1. Expanding Clinical Research Beyond Borders: The Importance of Latin America Dr. Marlene Llopiz Venn Life Sciences Mexico

2. Growing markets Introduce Latin America (LATAM) Describe what Latin America has to offer What is available in LATAM? What about quality? What about timelines? Assess the possibility of conducting global trials in LA Analyze the overall challenges for Latin American countries Aims and Objectives 2 www.diahome.org Drug Information Association

4. Central America

5. Caribbean

7. Argentina

8. Guatemala

9. Costa Rica

10. Panama

11. Colombia

12. Venezuela

13. Peru

14. Chile

16. In recent years, several regions around the world have provided new frontiers for conducting phase I-IV clinical trials. Latin America has come into the limelight for pharmaceutical studies. Introduction: The Importance of LA 5

18. rapid compliant patient recruitment,

19. motivated and experienced investigators,

20. USA and EC-equivalent medical standards, as well as

21. highly experienced monitoring and project management teams thoroughly trained on GCP and ICH guidelines. What is available in LA? 6

23. a diverse population of over 560 million inhabitants with massive patient populations in all therapeutic indications

24. a ready and professional supply of research facilities and

27. Cardiovascular

28. Gastroenterology

29. Neurology

30. Orthopedic/DVT

31. Hematology

32. HIV/AIDS

33. Osteoporosis

34. Immunology

35. Endocrine/Metabolic

36. Respiratory

37. Urology

38. Dermatology

39. Psychiatry

40. Paediatric experience

41. Women’s Health

43. Careful selection is made of each Latin American country to participate in global trials dependent on the shortness and complexity or lack thereof of complications for study conduction and of course, patients, sites and investigator availability. Country Selection Drug Information Association www.diahome.org 11

44. Principal investigators and sites are adequately selected meeting and complying with protocol and study needs and requirements with the necessary experience. Site and PI Selection Drug Information Association www.diahome.org 12

45. Non-disclosure agreements signed Reception of protocols (or synopsis) and request for proposal from clients (at a local or corporate level) are received Protocols (or protocol synopsis) are reviewed Therapeutic indication is carefully analyzed (incidence and prevalence of the disease in each country) Proposals with budgets are submitted dependent on country, sites, patients, complexity of trial, etc. Steps to be Taken for Clinical Trials in LA Drug Information Association www.diahome.org 13

46. Confidentiality agreements are signed with investigators and site facilities that are pre-selected dependent on client indication Feasibility studies are conducted or recommended sites and investigators reviewed (based on protocol purpose, therapeutic indication, patient recruitment, etc.) Once sites are selected, all documents are translated into Spanish (and Portuguese for Brazil). Powers of Attorney must be obtained for the CRO to manage the trial. Steps to be Taken for Clinical Trials in LA Drug Information Association www.diahome.org 14

47. A description letter of the study is submitted to the Ethics Committee (EC) together with: the protocol, informed consent form, investigator´s brochure, patient diaries and CRF´s (Documents submitted in the language of submission (Spanish) in addition to English) Each site will have a fee that must be paid. Steps to be Taken Drug Information Association www.diahome.org 15

48. Once approval from EC is obtained and a letter of authorization is obtained, Ministry of Health (MoH) submission must be officially made submitting all study and site documents in English and Spanish. In certain countries, after approval from a local EC is obtained, then documents must be submitted to a national EC Once MoH approval is obtained, an import license must be solicited providing the manufacturer´s and supplier´s name and address and a description of the product and quantity. At each institution, a fee will have to be paid for each procedure. Steps to be Taken Drug Information Association www.diahome.org 16

49. Certified warehouses are contracted for study supply receipt and distribution to sites. In sum, regulatory submission and approvals vary per country. Regulatory Timelines Drug Information Association www.diahome.org 17

50. Drug Information Association www.diahome.org 18 Regulatory TimelinesLATAM Country Comparison Drug Information Association www.diahome.org 18

51. Recommended Label Requirements In Spanish Protocol reference number/title Contents Administration route Lot/reference number Expiration date Storage conditions For Investigational Use Only Keep out of reach of children Manufacturer or Sponsor´s name and address. Drug Information Association www.diahome.org 19

52. Import License – after protocol approval Timeline: 2-3 weeks Rule 4.3: to import samples from an approved protocol (non-controlled drugs and lab kits). Exportation: rule 4.3 also allows to export human tissue or serum samples. Import/Export Process Drug Information Association www.diahome.org 20

53. Serious Adverse Reactions (SARs): 7 days after site´s notification plus 8 days to complete the information. Non-serious adverse reactions to be reported at the end of the study. Safety letters should be sent every 6 months for phase IV studies. For Phase I-III trials, the reports are sent at the end of the study. Pharmacovigilance Standard (NOM-220-SSA1-2002) Official Communications from CNFV Safety Report Drug Information Association www.diahome.org 21

54. Clinical Trial Approval in Mexico Drug Information Association www.diahome.org 22 Clinical Trial Approval in Mexico Final Protocol (Spanish) Investigator’s Drug Brochure (Spanish) Informed Consent Form (Spanish) Power of Attorney Details on importation of CTM, labs 4-8 weeks IRB/EC SSA / Secretaria de Salud (MOH) 4 – 6 weeks Clinical Trial Approval Letter 2 – 3 weeks Import License Study Start

56. Import/export challenges

57. Competition for investigators and patients as more CROs and pharmaceutical companies conduct trials in the region

59. Disease patterns that reflect both the West and the developing world Opportunities for time efficiencies with seasonal disease trials Region primarily uses just two languages: Portuguese (Brazil) and Spanish Quality of data comparable to that of data collected in North America Growing pharmaceutical market Advantages of Conducting Trials in Latin America Drug Information Association www.diahome.org 25

60. One of their main concerns is the timely fashion and quality of regulatory strategies to follow and comply with related to their studies to bring new drugs to market in these parts of the world. Timelines Drug Information Association www.diahome.org 26

61. Timely submissions and project start-ups are often difficult tasks due to the complexity of the necessary documentation required and delays in their delivery in each Latin American country versus differences with other continents. Timelines Drug Information Association www.diahome.org 27

63. a reduction in costs with strategic multi-centered studies, and

64. credible and objective results for submission to higher regulatory authorities for marketing approvals.

65. International trial results could have significant medical importance and may have an impact on future products. Advantages to Studies in LATAM Drug Information Association www.diahome.org 28

66. The fact that a given study is approved by FDA / EMEA does not necessarily mean that it will be approved by local MoHs throughout Latin America. Avoid as much as possible the need to clarify or submit extra documents to the Ethics Committees and/or MoH after submitting the protocol for review. This significantly delays protocol approval. Submit all documents together. Do not submit in bits and pieces. Submit the protocol with as many amendments as possible. Final Considerations Drug Information Association www.diahome.org 29

67. Dr. Marlene Llópiz Regional Director for Latin America Venn Life Sciences Clinical Research +52 55 9171- 0288 +52 1 55 3335 - 2952 (Mexico City) marlene.llopiz@vlsworldwide.com marlene.llopiz@post.harvard.edu Contact Information Drug Information Association www.diahome.org 30

68. Questions? Clinical Trials and Regulatory Affairs in LA Drug Information Association www.diahome.org 31