1. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl Registration of medicinal products in European Union and Poland Andrzej Czesławski Deputy Director of Department for Medicinal Product Registration

2. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 2 Agenda Legal basis Types of procedures Presentation of the dossier – –Module 1 – –Types of applications Documentation in Electronic Format

3. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 3 Marketing Authorisation - legal basis Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human us Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency

4. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 4 Marketing Authorisation – legal basis – Polish legislation Act of 18 March 2011 – establishing Office for Registration of Medicinal Products, Medical Devices and Biocides(Journal of Laws from 2011, No. 82, item 451) Act of 6 September 2001 - Pharmaceutical Law (Journal of Laws from 2008, No. 45, item 271 as amended) and national regulations concerning: Fees - (Journal of Laws from 2008, No. 216, item 1378) and Journal of Laws from 2009, No. 223, item 1792) Application Form - (Journal of Laws from 2010, No. 36, item 2002) Presentation of the dossier – CTD - (Journal of Laws from 2010, No. 82, item 538) Labelling an leafleat - (Journal of Laws from 2009, No. 39, item 321

5. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 5 European Commission - EUDRALEX Eudralex – „The rules governing medicinal products in the EU” http://ec.europa.eu/health/documents/eudralex/index_en.htm VOLUME 1 - EU legislation in the pharmaceutical sector – human medicinal products Guidelines - human medicinal products: VOLUME 2 – Pharmaceutical Legislation Notice to applicants and regulatory guidelines Vol 2A - Procedures for marketing authorisation Vol 2B - Presentation and content of the dossier Vol 2C – Regulatory guidelines VOLUME 3 – Scientific guidelines VOLUME 4 – Good Manufacturing Practice (GMP) Guidelines VOLUME 9 – Guidelines for Pharmacovigilance (revision ongoing) VOLUME 10 – Guidelines for clinical trials

6. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 6 Marketing authorization procedures National Competent Authority (NCA) responsible for: National procedure Mutual recognition procedure Decentralised procedure European Medicines Agency (EMA) responsible for: Centralised procedure – European Commission decission National decission

7. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 7 National procedure (NP) strictly limited to medicinal products which are not to be authorised in more than one Member State or to the initial phase of mutual recognition (granting of the marketing authorisation by the Reference Member State) extensions of nationally authorised medicinal products as far as no a priori harmonisation has been achieved for the initial marketing authorisation for registration of a generic medicinal product (in one member state) of a reference medicinal product authorised in a centralized procedure if the Product Characteristic is in compliance with the reference medicinal product characteristic

8. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 8 National procedure (NP) Applicant is invited to our Office for pre-submission meeting and requested for a short presentation of the planed submission. At the pre-submission meeting discussion is taking place with Office’s experts concerning main aspects of the intended dossier of the medicinal product.

9. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 9 National procedure (NP) Processing of National Applications (no longer then 210 days): 1. 1.Submission of the application form and documentation 2. 2.Validation (no longer then 30 days) 3. 3.Assessment of the documentation – –Pharmaceutical – –Preclinical – –Clinical 4. 4.Review of SPC, labelling, leaflet 5. 5.Granting of authorisation by President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

10. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 10 European procedures Mutual recognition procedure (MRP) Decentralised procedure (DCP) Both procedures are based on the recognition by national competent authorities of a first assessment performed by the authorities of one Member State Granting of authorisation by President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

11. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 11 Mutual recognition procedure (MRP) The mutual recognition procedure is to be used in order to obtain marketing authorisations in several Member States where the medicinal product in question has received a marketing authorisation in any Member State at the time of application The concerned Member State refers to the reference Member State that issued the national marketing authorisation on which the mutual recognition procedure is based Member States have to approve during the procedure the assessment report, the summary of product characteristics, the package leaflet and the label At the end of the mutual recognition procedure, a national marketing authorisation is issued in the concerned Member State(s)

12. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 12 Assessment report prepared by RMS Recognition of the assessment report by the CMS Granting of national marketing authorisation in RMS – national procedure Granting of national marketing authorisation in CMS 210 days 90 days 30 days

13. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 13 Flow Chart of the Mutual Recognision Procedure Approx. 90 days before submission to CMS – –Applicant requests RMS to update Assessment Report (AR) and allocate procedure number Day -14 – –Applicant submits the dossier to CMS. – –RMS circulates the AR including SmPC, PL and labelling to CMSs. – –Validation of the application in the CMSs.

14. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 14 Flow Chart of the Mutual Recognision Procedure Day 0 – –RMS starts the procedure Day 50 – –CMSs send their comments to the RMS, CMSs and applicant Day 60 – –Applicant sends the response document to CMSs and RMS Until Day 68 – –RMS evaluates and circulates a report on the applicant’s response document to CMSs

15. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 15 Flow Chart of the Mutual Recognision Procedure Day 75 – –CMSs send their remaining comments to RMS, CMSs and applicant. Until Day 80 – –A break-out session (BOS) can be organised around Day 75 (but may take place between days 73 – 80). Day 85 – –CMSs send any remaining comments to RMS, CMSs and applicant.

16. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 16 Flow Chart of the Mutual Recognision Procedure Day 90 – –CMSs notify RMS and applicant of final position (and in case of negative position also the CMDh secretariat of the EMA). – –If consensus is reached, the RMS closes the procedure. – –If consensus is not reached, the points for disagreement submitted by CMSs are referred to CMDh by the RMS within 7 days after Day 90. Day 150 – –Final position adopted by the CMDh: If consensus is reached at the level of CMDh, the RMS closes the procedure. If consensus is not reached at the level of CMDh, the RMS refers immediately the matter to EMA for CHMP arbitration

17. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 17 Flow Chart of the Mutual Recognision Procedure 5 days after close of procedure – –Applicant sends high quality national translations of SmPC, PL and labelling to CMSs and RMS. 30 days after close of procedure – –Granting of national marketing authorisations in the CMSs subject to submission of acceptable translations. All days mentioned in this document should be regarded as calendar days.

18. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 18 Decentralised procedure (DCP) The decentralised procedure is to be used in order to obtain marketing authorisations in several Member States where the medicinal product in question has not yet received a marketing authorisation in any Member State at the time of application The documentation is submitted in RMS and CMS(s) at the same time Member States have to approve during the procedure the assessment report, the summary of product characteristics, the package leaflet and the label At the end of the procedure with a positive agreement, a national marketing authorisation will be issued in the reference Member State and the concerned Member State(s)

19. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 19 Assessment step II CMS(s) approve the (Draft) Assessment Report Granting of national marketing authorisation in CMS 120 days (+ 3 months clock-stop) 90 days Assessment step I RMS prepares Draft Assessment Report 30 days

20. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 20 Flow Chart of the Decentralised Procedure Pre-procedural Step Before Day -14 – –Applicant discussions with RMS. – –RMS allocates procedure number. Day -14 – –Submission of the dossier to the RMS and CMSs – –Validation of the application

21. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 21 Flow Chart of the Decentralised Procedure Assessment step I Day 0 – –RMS starts the procedure Day 70 – –RMS forwards the Preliminary Assessment Report (PrAR) (including comments on SmPC, PL and labelling) on the dossier to the CMSs and the applicant Until Day 100 – –CMSs send their comments to the RMS, CMSs and applicant

22. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 22 Flow Chart of the Decentralised Procedure Until Day 105 – –Consultation between RMS and CMSs and applicant. – –If consensus not reached RMS stops the clock to allow applicant to supplement the dossier and respond to the questions. Clock-off period – –Applicant may send draft responses to the RMS and agrees the date with the RMS for submission of the final response. – –Applicant sends the final response document to the RMS and CMSs within a period of 3 months, which can be extended by a further 3 months. Day 106 – –RMS restarts the procedure following the receipt of a valid response or expiry of the agreed clock-stop period if a response has not been received.

23. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 23 Flow Chart of the Decentralised Procedure Assessment step II Day 120 (Day 0) – –RMS sends the DAR, draft SmPC, draft labelling and draft PL to CMSs and the applicant Day 145 (Day 25) – –CMSs send comments to RMS, CMSs and the applicant Day 150 (Day 30) – –RMS may close procedure if consensus reached – –Proceed to national 30 days step for granting MA

24. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 24 Flow Chart of the Decentralised Procedure Until 180 (Day 60) – –If consensus is not reached by day 150, RMS to communicate outstanding issues with applicant, receive any additional clarification, prepare a short report and forward it to the CMSs and the applicant Day 195 (at the latest) – –A Break-Out Session (BOS) may be held at the European Medicines Agency with the involved MSs to reach consensus on the major outstanding issues Between Day 195 and Day 210 – –RMS consults with the CMSs and the applicant to discuss the remaining comments raised

25. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 25 Flow Chart of the Decentralised Procedure Day 210 (Day 90) – –Closure of the procedure including CMSs approval of assessment report, SmPC, labelling and PL, or referral to Co- ordination group – –Proceed to national 30 days step for granting MA Day 210 (at the latest) – –If consensus on a positive RMS AR was not reached at day 210, points of disagreement will be referred to the Co-ordination group for resolution Day 270 (at the latest) – –Final position adopted by Co-ordination Group with referral to CHMP/CVMP for arbitration in case of unsolved disagreement

26. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 26 Flow Chart of the Decentralised Procedure National step 5 days after close of procedure – –Applicant sends high quality national translations of SmPC, labelling and PL to CMSs and RMS 30 days after close of the procedure – –Granting of national marketing authorisation in RMS and CMSs if outcome is positive and there is no referral to the Co-ordination group – –National Agencies will adopt the decision and will issue the marketing authorisation subject to submission of acceptable translations All days mentioned in this document should be regarded as calendar days.

27. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 27 Centralised procedure Marketing authorisation is granted in accordance with Regulation (EC) No 726/2004 for the entire European Union (a European Union authorisation – Commission decision). The scientific evaluation of the application is carried out within the Committee for Medicinal Products for Human Use (CHMP) of the EMA, and a scientific opinion is prepared. The opinion is sent to the European Commission which drafts a Decision. Having consulted the Member States through the relevant Standing Committee, the Commission adopts the Decision and grants a marketing authorisation. Such a marketing authorisation is valid throughout the European Union and confers the same rights and obligations in each of the Member States as a marketing authorisation granted by that Member State.

28. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 28 Centralised procedure Mandatory scope: Medicinal products developed by means of one of the following biotechnological processes: recombinant DNA technology, controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells, hybridoma and monoclonal antibody methods. Advanced therapy medicinal products Orphan medicinal products

29. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 29 Centralised procedure Mandatory scope: Medicinal products for human use containing a new active substance not authorised in the European Union, for which the therapeutic indication is the treatment of any of the following diseases: acquired immune deficiency syndrome, cancer, neurodegenerative disorder, diabetes, auto-immune diseases and other immune dysfunctions, viral diseases.

30. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 30 Centralised procedure Optional scope: products containing new active substances, products which constitute a significant therapeutic, scientific or technical innovation, products for which the granting of a European Union authorisation would be in the interest of patients or animal health at European Union level, a generic medicinal product of a centrally authorised medicinal product The applicant has to request confirmation that the product is eligible for evaluation through the centralised procedure and the EMA will decide on the matter.

31. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 31 Presentation of the dossier – Common Technical Document (CTD) The Common Technical Document (CTD) was agreed in 2000 by 5th International Conference on Harmonisation (ICH) CTD is organized into five modules: Module 1 - Regional Administrative Information Module 2 – Quality, Nonclinical and Clinical Overviews and Summaries Module 3 - Quality Module 4 – Nonclinical Study Report Module 5 – Clinical Study Report 31

32. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 32 Presentation of the dossier – Common Technical Document (CTD) The content of regional Module 1 is defined by the European Commission in consultation with the competent authorities of the Member States, the European Medicines Agency and interested parties Concerning the structure of Modules 2, 3, 4, and 5 they are common for all ICH regions (Europe, US, Japan) The current requirements for the format and content of the marketing authorisation dossier are set out in Annex I to Directive 2001/83/EC as amended 32

33. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 33

34. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 34 MODULE 1 Provides aministrative, regional or national information Specific EU-requirements for the administrative data, for example: – –application form – –the proposed summary of product characteristics, labelling and package leaflet

35. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 35 Module 1 - table of contents 1.0 Cover Letter 1.1 Comprehensive Table of Contents 1.2 Application Form 1.3 Product Information – –1.3.1 SPC, Labelling and Package Leaflet – –1.3.2 Mock-up – –1.3.3 Specimen – –1.3.4 Consultation with Target Patient Groups – –1.3.5 Product Information already approved in the Member States – –1.3.6 Braille 1.4 Information about the Experts – –1.4.1 Quality – –1.4.2 Non-Clinical – –1.4.3 Clinical

36. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 36 Module 1 - table of contents 1.5 Specific Requirements for Different Types of Applications – –1.5.1 Information for Bibliographical Applications – –1.5.2 Information for Generic, ‘Hybrid’ or Bio-similar Applications – –1.5.3 (Extended) Data / Market Exclusivity – –1.5.4 Exceptional Circumstances – –1.5.5 Conditional Marketing Authorisation 1.6 Environmental Risk Assessment – –1.6.1 Non-GMO – –1.6.2 GMO

37. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 37 Module 1 - table of contents 1.7 Information relating to Orphan Market Exclusivity – –1.7.1 Similarity – –1.7.2 Market Exclusivity 1.8 Information relating to Pharmacovigilance – –1.8.1 Pharmacovigilance System – –1.8.2 Risk-management System 1.9 Information relating to Clinical Trials 1.10 Information relating to Paediatrics Responses to Questions Additional Data

38. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 38 Module 1 – Application Form Common for all procedures – –National Procedure – –Mutual Recognition Procedure – –Decentralised Procedure – –Centralised Procedure 22 Annexes

39. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 39 Application Form - annexed documents 5.1 - Proof of payment 5.2 - Informed consent letter of marketing authorisation holder of authorised medicinal product. 5.3 - Proof of establishment of the applicant in the EEA. 5.4 - Letter of authorisation for communication on behalf of the applicant/MAH. 5.5 - Curriculum Vitae of the Qualified Person for Pharmacovigilance.

40. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 40 Application Form - annexed documents 5.6 - Manufacturing Authorisation required under Article 40 of Directive 2001/83/EC (or equivalent, outside of the EEA where MRA or other Community arrangements apply); any proof of authorisation in accordance with Article 8(k) of Directive 2001/83/EC. 5.7 - Copy of the ‘Qualification of SME Status’. 5.8 - Flow-chart indicating all manufacturing and control sites involved in the manufacturing process of the medicinal product and the active substance. 40

41. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 41 Application Form - annexed documents 5.9 - GMP certificate(s) or other GMP statement(s); Where applicable a summary of other GMP inspections performed. 5.10 - Letter(s) of access to Active Substance Master File(s) or copy of Ph. Eur. Certificate(s) of Suitability. 5.11 - Copy of written confirmation from the manufacturer of the active substance to inform the applicant in case of modification of the manufacturing process or specifications according to Annex I of Directive 2001/83/EC.

42. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 42 Application Form - annexed documents 5.12 - Ph. Eur. Certificate(s) of suitability for TSE. 5.13 - Written consent(s) of the competent authorities regarding GMO release in the environment. 5.14 - Scientific Advice given by CHMP and/or by member state(s).

43. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 43 Application Form - annexed documents 5.15 - Copy of Marketing Authorization(s) required under Article 8(j)-(L) of Directive 2001/83/EC in the EEA and the equivalent in third countries on request (a photocopy of the pages which give the marketing authorization number, the date of authorisation and the page which has been signed by the authorizing competent authority will suffice).

44. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 44 Application Form - annexed documents 5.16 - Correspondence with European Commission regarding multiple applications. 5.17 - List of Mock-ups or Samples/specimens sent with the application, as appropriate (see Notice to Applicants, volume 2A, chapter 7). 5.18 - Copy of the Orphan Designation Decision.

45. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 45 Application Form - annexed documents 5.19 - List of proposed (invented) names and marketing authorisation holders in the concerned member states. 5.20 - Copy of EMEA certificate for a Vaccine Antigen Master File (VAMF). 5.21 - Copy of EMEA certificate for a Plasma Master File (PMF).

46. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 46 Application Form - annexed documents 5.22 - For each active substance, attach a declaration(s) from the Qualified Person of the manufacturing authorisation holder in Section 2.5.1 and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section 2.5.2 where the active substance is used as a starting material that the active substance is manufactured in compliance with the detailed guidelines on good manufacturing practice for starting materials. Alternatively, such declaration may be signed by one Qualified Person on behalf of all QPs involved (provided this is clearly indicated).

47. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 47 APPLICATION TYPES Full dossier Generic application Hybrid application Similar biological application Well-established use application Fixed combination application Informed consent application

48. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 48 APPLICATION TYPES full dossier Application according to article 8(3) of Directive 2001/83/EC (art. 10 of Polish Pharmaceutical law) – Full dossier – Reference Medicinal Product The documentation consists of: – –pharmaceutical (physico-chemical, biological or microbiological) tests, – –preclinical (toxicological and pharmacological) tests, – –clinical trials Modules 1-5 CTD Protection period: 6/10 or 10 or 8+2+1

49. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 49 APPLICATION TYPES full dossier – protection period Protection period (data exclusivity + market exclusivity) 8+2+1 centrally or nationally authorised reference medicinal products for which an application for authorisation has been submitted after 30 October 2005 6/10 (Poland 6 years) nationally authorised reference products – applications has been submitted before 30 October 2005 10 years centrally authorised reference products - applications has been submitted before 30 October 2005

50. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 50 Data exclusivity and market exclusivity Data exclusivity: 8 + 2 + 1 The period of 8 years from initial authorisation of the reference product provides a period of so-called “data exclusivity”, after which valid applications for generic products can be submitted and lead to the granting of a marketing authorisation The period of 10 years from initial authorisation of the reference product provides a period of so-called “market exclusivity” after which generic products authorised in this way can be placed on the market 10 years period shall be extended to 11 years if during first 8 years the MAH obtain authorisation of one or more indications of significant clinical benefit

51. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 51 APPLICATION TYPES Generic application Application according to article 10(1) of Directive 2001/83/EC (art. 15(1) point 2 Polish Pharmacutical Law) A generic medicinal product has the same qualitative and quantitative composition in active substances the same pharmaceutical form as the reference medicinal product whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies

52. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 52 APPLICATION TYPES Generic application Dossier: Module 1 - complete administrative data Module 2: 2.3 Quality Overall Summary, 2.4 Non-clinical Overview, 2.5 Clinical Overview Module 3 Module 5.3.1.2 – Bioequivalence EMA Guideline on the investigation of Bioequivalence London 20 Jan 2010 CPMP/EWP/QWP/1401/98/Rev. 1 Exemptions from the need to demonstrate bioequivalence (i.e. where bioequivalence may be presumed) are included in guidelines but should be adressed in the dossier

53. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 53 APPLICATION TYPES Hybrid application Applications according to Article 10(3) of Directive 2001/83/EC (art. 15(12) of Polish Pharmaceutical Law) Hybrid application considers following circumstances: where the medicinal product does not fall within the definition of a generic medicinal product where the bioequivalence cannot be demonstrated through bioavailability studies where there are changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration of the product compared to the reference medicinal product In this case the results of the appropriate nonclinical tests or clinical trials shall be provided ( in Module 4 and/or 5)

54. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 54 APPLICATION TYPES Hybrid application Dossier: Module 1 - complete administrative data Module 2 - Overviews and Summaries Module 3 – complete quality data Module 4 and 5 - results of the appropriate nonclinical tests or clinical trials shall be provided

55. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 55 APPLICATION TYPES Similar biological application Applications according to Article 10(4) of Directive 2001/83/EC (art. 15(7) of Polish Pharmaceutical Law) Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic product, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological product and the reference biological product, the results of appropriate nonclinical tests or clinical trials relating to these conditions must be provided The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I of Directive 2001/83/EC and the related detailed guidelines

56. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 56 APPLICATION TYPES Similar biological application Dossier: Module 1 - complete administrative data Module 2 - Overviews and Summaries Module 3 – complete quality data Module 4 and Module 5 - results of appropriate nonclinical tests or clinical trials CHMP Guideline on Similar Biological Medicinal Products CHMP/437/04 London 30 October 2005

57. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 57 APPLICATION TYPES Well-established use-WEU (bibliographical application) Applications according to Article 10a of Directive 2001/83/EC (art. 16(1) of Polish Pharmaceutical law) Results of nonclinical tests or clinical trial are replaced by appropriate scientific literature Active substances of the medicinal product have been in well- established medicinal use within the European Union for at least 10 years, with recognised efficacy and an acceptable level of safety in terms of the conditions set out in Annex I of Directive 2001/83/EC The period of time required for establishing a well established medicinal use must not be less than 10 years from the first systematic and documented use of that substance as a medicinal product in the European Union

58. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 58 APPLICATION TYPES Well-established use-WEU (bibliographical application) The criteria to demonstrate well-established medicinal use: the time over which a substance has been used with regular application in patients quantitative aspects of the use of the substance, taking into account the extent to which the substance has been used in practice the extent of use on a geographical basis the extent to which the use of the substance has been monitored by pharmacovigilance or other methods the degree of scientific interest in the use of the substance (reflected in the published scientific literature) and the coherence of scientific assessments

59. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 59 APPLICATION TYPES Well-established use-WEU (bibliographical application) Dossier: Module 1 - complete administrative data Module 2: 2.3 Quality Overall Summary, 2.4 Non-clinical Overview, 2.5 Clinical Overview, 2.6 Non-clinical Summary, 2.7 Clinical Summary Module 3 – complete quality data Module 4 and 5 -the test and trial results shall be replaced by appropriate scientific literature

60. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 60 APPLICATION TYPES Well-established use-WEU (bibliographical application) Documentation (NtA Vol. 2A Chapter 1): published scientific literature – freely available in the public domain, published by reputable sources scientific monographs may be used in addition detailed description of the strategy used for the search of published literature justification for inclusion of references in the application all documentation, both favourable and unfavourable should be communicated if parts of the dossier are incomplete – explanation in the overviews/summaries why

61. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 61 APPLICATION TYPES Well-established use-WEU (bibliographical application) Documentation (NtA Vol. 2A Chapter 1) cont.: post-marketing experience with other products containing the same constituents is of particular importance copies of the full text of the literature (translations must be submitted EPARs from centralised procedure cannot be considered to supply sufficient information The dossier should cover all aspects of 10 years medicinal use and must include a review of the relevant literature, taking into account pre- and post-marketing studies and published scientific literature concerning experience in the form of epidemiological studies and in particular of comparative epidemiological studies

62. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 62 APPLICATION TYPES Fixed combination application Applications according to Article 10b of Directive 2001/83/EC (art 16 (3) of Polish Pharmaceutical law) Medicinal product containing active substances used in the composition of authorised medicinal products but not hitherto used in combination for therapeutic purposes: the results of new nonclinical tests or new clinical trials relating to that combination shall be provided It shall not be necessary to provide scientific references relating to each individual active substance Applications for fixed-combination medicinal products can be accepted on condition that the individual substances have been authorised in medicinal products in EEA

63. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 63 APPLICATION TYPES Informed consent application Application according to Article 10c of Directive 2001/83/EC (art. 16 (5) of Polish Pfarmaceutical law) Following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, pre-clinical and clinical documentation contained in the file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form The consent must relate to all four modules, the applicant can not have its own Module 3 (Quality), MAH may be the same or different

64. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 64 Application requirements Marketing Authorisation may only be granted to an applicant established in the European Union Application form: National procedure – only Polish should be used European procedures (MRP, DCP, CP) - Polish or English should be used National requirements should be fullfield: registration, eCTD, application form information available on website; www. urpl.gov.pl Manufacturing sites of active substances and medicinal products authorised in EEA must comply with Good Manufacturing Practice (GMP) Batch control and batch release must take place in the European Union

65. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 65 Documentation in Electronic Format Since 1th January 2010 Polish Office accepts documents submitted in electronic format (NeeS, eCTD), Application form and any of the documents mentioned in Tables 1, 2,3 and 4 attached to the guidance must be submitted in paper format in addition to being submitted in electronic format, The electronic format is not mandatory. Any documents submitted on paper is still accepted by the Office. The choice of format remains within the discretion of the applicant, Guidance for Marketing Authorization Holders on Submitting Documents in Electronic Format – published in January 2010 (amended in September 2012).

66. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 66 Guidans for Marketing Authorization Holders on submitting documents in electronic format Guidance for Industry on Providing Regulatory Information in Electronic Format: eCTD electronic Submission, Version 1.0, May 2009 Guidance for Industry on Providing Regulatory Information in Electronic Format: Non-eCTD electronic Submission (NeeS), Version 1.4, January 2008 The EMEA website on the eSubmission project – http://esubmission.emea.europa.eu http://esubmission.emea.europa.eu The ICH Organisation website – http://ich.org, http://estri.ich.orghttp://ich.orghttp://estri.ich.org The European Commission website – http://ec.europa.euhttp://ec.europa.eu Volume 2B Notice to Applicants – Presentation and format of the dossier Common Technical Documentation CMDh website – http://www.hma.eu/277.htmlhttp://www.hma.eu/277.html

67. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 67 Guidans for Marketing Authorization Holders on submitting documents in electronic format The Office accepts documents concerning human medicinal products submitted in electronic format, including: – –New Applications – –Renewal Applications – –Variation Application – –Periodic Safety Update Reports (PSUR) – –ASMF documentation – –Marketing authorisation transfer – –MA withdrawal – –Procedure withdrawal in all types of procedures, i.e. national, MRP, and DCP.

68. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 68 Guidans for Marketing Authorization Holders on submitting documents in electronic format Irrespective of the procedure type, the Office requires submission of the original paper version of the documents mentioned in: – –Table 1 – marketing authorisation – –Table 2 – renewal/MA withdrawal – –Table 3 – variation – –Table 4 – marketing authorisation transfer The documents included in the tables form part of eCTD documentation.

69. THE OFFICE FOR REGISTRATION OF MEDICINAL PRODUCTS, MEDICAL DEVICES AND BIOCIDAL PRODUCTS www.urpl.gov.pl 69 Thank you for your attention