Disclaimer. The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be

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1 Ending the Myths: Best Practice in Trial Conduct in Latin America Katie Margules Global Vice President Alliance Management Covance Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. ( DIA ) DIA), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. 2 1

2 End Myths, Manage Outcomes: Best Practices Myths and concerns some examples Lack of predictability of regulatory processes Long start up timelines Lack of quality Lack of harmonization i of regulation Very burdensome processes to import and export clinical trial goods Poor IP protection Contracts signatures are nightmares Sites are saturated Cost is high Enrollment rates not that great What about retention? Compassionate use post trial a barrier to placing trial Confusion about placebo acceptability No much interest to go to Latin America anymore Essential to get the broader context and apply best practices to run successful trials in the region Clinical Trial Distribution in LA Source: ClinicalTrials.gov 4 2

3 Distribution of Study Market Be prepared LA growth is 3 times worldwide growth! Audited Market 2008 US$bn Sales % Market Share % Growth (Const US$) 2008 CAGR Worldwide $ North America Europe AAA Japan Latin America Key Markets Source: Regional Sales and Growth Audited Market Trends in the globalization of clinical trials Trial density in LA is low compared to other regions and is increasing due to increased infrastructure in the region providing adequate quality data and higher enrollments rates with good patient retention Source : Nature Reviews Drug Discovery, 2 Nov,

4 Higher enrollments per LA site translate in a competitive per patient cost Quality in Latin America High quality is observed and 92% of site staff has GCP-ICH training FDA Inspections findings of Clinical Sites US (2007) ( ) 8% 2% LA 43% 49 % 49% 49% US n=244 LA n=53 4

5 Best Practices for Better Outcomes - A Series of Experience-Based Examples 9 Get the Basics Right Take time to perform right and intensive feasibility and site/country selection Anticipate clinical trials challenges and regulatory questions Take advantage of longer regulatory and startup process for working through issues Establish good communication Understand difference in cultural aspects Ensure team building with the CRO and sites Remember the patient always comes first! 10 5

6 Study Planning & Management Metrics Have a contingency plan (and use it) Prioritizing critical documents for Latin America Tailored and timely investigator meeting Turn start up/regulatory delays to an opportunity Plan to boost enrollment 11 During Start Up Phase Importation and Exportation Verify Importer status Assess changes in regulation Use couriers/brokers network and experience Ensure discussion on stability conditions storage and control Site contracts Languages Institution templates and processes Prerequisites for signature (IRB approval, Budget approval, etc..) Prepare for complying with country specific safety reporting requirements 12 6

7 Feasibility & Site Selection Understand the protocol and the indication Evaluate the local context Expected approval challenges Healthcare systems and standard of care Competitive studies landscape Understand patients and epidemiology Ethical and local issues Pre-Study Visit Previous experience, infrastructure, team, institution, etc. Strategic site and country distribution Be open to leverage new locations/sites Training, support, IT and equipment Few investment and long term relationship can increase ROI 13 Strong Therapeutic Areas in LA ARGENTINA - Oncology (Breast cancer, Lung Cancer) - CNS (Depression, Alzheimer) - Cardiovascular - Infectious Diseases (HIV, Skin Infections) - Respiratory PERU - Infectious Diseases (Tuberculosis) - Endocrinology (Diabetes) - Cardiovascular - Oncology - Respiratory - Vaccines (Pediatrics) - Rheumatology - Immunology (Lupus) BRAZIL - Oncology (All types) - Transplant (Renal, Liver) - Infectious Disease - Cardiovascular - Endocrinology (Diabetes) - CNS - Respiratory - Ophtalmology MEXICO - Endocrinology (Diabetes) - Oncology (Solid tumors) - CNS (Epilepsy ) - Rheumatology - Infectious Diseases - Respiratory - Urology - Immunology (Lupus, MS) - Renal transplant CHILE - Vaccine (Pediatrics) - Rheumatology - Cardiovascular - Oncology (gastric cancer, palliative care) - CNS - Endocrinology (Diabetes) COLOMBIA - Infectious Disease - Cardiovascular - Respiratory - Endocrinology (Diabetes) - Oncology Choose the right study for the right country 14 7

8 Regulatory Customize the regulatory strategy Proactive involvement and quick query answer Thorough review of documents Use documentation checklists Provide sites with additional training Completion of essential documents Submissions to EC and MOH Know the changes of IRB and MOH process and impact on timelines. Have contingency plans Attend local congresses and use CRO associations and Pharma association for representation with MOH Be prepare for local MOH inspections 15 Placebo Study Design Acceptability Specific regulation on placebo study design acceptability in LA countries do not exist (except in Brazil) and all want: Alignment with the spirit of the Helsinki Declaration Study design where benefits must outweigh risk for patient safety Look after patients safety and well being Brazil: The benefits, risks, burdens, and effectiveness of a method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. In some protocol designs it is not scientifically and ethically justified Positive risk-benefit ratio is required by IRBs and MOHs worldwide Breaks misconceptions around guinea pigs Proactively provide letter of justification to give the science and ethics behind its use There is no single answer on placebo study acceptability - so we need to assess case by case 16 8

9 Compassionate Use Compassionate use regulation in Brazil was established since 1997 i.e. Resolution 196/96 and reinforced with Resolution 404 in 2008 Specifically at the end of the study every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic method as identified by the study. Over 500 studies active today in Brazil and since 1997 regulation, no claims ever reported by sites Regulation is not applicable for non-chronic diseases There are barriers to provide study drug post trial Investigator not willing to prescribe investigational drugs - Investigators are responsible for subject healthcare oversight - Additional costs to institution and lack of Institution support - ANVISA is looking for donations - Awareness of potential law suits liability - Lack of safety data and reporting procedures All in spirit of compliance with the Helsinki Declaration 17 Unexpected Events Some countries in region may suffer social, economical, political unrest during clinical study Natural disasters and changes in regulations affect clinical research Earthquake in Haiti - Port-au-Prince, January 12, 2010 Iceland volcano eruption Iceland, April 15 th, 2010 Nashville flood Tennessee, May 2 nd, 2010 Hurricane Katrina - New Orleans, August 19 th, 2005 EU Clinical Trials Directive Europe, April 4, 2001 (May 1 st, 2004) Costa Rica hold to new studies in clinical research San Jose, May 19 th, 2010 The key is to have contingency and mitigation plans in place to adapt and change accordingly! 18 9

10 Focus on Communication & Relationships Respect language and cultural differences Understand customs and particularities Doctor-patient ti t relationship Need for increased monitoring frequency and close communication Translations Variations in Spanish Certification Work together with local affiliates Foster team building opportunities Visit the sites and the CRO Trust local advice/experience Open and transparent communication Motivation 19 In Conclusion Communicate Think globally - but act locally Plan with the end in mind Be patient but proactive and persistent Have contingency plan Know your region learn from others Choose well and trust your partners Eliminate the myths through applying best practices. Latin America is the place to go for running successful trials for the benefit of the patients, the industry and the region!! 20 10

11 THANK YOU! ANY QUESTIONS? 21 11