Roadmap to Emerging Regions: Clinical Trials in Developing Countries International Clinical Trials Conference New York, 26 February 2009 Written By: Cristiana Spontoni Partner Squire, Sanders & Dempsey L.L.P. Brussels Presented by: Squire, Sanders & Dempsey L.L.P. www.ssd.com Michael A. Swit, Esq. Vice President The Weinberg Group Inc. San Diego, California US and EU Data on Trials in Emerging Regions Squire, Sanders & Dempsey L.L.P. www.ssd.com The Global Landscape 69,175 clinical trials are being carried out in 161 countries1 Majority of trials are conducted in the U.S. and Western Europe Increasingly being conducted in Central & Eastern Europe, Latin America and Asia Trials increasingly outsourced to Clinical Research Organizations 3 www.ssd.com Globalization of Trials: European Data According to the EMEA, around one quarter of patients recruited in pivotal trials submitted in MAAs to EMEA between 2005 and 2008 were recruited in: • Latin America • Asia • CIS • Africa 4 www.ssd.com Recurrent Themes in Global Trials • Good central coordination but flexibility to local requirements/habits/culture (eg, CTA templates) • Sound use of resources: CRO, PIs, Sites: how much should be delegated and how much should be kept under control (eg, negotiating/entering CTAs, filing for regulatory approvals) • All the more true in emerging economies… 5 www.ssd.com Advantages and Challenges Squire, Sanders & Dempsey L.L.P. www.ssd.com Advantages Of Emerging Economies • Limited costs: drugs, hospitalisation, travel and other general expenses, basic support services • Higher number of patients, especially naive patients (i.e., patients who never received a treatment) • Large patient populations with diseases of both developed and developing countries (e.g., HIV/AIDS) • Multi-ethnic/multiracial populations • Wide spectrum for diseases • Potential new markets (e.g., China) • Competent/motivated PIs 7 www.ssd.com Clinical Trials in Emerging Regions • Conducting trials in emerging regions poses a number of challenges: – Different treatments and standard of care – Differing levels of clinical research experience and sophistication – Different capabilities of CROs in the region • Requires greater direct management efforts • Many apparent similarities in challenges requiring different responses 8 www.ssd.com Challenges of Conducting These Clinical Trials • Regulatory – Trial Designs – Regulatory Authorities and IRB/ECs – Translation requirements – Import/Export licenses • Legal – Contracts/Clinical Trial Agreements – Insurance requirements – Intellectual property issues • Other – CRO Partnering – Site/Investigator Identification – Adherence to Good Clinical Practice – Assuring the Ethical Conduct of the Trial – Quality Control issues – Cultural and infrastructure considerations 9 www.ssd.com An ordinary day in an ordinary global trial -- Some real life experiences -- Squire, Sanders & Dempsey L.L.P. www.ssd.com Practical Challenge: Control of Temperature • “Control of storage and transportation temperatures is essential in maintaining the quality of medicines and in helping to protect patients from sub-standard or ineffective medicines that may result from inadequate control” (J. Taylor, Quality and Standards Manager, MHRA) • Increased risks for biotech products, vaccines, blood products, semi-solids, chemically unstable at certain temperatures, and of course, study drugs. 11 www.ssd.com Let’s Get a Fridge! • Sponsor wants to perform a study at site x • Site x does not have a way of keeping Study Drug at appropriate controlled temperature • Let’s get a fridge there! OK BUT… • Can sponsor sell/donate the fridge? – To whom? Under what circumstances? Do we need a written contract? Do we need to get prior authorizations? From whom? • What if Site is a public hospital? • What if we are talking about very expensive medical devices? • Can the fridge be imported in country x? 12 www.ssd.com 13 www.ssd.com Legal Challenge: Study in 21 Jurisdictions in the EMEA Region • Can a CTA be entered by a non-local Sponsor? Answer: - Yes, BUT -- in one jurisdiction, still need to go through local entity or mediator - Yes BUT -- in Israel, sites often will object to contracting with a non-Israeli entity - Yes BUT -- certain regulatory procedures will have to be performed by local entities either because it is required by law (e.g., Ukraine) or because -- that’s the way we do things here (Middle East) 14 www.ssd.com Legal Challenge 2: What’s the Right Price? • Sponsor sells x vials of Study Drug to a non EU European country • Custom authorities google name of Study Drug and find its price in the US: 10,000 USD • Custom authorities apply a custom duty considering that value of the Study Drug • Should Sponsor pay? • What’s the practice in other countries? 15 www.ssd.com Ethical Challenge: Unusable Data • Violations result in unusable data: in requesting marketing authorisation, a company submits a file to the EMEA, which includes the description of the trial performed. In examining the file, the EMEA evaluates the respect of GCP, the granting of informed consent and the approval by ECs. – Illustrates just how important compliance with GCP will be 16 www.ssd.com The Emerging European Jurisdictions and Their Rules Squire, Sanders & Dempsey L.L.P. www.ssd.com The Rules in Emerging EU Jurisdictions • Estonia, Hungary, Latvia, Lithuania, Czech Republic, Slovakia, Slovenia, Poland, Bulgaria, Romania, Malta, Cyprus: now all EU countries • Directive 2001/20/EC on clinical trials applies: - GCP standards - Uniform regulatory requirements - BUT: local challenges still remain • Highly educated and competent investigators 18 www.ssd.com The EU Directive on Clinical Trials • Same rules (in principle!) across 27 jurisdictions • Commercial + Non-commercial trials • Phases I,II,III,IV • All trials except “non-interventional” trials 19 www.ssd.com The Sponsor • Industry, Government, Research Council, University, … • Does not need to be EU-based but must appoint EU-based representative that bears civil and criminal liability as EU-based sponsors • Sponsor can delegate (NOT transfer!) sponsor responsibilities to third parties (e.g., CROs) BUT sponsor bears ultimate responsibility 20 www.ssd.com Protection of Trial Subjects • Informed consent • Special consideration for children and incapacitated adults • Data protection: – Directive 95/46/EC regulates strictly any processing or transfer of data outside the EU – Medical data qualifies as “sensitive” – The US is considered not a “safe place” for the purpose of data protection 21 www.ssd.com Commencement of Trials in the EU Sponsor applies for EUDRACT number Application to EC Favorable Opinion of EC Notification to CA • 60 days max 1 x clock stop for info. • 60+30+90 days max • No Time Limit (exception) CA no grounds for non-acceptance Explicit authorization required only in certain cases Separate procedures but can run in parallel One opinion per MS 22 www.ssd.com Conduct of a Trial – Reporting Obligations • Substantial amendments to be notified to ECs and CAs (35 days max) • Safety measures adopted to protect safety of subjects • Notification of trial end (90 days or 15 if early termination) • Notification of SUSARs – fatal or life threatening: 7 days – other SUSARs: 15 days – annual reporting • Notification of Serious Adverse Events Guidance on reporting and standard forms 23 www.ssd.com IMPs – Investigational Medicinal Products • Manufacture/importation authorisation • Authorisation holder must have QP at disposal: check compliance with EU GMPs or standards that are “at least equivalent” • IMPs must be supplied free of charge 24 www.ssd.com Suspension of Trials - Infringements • CAs can suspend or prohibit trials if: – conditions for granting authorisation for trial conduct are not met anymore – doubts about safety/scientific validity • Must consult with sponsor/investigator except in cases of “imminent risk” • CA will inform other CAs, EMEA and European Commission • You may have duty to inform FDA as well 25 www.ssd.com Inspections on GCP/GMP Compliance • Before, during or after completion of a trial • As part of marketing authorisation process or follow-up to it • At: trial sites, IMP manufacturing site, any laboratory used in the trial, or at sponsor’s premises • Conducted by CAs 26 www.ssd.com GCP Violations = Unusable Data • Drugs reviewed by the EMEA can be granted a marketing authorization only if they are based on clinical trials conducted in compliance with the Declaration of Helsinki • In requesting marketing authorisation, a company submits a file to the EMEA, which includes the description of the trial performed. In examining the file, the EMEA evaluates the respect of GCP, the granting of informed consent and the approval by ECs. • When problems are identified, namely regarding ethical aspects, the EMEA can advise the Commission to refuse the marketing authorisation or can advise the withdrawal of marketing authorisation already delivered by Member States. This information is also made public. • However, the EMEA intervention happens after the clinical trial is finalised and presented in the file and not before or during the trial. 27 www.ssd.com Inconsistent Approach/Interpretation An example… • Question: can sponsor be non-EU based? • EU law answer: yes, if it appoints a EU-based representative – Answer in BG, Czech Rep., Estonia, Latvia, Lithuania, Malta, Romania, Slovakia, Slovenia: yes, if it appoints an EU representative – Answer in Cyprus: NO! 28 www.ssd.com EU Rules on Trials Conducted in Third Countries Squire, Sanders & Dempsey L.L.P. www.ssd.com EU Rules on Trials in Third Countries • Financial penalties apply in case of failure to comply with clinical trials requirements • Sites in third countries can be inspected by the competent authorities of Member States. The EMEA has a system of GCP inspections in third countries since 2006 which has led to an increasing number of inspections in Latin America, Africa and Asia • Inspections concentrate primarily on: informed consent and appropriate EC (IRB) approvals • EU assisting on GCP capacity building/inspections a number of countries - in last EMEA GCP Inspectors’ WG workprogramme: Croatia, Macedonia, Turkey 30 www.ssd.com Increased Regulatory Scrutiny • A European Commission paper of 2002 indicated that: – The regulatory framework for clinical trials is expected to adapt to the globalization. – the budget and number of international/national GCP inspectors is expected to increase – more information on all these clinical trials should be available through an international database – the key role of IRBs and of capacity building in this area 31 www.ssd.com Increased Regulatory Scrutiny … • Opinion 17 of the European group on ethics in science and new technologies to the European Commission: “Ethical aspects of clinical research in developing countries” (February 2003) • 2006-2008: Series of Parliamentary Questions on trials in poor countries • On 5 December, the EMEA issued a strategy paper on: “Acceptance of clinical trials conducted in third countries for evaluation in Marketing Authorisations” 32 www.ssd.com EMEA Action Plan: Watch This Space! Three-year-s action plan includes: • Clarify application of ethical standards • Consider issues driving recruitment of subjects in third countries • Consider tools to respond to non-compliance/step up GCP inspections • Training of EMEA/sponsors/experts • Increased transparency: EPAR should include a clear description of the assessment of ethical standards of trials in emerging economies • Promote capacity building also through EU funding instruments 33 www.ssd.com Wrap-Up • Clear opportunities ahead of sponsors in emerging regions • Require strong central coordination and resource management • But, also must understand need for flexibility in approach and understanding of local specificities • Beware of compliance pitfalls no matter where you conduct your trial! 34 www.ssd.com Thanks!! Cristiana Spontoni, Partner T: 011.322.627.11.05 E: email@example.com www.ssd.com Roadmap to Emerging Regions: Sponsor Experiences in Central Europe and Asia Carlos F. Peza February 26, 2009 Recent Experiences in Emerging Regions Phase IV trial in Oncology conducted in 5 countries (France, Germany, Greece, Italy, Slovenia) 250 sites 8,448 valid subjects (3,719 valid controls) Field period from November 2005 to October 2008 Cross-Sectional Survey on Tobacco Prevalence in Indonesia Inclusion criteria similar to control inclusion criteria in European study 11 sites 1,500 valid subjects Field period from January to October 2007 Research was financially supported by Philip Morris International 37 Slovenia 38 Why Slovenia? Small number of sites provided access to almost every subject in the country who was suffering from the target condition Regulatory Agency and Central Ethics Committee are among the most efficient in Europe Highly educated and motivated Investigators Local CROs charged competitive fees for their services Relatively few challenges for study start up and conduct 39 Specifics of Slovenian Situation Small country, well reachable Centralized healthcare system with developed referral network Approximately 100 clinical trials are performed annually Laws and regulations for conducting clinical trials are based on EU Clinical Trials Directive (2001/20/EC) Agency for Medicinal Products and Medical Devices (JAZMP) is the competent authority for clinical trial authorization EC approval given at the national level by the National Medical Ethics Committee National Cancer Registry 40 Overcoming the Challenges in Slovenia Challenge: Identifying and vetting the appropriate CRO Identify the strength and weaknesses of potential vendors Understand how you will have to supplement for the potential weaknesses Our approach: Vetted international and national CROs Decided on National/Local CRO Identified its strengths Worked with them to shore up their potential weaknesses 41 Overcoming the Challenges in Slovenia Challenge: Obtaining ethics approval for a controversially funded study Our approach: Recruited Principal Investigator wisely Provided him with the information needed to fully understand and promote the study Became invested in the study Good reputation, leadership skills, and willing to act as a key advocate of the study Set the stage with Ethics Committee Identified, recruited and developed good working relationship with Key Opinion Leaders in order to understand local considerations Understood the potential concerns of the members Addressed these during the submission Gained support of stakeholders and who demonstrated this support to EC 42 Overcoming the Challenges in Slovenia Challenge: Achieving potential subject recruitment Our approach: Developed Principal Investigator and sub-investigators as key promoters and coordinators Coordination and promoting activities of different sites Coordinating and promoting study within site Developed investigator network where subjects were identified in the periphery and “treated” in the central location Motivated site team Actively recognize the role of each site member CRA partnership with sites Kept site team informed and involv 43 Slovenian Participation in the Study 1 Local/National CRO 16 Sites 1 Country Principal Investigator, 24 investigators/subinvestigators, more than 20 study nurses Comparably high recruitment rate First patient in: April 2007 1,391 valid subjects (721 valid controls) 16% of total study subjects recruited within one year Recruitment rate stable over the year (no holiday gaps) 44 Our Experience in Slovenia Excellent experience in Slovenia High subject recruitment rate Qualified and motivated medical professionals Uniformed regulatory issues as in Western Europe EU Clinical Trials Directive, ICH and GCP already implemented Relatively lower CRO costs to conduct the trial 45 Indonesia 46 Indonesian Smoking Prevalence Study Originally intended to conduct a series of studies to understand the relative risks of smoking for a several disease end point Planned to conduct several case-control studies for each of the disease endpoints In planning the studies, it was determined that there did not exist valid epidemiological data to be able to guide the design of the studies A pilot study of patients in hospitals to be used in the case-control studies was conducted 47 Specifics of the Indonesian Situation Large Country Very few trials being conducted, but numbers are growing. Government and investigators receptive to industry knowledge GCP implemented into national laws and guidelines governing clinical trials ECs to be established at institutional, regional/provincial, and national levels according to need National Agency for Drug and Food Control is competent authority for clinical trial authorization Lack of population-based registries Hospital based-cancer registries in 13 cities 48 Indonesian Smoking Prevalence Study Cross-sectional study on the smoking prevalence of Indonesian male hospital patients Study performed to regulated standards of a clinical trial 11 hospital sites in Jakarta, Solo, Surabaya, Padang 1 Principal Investigator, 22 investigators/subinvestigators, 60 CRA/interviewers More than 18,000 medical records evaluated 1,533 valid subjects recruited 38 week field period 49 Overcoming the Challenges in Indonesia Challenge: Designing a clinical trial to account for the specifics of the region Cultural issues Inclusion/Exclusion Criteria Trial Length and approval timings Infrastructure issues Investigator and Staff Training Our approach: Trial designed to account: Differences in medical practice (disease diagnosis, investigator-patient relationship) Translation of study/regulatory documents Validation of measurement scales (patient questionnaire) Understood need to apply “partnership approach” to build supportive relationships 50 Overcoming the Challenges in Indonesia Challenge: Identifying and vetting the appropriate CRO partner No local CROs Only a handful of Regional CROs working in Indonesia Our approach: Decided on one regional CRO Worked on setting clear expectations on how the study should be conducted Task distribution (assigning of responsibility) Which SOPs were going to be used Increased communication Thorough training of CRO staff and co-monitoring visits 51 Overcoming the Challenges in Indonesia Challenge: Investigators and Staff experience Lack of clinical trial experience Gaps between concept and reality in the field Our Approach: Incorporation of GCP, ethical practices, clinical management training into Investigator Meetings, CRA/interviewer training, monitor training Special emphasis on informed consent process The training methods paralleled the expected performance of the study team Site based CRAs conducting SDVs during patient recruitment process Increased site monitoring 52 Overcoming the Challenges in Indonesia Challenge: Local infrastructure and sites constraints Lack computerized central patient database systems Lack of secure storage space Difficult internet and phone access Understaffing Our approach: Site auditing prior to contract signature Financial investments made into resources and personnel Regular monitoring 53 Overcoming the Challenges in Indonesia Challenge: Cultural Complexities Hierarchical social structure impacts recruitment Investigator Site Patient Our approach: Build trust and cultivate relationships Principal Investigator Key Opinion leaders Involve hospital administration in site selection and start up activities Train and inform on “foreign” practices and international expectations 54 Our Experience in Indonesia Untapped potential Large patient pool Many potential sites Government and Investigators very eager to bring more clinical research into the country Need for capacity building Limited infrastructure Continued need to help local authorities adjust their regulatory environment to allow high quality clinical research 55 Approaches to Consider Advance preparation and strategy development Thorough knowledge of local processes and operations Design trial with an implementable protocol Upfront dialogue and partnership-oriented approaches Identify a CRO that is suitable for you Know your limitations and how much you are willing to concede to your vendors Audit CRO, site and monitors GCP training before start of the study Close monitoring during the study What is your plan B? 56 Questions? Carlos F. Peza Consultant The Weinberg Group Inc. One Embarcadero, Suite 500 San Francisco, CA 94111 P +1 415.293.1031 firstname.lastname@example.org About Your Speaker Carlos Peza is a Consultant at The Weinberg Group. He recently served as Project Manager for a large international Phase IV oncology trial. The study was carried out in more than 250 sites in five European countries and enrolled more than 8,500 valid subjects. Mr. Peza also managed a cross-sectional study on smoking prevalence in Indonesia. The study field period took place over a period of 38 weeks in 2007 in 11 sites in Indonesia. More than 18,600 medical records were reviewed and valid data was collected from more than 1,500 subjects. His main tasks in these studies were interacting with international, national, and regional CROs to assure comprehensive management of the studies. In addition, he managed the development and implementation of the data collection instruments and all interview-related project components, including the development of a computerized questionnaire instrument for the European study, translation of the data collection instruments into the appropriate country languages, as well as the training and monitoring of interviewers. Through his experience at The Weinberg Group, Mr. Peza has developed a significant knowledge of protocol design, questionnaire design, data collection methods, survey quality, coverage error, and interviewer effects.