regarding to generic applications Analysis of EU MRP/DCP procedures regarding to generic applications Dr.Raimonds Lozda, FMS Baltic Ltd

EU Authorities EU-Commission Enterprise DG(Enterprise Directorate-General) Unit F2: Pharmaceuticals Regulatory framework and Market authorisations EMEA The European Agency for the Evaluation of Medicinal Products CPMP Committee for Proprietary Medicinal Products National Regulatory Authorities

AIMS of the EU-Commission – Ensure a high level of protection of public health – Bring about a single market in pharmaceuticals – Foster a stable and predictable environment for pharmaceutical innovation

Regulatory policy and tasks of the EC – Ensure appropriate standards of consumer protection – Maintain, update and simplify EU pharmaceutical legislation – Draft new legislation – Provide guidance on pharmaceutical legislation and ensure that it is properly implemented within the EU – Support the mutual recognition of national marketing Authorisations – Check that centralised authorisations comply with community law and turn the EMEA opinion into a binding decision for all the Member States (issue the authorization)

Legally binding acts and „soft laws“ • Regulation (e.g. EEC No. 2309/93) • Directive (e.g. 2001/83/EC) • Decision (e.g. N°74/1999) „Soft laws“: • Resolution • Communication (e.g. 98/C229/03) • Guideline (e.g. GCP, GMP, GLP) • Notice to Applicants (e.g. Notice to Applicants NTA)

Regulation vs. Directive Regulations (EEC) no. 726/2004 (EMEA): – Binding legislation which automatically enters into force in all Member States Directives 2004/27/EC and 2004/24/EC – Require transposition into national law (normally within 18 months) leaving to national authorities decision as to form and means for achieving desired aim of law

Legally binding acts regulating MRP/DCP MA legislation in the EU In 2001 a comprehensive reform of the EU pharmaceutical legislation, commonly referred to as “Review 2001” took place. The following directive was published: Directive 2001/83/EC on human medicines including rules for marketing authorisation (MRP and DP), authorisation procedure, manufacture and importation, labelling, pharmacovigilance as well as advertising

Review 2001 Objectives of the review: – guarantee a high level of public health protection for Europeans – create basic legal conditions for improving the competitiveness of the European pharmaceutical industry – meet the challenge of EU-enlargement – rationalise and simplify the medicines authorisation systems

Finalisation of the “Review 2001” • Regulation 726/2004 Community procedures for authorisation of medicinal products for human and veterinary use – centralised procedure (replaces Regulation 2309/93) • Directive 2004/27/EC amending Directive 2001/83/EC related to medicinal products for human use • Directive 2004/24/EC amending Directive 2001/83/EC related to traditional herbal medicinal products – The most parts of the regulation came in force on 20 November 2005 – all EU member states had to implement the revised directives by 30 October, 2005

Objectives for the finalisation: – New measures to eliminate the remaining obstacles to free movement – Revision of MRP: Formalisation of Cooperation between Member States – Clear definition of medicinal products to avoid “borderline” products – Clear position, which products have to be authorised by centralised procedure – Renewal and invalidity of marketing authorisation after granting of MA – Harmonisation of data protection – Facilitating the access of generics to the market – Specialities for bio-similars – Quality aspect for MP was enlarged to requirements on active substances – Proper use of medicinal products

Which procedures are possible for generics ? Mutual Recognition Procedure (MRP) Decentralised Procedure (DCP)

THE MUTUAL RECOGNITION PROCEDURE Generic Case Study

What is a generic medicine in EU ? “reference medicinal product” shall mean a medicinal product authorised under Article 6, in accordance with the provisions of Article 8; “generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitativecomposition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines. DIRECTIVE 2004/27/EC

What is Data Exclusivity ? Data Exclusivity guarantees market protection for branded pharmaceuticals by preventing health authorities from accepting applications for generic medicines during a given period (6 or 10 years after the first authorisation in the EU of theoriginator product).

Data exclusivity in EU • for all MA-application after the 20.11.2005: – The new data protection is valid: • 8 + 2+ 1 for all products - independent of the approval procedure: • 10 (8+2) years market exclusivity 8 years data protection and receive a MA – the generic MAH is not allowed to place his product on the market until 10 years have expired • 11 (8+2+1) for a new indication with a significant clinical benefit in comparison with existing therapies, a year supplementary protection is given

What is Bolar Provision? A “Bolar” provision allows all development, testing and experimental work required for the registration of a generic medicine to take place before expiry of the term of the patent protection of the original product. EU generic companies are forced to develop their products in countries with Bolar provisions and then import after patent expiry. Bolar implentation in some countries – UK October 2005, DE September 2005, IT March 2005 LV March 2007.

MRP If a national marketing authorisation exists, only the Mutual Recognition Procedure is possible What does it mean ? If you have a MA in one or more countries and in order to get a MA in some other country the only possibility is : MRP

MRP exceptions … except • Medicinal products subject to the centralized procedure • Line-extensions for non-harmonized products approved by national procedures (Only PL,LT possible ?) • Medicinal products not yet reviewed, e.g. products under reevaluation (No such products presently) • Homeopathic products

What are MRP difficulties ? RMS – reference member state Presently all EU national Agencies dealing with MRP are booked till 2009 Points to consider • Scientific expertise and knowledge in the therapeutic area • Reputation in the regulatory community • Reliability • Duration of assessment • Good project management and co-ordination skills • Transparency of communication • Market size of RMS (1st approval offers the chance for an early entry into a big market)

CMS- concerned member state Applications in Concerned Member States The applications must be submitted to the competent authorities of all CMS accompanied by the following confirmations: • the dossier is identical to that approved by the RMS • the Summary of Product Characteristics (SPC) is Identical • dossier and SPC as submitted are identical for all CMS

MRP flow-chart ~ 330 days total

MRP process description – Submission of the dossier (CTD, SPC, PIL, label) only in the Reference Member State (RMS) for national marketing authorisation – after 210 d: first marketing authorisation: RMS sends assessment-report to Concerned Member State (CMS); national process – In further 90 days resolution and agreement to dossier and final SPC – Further national marketing authorisation in 30 calendar days (translation etc)

MRP flow-chart

MRP process description

THE DECENTRALIZED PROCEDURE Generic Case Study

DCP If no marketing authorisation exists, the decentralised procedure can be choosen if the authorisation is planned in more than one Member State

MRP flow-chart ~ 210 days total

DCP process description – Submission of the dossier (CTD, SPC, PIL, label) in the RMS and all CMS – After 210 days: national marketing authorisations in RMS and CMS

DCP process description

MRP, DCP issues

What are main threats in MRP, DCP ? Validation of the dossier according to NTA 1) Preparation of dossier - Language

What are main threats in MRP, DCP ? Validation of the dossier according to NTA 1) Preparation of dossier – number of copies EE Modules 4 and 5 should be provided on CD-ROM version only. Paper copy should be available on request LT Mutual Recognition Procedure where LT acts as CMS: a paper copy of 1&2 modules +all modules on CD-ROM LV Additional copy of all modules on CD – ROM

What are main threats in MRP, DCP ? Validation of the dossier according to NTA 2) Samples, mock-ups EE in the presentation authorised in RMS LV 2 samples in the form of final sales presentation of the medicinal product

What are main threats in MRP, DCP ? Validation of the dossier other issues Payments 1) When and where to pay ? 2) What documents support payment ? Reference product Brand name issues

What are main threats in MRP, DCP ? During the procedure Strict follow to timeframes set in procedure The duration of the clock stop can be strongly influenced by the applicant !!!

What are main threats in MRP, DCP ? During the procedure „User test“ (Art. 59 (3) and 61(1) on the patient information has to be done – • here the tests only in one EU-language is necessary –the result has to be presented in English

What are main threats in MRP, DCP ? During the procedure What is the User test ? The action which increases the cost of MA “The package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use” and “The results of assessment carried out …with target patient groups shall also be provided to the competent authority”

What are main threats in MRP, DCP ? National phase Almost never completed within 30 days MRP and 90 DCP Not only the SPC but also the package leaflet (PL) and labelling has to be identical – the „blue box“ concept will allow adequate national information like national marketing authorisation number, special warnings proposals of labelling, patient information and summary of product characteristics has to be submitted in one language for applications for marketing authorisation - the translations of the agreed SPS, PL and labelling have to be submitted at latest 5 days after the end of the procedure to the national competent authorities

What are main threats in MRP, DCP ? National phase On the packaging the name of the product has to be printed in Braille-format • Mock-ups of the packaging including the Braille signs have to be submitted with the SmPC Check the product - hospital or not

Nightmare What are main threats in MRP, DCP ? National phase Common Baltic Pack – reality ? Nightmare „blue box“ too big.

MRP, DCP statistics- generics

MRP, DCP statistics- generics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP statistics

MRP, DCP tips and tricks What to do if you have a product you want to sell to different clients ? Multiple applications Same dossier (photocopies) • Same legal basis Art 8.3 (i) or Art 10.1 Dir 2001/83/EC • Different trade names • Same or linked applicant or different applicant

MRP, DCP tips and tricks What to do if a product was under MRP/DCP but you want to add one country where is no MA ? Find a company which will Apply as MAH and after granting transfer MA

Key lessons from MRP,DCP To go your own is not the cheapest way Local contact in each country is mandatory Paper work is too complicated that SOPs (Standart Operation Procedures) on spot are of high relevance

E-mail: raimonds@farma.lv Contact details: E-mail: raimonds@farma.lv Tel:+37129218104 www.farma.lv