1. Ivowen Ltd1 Ivowen Limited Preparation and Submission of a Traditional Herbal Medicinal Product Application

2. Ivowen Ltd2 Directive 2004/24/EC Traditional Herbal Medicinal Products Directive 2004/24/EC introduces a simplified registration procedure for traditional herbal medicinal products. This directive was transposed into Irish law – (SI No. 540 of 2007) on 23 July 2007. IMB established a Traditional Herbal Medicines Products Registration Scheme. An applicant can apply for a certificate of traditional- use registration for a THMP. This registration is called a traditional-use registration.

3. Ivowen Ltd3 National Regulation No medicinal product can be placed on the market without a prior MA (marketing authorisation) or certificate of traditional-use registration. The regulation however provides an exemption until 30 th April 2011 for THMP already on the market prior to the regulations coming into force. However IMB can request that applicants apply for a certificate of traditional-use registration before this date e.g. January 2010.

4. Ivowen Ltd4 First Steps Before Submission Familiarise yourself with EU legislation, Notice to Applicants, IMB guidance and HMPC guidance. Be sure that your product fulfils the criteria of a traditional herbal medicinal product. Prepare the documentation in the correct format and address all modules (where applicable). Obtain a company number and a product number (e.g. TR/xx/yy/zz) from The Receipts and Validation Section, IMB.

5. Ivowen Ltd5 Dossier Format Format of dossier is Common Technical Document (CTD). Guidance available specific for Herbals. The CTD is organised into five modules.

6. Ivowen Ltd6 CTD structure

7. Ivowen Ltd7 CTD structure Common Technical Document (CTD) Module 1: Administrative Information Module 2: CTD Summaries Module 3: Quality Module 4: Non-clinical Study Reports Module 5: Clinical Study Reports Each Module should be bound separately.

8. Ivowen Ltd8 Module 1 Module 1.1 – Comprehensive table of contents (Modules 1 – 5) Module 1.2 – Application form Module 1.3 – Product Information –1.3.1 – Summary of Product Characteristics, Labelling and Leaflet –1.3.2 – Mock-Up –1.3.3 – Specimen (NOT REQUIRED) –1.3.4 – Consultation with target patient groups –1.3.5 – SmPCs- already approved in Member States –1.3.6 – Braille

9. Ivowen Ltd9 Module 1 Module 1.4 - Information about the experts -1.4.1 Quality -1.4.2 Non-Clinical -1.4.3 Clinical Module 1.5 - Specific requirements for different types of applications

10. Ivowen Ltd10 Module 1.2 Application Form The application form for a certificate of traditional-use registration in Ireland is the EU application Form. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol- 2/b/update_2007-03/applicformrevised_final.pdf http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol- 2/b/update_2007-03/applicformrevised_final.pdf Summary of information required to complete form: –Product name + strength + form –Proposed Applicant/Marketing Authorisation Holder –Pharmacovigilance contact –Manufacturer of Substance + Product (including manufacturers authorisations)

11. Ivowen Ltd11 Module 1.3.1 Product Information SmPC –As per Directive 2001/83/EC, Art. 11, as amended. –Includes the name, strength, form, quantity of active, posology, method of administration, indications, contraindications, excipients, shelf life and any special warnings and precautions for use (section 1- 4). Section 5 is not usually required.

12. Ivowen Ltd12 Module 1.3.1 Product Information Labelling & Package Leaflet –Directive 2001/83/EC, Art 54 – 69, as amended. –The package leaflet should be drawn up in accordance with the Summary of Product Characteristics (SmPC). –Mock-ups (label/carton & Package leaflet) must be provided before final approval will be given.

13. Ivowen Ltd13 Module 1.3.4 Consultation with Target Patient Groups Directive 2001/83/EC, Art 59-61, as amended. –Introduction of ‘user-testing’ to ensure that leaflets are easy to read and can be understood by the patient (patient-friendly language).

14. Ivowen Ltd14 Module 1.3.6 Braille Directive 2001/83/EC Article 56 states that the name of the medicinal product should be expressed in Braille format on the packaging. You should include here the proposed braille text (in normal font) which will be printed on the outer carton along with the actual braille which is indicated with dots on the mock- ups. IMB request an additional braille statement to be included in this section.

15. Ivowen Ltd15 Module 1. 4 Information about the Experts 1.4.1 Quality –Signature page along with CV from expert who prepared Module 2.3. 1.4.2 Non-Clinical –Signature page along with CV from expert who prepared Module 2.4. 1.4.3 Clinical –Signature page along with CV from expert who prepared Module 2.5.

16. Ivowen Ltd16 Module 1.5 Specific Requirements A brief summary/paragraph stating how this application meets the requirements for a traditional-use registration.

17. Ivowen Ltd17 Module 2 Module 2.1CTD Table of Contents Module 2.2Introduction Module 2.3Quality Overall Summary Module 2.4Nonclinical Overview Module 2.5Clinical Overview Module 2.6Nonclinical Summary Module 2.7Clinical Summary

18. Ivowen Ltd18 Module 2.3 Summary of Module 3. Cannot have additional data not already presented in Module 3. Sufficient information to provide assessor with complete overview of Module 3. Not more than 40 pages of text. Prescribed layout.

19. Ivowen Ltd19 Module 2.4 Summary of Module 4. Integrated and critical assessment of safety data of proposed product. Expert compiling this report must have appropriate experience and qualifications.

20. Ivowen Ltd20 Module 2.5 Summary of Module 5. The bibliographic or expert evidence of traditional-use (proof that the traditional herbal medicinal product or a corresponding product has been in medicinal use for at least 30 years (15 years must be in the EU) should be discussed.

21. Ivowen Ltd21 Module 3 Drug substance – 3.2.S Drug product – 3.2.P Regional information – 3.2.R Literature references – 3.3

22. Ivowen Ltd22 Module 3.2.S Drug substance – 3.2.S –3.2.S.1 General information –3.2.S.2 Manufacture –3.2.S.3 Characterization –3.2.S.4 Control of drug substance –3.2.S.5 Reference standards or materials –3.2.S.6 Container closure system –3.2.S.7 Stability

23. Ivowen Ltd23 Module 3.2.P Drug product – 3.2.P –3.2.P.1 Description and composition of the drug product –3.2.P.2 Pharmaceutical development –3.2.P.3 Manufacture –3.2.P.4 Control of excipients –3.2.P.5 Control of drug product –3.2.P.6 Reference standards or materials –3.2.P.7 Container closure system –3.2.P.8 Stability

24. Ivowen Ltd24 Module 3.2.A Facilities and equipment – biotech only. Adventitious agents safety evaluation. –TSE is most common entry in this section Novel excipients.

25. Ivowen Ltd25 Module 3.2.R Process validation scheme for the 3 consecutive production batches. Certificates of Suitability of Monographs of the European Pharmacopoeia. TSE certificates of suitability together with completed Table A on ‘Materials of animal origin’.

26. Ivowen Ltd26 Module 3.3 Literature references Any literature references used throughout the completion of Module 3 should be included in this section.

27. Ivowen Ltd27 Module 3-Summary In assembling the dossier for traditional-use registrations the applicant needs to take into account the scientific guidelines adopted by the CHMP/HCMP/Commission. Applicants need to be aware of all guidelines both general and specific and keep up to date with any revisions to guidance documents. European Pharmacopoeia standards are legally binding.

28. Ivowen Ltd28 Module 4 Safety Module 4.1 Introduction Module 4.2 Study Reports Module 4.3 Literature References –The bibliographic review should cover all safety aspects and should refer to a review of literature references and relevant published scientific literature. –More data may be requested in order to assess the safety of the product. –If the herbal substance (preparation/combination) is on the ‘list’, the data do not need to be provided.

29. Ivowen Ltd29 Module 5 Traditional-Use 5.1 Module 5 Table of Contents 5.2 Tabular Listing of All Clinical Studies 5.3. Clinical Study Reports 5.4 Literature References –Applicants should produce bibliographic or expert evidence documenting the traditional-use of the product for the proposed indication. – Evidence of use may be based on a similar product (same actives, strength, posology).

30. Ivowen Ltd30 Final Steps Ensure that each Module is bound separately, each section is clearly identified and each page is numbered. Ensure the correct number of copies (Electronic and/or Paper) is submitted. Ensure the correct fees are paid. Ensure the application is delivered to the correct address.

31. Ivowen Ltd31 After Submission An estimated 210 days to obtain a certificate of traditional-use registration. –Dependant on both the applicant and the agency.

32. Ivowen Ltd32 Ivowen Limited Any questions??