Protection of Human Subjects in Research

1. Protection of Human Subjects in Research Part I: History and Ethical Principles Nancy r. King Director UH Committee on Human Studies March 20, 2012

2. About this Presentation • This presentation is intended to provide an introduction to the field of human subjects protection for UH students and faculty. • Part I covers the history behind the current regulations and the ethical principles on which they are based. It also summarizes institutional and investigator obligations to apply these principles and laws. • Part II covers the basics of human subjects research and informed consent.

3. Early Human Subjects Research • Early experiments were vaccine trials conducted in the 1700s. For example, • Physician Edward Jenner tested smallpox vaccines on his son and other children in his neighborhood. • Johann Jorg tested drugs on himself. He took 17 drugs in various doses and recorded his experiences.

4. 20th Century Developments • Signaling the launch of the era of modern medical research, Walter Reed performed experiments to develop a vaccine for yellow fever with the informed consent of the study subjects. • The experiments performed in the Nazi concentration camps brought the world’s attention to atrocities committed on prisoners of war in the name of research. • After WWII, 23 Nazi regime physicians and scientists were tried by the Nazi War Crimes Tribunal for the murder of concentration camp inmates who had been used as research subjects.

5. The Nuremberg Code • In 1947, the Nazi War Crimes Tribunal issued the Nuremberg Code, which was the first internationally-recognized code of research ethics. • It contained 10 points describing required elements for conducting research involving human research subjects, including: • Informed Consent is essential • Research on humans should be based on prior animal studies • Research risks should be justified by anticipated benefits • Only qualified scientists can conduct research • Physical and mental suffering must be avoided • Research in which death or disability is expected should not be performed • The Nuremberg Code had limited impact because it was not codified into law and only applied to non-therapeutic research; however, it set the stage for future developments in research ethics.

6. Declaration of Helsinki • In 1964, the Nuremberg code was reinterpreted by the World Medical Association, focusing on medical research with therapeutic intent. • This new code of research ethics was known as the Declaration of Helsinki. • It made informed consent a central requirement for ethical research, and allowed for surrogate consent for research subjects who were determined to be incapable of consenting on their own behalf. • It established other rules to protect the rights of vulnerable populations (children, prisoners and others). • This was a foundational document that led the way to current regulations that govern human subjects research and IRBs.

7. The Beecher Article • In 1966, the NEJM published an article written by Dr. Henry Beecher titled, “Ethics and Clinical Research.” • This article documented 22 studies with controversial ethics that had been conducted by reputable researchers and published in major journals. • This article played an important role in challenging the conventional wisdom that unethical research could only be performed by “evil” people like the Nazis.

8. Unethical Research: An Example • The Willowbrook Studies (1963 – 1966) • Performed at the Willowbrook School, a NY state institution for “mentally defective persons.” • Studies were designed to gain an understanding of the natural history of infectious hepatitis and, later, the effects of gamma globulin to prevent and treat the disease. • In order to perform the study, subjects (all children) were deliberately infected with the hepatitis virus. • Researchers justified the study by saying that it was likely that the children would get hepatitis anyway if they stayed at the school.

9. Unethical Research (continued) • The Jewish Chronic Disease Hospital Study • In 1963, studies were undertaken at New York City’s Jewish Chronic Disease Hospital to develop information on the human transplant rejection process. • These studies involved the injection of live cancer cells into hospitalized patients. • Oral consent was obtained, but subjects were not informed that they would be injected with live cancer cells.

10. Unethical Research (continued) • Milgram Study (Yale University, 1961) • To study the extent to which people would perform acts that violated their personal conscience when under orders to do so by an authority figure, researchers told volunteers to punish student errors by administering increasing levels of electric shock. (The students were confederates of the researcher and faked the pain.) 63% of volunteers administered what they believed could be lethal shocks to the students. • San Antonio Contraception Study (1971) • Mexican-American women participated in a study to evaluate the side effects of an oral contraceptive. Without their knowledge or consent, half of the women were given a placebo. Ten of the 76 subjects became pregnant while taking the placebo.

11. The Tuskegee Syphilis Experiment • In a study of syphilis in African American men conducted between 1932 and 1972 and funded by the US Public Health Service, 600 black men (with and without syphilis) were enrolled. Most were illiterate sharecroppers. • Study subjects were deceived about the purpose of the study (they were told it was a study of “bad blood”) and were not informed of certain study procedures (including a spinal tap and autopsy). • Subject compensation included free medical exams, free meals during study visits, and burial insurance.

12. Tuskegee (continued) • After penicillin was found to be a safe and effective treatment for syphilis (1940s), study subjects were deliberately denied treatment so researchers could continue to study the natural history of the disease. • By the end of the study, 128 men had died of syphilis or related complications, 40 of their wives had been infected, and 19 of their children were born with congenital syphilis. • In 1972, based on information from a whistleblower, an article was published in the Washington Star exposing the treatment of the study subjects. In response to the public outcry, the PHS finally ended the study. • Some children of the study subjects are still receiving compensation from the U.S. Government as part of a settlement that resulted from a class action law suit.

13. Ethical Problems • Ethical problems with the Tuskegee and other studies included: • Lack of informed consent • Use of coercion or undue influence on vulnerable populations • Withholding information from study subjects about procedures, alternatives, risks, etc. • Placing the goals of the research above the safety and wellbeing of the study subjects • Withholding available treatment • Deceiving study subjects to gain their participation • Violating study subjects’ human rights

14. Tuskegee’s Aftermath • Following public exposure of the Tuskegee syphilis study, Congress formed a panel that recommended the development of federal regulations to protect human research subjects. • Eventually, the National Research Act, comprehensive regulations covering federally-funded research and FDA-regulated research were enacted into law. • These laws were written to prevent the kinds of unethical treatment of subjects previously described. • They continue to provide the foundation for the protection of human subjects research.

15. The Belmont Report • In 1974, Congress authorized the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. • This Commission was asked to identify the basic ethical principles that underlie the conduct of human research. • The Commission was also asked to develop guidelines for implementation of the ethical principles. • 5 years later, the Commission released the Belmont Report.

16. The Belmont Report • The Belmont Report identified 3 basic ethical principles that must apply to all human subjects research. They are: • Respect for Persons • Beneficence • Justice

17. Respect for Persons • The principle of respect for persons requires researchers to treat individuals as autonomous human beings and not as a means to an end. • It requires researchers to provide extra protection to people with limited autonomy (vulnerable populations). • Also, research must involve voluntary and ongoing informed consent, and research subjects must have the right to withdraw from the study at any time with no negative consequences.

18. Beneficence • The principle of beneficence requires researchers to minimize the harms and maximize the benefits to study subjects. • Research must have social and scientific value, and it must have a favorable risk-benefit ratio. • Research without a favorable risk-benefit ratio must not be conducted.

19. Justice • The principle of justice requires researchers to treat people fairly and to equitably distribute the burdens and benefits of participation in a study. • This principle requires that researchers select study subjects fairly. • This principle affects primarily inclusion and exclusion criteria for the study as well as the recruitment methods.

20. Balancing the Belmont Principles • The National Commission intended for each of the three ethical principles to have equal moral force. • Sometimes, these principles conflict with one another (e.g., involvement of children in research in which “respect for persons” may conflict with “justice”). • Researchers are required to consider each principle separately and in light of all three principles.

21. Vulnerable Populations • In some cases, federal regulations establish a population as “vulnerable:” • Children and minors (in Hawaii, a minor is under age 18) • Prisoners • Pregnant women, fetuses & neonates • The IRB can determine that other populations are vulnerable: • People with cognitive impairments • People with physical or mental disabilities • People in institutions other than prisons (e.g., skilled nursing facilities) • People with life-threatening illnesses • People who are economically and educationally disadvantaged • People with psychiatric illnesses and substance abuse problems • Students (when researchers are in a position of authority over them) • Any population that is vulnerable to coercion or undue influence

22. Federal Regulations (DHHS) • Title 45, Code of Federal Regulations, Part 46 Protection of Human Subjects (written in 1981) and known as the Common Rule is written in 4 parts: • A. Policy for the Protection of Human Subjects, addresses requirements: • For assuring compliance by research institutions, • For researchers to obtain and document informed consent, and • For IRB composition, function, operations, research review & record-keeping • B. Additional Protections for Pregnant Women, Human Fetuses, and Neonates Involved in Research • C. Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects • D. Additional Protections for Children Involved as Subjects in Research

23. Federal Regulations (FDA) • FDA research regulations (21 CFR 50 & 56), also written in 1981, applies to research conducted under an IND or IDE or whenever research data is intended to be used in an FDA marketing application. • Based on the Guideline for Good Clinical Practice (GCP), an international quality standard pertaining to clinical trials involving human subjects. • Addresses responsibilities of investigators, sponsors and IRBs. • Over the years, DHHS and FDA regulations have been harmonized to eliminate most discrepancies in requirements.

24. Institutional Responsibilities • Enter into and maintain a Federalwide Assurance (FWA) with DHHS (OHRP). • Appoint a FWA Institutional Official who bears overall responsibility for compliance with federal regulations. • Register (with OHRP) and maintain or designate an Institutional Review Board (IRB) to review human subjects research. • Develop written policies and procedures that comply with applicable regulations. • Ensure that IRB staff, members and others have the necessary training and support to perform their responsibilities.

25. More Institutional Responsibilities • Ensure that non-exempt human subjects research is performed with prior approval of a federally-approved IRB. • Ensure that the IRB continues to monitor the progress of approved research until the study is complete. • Continuing Review • Review and approval of study modifications • Review of unanticipated problems • Review of protocol violations • Review of DSMB reports, etc. • Ensure that the IRB reports serious or continuing non-compliance and unanticipated problems involving risk to subjects or others to institutional leadership and the OHRP (and possibly the FDA).

26. Authority of the IRB • Under federal regulation and the institution’s agreement with the federal government, the IRB has the authority to: • Approve or disapprove proposed research; • Require modifications in proposed research as a condition of approval; • Require modifications to ongoing research and/or to research documents based on considerations of participant protection; • Suspend or terminate ongoing research as necessary to protect current or potential participants; • Requirethat specific information be provided to participants to fully inform them of study procedures, risks, and benefits that may affect their willingness to participate in the research; • Require, waive, or alter informed consent (or documentation thereof) consistent with federal regulation; and • Monitor any part of the research process.

27. IRB Approval Criteria • IRBs may not approve (non-exempt) human subjects research unless all of the following criteria are met: • Risks to subjects are minimized; • Risks to subjects are reasonable in relation to anticipated benefits, if any, and to the importance of the knowledge that may reasonably be expected to result; • Selection of subjects is equitable; • Informed consent will be sought from each prospective subject or his/her legally authorized representative; • Informed consent will be properly documented (usually with a signature on the consent form);

28. IRB Approval Criteria, continued • When appropriate, there are adequate provisions for monitoring the data to ensure the safety of subjects; • When appropriate, there are adequate provisions to protect the privacy of subjects to maintain the confidentiality of data; and • When some or all of the subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included to protect their rights and welfare. • These criteria apply to research reviewed by a convened IRB or under an expedited review procedure.

29. Research Problems in the Post-IRB Era • Death of a Normal Volunteer (1996) • A 19-year-old student volunteered to participate in as study performed by the University of Rochester in which they would undergo bronchoscopy to harvest macrophages. The bronchoscopy was difficult for this subject and required multiple doses of topical lidocaine. The subject agreed to these treatments and indicated her desire to continue in the study. A few days later, she returned to the hospital in cardiac arrest that was determined to be caused by an overdose of lidocaine and she died. An investigation into this death revealed that the doses were not documented, that the subject was not observed after the bronchoscopy, and that the concentrations of lidocaine were increased without IRB approval.

30. Another Post IRB-Era Research Problem • Death in a Gene Therapy Research Project (1999) • An 18-year-old man with a rare metabolic disorder (under control with diet and medication) volunteered to participate in a study being performed by the University of Pennsylvania, testing an experimental gene transfer technique. • Following the procedure, the subject experienced multiple organ failure and died. An investigation revealed serious concerns about the informed consent process, researcher conflicts of interest, and inadequate safety monitoring. • This case has had a significant impact on current thinking on research ethics and the protection of human research subjects.

31. Applying Ethical Principles: Researcher Responsibilities • Researchers must assure that: • The study is properly designed, scientifically sound and will potentially yield valid results; • Participants meet selection and eligibility requirements; • The study is approved by the IRB and is conducted according to the approved protocol; • Protocol changes are approved by the IRB prior to their implementation and unanticipated problems are reported to the IRB; • The rights and welfare of study subjects are continually monitored; • The research team is qualified and trained in the protection of human research subjects; and • Complete and accurate records of the research study are maintained.

32. Applying Ethical Principles: Researcher Responsibilities • Researchers must manage their authority relationships with their staff and colleagues by: • Encouraging questions and managing dissent. • Not allowing intimidation by self or others in authority positions. • Proactively building and supporting an effective team environment. • Researchers must manage their relationships with study subjects by: • Placing subject safety, welfare and rights above personal and scientific concerns, including the success of the study. • Insisting that subjects understand the study and their rights prior to enrolling them in a study. • Avoiding conflicts of interest and the appearance of such conflicts (e.g., managing the dual role of treating physician and investigator).

33. Researcher Responsibilities: Key Messages • Researchers must seek approval of the appropriate IRB prior to initiation of their research, including any contact with potential study subjects or private identifiable information to be used for research purposes. • Human subjects research cannot begin without documented IRB approval. • Researchers must understand and comply with IRB policies and procedures, and with conditions imposed on individual research projects by the IRB, which will be documented in written correspondence from the IRB to the PI. • Researchers must maintain effective communication with the IRB throughout the conduct of their studies.

34. Quotation “The extraordinary promise of science and technology carries with it extraordinary responsibilities. It is incumbent upon both scientists and public servants to ensure that science serves humanity always, and never the other way around.” Clinton, 279 Science 1111 (1998)

35. Protection of Human Subjects in Research Part II: What is Human Subjects Research & Informed Consent?

36. What is Research? • Is it Research? • Research is, “A systematic investigation, including research, development, testing, and evaluation designed to develop or contribute to generalizable knowledge.” (45 CFR 46) • Generalizable means that the findings developed from a sample population is intended to be used to describe a broader population. • Some people equate generalizable with “intent to publish.” This is often, but not always, an adequate test.

37. What is Human Subjects Research? • What is a human subject? • A human subject is a living individual about whom an investigator obtains: • Data through intervention or interaction with the individual, or • Identifiable private information • Therefore, human subjects research is a systematic investigation in which data is obtained through an intervention or interaction with a living human being, or identifiable private information about a living human is obtained for the purpose of developing or contributing to generalizable knowledge.

38. Examples of Human Subjects Research • Research that evaluates an experimental drug or device • Research that evaluates a behavioral intervention (e.g., smoking cessation) • Research involving surveys performed on paper or online • Research involving interviews or focus groups (sometimes) • Analyses of existing information in which individuals can be identified • Graduate-level theses and dissertations • Oral histories (sometimes) • Case studies (sometimes) • Studies that collect and/or analyze identifiable biological materials • Collection of data from voice, video, digital, or image recordings • Evaluations of programs, curricula, etc. (sometimes), etc. • If it’s Human Subjects Research, it must be approved by CHS or the IRB. • If it’s not Human Subjects Research, it does not require IRB approval.

39. Who Decides? • UH has established the Human Studies Program (previously the Committee on Human Studies or CHS) to ensure compliance with applicable regulations and University policies relating to the protection of human research subjects. • Staff are trained to help researchers make these determinations. • Staff are available at 956-5007 or through email (uhirb@hawaii.edu) to answer researchers questions about human subjects protection and how to work with the IRB. • Application forms and guidance documents are available online at www.hawaii.edu/irb

40. Types of Human Subjects Research • Exempt • Exempt research must be conducted applying the principles of the Belmont Report • Federal regulations do not necessarily apply (institutional discretion) • At UH, CHS must approve a study as exempt • Non-Exempt • All applicable regulations apply • Institutional policies may impose higher standards than required under regulation • Must be approved by a convened IRB or, if it qualifies, under an expedited review procedure

41. What Research is Exempt? • Categories of exempt research are defined by federal regulation. Categories include: • Research conducted in established or commonly-accepted educational settings, involving normal education practices. (Some exceptions apply.) • Research involving the uses of educational tests, survey or interview procedures, or observations of public behavior. (If this research involves children or minors, it is not exempt.) • Research involving collection or study of existing data, documents, records, or pathological or diagnostic specimens. (OHRP defines existing as not collected for the proposed study.) Study information is publicly available or recorded in such a manner that subjects cannot be identified, directly or indirectly through identifiers (codes) linked to the subjects.

42. Exempt Categories (continued) • Research studying, evaluating or examining public benefit or service programs. • Research involving taste and food quality evaluation or consumer acceptance studies. • All research involving prisoners is non-exempt. CHS has a special application for exempt research. Such research must not begin until the PI has received a letter from CHS, documenting approval of the proposed study as exempt.

43. Expedited Review • Expedited review is a process that is permitted under and defined by federal regulation. • Expedited review is performed by an experienced member of the IRB (or by a subcommittee) outside the convened IRB meeting. • Expedited review doesn’t always mean, “fast” or even “faster” than review by the convened IRB. • To qualify for review under an expedited procedure, research must be “minimal risk” and identification of subjects cannot put them at risk of criminal or civil liability or be socially or economically damaging.

44. What is Minimal Risk? • By regulation… Minimal risk means that the probability and magnitude of physical, psychological, social, or economic harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life (by the “average person” in the general population, not necessarily by the study population) or during the performance of routine physical or psychological examinations or tests.

45. Expedited Review Categories • To qualify for review under an expedited procedure, research must also involve procedures included in one or more of the following categories: • Certain studies of drugs and medical devices (no IND or IDE) • Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture (in certain populations) • Prospective collection of biological specimens for research purposes by noninvasive means. • Collection of data through noninvasive procedures routinely employed in clinical practice.

46. More Expedited Review Categories • Research involving materials (data, documents, records or specimens) that have been collected or will be collected for non-research purposes. • Collection of data from voice, video, digital, or image recordings made for research purposes. • Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.

47. More Expedited Review Categories • Continuing Review of research approved by the convened IRB as follows: • Where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or • Where no subjects have been enrolled and no additional risks have been identified; or • Where the remaining research activities are limited to data analysis; or • Where the IRB has determined at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified. • Minor modifications to IRB-approved research.

48. Review by the Convened IRB • All human subjects research that is non-exempt and does not qualify for expedited review must be approved by the convened IRB. • At UH, the IRBs meet monthly, generally during the third week of the month. • Deadlines for submission of applications for review by the convened IRB is the first working day of the month. • Unless CHS approves use of another (non-UH) IRB, human subjects research must be approved by a CHS IRB. • Once approved, all non-exempt research must be re-approved by the IRB, under a continuing review procedure, at least annually.

49. What is Informed Consent? • Informed consent: • Is a process of educating potential study subjects about the study subject, including the purpose of the research, procedures to be performed, anticipated risks and benefits of participation, alternatives to participation, etc. • Is based on internationally accepted ethical principles and governed by federal regulations and institutional policies. • Usually involves a signature on a consent form, by the subject or his/her legally authorized representative. • Begins with the recruitment of potential study subjects and continues until their participation in the study is complete.

50. Special Rules & Exceptions • Federal regulations (DHHS and FDA) include special rules that apply: • When research is being performed in emergency medical situations • When non-English speakers are being recruited to participate in a study • When documentation of informed consent can be waived • When use of a consent form can be waived • When children and minors under the age of consent, prisoners, and pregnant women are being recruited to participate in a study. • When informed consent can be waived. • All of these rules and exceptions must be approved by an IRB and only when specific criteria are met.