International Research Bridging Bioethics and Practice

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1 International Research Bridging Bioethics and Practice Sergio Litewka M.D., M.P.H University of Miami Ethics Programs CITI Program at the University of Miami

2 Talking points Current status on U.S. sponsored trials in developing countries Bioethical concerns about carrying out clinical trials in developing countries Cultural and logistical challenges U.S. Presidential Commission for the Study of Bioethical Issues recommendations for human subjects protection on international research

3 Developing countries Low-income and middle-income economies are sometimes referred to as developing economies. The use of the term is convenient; it is not intended to imply that all economies in the group are experiencing similar development or that other economies have reached a preferred or final stage of development. Classification by income does not necessarily reflect development status Economies are divided according to 2011 GNI per capita, calculated using the World Bank Method. The groups are: low income, $1,025 or less; lower middle income, $1,026 - $4,035; upper middle income, $4,036 - $12,475; and high income, $12,476 or more

4 Globalization of clinical trials Source: Clinicaltrials.gov ( September )

5 Research Ethics and globalization HHS regulations define research at 45 CFR (d) as follows: A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge Production of valid, reliable, and generalizable knowledge (Knowledge is organized information) Each community gives a special accent to the activity Influence of the dominant paradigms. Cultural and regulatory framework Information obtained in different settings may contribute to generate reliable and valid data that might benefit diverse populations Perceived opportunities for investigators from developing countries in collaborative research

6 The Globalization of Clinical Research- Regulatory Issues Clinical trials funded by HHS and conducted outside the U.S. must comply with the Common Rule or equivalent protections, as determined by OHRP International sites engaged in HHS-funded research must have an OHRP-approved FederalWide Assurance (FWA) Local IRBs may be ill-prepared to review complex research protocols Informed consent issues Local needs Country-specific accreditation of clinical trial sites is variable. Ideological tensions about the meaning of research ( and the meaning of clinical trials) Disparities in health infrastructure

7 International Clinical Trial Density Top 10 Bottom 10 U.S Canada New Caledonia, Vanuatu, Guyana, Suriname, Brunei Darussalam, Djibouti, Mauritania Solomon Islands, Bhutan, Lao s Democratic Republic, Yemen 1 2 Germany Angola, Chad, Togo, Azerbaijan, Uzbekistan 3 France Burundi, Central African Republic, Lesotho, Liberia, Libyan Arab Jamahiriya, Swaziland, Kyrgyzstan 5 U.K Fiji 6 Italy 6640 Mongolia, Guinea, Sierra Leone, Nicaragua, Trinidad and Tobago 7 Spain 6099 Myanmar, Madagascar 9 Netherlands 5229 Congo 10 South Korea 5150 Montenegro 12 Belgium 5029 Papua New Guinea, Syrian Arab Republic 13 Clinicaltrials.gov, March 4, 2014

8 Globalization Registered Trials Source: Clinicaltrials.gov ( September )

9 Globalization.Recruitment Source: Clinicaltrials.gov ( September )

10 Developing countries: What makes clinical research ethical? Collaborative partnership Social value Scientific validity Fair selection of study population Favorable risk-benefit ratio Independent review Informed consent Respect for recruited participants and study communities Emanuel E. Wendler D. Killen J. Grady C. What makes clinical research in developing countries ethical?. The benchmarks of ethical research. Journal of Infectious Diseases 2004;189:930-7

11 Bioethical concerns about biomedical research in developing countries Exploitation Vulnerability: Those who are relatively or absolutely incapable of protecting their own interests because they may have insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their interests.- CIOMS guideline 13 To exploit a person involves the harmful, merely instrumental utilization of him or his capacities for one s own advantage of for the sake of one s ends ( Wertheimer) Concerns about being culturally sensitive, respecting local beliefs and traditions: Could local traditions or beliefs be harmful for subjects? Concerns about the standard of care that should apply in low resource settings: Best current method vs. established effective intervention Should social and economical conditions to be considered in the design and conduction of the study? Local standards or sponsor s standards?. Should legal and ethical standards and practices be the same in resource rich and resource poor settings?. What is the role of economic context?. ( Research Across Borders. Proceedings of the International Research Panel of the Presidential Commission for the Study of Bioethical Issues. September 2011)

12 Bioethical concerns Justice: Reasonably availability requirements The sponsoring agency should agree in advance of the research that any product developed [ knowledge generated] through such research will be made reasonably available to the host community or country at the completion of successful testing [ for the benefit of that population or community] ( CIOMS 1993/ 2002, Guideline 10) Phase III trials. What about phase I and II? Who will be responsible for making the product available? Who is entitled to receive it, when the product should be deemed safe, considering the possibility of unknown long term adverse events? Who should decide what post-trial benefits are to be shared with the community? Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Moral Standards for Research in Developing Countries: From Reasonable Availability to Fair Benefits, Hastings Center Report 34, no. 3 (2004):14-27

13 Bioethical concerns Fair benefits: To the research participants To the population during research Benefits to the participants and population after completion of the research Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Moral Standards for Research in Developing Countries: From Reasonable Availability to Fair Benefits, Hastings Center Report 34, no. 3 (2004):14-27 Transparency Responding to the host needs

14 The 076 protocol in Uganda By 1993 Zidovudine was effective in the U.S. in reducing HIV maternal-fetal transmission 100 mg of Zidovudine, orally, 14 weeks before due date for mothers Intravenous Zidovudine during birth ( mother) Oral Zidovudine for infant every 6 hours for 6 weeks Short term treatment clinical trial. Placebo controlled trial in Uganda and other poor resource settings Problems in poor resource settings: Cost Healthcare infrastructure Pre-natal control Breastfeeding Letter from the Public Citizen Health Research Group Critical editorials from the New England Journal of Medicine ( Marcia Angell)

16 Whose standard of care? In a letter to Satcher and Varmus, which they quoted in their New England Journal of Medicine article, Edward Mbidde, chairman of the AIDS Research Committee of the Uganda Cancer Institute, wrote: "These are Ugandan studies conducted by Ugandan investigators on Ugandans. Due to lack of resources we have been sponsored by organizations like yours.... It is not NIH conducting the studies in Uganda but Ugandans conducting their study on their people for the good of their people." Furthermore, these critics maintained, the clinical trials had been carefully examined by ethical review committees in the sponsoring and host countries; they conformed to international standards, yet were tailored to suit the realities of medical care in their communities. Table Extracted from: Wendler D, Emanuel E,Reidar K: The Standard of Care Debate. Can Research in Developing Countries can be both Ethical and Responsible for Those Countries Health s Needs. Am J. of Public Health (2004), 94(6)

17 Cholera Vaccine: Ethical questions for a single dose protocol The vaccine is approved at 2 doses There is little stockpiled There is some evidence that one dose or shot gives some protection Would it be ethical to test one dose on human subjects to see if it is protective since in a sudden large epidemic vaccines would only reach a small percentage of people? Would one dose be good enough in an emergency Arthur Caplan PhD. Center for Vaccine Ethics and Policy IVI OCV Trial Ethics Meeting May 2012, Philadelphia, USA

18 Subject population for the cholera vaccine study Find population where? cholera is endemic to study efficacy of one dose Poorest of the poor with no access to any vaccine How to prepare local community for such a study Recruitment -- incentives, options Length of study Following refusals? Exclusions HIV, pregnant women Arthur Caplan PhD. Center for Vaccine Ethics and Policy IVI OCV Trial Ethics Meeting May 2012, Philadelphia, USA

19 Ebola Vaccine Trials

20 DoH 2013

21 Governance, research ethics and globalization Governance, from the Latin root gubernare. Less formal means of directing actions or regulating behavior, not necessarily through the law Capron A.M. The governance of Scientific Collaborations, In International Research Collaborations. Routledge 2009 International research, as a global enterprise presents very specific challenges: Transnational problems Interdependent solutions Lack of existing overarching authority Independence of the actors Rosenau 1999

22 Governance and international research Traditions and institutions by which authority in a country is exercised Process by which governments are selected, monitored and replaced Voice and accountability Political stability and absence of terrorism/violence Capacity of a government to effectively formulate and implement sound policies Government effectiveness Regulatory quality Respect of the citizens and the state for the institutions that govern interactions among them Rule of law Control of corruption Kaufmann D, Kraay A, Mastruzzi M. Global Economy and Development. Brookings Institutions. September World Bank Institute

26 Cultural and logistical challenges in developing countries Legal framework Informed consent may be based in a legalistic vision from the sponsor s country Excessive centralization Weak enforcement Normative polyphony Regulatory framework may be related to GCP-ICH only IRBs Training and education of its members Resources Clinical ethics committees acting as research ethics committees Conflicts of interests and lack of IRBs independence Deficiencies in assuring privacy and confidentiality Difficult oversight and follow up of clinical trials Outsourcing of clinical trials

27 Transparency International

28 More challenges for implementing reforms in developing countries Whose bioethics? : Many scholars from developing countries ( and also some from industrialized ones) resist the idea of what they perceive as a U.S. bioethics Supporters of hard bioethics are calling to challenge the current division between central and peripheral countries, blaming the latter for an unjust order that must be combated The international guidelines for research ethics are more aspirational than effective

29 U.S. Presidential Commission for the Study of Bioethical Issues: International Research Panel Findings Over the past five decades, the United States has made significant progress in developing rules, standards, and practices for protecting human subjects in research Rules, standards, and practices vary greatly around the globe. Biomedical research is expanding around the globe, with an increasing number and frequency of trials outside the United States Community engagement is important to (i) demonstrate respect for host and collaborative communities by engaging them as partners in research, (ii) enhance understanding of how U.S. standards can be applied in other cultural contexts, and (iii) provide opportunities for ongoing oversight and monitoring of research activities Individual informed consent or its moral equivalent, for example, surrogate consent for children, is always required in interventional clinical research with human subjects, and is universally regarded as playing a central role in protecting subjects, regardless of where research is conducted

U.S. Presidential Commission for the Study of Bioethical issues: International research 1. Increase accountability 2. Helping those who are harmed as a result of research participation 3.

30 U.S. Presidential Commission for the Study of Bioethical issues: International research 1. Increase accountability 2. Helping those who are harmed as a result of research participation 3. Respecting equivalent protections of international partners 4. Promoting a culture of responsibility 5. Evaluating site selection and the justification for chosen study design 6. Engaging communities at all levels of research

31 Towards an effective international collaboration on research ethics Research ethics experts that are knowledgeable on the basics of research methodology Databases with updated information about unethical research Fostering research ethics education By whom? Cultural sensitivity Understanding geopolitical affairs Common sense

32 Some conclusions Guidelines and regulations are not a substitute for critical thinking or research integrity Politics, ideology and scientific research are (almost) always related Transparency and accountability are sine qua non requirements for mitigating potential abuses and fraudulent practices Educational programs with a practical approach to research ethics and human subject protection should be considered when deciding research sites in developing countries Research in developing countries should be governed by a more comprehensive understanding of expected benefits and potential social value of the research rather than a merely legalistic approach

33 International Research. Bridging Bioethics and Practice Sergio Litewka M.D. M.P.H University of Miami Ethics Programs CITI Program

What the case of Guatemala has taught us

Washington University School of Medicine Digital Commons@Becker 2011 Conversations with Sergio Litewka, MD, MPH Conferences 2011 What the case of Guatemala has taught us Sergio G. Litewka University of