Human Subjects in Research A primer on ethical principals including bioethics

1. Human Subjects in Research � A primer on ethical principals including bioethics Matthew Ronning Associate Vice Chancellor for Research North Carolina State University

2. Introduction Conflicts of Interest Integrity in science Animal Subjects in Research Hazardous Materials and Waste Including Chemo, Bio, and Radio Human Subjects in Research

3. Construct and organization of compliance Where danger looms How to mitigate non-compliance Sustainability of research endeavors Where and when to turn for guidance

4. Conflicts of interest Real or perceived? Is there a difference? Objectivity impaired Objectivity questioned Compromising human health � it can happen and it does happen. Nullification of earlier results Disaster for future results

5. Mitigating the Risks of Impaired Objectivity Selective reporting of results is absolutely wrong. Achieving the null hypothesis is as valid as new discovery Conclusive results, whether favorable or not favorable should be included in your reports Where you have an interest outside of your scientific career you MUST fully disclose and search for opportunities to ensure objectivity Ensure your subordinates are properly shielded from the conflict It is inappropriate to NOT disclose to your subordinates your conflicts and to establish methods for them to �seek shelter� if the objectivity in their work becomes compromised by pressures from senior staff Add an oversight body to ensure objectivity Identify independent party for certain activities

6. Integrity is paramount Defend the results of your research and the design that leads you to your results. Monitoring your progress is hard enough. Without good documentation the quality of the research programs can be compromised severely Impact of contribution to knowledge (not just scholarship) Intellectual Property � Patents, Copyrights � Licensing and royalties Reliability of scientific record. Trusting the unreliable record can be a major waste of time. Fame, maybe not fortune�

7. Recap on Definitions Fabrication - making up data or results and recording or reporting them Falsification - manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record Plagiarism - the appropriation of another person's ideas, processes, results, or words without giving appropriate credit Other non-scholarly behaviors Fiduciary � management of financial and administrative matters Egocentricity � don�t let your ego get the best of you � focus on the science Personal Misconduct Harassment � Sexual misconduct � Sensitivity to different cultures

8. Where are the bear-traps in scientific misconduct? Lack of documentation Lack of communication Lack of caring Pressure to finish Leadership is missing Integrity in science starts early and must be a lifelong pursuit

9. U.S.A. Misconduct Case Statistics

10. Ronning�s basic fundamentals in academic research Record Review Instruct Counsel Think! Double Check Heal

12. Funding for Research � Ethical Considerations Dual Funding for Same Project It is always inappropriate to request and receive funding for the exact same experiments It is appropriate to request supplementary funding or funding to run the same experiments for substantiation purposes. Ensure the sponsor knows of the dual funding � it actually makes your project more competitive for extramural funding Provided the dual funding illustrates better than 1:1 leverage of benefit In US, most federal sponsors try to coordinate funding but only do so when they know the funding request is under consideration by more than one agency

13. Funding for Research � Ethical Considerations Paramount to your success in requesting funding is to convince the reviewer that the objectives are attainable: Support your objectives with a careful literature review. Support your ideas with references to supporting or foundational research published in the scientific literature. Do not ignore opposing positions � embrace them and discuss openly. Any literature that you use in formulating and defending your position must be referenced. Consider�.

14. Other than ethics, citing other�s work is collegial ��scientists who routinely fail to cite the work of others may find themselves excluded from the fellowship of their peers. This consideration is particularly important in one of the more intangible aspects of a scientific career-that of building a reputation.� -- On Being a Scientist: Responsible Conduct in Research, Second Edition (1995)Committee on Science, Engineering, and Public Policy

15. Brief overview of animals as research subjects Animals have rights. Humans must protect animals from abuse Minimization of animals in research is critically important Use of animals in research is necessary Alternatives models are sometimes available � where practical these methods should be used

16. Animals, continued Construct of animal regulations is similar in some respects to human subjects Of course, we�ll talk about vulnerable populations and informed consent later. Client owned animals (pets) is a unique area of concern.

17. Animals � ethical considerations Animals can�t give consent. Animals do have rights and humans must protect them. Animal contributions to human health is priceless Without these contributions, human health and quality of life would be centuries outdated. Other considerations?

18. Animals in Research � Considerations for Compliance Use of animals for any reason is not a right, it is a privilege Who is the most responsible and important party for any compliance program (animals especially)? YOU! The user

19. Brief overview of hazardous substances and waste remediation Radiological materials Biological Infectious microorganisms Toxic biological substances Biological allergens Any combination of the above Hazardous Waste and Chemical Safety

20. Hazardous materials, cont�d

21. Human Subjects in Research, Biomedical and Behavioral/Social A brief world tour Focus in on the Belmont Report Definitions and construct of US Regulations Construct and benefit of committees Informed Consent Transparency and confidentiality Special issues in epidemiological studies Reconciliation of biomedical and social/behavioral issues

22. Development of world regulations Nuremburg (1949) Declaration of Helsinki (1964) USPHS Syphilis Study � Tuskegee (1972 exposed) Belmont Report (1979)

23. Development of world regulations International Conference on Harmonization � Guideline for Good Clinical Practice US National Research Act � Codification of US Regulations (1974) CIOMS International Ethical Guidelines Canadian Tri-Council Policy Statement Indian Council of Medical Research

24. Development of world regulations US Regulations 45 CFR 46 and 21 CFR 50/56 (1981) US Common rules adopted by all federal agencies (1991)

25. Construct and reasoning for human subject protection From the Belmont Report Guiding principles Written as result of past abuses of human subjects Beneficence Respect for Persons Justice Mentally Retarded Irradiated Milk Henry Beecher (New England Journal of Medicine � 1966) Imprisoned

26. The Belmont Report (1976) It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other The term "practice" refers to interventions that are designed solely to enhance the well-being of an individual patient or client The term "research' designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge Research and practice may be carried on together. If there is any element of research in an activity, that activity should undergo review for the protection of human subjects

28. The Belmont Report (1976) Three ethical principles of the Belmont report Respect for Persons The principle of respect for persons divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy Beneficience 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. The different claims covered by the principle of beneficence may come into conflict and force difficult choices

29. The Belmont Report (1976) Justice An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Conceptions of justice are relevant to research involving human subjects: the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability

30. The Belmont Report (1976) When research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both: that these not provide advantages only to those who can afford them, and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research

31. Break Here

32. In action, achieving Belmont principals Components Informed consent Measuring risks and benefits Selection of subjects

33. Relationship to US federal regulations Some Definitions (45CFR46.102 et.seq) A human subject is: a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information.

34. Definitions, cont�d Research is: a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.

35. Definitions, cont�d Minimal risk means: that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

36. Construct of regulation is based on risks and benefits Exemptions � US regulations provides for minimal risk research scenarios that are exempt from regulation. Certain caveats exist in the following regulatory citation. Exemptions can not be made by the investigators. 45CFR46.101(b) Expedited review � one or more committee members can review and approve in certain circumstances 45CFR46.110 Full board reviews

37. Why a committee? Input from independent parties, including colleagues and lay people provides critical insights See past the bureaucracy both as a principal investigator and as a committee member. Use the IRB approval process as part of designing the study. Capitalize on its strengths A facilitator focus by the committee is critical to maximum advancement of science. But, an investigator or investigative team is where compliance with the ethical construct rests.

38. Committee construct 5 members with varying backgrounds and competence no selection is made to the IRB on the basis of gender, race, ethnicity, etc. including profession minimum of one scientist and one non-scientist unaffiliated member

39. Committee Competence Local IRB � Ensures that the local customs, risks, concerns are dealt with in the review and approval. Example: An upper Manhattan IRB may not be the best qualified to review and approve an HIV study in Sudan. Expertise � It is critical that the committee has the capacity to understand and challenge the discipline of study carefully. Not every member but some. Education on purpose, scope and methods is necessary. Committees, especially those in biomedical settings, often make decisions without fully understanding the protocol. The largest risks I see are biomedical committees having too high of tolerance for risk. Seek external guidance/competence

40. Primary principle � Informed Consent �no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence.�

41. Basic considerations for informed consent Purpose and scope of study (ping: influence outcomes?, Deception?) Reasonably foreseeable risks. The benefits subjects shall accrue (ping: may not be directly individual) particular vulnerability: last resort treatments Placebo recipients MUST benefit ultimately, from successful treatments discovered. In some cases, it may even be better to halt the study in order to provide the non-treatment subjects to benefit from new discovery One purpose of a Data Safety Monitoring Board discussed later on

42. Basic considerations for informed consent Alternative procedures available This is research, not treatment. Make this absolutely clear. Standard care must be available and offered. Confidentiality provisions � Discussed later today Compensation and additional risks particular vulnerability: impoverished diminished reasoning skills, etc. Whom to contact if harmed Refusal or termination not penalized

43. Dangers and concerns on consent Subjects understand consent? Signatures necessary? What constitutes a legal representative? Last resort treatments Does the concept of minimal risk change? A philosophical debate Smokers, for example, have a different threshold than non-smokers in defining minimal risk in a study of the effects of smoking Certain groups consider research as their only hope for survival. But consider carefully the differences between radical treatments and exploratory research.

44. Criteria for IRB approval of research Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design, and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research.

45. Criteria for IRB approval of research Selection of subjects is equitable. In making this assessment, the IRB should take into account the purposes of the research, and the setting in which the research will be conducted, and should be particularly aware of the special problems of research involving vulnerable populations. Informed consent will be sought from each prospective subject or the subject's legally authorized representative, and will be appropriately documented When appropriate, the research plan makes adequate provision for monitoring the data collected, to ensure the safety of subjects. Consider a Data Safety Monitoring Boards Data Safety Monitoring Boards determine when a study should be stopped (if too many adverse events), and also make calls about changing treatment arms based on the emerging results (supposedly for the best for the subjects) When appropriate, there are adequate provisions to protect the privacy of subjects, and to maintain the confidentiality of data.

46. Transparency of Research Confidentiality between researcher and subject Researchers should arrange to protect the confidentiality of personal information by omitting information that might lead to the identification of individual subjects, limiting access to the information, anonymizing data, or other means. During the process of obtaining informed consent the researcher should inform the prospective subjects about the precautions that will be taken to protect confidentiality Prospective subjects should be informed of limits to the researchers' ability to ensure strict confidentiality

47. Transparency of Research Confidentiality between physician and patient A treating physician should not disclose any identifying information about patients to an investigator unless each patient has given consent to such disclosure and unless an ethical review committee has approved such disclosure Risks to groups of persons Research in certain fields may present risks to the interests of communities, societies or racially or ethnically defined groups of people Plans to conduct such research should be sensitive to such considerations, to the need to publish the results in a way that is respectful of the interests of all concerned, or in certain circumstances not to publish them

48. Transparency of Research Epidemiological studies Epidemiologic studies present several unique problems because they often use sensitive private documents, such as medical records, and link them with other data, such as employment, insurance, or police records Access to those records without prior consent of the subject raises concerns about the violation of the ethical principle of respect for persons With respect to confidentiality, disclosure of information such as that usually collected in epidemiologic studies also presents an ethical concern that IRBs should address

49. Transparency of Research Epidemiological Studies Some ways to ensure adequate confidentiality include: all information collected as part of a study must be stored in a secure manner and must not be shared inappropriately where identifiers are not required by the design of the study, they are not to be recorded If identifiers are recorded, they should be separated, if possible, from data and stored securely, with linkage restored only when necessary to conduct the research No lists should be retained identifying those who elected not to participate Participants must be given a fair, clear explanation of how information about them will be handled. Conflicts of Interest (revisited) Make absolute certain that subjects know and understand when the researcher has a vested interest in the outcome of a study

50. Reconciling between behavioral and biomedical Surprising risks in social and behavioral research Reputation Employability AIDS research (behavioral) Cancer research (behavioral) Substance abuse And many other examples

51. Reconciling between behavioral and biomedical Personal relationships Child abuse Sexual conduct/promiscuity And many other examples Mental health Resurfacing suppressed emotions

52. Case Studies See the module �Research with Human Subjects� by Matt Ronning, et.al.