1. VICH Task Force for Efficacy Studies for Combination Products Progress Report for the 32 th SC /6 th VOF meeting (Final)

2. Introduction  At the 3 rd VOF meeting in Nov 2013, China PR presented a Concept Paper for a VICH guideline on “efficacy studies for combination drug products”.  The SC & VOF members welcomed the proposal confirming that it is an important topic where guidance is currently lacking.  The scope of this topic is very broad and could lead to several GLs.  It would be useful to identify the different combinations available in order to reach agreement on which GLs should be developed. The SC decided to create a task force (TF) chaired by JMAFF.

3. Mandate for TF  To elaborate a discussion paper proposing a more focused scope for the development of a VICH GL for efficacy studies for combination products. <<< Concept paper from China  The TF will  Prioritize the target products  Explore the possibility of a general policy document >Explore Major combination >Analyse GLs already in Place

4. TF members VICH members JMAFF (chair)K. Noda JVPAE. Oishi IFAH-EUM. Bobey EUK. Healey US FDAC. Groesbeck AHIB. McKusick Observer South Africa, Nat. Dept. healthV. Naidoo VOF members China PR, IVDCS. Xu Argentina, SENASAL. Sbordi Taiwan, Council of AgricultureT-R. Jan UEMOAK.Th. Domagni CAMEVETL. Sbordi Additional contributors Australia, APVMAP. Reeves NZ, Min. Primary IndustryW. Hughes

5. Part 1 Major Combination

6. How to categorize the products? Categorization elements Code Antiparasitics AnthelminticsAP-Hl AntiprotozoalsAP-Pr EctoparasiticidesAP-Ec EndectocidesAP-EnEc Other AntiparasiticsAP-X Antimicrobials AntibacterialsAM-Bc AntimycoticsAM-Mc AntiviralsAM-Vr Intramammary antibacterials AM-IM-Bc Other AntimicrobialsAM-X Anti-inflammatoriesAI AntisepticsAS DisinfectantsDI (others, if any)X

7. Combination-category VICH membersObserverVOF members Sub- total Total JMAFFJVPAEU IFAH- EU US FDAAHIS.AfricaAsust.NZChinaPR Argentina/ CAMEVET TaiwanUEMOA AP-Hl1 1111111 1 9 37 AP-Pr1 1 1 1 4 AP-Ec1 11 111 1 7 AP-EnEc1111 1 1 1 7 AP-HlAP-Pr 11 2 AP-HlAP-Ec 1 1 2 AP-HlAP-EnEc 1 1 AP-HlAP-x 1 1 2 AP-HlX 1 1 AP-EcAP-x 1 1 AP-EnEcAP-x 1 1 AM-Bc1111 111 111 10 16 AM-Mc 0 AM-Vr 0 AM-IM-Bc 11 11 1 5 AM-BcAM-Mc 0 AM-IM-BcAM-Bc 1 1 AM-McAI 111 1 4 15 AM-BcAI 111111 1 7 AM-BcAI Analgesics 1 1 AM-BcAP-Pr 1 1 2 AM-BcHormones 1 1 AI 11 22 AS 1 11 DI 1 11 1 11 Vitamins1 11 Minerals1 11 Gastrointestinal1 11 Hormones1 1 22 Cardiology 11 22 X 1 11 Total / legislation104 657 35740 81 Total / member status45201681 Major combination-products

8. Major Combination-products

9. Combination category Ingredients Number of Country/Region AP-HI Abamectin +Derquantel 1 Abamectin +albendazole +selenium +cobalt 1 Albendazole +closantel, 1 Emodepside +Praziquantel 3 Fenbendazole +levamisole, 1 Fenbendazole+Praziquantel 1 Febantel+pyrantel 1 Febantel +Praziquantel +Pyrantel 5 Ivermectin +Clorsulon 2 Ivermectin +closantel 1 Ivermectin+pyrantel 1 Levamisole +Abamectin, 1 Levamisole +Albendazole, 1 Levamisole +closantel +albendazole +abamectin, 1 MilbemycinOxime+praziquantel 1 Moxidectin+triclabendazole 1 Oxfendazole +Levamisole, 1 AP-Pr Amprolium +ethopabate, 1 Amprolium +Ethopabate +Sulfaquinoxaline 2 Dinitolmide+glycarbylamide 1 Pyrimethamine+sulfadimethoxine 1

10. Combination category Ingredients Number of Country/Region AP-Ec Amitraz+Fipronil+(S)-methoprene 1 Amitraz +cypermethrin, 1 Amitraz+Metaflumizone 1 Betacyfluthrin +piperonyl butoxide, 1 Cipermethrin+ethion 1 Cymiazol +cypermethrin, 1 Diazinon +pyriproxyfen, 1 Dicyclanil +diflubenzuron, 1 Dinotefuran+permethrin+pyriproxyfen 1 Fipronil+cyphenothrin 1 Fipronil+(S)-methoprene 1 Fipronil+permethrin 1 Imidacloprid+flumethrin 1 Imidacloprid+moxidectin 1 Imidacloprid +permethrin, 1 Imidacloprid+permethrin+piperonyl butoxide 1 Indoxacarb+permethrin 1 Pyrethrins +piperonyl butoxide 1 AP-EnEc Abamectin +levamisole,1 Abamectin +praziquantel, 1 Closantel+ivermectin 1 Closantel+mebendazole, 1 Clorsulon+Ivermectin 1 Eprinomectin+fipronil+praziquantel+(S)-methoprene 1 Fluazuron +ivermectin, 1 Imidacloprid+Ivermectin, 1 Imidacloprid+Moxidectin, 3 Ivermectin+Pyrantel 2 Ivermectin+Praziquantel, 2 Milbemycin+Spinosad 1 MillbemycinOxime+Lufenuron 3 MilbemycinOxime+Lufenuron+Praziquantel 2 MilbemycinOxime+spinosad 1

11. Combination category Ingredients Number of Country/Region AP-HlAP-Pr Emodepside+toltrazuril 1 AP-HlAP-Ec Emodepside+praziquantel 1 Fipronil+methoprene+amitraz 1 Ivermectin+albendazole 1 Narasin+nicarbazin 1 AP-HIAP-EnEc Levamisole HCI +praziquantel, 1 Levamisole HCI +oxyclosanide, 1 Albendazole +closantel, 1 Levamisole HCI +rafoxanide, 1 AP-HIX Levamisole +Sodium Selenate, 1 Albendazole +Sodium Selenate, 1 Abamectin +Sodium Selenate, 1 Levamisole +Disodium Cobalt EDTA, 1 AP-HlAP-x Albendazole+praziquantel 1 fenbendazole+praziquantel+pyrantel 1 MilbemycinOxime+lufenuron, 1 MilbemycinOxime+lufenuron+Praziquantel 1 AP-EcAP-x Moxidectin + imidacloprid, 1 Ivermectin + closantel, 1 AP-EnEcAP-x abamectin+Ivermectin 1 clorsulon+Ivermectin 1 Ivermectin+nitroxinil 1

12. Specific consideration #1  The EU member insisted not to include AM combination as a target category, supported by other countries.  Regulators do not wish to encourage new developments of AM combination.  A VICH GL on such combination products could be misunderstood as encouragement for their development.

13. Specific consideration #2  Antimicrobial agents and coccidiostats for “growth/ feed efficiency promotion” is regulated under the “feed safety legislation” rather than “pharmaceutical legislation” in Japan.  Some antiseptics (AS) and an antiprotozoal (AP-Pr) are not within the remit of VMP authority in Australia.  Chemicals used in animal barn and/or fish preserve may be regulated under “environmental legislation” in some countries. Currently outside the reach of VICH

14. Part 2 Guidelines in Place

15. ItemTitle Product Category Type of document #1 Guidance on pharmaceutical fixed combination products (EMEA/CVMP/83804/05) General Technical requirement guideline #2 Questions and answers on the CVMP guideline on fixed combination products (EMEA/CVMP/83804/2005) APAdditional document to #1 #3 European Legislation (EU Directive 2001/82/EC ), (p16)Art 13b GeneralLegal basis for #1 and #2 #4 CVM GFI #24 Drug Combinations for Use in Animals GeneralTechnical requirement guideline #5 WAAVP guideline: Anthelmintic combination products targeting nematode infections of ruminants and horses AP Technical requirement guideline #6 Australian Pesticide and Veterinary Medicine Agency: Preamble for WAAVP guideline: Combination anthelmintic products for ruminants and horses AP Statement adopting #5 WAAVP GL as National GL Guidelines/Guidance in Place

16. Item TitleCategoryScope #1 Guidance on pharmaceutical fixed combination products General EU data requirements for efficacy, safety and residues documentation for veterinary medicinal products, containing 2 or more active substances. #4 CVM GFI #24 Drug Combinations for Use in Animals General Information and data to demonstrate that the combination of drugs provides a benefit that cannot be obtained by the use of each of the drugs individually #5 WAAVP guideline: Anthelmintic combination products targeting nematode infections of ruminants and horses AP A scientific basis for the approval Anthelmintic products with two or more constituents with similar spectra of activity from different pharmacological classes For use in addition to the existing requirements/GLs for single-API products. Technical Requirement GLs in Place

17. Parts#1: EMEA/CVMP/83804/05#4: FDA/ CVM GFI #24 Introductory part  Introduction (background)  Scope  Legal Basis  Introductory statement Discussion part  Justification of the Combination  Interactions  Indications  Potential Advantages Improvement of activity Broadening of the activity spectrum Use of a combination product versus combined use of single substances  Risk-Benefit assessment  Non-Interference  Rational  Titration  Ranges  General Efficacy  Combination Claims and Treatment Comparisons (very in detail) Dossiers Requirements part  General requirements  New fixed combination products  Combination products that meet the criteria for well established use  Combination products that meet the criteria for generic application  Specific Requirements  Safety and residues documentation  Preclinical and clinical documentation (Preclinical data, Dose-finding, Tolerance, Clinical data, Resistance, Exceptions) Structure –General GLs-

18. Parts#5: WAAVP/Australia Introductory part  Introduction (general)  Combining anthelmintics: current situation  Objectives of the anthelmintic combination guideline Discussion part  Rationales for the use of anthelmintic combination products Managing existing resistance Delaying anthelmintic resistance Specific targeting of dose-limiting species Maximizing breadth of spectrum  Concerns about fixed-dose anthelmintic combination products Drug–drug interactions Common mechanisms of resistance Best-practice management of combination anthelmintics Dossiers Requirements part  Justification for the combination  Dose determination data on the anthelmintic constituent actives in the combination  Target animal safety and pharmacokinetic data showing non- interference and acceptable safety  Product bioequivalence  Dose confirmation studies  Field efficacy studies Structure –AP GL –

19. Conclusion  General combination GL  EU(#1) and US(#4) are the representative General GLs.  Internationally harmonized GL by extracting appropriate elements from them.  Specific combination GL  Main target : Anti-Parasitics  Drug resistance control will be a main objective.  Inclusion of WAAVP(#5)GL into VICH framework should be explored in collaboration with the Anthelmintics-EWG.  Other specific combination may be a target in the future.  After some experiences  Further discussion by the VOF and SC members needed

20. Mission Completed Thank you 感謝