Requerimientos para la Exportation

Transcription

1 Requerimientos para la Exportation Registro de Productos Farmacéuticos en Países que Adoptaron el CTD Check List de contenidos fundamentales del CTD Requerimientos para la Exportation GAP y Fortalezas

2 Contents 1. Brief outline on the EU Marketing Authorisation Procedures 3 2. An overview on CTD Maintenance Of The Marketing Authorisation: Variations And Renewal Assistance to Drug Development & Support to Innovation (Incentives) Advanced Therapies Requerimientos para la Exportation GAP y Fortalezas

3 1. Brief outiline on the EU Marketing Authorisation Procedures Courtesy of: Regulatory Pharma Net - PISA ITALIA Strategy: EU Marketing Authorisation Procedures MRA DCP Centralised Procedure 3 Requerimientos para la Exportation GAP y Fortalezas

4 MA in Europe What are the Routes to obtain an MA in Europe? National Procedure one Member State only Mutual Recognition Procedure a selected number of Member States (chosen by the applicant). A MA in the EU must be available Decentralised Procedure a selected number of Member States (chosen by the applicant) Centralised Procedure all Member States simultaneously 4 Requerimientos para la Exportation GAP y Fortalezas

5 MA in Europe How are Medicines Regulated? EU Pharmaceutical Legislation Principal Directive /83/EC of the European Parliament and the Council as amended by Directive 2002/98/EC, Directive 2004/24/EC and Directive 2004/27/EC. Principal Regulation (EC) No. 726/2004 of the European Parliament and the Council laying down Community procedures for the authorisation and supervision of medicinal products Italian Legislation Decree 219/06 implementing the EU Directive 2001/83 as amended 5 Requerimientos para la Exportation GAP y Fortalezas

6 MA in Europe Criteria for evaluating medicinal products: 6 Requerimientos para la Exportation GAP y Fortalezas

7 National Procedure National Procedure (eg: ITALY) Application to the competent regulatory authority (AIFA) Administrative validation (Day 0) Assessment of the quality, preclinical and clinical data ( 210 days ) Price & Reimbursement Procedure* MA granting In Italy the P&R procedure is a mandatory step that precedes the MA granting 7 Requerimientos para la Exportation GAP y Fortalezas

8 MRP & DCP Procedure Mutual Recognition Procedure (MRP) Decentralised Procedure (DCP) 8 Requerimientos para la Exportation GAP y Fortalezas

9 Mutual Recognition Procedure (MRP) Only applicable if the applicant already has a national marketing authorisation Procedure: MRP Procedure Application to "Reference" Member State (RMS) First authorisation granted by RMS Applicant requests "mutual recognition" Dossier "consolidated" for submission to other "concerned Member States (CMSs) Approval from CMSs within 90 days 9 Requerimientos para la Exportation GAP y Fortalezas

10 MRP Procedure Mutual Recognition Procedure (MRP) 10 Requerimientos para la Exportation GAP y Fortalezas

11 MRP Procedure Mutual Recognition Procedure (MRP) 11 Requerimientos para la Exportation GAP y Fortalezas

12 DCP Procedure Decentralised Procedure (DCP) Available pathway if the product has no existing MA in any Member State Timeline for the DCP is approval in 150 to 300 days Procedure: Identical dossiers sent to RMS and CMS RMS prepares preliminary assessment report and sends to CMS Day 70 CMS sends any comments to RMS - Day 100 If consensus on draft assessment report at Day 120, RMS closes DCP, each Member State adopts a decision based on the assessment, within 30 days If RMS and CMS cannot reach agreement by Day 150 it referred to the CMD(h) 12 Requerimientos para la Exportation GAP y Fortalezas

13 DCP Procedure Decentralised Procedure (DCP) 13 Requerimientos para la Exportation GAP y Fortalezas

14 MRP & DCP Procedure 14 Requerimientos para la Exportation GAP y Fortalezas

15 MRP & DCP Procedure 15 Requerimientos para la Exportation GAP y Fortalezas

16 Centralised Procedure Centralised procedure EC Regulation 726/2004 One application sent centrally to the European Medicines Agency (EMEA) Involves the scientific assessment by a specific body within the EMEA, the Committee for Medicinal Products for Human Use (CHMP) Following the positive opinion by the CHMP the EU Commission grants the MA in all 27 Member States 16 Requerimientos para la Exportation GAP y Fortalezas

17 Centralised Procedure Parties involved in the centralised procedure 17 Requerimientos para la Exportation GAP y Fortalezas

18 Centralised Procedure Overview of the Centralised Procedure 18 Requerimientos para la Exportation GAP y Fortalezas

19 Centralised Procedure Submission-Validation phase 19 Requerimientos para la Exportation GAP y Fortalezas

20 Centralised Procedure Primary Evaluation phase 20 Requerimientos para la Exportation GAP y Fortalezas

21 Centralised Procedure Clock Stop 21 Requerimientos para la Exportation GAP y Fortalezas

22 Centralised Procedure Secondary Evaluation Phase 22 Requerimientos para la Exportation GAP y Fortalezas

23 Centralised Procedure Secondary Evaluation Phase 23 Requerimientos para la Exportation GAP y Fortalezas

24 Procedure Global marketing authorisation When a medicinal product has been granted an initial marketing authorisation, any additional strengths, pharmaceutical forms, administration routes, presentations as well as any variations and extensions shall also be granted an authorisation or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10(1) of the directive, which relates to the procedure for the authorisation of generic products and lays down rules on data and market exclusivity and on the so-called European Reference Product. 24 Requerimientos para la Exportation GAP y Fortalezas

25 MA Procedures Products and access to the different MA procedures Type of application and relevant documentation Access to Special/Accelerated procedures 25 Requerimientos para la Exportation GAP y Fortalezas

26 Centralised Procedures Centralised Procedure Mandatory Scope EC Regulation 726/2004 Medicinal products developed by means of one of the following biotechnological processes: Recombinant DNA technology Controlled expression of genes coding for biologically active proteins Hybridoma and monoclonal antibody methods Mandatory for all Advanced Therapy Medicinal Products - gene therapy, cell therapy and tissue - engineered products Similar biological ( biosimilar ) medicinal products which are developed by one of the above biotechnological processes also fall under the mandatory scope of the centralised procedure. 26 Requerimientos para la Exportation GAP y Fortalezas

27 Centralised Procedures Centralised Procedure Mandatory Scope As of Nov. 2005, mandatory also for: New active substances (not licensed before coming into force of regulation EC 726/2004) for the indications: - Diabetes - Cancer - AIDS - Neurodegenerative disorder (Alzheimer,..) Orphan medicinal products pursuant to Regulation (EC) No 141/2000. And from 20 May 2008, for: Auto-immune diseases and other immune dysfunctions Viral diseases 27 Requerimientos para la Exportation GAP y Fortalezas

28 Centralised Procedures Centralised Procedure Optional Scope: EC Regulation 726/2004 Medicinal products containing a new active substance (which, on the day of entry into force of the Regulation (Nov 2005) were not authorised in the Community) which constitute a significant therapeutic, scientific or technical innovation Medicinal products which constitute a significant therapeutic, scientific or technical innovation or that the granting of authorisation is in the interest of patients at Community level. 28 Requerimientos para la Exportation GAP y Fortalezas

29 Registration Dossier Registration Dossier Structure 29 Requerimientos para la Exportation GAP y Fortalezas

30 MA Application Type of MA applications Full application (Article 8(3)(i) of Directive 2001/83/EC, as amended): should be supported by a full dossier with, quality, pre-clinical and clinical data. Abridged application: the applicant is not required to provide the results of pharmacological and toxicological tests or the results of clinical trials as they refer to information that is contained in the dossier of another original authorisation. 30 Requerimientos para la Exportation GAP y Fortalezas

31 MA Application Type of MA applications Different types of Abridged applications: Informed consent application (Article 10(1)(a)(i) of Directive 2001/83/EC, as amended): application for an essentially similar medicinal product for which consent has been given by the Marketing Authorisation Holder to refer to his dossier being used for examining the application in question 31 Requerimientos para la Exportation GAP y Fortalezas

32 MA Application Type of MA applications Generic application (Article 10(1)(a)(iii) of Directive 2001/83/EC, as amended): application for a medicinal product, essentially similar to a medicinal product, which has been authorised in the Community for not less than 6/10 years. The applicant is required to provide quality data + bioequivalence data (if applicable) to the reference product Two medicinal products are essentially similar when they have the same qualitative and quantitative composition in terms of active substances, when their pharmaceutical form is the same and, where necessary, their bioequivalence has been demonstrated by means of appropriate bioavailability studies. By extension, the concept of essential similarity also applies to different oral forms (e.g. tablets and capsules) with the same active substance for immediate release. 32 Requerimientos para la Exportation GAP y Fortalezas

33 MA Application Type of MA applications Biosimilar application (Article 10(1)(a)(iii) of Directive 2001/83/EC, as amended): application for a new biological medicinal product claimed to be similar to an original reference medicinal product which has been granted a marketing authorisation in the Community. The applicant should submit data providing demonstration of the similar nature of the two biological medicinal products. Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the reference medicinal product. 33 Requerimientos para la Exportation GAP y Fortalezas

34 MA Application Type of MA applications Bibliographical application (Article 10(1)(a)(ii) of Directive 2001/83/EC as amended) For products with a well-established use in the Community: should be supported by quality data + pre-clinical and clinical literature references establishing recognised efficacy and an acceptable level of safety. It is submitted and processed following the complete/full and independent marketing authorization dossier requirements 34 Requerimientos para la Exportation GAP y Fortalezas

35 MA Application Type of MA applications New fixed combination products Application according to Article 10b of Directive 2001/83/EC, relating to applications for In the case of medicinal products containing active substances used in the composition of authorised medicinal products but not hitherto used in combination for therapeutic purposes, the results of new pre-clinical tests or new clinical trials relating to that combination shall be provided in accordance with Article 8(3)(i), but it shall not be necessary to provide scientific references relating to each individual active substance". 35 Requerimientos para la Exportation GAP y Fortalezas

36 Generic Protection Protection/exclusivity for generic applications 10 years of protection (8 + 2) Data protection: a generic application can be submitted when the reference medicinal product has been authorised for not less that 8 years in a MS or in the Community Market exclusivity: the generic product shall not be placed on the market until 10 years have elapsed from the initial authorisation of the reference product. Maximum 11 years of marketing protection (8+2+1) if the MAH obtains the authorisation for a new therapeutic indication during the first 8 years of the 10 years of marketing protection 36 Requerimientos para la Exportation GAP y Fortalezas

37 Approval Time Possibilities in the EU to speed up the regulatory approval Accelerated assessment by CHMP Granting of a MA under exceptional circumstances Granting of a conditional MA 37 Requerimientos para la Exportation GAP y Fortalezas

38 Approval Time Accelerated assessment When a MA application is submitted for a product which is of major public health interest, in particular from the viewpoint of therapeutic innovation the applicant may request an accelerated assessment procedure If accepted by the CHMP, the standard timetable of 210 days will be reduced to 150 days. 38 Requerimientos para la Exportation GAP y Fortalezas

39 Relevant to products for: Authorisation Time Conditional MA - Chronic, seriously debilitating or life-threatening diseases - Orphan conditions - Emergency situations - public health threats Data submitted demonstrate a positive benefit-risk balance, based on scientific data, pending confirmation MA granted subject to certain specific obligations, to be reviewed annually Authorisation valid for one year, on a renewable basis Once the pending studies are provided, it can become a "normal" marketing authorisation 39 Requerimientos para la Exportation GAP y Fortalezas

40 Authorisation Time MA under exceptional circumstances The applicant is unable to provide comprehensive data on the efficacy and safety under normal conditions of use Reasons - Indications too rare - State of scientific knowledge not enabling - Medically not ethical MA valid for 5 years but subject to an annual reassessment of the risk-benefit balance Will normally not lead to the completion of a full dossier and become a "normal" marketing authorisation 40 Requerimientos para la Exportation GAP y Fortalezas

41 2. An Overview on CTD Common Technical Document General Structure Module 1 General Structure Module 1 Contents 41 Requerimientos para la Exportation GAP y Fortalezas

42 CTD Common Technical Document (CTD) MODULE 1 Administrative data (application form, proposed Summary of Product Characteristics (SPC), labelling and package leaflet, etc.) 42 Requerimientos para la Exportation GAP y Fortalezas

43 CTD Common Technical Document (CTD) 43 Requerimientos para la Exportation GAP y Fortalezas

44 CTD Module Cover Letter Module 1 Table of Content (1/2) 1.1 Comprehensive Table of Contents 1.2 Application Form 1.3 Product Information SPC, Labelling and Package Leaflet Mock-up Specimen Consultation with Target Patient Groups Product Information already approved in the Member States Braille 1.4 Information about the Experts Quality Non-Clinical Clinical 44 Requerimientos para la Exportation GAP y Fortalezas

45 CTD Module 1 Module 1 Table of Content (2/2) 1.5 Specific Requirements for Different Types of Applications Information for Bibliographical Applications Information for Generic, Hybrid or Bio-similar Applications (Extended) Data/Market Exclusivity Exceptional Circumstances Conditional Marketing Authorisation 1.6 Environmental Risk Assessment Non-GMO GMO 1.7 Information relating to Orphan Market Exclusivity Similarity Market Exclusivity 1.8 Information relating to Pharmacovigilance Pharmacovigilance System Risk-management System 1.9 Information relating to Clinical Trials 1.10 Information relating to Paediatrics 45 Requerimientos para la Exportation GAP y Fortalezas

46 CTD Module 1 Module 1.2 Application Form 46 Requerimientos para la Exportation GAP y Fortalezas

47 CTD Module 1 Module 1.3 Product Information SPC, Labelling and Package Leaflet Mock-up Specimen Consultation with Target Patient Groups Product Information already approved in the Member States Braille 47 Requerimientos para la Exportation GAP y Fortalezas

48 CTD Module 1 Module SPC, Labelling and Package Leaflet The SPC is the basis of information for healthcare professionals on how to use the medicinal product safely and effectively The Package Leaflet shall be drawn up in accordance with the SPC The SPC sets out the agreed position of the medicinal product as distilled during the course of the assessment process The content cannot be changed except with the approval of the competent authority. 48 Requerimientos para la Exportation GAP y Fortalezas

49 CTD Module 1 Module SPC, Labelling and Package Leaflet The competent authorities have published templates in all EU languages for the presentation of product information (Summary of Product Characteristics (SPC), labelling and package leaflet) 49 Requerimientos para la Exportation GAP y Fortalezas

50 CTD Module 1 Summary of Product Characteristics 50 Requerimientos para la Exportation GAP y Fortalezas

51 CTD Module 1 Labelling and Patient leaflet 51 Requerimientos para la Exportation GAP y Fortalezas

52 CTD Module 1 Module Mock-up A mock-up is a copy of the flat artwork design in full colour, providing a replica of both the outer and immediate packaging, providing a two-dimensional presentation of the packaging/labelling of the medicinal product. It is generally referred to as a paper copy or computer generated version. 52 Requerimientos para la Exportation GAP y Fortalezas

53 CTD Module 1 Module Specimen A specimen is a sample of the actual printed outer and immediate packaging materials and package leaflet. 53 Requerimientos para la Exportation GAP y Fortalezas

54 CTD Module 1 Module Consultation with Target Patient Groups Articles 59(3) and 61(1) of Directive 2001/83/EC require that the package leaflet reflects the results of consultations with target patient groups to ensure that it is legible, clear and easy to use, and that results of assessments carried out in cooperation with target patient groups be provided to the competent authority 54 Requerimientos para la Exportation GAP y Fortalezas

55 CTD Module 1 Module Consultation with Target Patient Groups 55 Requerimientos para la Exportation GAP y Fortalezas

56 CTD Module 1 Module Braille In accordance with Article 56a of Directive 2001/83/EC the name of the medicinal product must be expressed in Braille format on the packaging The Braille text (in normal font) which will be printed on the outer carton in Braille needs to be included in section 16 of the outer carton product information templates (if applicable) and should be indicated with dots on the mock-ups (where applicable and feasible) 56 Requerimientos para la Exportation GAP y Fortalezas

57 CTD Module 1 Module 1.4 Information about the Experts Quality Non - Clinical Clinical A declaration signed by the experts A brief information on the educational background, training and occupational experience 57 Requerimientos para la Exportation GAP y Fortalezas

58 CTD Module 1 Module 1.5 / Specific Requirements for Different Types of Applications Information for Bibliographical Applications Information for Generic, Hybrid or Bio-similar Applications (Extended) Data/Market Exclusivity Exceptional Circumstances Conditional Marketing Authorisation 1.6 Environmental Risk Assessment Non-GMO GMO 1.7 Information relating to Orphan Market Exclusivity Similarity Market Exclusivity 1.8 Information relating to Pharmacovigilance Pharmacovigilance System Risk-management System 1.9 Information relating to Clinical Trials 1.10 Information relating to Paediatrics 58 Requerimientos para la Exportation GAP y Fortalezas

59 CTD Module 1 Module Environmental Risk Assessment An ERA is required for: - all new marketing authorisation applications (included generic, bibliographical, well established use - type II variation or line extension if an increase in environmental exposure is expected (e.g. patient population increased, use of a dermal patch) 59 Requerimientos para la Exportation GAP y Fortalezas

60 CTD Module 1 Module Risk-management System The detailed description of a risk management system should be provided in the form of an EU Risk Management Plan for MAA of: - any product containing a new active substance - a similar biological medicinal product - a generic/hybrid medicinal product where a safety concern requiring additional risk minimisation activities has been identified with the reference medicinal product - with an application involving a significant change in a marketing authorisation (e.g. new dosage form, new route of administration, significant change in indication) unless it has been agreed with the Competent Authorities that submission is not required 60 Requerimientos para la Exportation GAP y Fortalezas

61 3. Maintenance of a Marketing Authorisation - Variation & Renewal Managing Variation & renewak Process Required Time Duration & Validity 61 Requerimientos para la Exportation GAP y Fortalezas

62 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL 62 Requerimientos para la Exportation GAP y Fortalezas

63 MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL A medicinal product may only be placed on the market in the European Economic Area (EEA) when a marketing authorisation has been issued by the competent authority of a Member State (or EEA country) for its own territory (national authorisation) or when an authorisation has been granted in accordance with Regulation (EC) No 726/2004 for the entire Community (a Community authorisation). The marketing authorisation is granted further the positive outcome of the evaluation of the necessary documentation submitted along with the application What is then the lifecycle Marketing Authorisation of the Marketing Authorisation? 63 Requerimientos para la Exportation GAP y Fortalezas

64 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL Throughout the life of a medicinal product the MAH is responsible for the product and is required to take into account technical and scientific progress, and to make any amendments that maybe required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods For this purpose VARIATIONS Administrative Chemistry Manufacturing and Control Non Clinical Clinical Pharmacovigilance Maybe submitted whenever necessary at any time and without any limit in the numbers 64 Requerimientos para la Exportation GAP y Fortalezas

65 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL In any case. Marketing authorisations granted in the Community shall have an initial duration of five years (Articles 14(1) of Regulation (EC) No 726/2004 and 24(1) of Directive 2001/83/EC). After these five years, the marketing authorisation may be RENEWED on the basis of a re-evaluation of the risk-benefit balance. For this purpose Must be submitted after 5 years RENEWAL Once renewed, the marketing authorisation shall be valid for an unlimited period unless the Commission or the national competent authority decides, on justified grounds relating to Pharmacovigilance, to proceed with one additional five-year renewal (Articles 14(3) of Regulation (EC) No 726/2004 and 24(3) of Directive 2001/83/EC). 65 Requerimientos para la Exportation GAP y Fortalezas

66 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL VARIATIONS THE LEGAL BASIS Regulation (EC) No 1234/2008 Communication from the Commission: 1. Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products 2. Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. CMDh Best Practice guides for the submission and processing of variations in the mutual recognition procedure 66 Requerimientos para la Exportation GAP y Fortalezas

67 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL According to Regulation EC 1234/2008 the variations are classified in 3 types: type IA type IB depending on the complexity of the variation type II The guideline on the details of the various categories of variations allows to classify each variation in the appropriate category (type IA or type II and type IB by elimination) and to define the documentation that has to be submitted along with the variation application The guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations provide details on the procedure for the submission of the variations and the relevant timelines for the evaluation/approval A different fee has to be paid for each type of variation. For national, MRP and DCP variation the fee to be due is regulated by local decisions 67 Requerimientos para la Exportation GAP y Fortalezas

68 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL MINOR VARIATIONS OF TYPE IA MINOR VARIATIONS OF TYPE IB MAJOR VARIATIONS OF TYPE II DO NOT REQUIRE PRIOR APPROVAL DO AND TELL PROCEDURE MUST BE NOTIFIED BEFORE IMPLEMENTATION TELL, WAIT AND DO PROCEDURE REQUIRE PRIOR APPROVAL BEFORE IMPLEMENTATION PRIOR AUTHORISATION PROCEDURE MUST BE NOTIFIED WITHIN 12 MONTHS FOLLOWING THE IMPLEMENTATION OR IMMEDIATELY AFTER IMPLEMENTATION (type IA IN ) THE MAH MUST WAIT A PERIOD OF 30 DAYS TO ENSURE THAT THE NOTIFICATION IS DEEMED ACCEPTABLE BY THE RELEVANT AUTHORITIES BEFORE IMPLEMENTING THE CHANGE THE MAH MUST WAIT FOR THE OFFICIAL APPROVAL 68 Requerimientos para la Exportation GAP y Fortalezas

69 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL - VARIATIONS Classification of variations Examples of Minor variations of type IA. Variations : (a) of purely administrative nature that are related to the identity and contact details of the holder or the manufacturer or supplier; (b) related to the deletion of any manufacturing site; (c) related to minor changes to an approved physico-chemical test procedure, where the updated procedure is demonstrated to be at least equivalent to the former test procedure; (d) related to changes made to the specifications of the active substance or of an excipient in order to comply with an update of the relevant monograph of the European Pharmacopoeia; (e) related to changes in the packaging material not in contact with the finished product; (f) related to the tightening of specification limits 69 Requerimientos para la Exportation GAP y Fortalezas

70 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL - VARIATIONS Examples of major variations of type II. Variations that may have a significant impact on the quality, safety and efficacy of the medicinal product such as: the addition of a new therapeutic indication or to the modification of an existing one; significant modifications of the summary of product characteristics due in particular to new quality, pre-clinical, clinical or pharmacovigilance findings; changes outside the range of approved specifications; substantial changes to the manufacturing process, formulation, specifications or impurity profile of the active substance or finished medicinal product which may have a significant impact on the quality, safety or efficacy of the medicinal product; 70 Requerimientos para la Exportation GAP y Fortalezas

71 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION:VARIATIONS AND RENEWAL NOTIFIED WITHIN 12 MONTHS FOLLOWING OR IMMEDIATELY AFTER IMPLEMENTATION TYPE IA DO AND TELL PROCEDURE The RMS reviews within 30 days following receipt By Day 30 RMS informs MAH and CMSs of the outcome RMS POSITIVE OPINION VARIATION APPROVED CMSs update the MA within 2 months or within 6 months for minor variations of Type IA requiring immediate notification RMS REQUESTS ADDITIONAL DOCUMENTATION MAH provide the missing documentation immediately MAH does not provide the missing documentation immediately RMS NEGATIVE OPINION VARIATION REJECTED MAH shall immediately cease to apply the rejected variation 71 Requerimientos para la Exportation GAP y Fortalezas

72 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION:VARIATIONS AND RENEWAL V A L I D A T I O N P H A S E TYPE IB TELL, WAIT AND DO PROCEDURE MAH must submit the variation simultaneously in all CMSs The RMS check within 7 calendar days if the notification is correct and complete and if it is appropriateto classify the variation as type IB RMS POSITIVE OPINION Processed as type IB RMS NEGATIVE OPINION, within 7 days CMSs agree with RMS Validation and Start date communicated to MAH CMSs do not agree with RMS, final decision on classification up to RMS MAH asked to re-submit variation as type II 72 Requerimientos para la Exportation GAP y Fortalezas

73 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION:VARIATIONS AND RENEWAL E V A L U A T I O N P H A S E POSITIVE OPINION Within 30 days the RMS notify the MAH of the outcome of the procedure NO OPINION Notification approved the MA is ameded within 6 months NEGATIVE OPINION The MAH may amend the notification within 30 days Notification amended Notification not amended Notification rejected 73 Requerimientos para la Exportation GAP y Fortalezas

74 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION:VARIATIONS AND RENEWAL TYPE II PRIOR AUTHORISATION PROCEDURE MAH must submit the variation simultaneously in all CMSs The RMS check if the notification is correct and complete Validation and Start date and timetable communicated to MAH 60-day evaluation timetable usually applied May be reduced to 30 days in case of urgency e.g. for safety issues May be extended to 90 days for addition of new therapeutic indications 74 Requerimientos para la Exportation GAP y Fortalezas

75 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION:VARIATIONS AND RENEWAL TYPE II 30 DAYS TYPE II 60 DAYS 75 Requerimientos para la Exportation GAP y Fortalezas

76 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION:VARIATIONS AND RENEWAL TYPE II 90 DAYS 76 Requerimientos para la Exportation GAP y Fortalezas

77 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL RENEWAL The marketing authorisation holder shall provide the EMEA or the national competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including all variations introduced since the marketing authorisation was granted, at least six months before the marketing authorisation ceases to be valid. Recommendations regarding the content of the consolidated file for the renewal are provided in the Guideline on the Processing of Renewals in the Centralised Procedure and MRFG Guideline on the processing of renewals in the mutual recognition and decentralised procedure 77 Requerimientos para la Exportation GAP y Fortalezas

78 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL RENEWAL TIMETABLE Day 0 Start of procedure Day 40 RMS to circulate preliminary assessment report to CMS Day 55 Receive comments from CMS Day 59 RMS to send request for supplementary information to marketing authorisation holder (if necessary) Clock-off up to 30 days (opportunity to prolong in exceptional circumstances only with agreement of RMS) Day 60 RMS to circulate finalised assessment report with draft decision Day 85 CMS to advise acceptance/non-acceptance of decision Day 90* Issue renewal or refer to Co-ordination Group, CMD(h), for 60 day referral procedure Within 30 days start referral Day 0 New Day 0 60 Follow procedure in CMDh SOP Disagreement in Procedures Referral to CMDh New Day 60* Issue renewal or refer to CHMP 78 Requerimientos para la Exportation GAP y Fortalezas * Allow 30 days for NCA to receive and approve updated PL, SPC and translations,

79 Marketing Authorisation MAINTENANCE OF THE MARKETING AUTHORISATION: VARIATIONS AND RENEWAL Extensions of marketing authorizations Substantial changes to a marketing authorisation are regarded not as variations but as extensions of the marketing authorisation and are authorized in accordance with the procedure for granting a new marketing authorisation Examples of changes leading to an extension of the MA 1. Changes to the active substance(s): (a) replacement of a chemical active substance by a different salt/ester complex/derivative, with the same therapeutic moiety, where the efficacy/safety characteristics are not significantly different; (b) replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (e.g. racemate by a single enantiomer), where the efficacy/safety characteristics are not significantly different; 2. Changes to strength, pharmaceutical form and route of administration: (a) change of bioavailability; (b) change of pharmacokinetics e.g. change in rate of release; (c) change or addition of a new strength/potency; (d) change or addition of a new pharmaceutical form; (e) change or addition of a new route of administration 79 Requerimientos para la Exportation GAP y Fortalezas

80 MA VALIDITY SUNSET CLAUSE Provision leading to the cessation of the validity of the marketing authorisation if: the medicinal product is not placed on the market within three years of the authorisation being granted or, where a medicinal product previously placed on the market is no longer actually present on the market for three consecutive years. Article 14(4-6) of Regulation (EC) No 726/ Requerimientos para la Exportation GAP y Fortalezas

81 4. Assistance to Drug Development & Support to Innovation (Incentives) EU Marketing Authorisation Procedures MRA DCP Centralised Procedure 81 Requerimientos para la Exportation GAP y Fortalezas

82 Drug Development Assistance to Drug Development & Support to Innovation (Incentives) Orphan Drug designation Scientific Advice/ Protocol Assistance Paediatric medicines Advanced Therapies SME 82 Requerimientos para la Exportation GAP y Fortalezas

83 ORPHAN DRUG Orphan Drug designation initiative 83 Requerimientos para la Exportation GAP y Fortalezas

84 ORPHAN DRUG WHICH IS THE REFERENCE RULE? Regulation (EC) No 141/2000 of 16 December 1999: laying down and the procedure for designation of orphan status the criteria establishing the Committee for Orphan Medicinal Products (COMP) within the Agency applicable as of April 2000 following Commission Regulation (EC) No 847/2000 of 27 April 2000 Objective: to stimulate research and development of medicinal products for rare diseases by providing incentives to the pharmaceutical industry. 84 Requerimientos para la Exportation GAP y Fortalezas

85 ORPHAN DRUG Which are the criteria for orphan designation in EU? Seriousness of the condition: life threatening or chronically/seriously debilitating or serious and chronic condition Rarity of the condition (prevalence): affecting not more than 5 in 10,000 people in the EU or insufficient returns on investment (unlikely to be developed without incentives) No satisfactory method exists for the disease in question or if such method exists the medicinal product will be of significant benefit to those affected by that condition 85 Requerimientos para la Exportation GAP y Fortalezas

86 ORPHAN DRUG Which are the criteria for orphan designation in EU? 86 Requerimientos para la Exportation GAP y Fortalezas

87 ORPHAN DRUG How to get the orphan medicinal product designation? Submission to the European Medicines Agency (EMA). Format and content of the application compliant with the relevant Commission guideline Demonstration that orphan criteria have been met. All claims should be supported by references Assessment by the EMA committee COMP (Committee for Orphan Medicinal Products) and opinion adoption Decision adoption by the European Commission (EC) following receipt of the COMP opinion. Inclusion in the Community Register of Orphan Medicinal Products Summaries of opinion on orphan designation published on the EMA web site 87 Requerimientos para la Exportation GAP y Fortalezas

88 ORPHAN DRUG Which are the timelines of the procedure? EMA COMP EC 88 Requerimientos para la Exportation GAP y Fortalezas

89 ORPHAN DRUG Which are the EU incentives? 89 Requerimientos para la Exportation GAP y Fortalezas

90 ORPHAN DRUG Which is the status of orphan designations to date ( )? 90 Requerimientos para la Exportation GAP y Fortalezas

91 ORPHAN DRUG Which is the status of orphan designations to date ( )? 91 Requerimientos para la Exportation GAP y Fortalezas

92 ORPHAN DRUG Which is the status of orphan designations to date ( )? 92 Requerimientos para la Exportation GAP y Fortalezas

93 ORPHAN DRUG Which is the status of orphan designations to date ( )? 93 Requerimientos para la Exportation GAP y Fortalezas

94 ORPHAN DRUG Which is the status of marketing authorisations for orphan designated medicines to date? 94 Requerimientos para la Exportation GAP y Fortalezas

95 ORPHAN DRUG Where finding information? 95 Requerimientos para la Exportation GAP y Fortalezas

96 ORPHAN DRUG What happens in other non-eu countries? Similar Orphan designation procedures exist in other non-eu countries (e.g. US, Japan, Australia) Different orphan designation criteria and incentives exist EU US JAPAN Rarity (prevalence) criteria not more than 5 per less than 200,000 ~7.5 per 10,000 not more than 4.2 per Market exclusivity Incentives 10 years 7 years 10 years 96 Requerimientos para la Exportation GAP y Fortalezas

97 5. Advanced Therapies Rules References 97 Requerimientos para la Exportation GAP y Fortalezas

98 Advanced Therapies 98 Requerimientos para la Exportation GAP y Fortalezas

99 Advanced Therapies Which is the reference rule? Regulation (EC) No 1394/2007 on advanced therapy medicinal products establishing rules to put on the market Advanced Therapy Medicinal Products (ATMPs), medicinal products for human use based on gene therapy, somatic cell therapy or tissue engineering. establishing the new expert Committee on Advanced Therapies (CAT), involved also in the discussion of the scientific advice Objectives: to facilitate access of ATMPs to the EU market to promote the competitiveness of European pharmaceutical companies in the field, while guaranteeing the highest level of health protection for patients. 99 Requerimientos para la Exportation GAP y Fortalezas

100 Advanced Therapies Incentives/support for development of ATMPs? Fee reductions for Scientific Advice procedure Support from Innovation Task Force (ITF), a multidisciplinary group with scientific, regulatory and legal competences : free of charge briefing meetings to facilitate the informal exchange of information and the provision of guidance early in the development process free of charge regulatory advice on whether new medicinal products for emerging therapies and borderline products are eligible for the Agency procedures 100 Requerimientos para la Exportation GAP y Fortalezas

101 Advanced Therapies Where finding information? Requerimientos para la Exportation GAP y Fortalezas

102 THANKS Muchas Gracias por su Atención Marco Benvenuti CTP SYSTEM +(39) Gilberto Rossi CTP SYSTEM +(39) Leandro Mbarak Latino América Consultores Gruppo CTP SYSTEM +[54] La presentación se puede descargar Requerimientos para la Exportation GAP y Fortalezas