Guidelines for the ethical conduct of research

1. Guidelines for the ethical conduct of research Marcalee Sipski, MD Professor and Director of Neuroscience Research University of Alabama Dept. of PM&R Adapted from NIH Offices of Human Subjects Research Guidelines for the Conduct of Human Subjects Research at the NIH

2. History

3. The Nuremberg Code • In 1946 23 Nazi physicians went on trial for crimes committed against POW. • Crimes included exposure of humans to extremes of temperature, performance of mutilating surgery and deliberate infection with a variety of lethal pathogens • Fundamental ethical standards for the conduct of research were codified

4. The Nuremberg Code • Reflected in the Declaration of Human Rights and accepted in principle by each of the 51 original signatory nations of the Charter of the United Nations. • 10 conditions that must be met in order to justify research involving human subjects • Voluntary informed consent of subjects • Scientifically-valid research design that would produce fruitful results for the good of society

5. 1953-NIH Clinical Center • The 1st US Policy for protection of human subjects • Gave special protection to adult health research volunteers who had little to gain from research participation • Prospective review of research from persons without direct involvement or investment in the work-the start of the IRB

6. 1960’s • With the greater increase in human rights, interest grew in the rights of research subjects • Newspaper reports of investigators in NY injecting elderly indigent people with live cancer cells (without their consent) to learn more about the immune system

7. 1966 • A highly respected anesthesiologist and physician-investigator shocked the medical community when he reported that unethical or questionally ethical practices were common in human subjects research in many of America’s premier research institutions

9. The Helsinki Recommendations • Biomedical research should conform to accepted scientific principles • IRB’s must be used • Research must be conducted under the supervision of an appropriately trained medical person • The question must be as important as the risk

10. The Helsinki Recommendations • Concern for the interests of the subject must always prevail over the interests of science and society. • The subject’s privacy must be protected along with their physical and emotional integrity • Research hazards must be predictable • When publishing results, they must be accurate • Each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. They must also know they can quit at any time. • The physician should then obtain the subject’s freely-given informed consent, preferably in writing. • The issues of dependent relationships, legal incompetence and minors should be consider when performing research • Research protocols should include a statement of the ethical considerations involved

11. Clinical Research • In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgement it offers hope of saving life, reestablishing health or alleviating suffering. • Potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods. • Every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic method. • Refusal of the patient to participate in a study must never interfere with the physician-patient relationship. • If the physician considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee • The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

12. Non-clinical biomedical research • It is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out. • Subjects should be volunteers • Investigator or the investigating team should discontinue the research if in his/her or their judgement it may, if continued, be harmful to the individual. • The interest of science and society should never take precedence over considerations related to the wellbeing of the subject.

13. 1966: HEW Policy • Applied to all human subjects research conducted or support by HEW • Prospective review of HSR, taking into account the rights and welfare of the involved subjects, the appropriateness of informed consent procedures, and the risks and potential benefits of the procedures. Consent was required to be documented and signed by subjects or their representatives

14. Tuskegee Syphilis Study

15. Tuskegee • The reason why Macon County was chosen was explained by The Health Service's Taliford Clark in a report, "Macon County, is a natural laboratory; a ready-made situation. The rather low intelligence of the Negro population, depressed economic conditions, and the common promiscuous sex relations not only contribute to the spread of syphilis but the prevailing indifference with regard to treatment." • Free medicine for the treatment of "Bad Blood" brought 600 subjects into the study, 399 were suffering from syphilis and the remaining 201 were a control group. None of the participants were ever told that they had the disease, nor were they ever told that an experiment was taking place. • Subjects of the experiment had treatment for syphilis deliberately withheld from them. During World War II, they were kept out of the draft by the PHS, because joining the army would have meant a blood test and treatment for the disease if it had been discovered. The subjects were kept out of national programs that would have led to a cure. • Experiment continued until 1972 whistle blower • Results contributed nothing: syphilis led directly to the deaths of 28 of the participants, a further 100 died of related complications, 40 spouses were infected and 19 children were born with congenital syphilis

16. Senate committee on labor and human resources • Held hearings on the Tuskegee study and other alleged health care abuses of prisoners and children which led to . . . . . . • 1)enactment of the National Research act of 1974 • 2)National Commission for Protection of Human Subjects of Biomedical and Behavioral Research • 3)Imposition of a moratorium on research conducted or supported by HEW involving live human fetuses until the National Commission could study and make recommendations on it

17. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • Functioned from 1974-78 • Evaluated the existing HEW system and recommended improvements • Issued reports on research involving pregnant women, live human fetuses, prisoners, children, the mentally disabled and the use of psychosurgery • Also, issued The Belmont Report

19. The Belmont Report: 3 principles • Respect for persons: acknowledges the dignity and autonomy of individuals. Requires informed consent for research and requires that people with diminished autonomy such as live human fetuses, children, prisoners, the mentally disabled, and people with severe illnesses be provided with additional protections

20. The Belmont Report: 3 principles • Beneficence requires us to protect individuals by maximizing anticipated benefits and minimizing harms. This requires carefully examination of study design along with risks and benefits including at times identifying alternative ways of obtaining benefits sought from research. Research risks must always be justified by expected research benefits.

21. The Belmont Report: 3 principles • Justice requires that we treat subjects fairly. Subjects should be carefully and equitably chosen to insure that certain individuals or classes of individuals such as prisoners,elderly people or financially impoverished people are not systematically selected or excluded unless there are scientifically or ethically valid reasons for doing so. • Unless there is justification for an exception, research should not involve persons from groups that are unlikely to benefit from subsequent applications of the research.

22. So what does this mean for your university? • Title 45 Code of Federal Regulations, Part 46 Protection of Human Subjects (45 CFR Part 46)—Framework in which investigators can ensure efforts have been made to protect the rights and welfare of research subjects • Each research institution studying human must have their policies for subject protection in an “assurance of compliance”

23. So what does this all mean for you? • Institutional Review Board • Principal investigators are responsible for protecting the rights and welfare of the human subjects who participate in their research

24. Does your research involve human subjects? • A “human subject” is a living individual about whom an investigator obtains either 1)data through interaction or intervention with the person or 2)identifiable private information • Many times the lines are blurred

25. Activities that are generally exempt. . . The collection and study of. . . . . • Samples from deceased individuals • Samples collected only for diagnostic purposes • Samples or data available from commercial or public repositories or registries • Established cell lines that are publicly available to qualified scientific investigators • Self-sustaining, cell-free derivative preparations including viral isolates, cloned DNA, or RNA

26. Six categories of Research that are generally exempt • Research conducted in established or commonly accepted educational setting, involving normal educational practices e.g.(i) research on regular and special education instructional strategies, or (ii) research on the effectiveness or comparison of instructional techniques, curricula, or classroom management methods • Research involving the use of educational tests, survey procedures, interview procedures or observation of public behavior, unless: (i) Information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subject's financial standing, employability, or reputation.

27. Six categories of Research that are generally exempt • Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (2) above if: (i) The human subjects are elected or appointed public officials or candidates for public office; or (ii) federal statutes(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. • Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

28. Six categories of Research that are generally exempt • Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine: (i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs. • Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency of the Food Safety and Inspection Service of the U.S. Department of Agriculture.

30. Elements of a Research Proposal • Must receive approval from the IRB before beginning your study • Proposal is a written description of, and scientific rationale for, the proposed research activity. It includes a discussion of the human subject protection issues that are relevant to the study and addresses, at a minimum: the risks to subjects; all procedures which are experimental; the anticipated benefits to subjects, if any; the anticipated number of subjects; the proposed consent document and consent process to be used, and appropriate additional safeguards if potentially vulnerable subjects are to be enrolled. e.g. • the elderly, prisoners, children, cognitively impaired individuals, or people who are economically or educationally disadvantaged.

31. What is the IRB evaluating? • Is study design consistent with sound scientific principles and ethical norms? • Does the protocol meet project assurance criteria for approval?

32. What is the IRB evaluating? • Have the necessary elements of informed consent been fulfilled? • Are additional appropriate safeguards provided if potentially vulnerable subjects are to be studied?

35. As one can see the IRB process can be quite painful and expensive. . . .

36. So, who is on the IRB anyway? • Representatives from various professional disciplines • Someone from the clergy • A consumer representative • Potentially someone to protect vulnerable parties

37. Elements of Informed consent: In Lay Language • Description of the study • Description of inclusion and exclusion criteria • Number of subjects • Anticipated risks • Anticipated benefits • Information about the study sponsor • Rights as a research subject • Who to contact • Financial information

38. Practical Issues with regards to Human Subjects Protection • You must indicate to the IRB how you will recruit and advertise for study subjects • Copies of Advertisements must be provided • It is fair game to approach your own patients verbally • It is often useful to come up with a consent to provide patients to be included on future mailing lists for involvement in clinical trials • When you do send out mailings it is the norm to provide a number where people call for information about the study

39. Practical Experiences from A Sex Researcher • Realize that many personalities exist on IRB’s • Realize that when you are younger, many senior people feel as if it is their perogative to direct you • Realize that the rules constantly change • Make sure you cross your ts and dot your is

41. HIPPA • Generally with most IRB applications you must also complete a HIPPA checklist and appropriate documentation • Potential data identifiers are lengthy

42. Practice makes perfect • An exercise to understand what you need to put in a consent form. . . .