEA at mrp@emea.europe.eu

MRP Timeframes Step 3 A: 

MRP Timeframes Step 3 A Submission to CMS, RMS will start procedure 5 working days after notification Validation of submission Day 0 Review of dossier by CMSs, questions to RMS and applicant Day 0-55 Answers to questions by applicant and RMS ( applicant by day 60) Day 55-65

MRA Timeframes Step 3 B: 

MRA Timeframes Step 3 B RMS evaluates responses from applicant and informs CMSs in writing Documentation 10 days in advance to Mutual Recognition Facilitation Group Dialogue between RMS, CMSs, Applicant http://heads.medagencies.org/mrfg/sops Guidances issued

MRA Timeframes Step 3 C: 

MRA Timeframes Step 3 C MRFG and break-out sessions to resolve outstanding issues Day 75 RMS and applicant respond to any pending issues, CMSs final opinion Day 75-85 Mutual Recognition granted Day 90 or arbitration ( decide by day 89) CMSs issue national licences: I month-1 year

Mutual Recognition Procedure: 

Mutual Recognition Procedure Quicker to first market Can withdraw application from critical CMSs Different trade names possible Second wave possible Harmonisation of SmPC often tricky 6/10 years data protection from first date Extensive co-ordinaton required

Regulatory Strategies: 

Regulatory Strategies Comparison and choice of regulatory system Reference member state Concerned member states Rapporteur and Co-rapporteuer Regulatory experiences Marketing requirements

GENERICS: 

GENERICS Same regulatory systems available Documentation primarily Quality Documentation Bioequivalence study with originator product

Generics: 

Generics European Commission draft regulation issued end October 2004 to allow generic manufacturers to produce patented pharmaceuticals under a compulsory licence order and export to eligible developing countries aligned with World Trade Organisation decision 2003

Generics: 

Generics Increasing importance also in Switzerland due to pricing, costs containment issues Some countries predominately generic Linked to pricing and reimbursement Not possible normally during patent protection Many large companies produce proprietary and generic products

Parallel Importation EU: 

Parallel Importation EU Centrally authorised medicinal product identical in all Member States of the EU Same labelling, package leaflets, languages “parallel distributor” independent of MAH May change language version or pack size as necessary.

Parallel Importation EU: 

Parallel Importation EU Notifications to the EMEA of parallel distribution of centrally approved medicinal products mandatory since 20 May 2004 based on Regulation 726/2004(EC) Details of a Notification to EMEA

Parallel Importation EU: 

Parallel Importation EU Details of parallel importer Contact person Medicinal product with EU register number Details of MAH Member States involved ( up to 25) Details of repackager Certification condition of product unaltered

Parallel Importation: 

Parallel Importation Marketing implication Pricing not harmonised throughout EU Multinational companies responses

Parallel Importation EU: 

Parallel Importation EU Fee 3480 Euros Mock ups or final package leaflet Mockups or copies of inner/outer packaging Wholesale distribution licence Manufacturing Authorisation ( if Repackager different from Parallel Distributor)

Parallel Importation: 

Parallel Importation Additional Questions and Answers

Parallel Importation: 

Parallel Importation EMEA Post-Authorisation Guidance on Parallel Distribution Final document released 19 May 2004 EMEA/Ho/2368/04/rev2 22 June 2004 www.emea.eu.int paralleldistribution@emea.europe.eu.

Parallel Importation CH: 

Parallel Importation CH Same manufacturer as for primary product Importation from one country with equivalent systems for MA and site licensing ( EU , USA, Japan, Canada and Australia Same format ( Strength and package size) Secondary packaging must comply with Swiss regulations ( D/E/I)

Parallel Importation CH: 

Parallel Importation CH Company in Switzerland requires licence for importation and wholesale No need for clinical data or Bioequivalence No quality data Need to repackage in Switzerland Changes of country of origin requires a revision of MA

Counterfeit drugs: 

Counterfeit drugs Many illegal and incorrect copies of products are made internationally Often dangerous or harmful Internet offers Beware! Swissmedic regularly issues warnings Applies also to dangerous drugs as such

Regulatory Headlines: 

Regulatory Headlines First use in man studies Clinical trial basis Withdrawals and financial consequences Regulators perspective

Regulatory Headlines: 

Regulatory Headlines Products already in development Need for new therapies Patent protection Criticism of Regulatory Authorities including FDA in the USA. Responses from EMEA. Restructuring of SWISSMEDIC

Regulatory Headlines: 

Regulatory Headlines “ Calls to overhaul the way drugs are approved are foolhardy. It would be hazardous to consider the notion of separating out the review of efficacy from the review of safety, because all drug decisions are based upon the balance of risk to benefit” Tachi Yamada , Head R+D, GSK

WEBSITES: 

WEBSITES www.swissmedic.ch www.emea.europe.eu www.fda.gov

Discussion matters: 

Discussion matters Topics for discussion Questions and answers Thank you for your attention!

Pharma International: 

Pharma International Innovation Centre, CH 4123 Allschwil Switzerland Telephone + 41- 61 483 09 78 Fax + 41- 61 483 09 79 Email alan.chalmers@datanetworks.ch