Ethics in Epidemiologic Research

1. Ethics in Epidemiologic Research Javier Lopez-Zetina, PhD, MA Associate Professor Health Science Department California State University, Long Beach

2. Module Outline 1. Overview of the IRB Principles of Beneficence, Justice and Respect for Persons 2. Overview of specific applications of IRB Principles • Informed Consent • Confidentiality • Disclosure of risks and benefits • Disclosure of conflict of interest 3. Current ethical dilemmas and controversies • Shared clinical decision-making • Genetic screening • International ethics and IRB review of international collaboration • Participant observation and community-based participatory research • Non federally-funded research: ethical framework

3. Overview of the IRB Principles of Beneficence, Justice, and Respect for Persons At the conclusion of this topic, the student will be able to: 1. Identify and summarize the three basic ethical principles governing academic research under IRB oversight. Students will read and comprehend the basic principles expounded in the Belmont Report. The Belmont Report is available online at the CSULB IRB website. 2. Explain and cite specific application of the principle of Beneficence in public health research 3. Recognize specific examples of application of the principle of Justice in bio-medical and community health research. 4. Summarize basic tenets of the principle “Respect for Persons”, particularly in the context of community-based research.

4. Presentation of Invited Speakers Depending on availability, professional staff from the California State University, Long Beach Institutional Review Board will be invited to provide a succinct summary of the Board’s mandate and activities.

5. Video Presentation In addition, a short video titled: The Belmont Report: Basic Ethical Principles and Their Applications, will be presented to the class for an extended overview of the IRB Principles. The video is produced by the National Library of Medicine for the National Institutes of Health and the Food and Drug Administration.

6. Overview The Belmont Report, a document developed by agencies of the U.S. government during the decade of 1960’s, constitutes the ideological and theoretical foundation of ethical research in U.S. academic institutions. U.S. academic institutions receiving federal funding for research are obligated to enforce compliance with these principles. As previously mentioned, three principles are recognized as fundamental components of ethical research. They are briefly summarized as follows.

7. The CSULB IRB policy document defines Beneficence as follows. “Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well being. Such treatment falls under the principle of beneficence. The term "beneficence" is often understood to cover acts of kindness or charity that go beyond strict obligation. In this document, beneficence is understood in a stronger sense as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms”.

8. CSULB IRB policy definition. Justice. “Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of "fairness in distribution" or "what is deserved." An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally. It is necessary, then, to explain in what respects people should be treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits. Each formulation mentions some relevant property on the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit”.

9. CSULB IRB policy definition. Respect for Persons. “Respect for persons incorporates at least two ethical convictions; first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy”.

10. Overview of specific applications of IRB Principles • Informed Consent • Confidentiality • Disclosure of risks and benefits • Disclosure of conflict of interest

11. Learning Objectives By the end of this section, the student should be able to: 1. Understand how the concept of informed consent is derived from the three IRB Principles. 2. Describe the concept of informed consent as it ultimately preserves the integrity and autonomy of the research subject. 3. Describe the basic components of an Informed Consent Document. a. Confidentiality b. Disclosure of Risks and Benefit c. Disclosure of Conflict of Interest 4. Recognize the importance of cultural factors (i.e. language preference) in developing informed consent documentation.

12. Overview Informed Consent and Confidentiality are the most important applications of the IRB principles. Essentially, this application recognizes long-standing concerns regarding the need to protect the physical and moral integrity and autonomy of research subjects. Although well-intentioned, the research paradigm prior to the development of the concept of informed consent, basically assumed that the researcher “knew” what was better for the research participants and that the integrity and autonomy of the participants needed not be discussed extensively with the research subjects. The informed consent concept stipulates that detailed information on potential risks and benefits must be given to the research subject as part of a decision-making process leading to a well-informed articulation of the participant’s values and expectations. Moreover, the protection and active defense of the autonomy and integrity of the participants is further extended to include safeguards for preserving confidentiality of the personal and research data obtained from participants. Two research approaches focusing on confidentiality has been developed to secure a balance between the ethical concerns of research and the scientific need for data: confidentiality of data and anonymity of study results. These applications of confidentiality will be reviewed as fundamental components of the study cases.

13. Case Study/Discussion Questions Vertical transmission of HIV continues to pose dramatic challenges to clinicians and public health experts in the U.S. and around the world. Over the past two decades several research protocols have been implemented nationally and internationally with the goal of determining pharmacologic modalities best suited for the prevention of HIV vertical transmission. One of these research protocols, PACTG 1002 was implemented among U.S. subjects, but was the subject of ongoing controversy over ethical issues.

14. Familiarize yourself with the suggested readings and answer the following questions: • Based on your knowledge of clinical trials, draw a simple diagram illustrating the arms of PACTG 1022 (JAIDS) • What was the endpoint of PACTG 1022 (JAIDS and Harper’s) •Search the internet (for example the FDA website) and describe in one paragraph what an FDA’s “Category C’ trial entails •What are the clinical features of a current AIDS diagnosis •Based on the newspaper report and without knowing the details of the natural history of disease, answer the question: What experimental issues are at stake when evaluating the efficacy of prophylaxis treatment to prevent vertical transmission of HIV (Harper’s) •Describe in one paragraph what might possibly explain that no signed consent form was found for the study subject (Ms. Hafford), and who died in the course of the PACTG 1022 study (Harper’s) •According to the article what are four reasons people participate in clinical trials (Harper’s) •PACTG 1022 was modeled after HIVNET 012, how many and what were the arms of HIVNET 012 (Harper’s) •Why the experimental design of HIVNET 012 called for not using a placebo (Harper’s) •Explain what the purpose of randomization is •Search the CSULB IRB webpage and report what rules are in place when encountering AEs (adverse effects) and SAEs (serious adverse effects).

15. References Hitti J; Frenkel LM; Stek AM; Nachman SA; Baker D; Gonzalez-Garcia A; Provisor A. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. Journal of acquired immune deficiency syndromes: JAIDS, 2004, 36. Farber, Celia. Out of control. AIDS and the corruption of medical science. Harper’s Magazine. March, 2006.

16. Current ethical dilemmas and controversies • Shared clinical decision-making • Genetic screening • International ethics and IRB review of international collaboration • Participant observation and community-based participatory research • Non federally-funded research: ethical framework

17. Learning Objectives By the end of this discussion, students will be able to: 1. Recognize how the three ethical principles of academic research are implemented in clinical settings. 2. List three controversies concerning mass genetic screening 3. Discuss ethical tensions and conflicts arising from international collaboration in research. 4. Cite one example in which modalities of community-based research and participant observation appear to be in conflict with the IRB doctrine. 5. Discuss the limitations of the IRB doctrine as it applies to non federally-funded research.

18. Overview Despite our comprehensive ethical framework, public health practitioners are constantly faced with new challenges arising from the evolving and extended nature of what constitutes “research”. For example, few or no regulations for the protection of human subjects are followed by private companies conducting research with their employees and with their own funds (McDaniel, Solomon et al. 2006). Another gray area posing unique ethical challenges is international research (Miller 1988; Kelley 2002; Hyder, Wali et al. 2004). Domestically, the growing tension between the IRB prescriptive translations of ethical principles and the specific need of community participatory research is generating ethical issues that are as yet, unresolved (Malone, Yerger et al. 2006). Next, but not last or least, examination of genetic variation in large communities and populations has often been met with heated controversy over whether such screening and testing, even under IRB protection, is bound to cast upon entire communities the stigma of being branded “genetically defective” (Sterling, Henderson et al. 2006). Using study cases, the final section of this ethics module will examine these specific examples and situations of ethical dilemmas and controversies.

19. Case Study/Discussion Questions Study Case 1. Genetic Screening Scientists are turning to genetic variation research in hopes of addressing persistent racial/ethnic disparities in health. Despite ongoing controversy, the advancement of genetic variation research is likely to produce new knowledge and technologies that will substantially change the ways in which we understand and value health. They also may affect the ways in which individuals and groups organize socially, politically, and economically. Addressing concerns that may exist in different communities is vital to the scientific and ethical advancement of genetic variation research. We review empirical studies of public willingness to participate in and opinions about genetic research with particular attention to differences in consent and opinion by racial/ethnic group membership, (Sterling, Henderson et al. 2006).

20. Questions 1. What is the impact of genetic screening in different communities. Cite at least two examples. 2. What are some of the factors hindering participation in genetic screening 3. How do consent, values and expectations vary by race/ethnic membership vis a vis genetic screening.

21. Study Case 2. International research collaboration BACKGROUND: Increasing collaboration between industrialized and developing countries in human research studies has led to concerns regarding the potential exploitation of resource deprived countries. This study, commissioned by the former National Bioethics Advisory Commission of the United States, surveyed developing country researchers about their concerns and opinions regarding ethical review processes and the performance of developing country and US international review boards (IRBs). METHODS: Contact lists from four international organizations were used to identify and survey 670 health researchers in developing countries. A questionnaire with 169 questions explored issues of IRB review, informed consent, and recommendations. RESULTS: The majority of the developing country researchers were middle aged males who were physicians and were employed by educational institutions, carrying out research on part time basis. Forty four percent of the respondents reported that their studies were not reviewed by a developing country IRB or Ministry of Health and one third of these studies were funded by the US. During the review process issues such as the need for local language consent forms and letters for approval, and confidentiality protection of participants were raised by US IRBs in significantly higher proportions than by host country IRBs. CONCLUSION: This survey indicates the need for the ethical review of collaborative research in both US and host countries. It also reflects a desire for focused capacity development in supporting ethical review of research, (Hyder, Wali et al. 2004).

22. Questions 1. What is the National Bioethics Advisory Commission? 2. List five ethical concerns of researchers in developing countries 3. What was the gender/age membership of most researchers surveyed in developing countries? What are some of the implications of this gender/age make-up for the development of an ethical framework in developing countries?

23. Study Case 3. Participant observation and community-based participatory research Community-based participatory research (CBPR) addresses the social justice dimensions of health disparities by engaging marginalized communities, building capacity for action, and encouraging more egalitarian relationships between researchers and communities. CBPR may challenge institutionalized academic practices and the understandings that inform institutional review board deliberations and, indirectly, prioritize particular kinds of research. We present our attempt to study, as part of a CBPR partnership, cigarette sales practices in an inner-city community. We use critical and communitarian perspectives to examine the implications of the refusal of the university institutional review board (in this case, the University of California, San Francisco) to approve the study. CBPR requires expanding ethical discourse beyond the procedural, principle-based approaches common in biomedical research settings. The current ethics culture of academia may sometimes serve to protect institutional power at the expense of community empowerment.

24. Questions 1. What is CBPR (Community-based participatory research)? 2. In the view of the research report’s authors, how the IRB deliberations hinder CBPR? 3. According to the authors, how the procedural, principle-based doctrine of the IRB help sustain institutional power at the expenses of community empowerment?

25. Study Case 4. Non federally-funded research: ethical framework In the United States, companies that use their own funds to test consumer products on their employees are subject to few regulations. Using previously undisclosed tobacco industry documents, we reviewed the history of that industry's efforts to create internal guidelines on the conditions to be met before employee taste testers could evaluate cigarettes made from tobacco treated with experimental pesticides. This history highlights 2 potential ethical issues raised by unregulated industrial research: conflict of interest and lack of informed consent. To ensure compliance with accepted ethical standards, an independent federal office should be established to oversee industrial research involving humans exposed to experimental or increased quantities of ingested, inhaled, or absorbed chemical agents.

26. Questions 1. Companies may test consumer products using their own employees. List three potential ethical problems with this approach. 2. Specifically, describe how conflict of interest may arise under this unregulated research approach 3. Specifically, list three potential ethical conflicts as a result of conducting research that lacks an informed consent process

27. Work Cited and Suggested Preliminary Module Bibliography (Appended) Hyder, A. A., S. A. Wali, et al. (2004). "Ethical review of health research: a perspective from developing country researchers." J Med Ethics 30(1): 68-72. Kelley, S. D. (2002). "The forum. A contextualized approach to IRB review for collaborative international research." Ethics Behav 12(4): 371-6. Malone, R. E., V. B. Yerger, et al. (2006). ""It's Like Tuskegee in Reverse": A Case Study of Ethical Tensions in Institutional Review Board Review of Community-Based Participatory Research." Am J Public Health 96(11): 1914-1919. McDaniel, P. A., G. Solomon, et al. (2006). "The ethics of industry experimentation using employees: the case of taste-testing pesticide-treated tobacco." Am J Public Health 96(1): 37-46. Miller, J. (1988). "Towards an international ethic for research with human beings." Irb 10(6): 9-11. Sterling, R., G. E. Henderson, et al. (2006). "Public Willingness to Participate in and Public Opinions About Genetic Variation Research: A Review of the Literature." Am J Public Health 96(11): 1971-1978. The Belmont Report [video] : basic ethical principles and their applications / Produced by the National Library of Medicine for the National Institutes of Health and the Food and Drug Administration. Imprint [Bethesda, MD] : National Library of Medicine, [1986?] Hitti J ; Frenkel LM ; Stek AM ; Nachman SA ; Baker D ; Gonzalez-Garcia A ; Provisor A . Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. Journal of acquired immune deficiency syndromes : JAIDS, 2004, 36. Farber, Celia. Out of control. AIDS and the corruption of medical science. Harper’s Magazine. March, 2006.