An Introduction to Human Subjects Research Office of Research Policies, Compliance, and Committees (ORPCC) Updated March 2011

HISTORICAL EVENTS: Nuremberg Code In 1947, the Nuremberg Tribunal condemned experiments that 23 German physicians and administrators were performing on concentration camp prisoners. They were convicted for the torture, mutilation and killing. The physicians argued that the experiments were “medically justified”. In the verdict, the judges included a section called “Permissible Medical Experiments.” This became known as the Nuremberg Code and formed the basis for international ethic codes. 2

HISTORICAL EVENTS: Tuskegee The most notorious example in the U.S. of prolonged and knowing violations to a vulnerable group of research participants was the long-term study of black males conducted in Tuskegee, AL, by the Public Health Service. More than 400 uneducated, poor black men were enrolled to follow the natural course of syphilis. The men were enrolled without informed consent and were deliberately misled about their disease and the medical treatment they received. By the 1940’s, penicillin was a common, effective treatment for syphilis. Instead of closing the study or adjusting the study to research penicillin on its effectiveness to treat syphilis, the researchers withheld penicillin as treatment. This led to the appointment of an advisory board to advise on how to ensure the experiments of this kind would not be conducted. 3

HISTORICAL EVENTS: Willowbrook School The vulnerability of children – especially institutionalized children – as research participants was demonstrated in a series of experiments conducted from 1963 to 1966 in the Willowbrook School. Willowbrook was a New York institution for “mentally defective” children. In order to understand the natural history of infectious hepatitis under controlled conditions, Willowbrook children were deliberately infected with the hepatitis virus. The children were coerced into the experiment by the school, which told parents of new patients that the only way to admit their child was to agree to their child’s participation in the study. 4

HISTORICAL EVENTS: The Belmont Report 1974: “Ethical Principles and Guidelines for the Protection of Human Subjects of Research”, also known as the Belmont Report, was published by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The commission was charged with determining the basic ethical principles to guide all investigators conducting human subjects research. 5

HISTORICAL EVENTS: The Belmont Report There were three basic principles established: RESPECT FOR PERSONS (autonomy) – acknowledges the dignity and freedom of every person. BENEFICENCE – requires the investigator to maximize the benefits and minimize the harms or risks. JUSTICE - requires equitable selection, recruitment and fair treatment of human research subjects. 6

Federal Regulations and Policy 45 CFR 46 – Basic DHHS Policy for Protection of Human Research Subjects (originally adopted May 1974, revised January 1981 and again June 1991) Also includes additional protections for vulnerable populations in Subparts B-D Federal Policy for the Protection of Human Subjects 7

HHS and FDA Regulations: Differences Basic requirements for IRBs and for Informed Consent are the same Differences center on differences in applicability HHS regulations based on federal funding of research FDA regulations based on use of FDA regulated products: drugs, devices or biologics 8

What is Research? RESEARCH is defined as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” 45 CFR (d) 9

What is a Human Subject? HUMAN SUBJECT means a living individual about whom investigator (whether professional or student) conducting research obtains: Data through intervention or interaction with the individual or Identifiable private information 45 CFR (f) 10

What does 45 CFR 46 say? Sets forth the IRB Membership requirements: at least 5 members with professional competence necessary to review research activities. must include one member whose primary concerns are in nonscientific areas and at least one member who is not affiliated with the institution. The IRB has the authority to approve, require modifications, or disapprove research. The IRB can only meet with a quorum present. The IRB must notify investigators of its decision in writing. 11

What does 45 CFR 46 say? In order to approve research, the IRB shall determine that all of the following have been satisfied: Risk to subjects is minimized Risk to subjects is reasonable in relation to anticipated benefits (if any) and the importance of the knowledge that may be expected 12

What is an Institutional Review Board (IRB)? UH’s IRB is called the Committee for the Protection of Human Subjects (CPHS). Reviews research applications and makes a determination based on the federal requirements. 13

What does 45 CFR 46 say? (continued) Required elements of informed consent Waiver of informed consent Documentation of informed consent 14

What does 45 CFR 46 say? (continued) SUBPART B – Additional Protections for Pregnant Women, Human Fetuses, and Neonates Involved in Research Provides definitions and guidance on conditions that must be met to include any of the populations in research. 15

What does 45 CFR 46 say? (continued) SUBPART C – Additional Protections for Biomedical and Behavioral Research Involving Prisoners as Subjects Additional safeguards are required – prisoners may be under constraints because of their incarceration which could affect their ability to make a truly voluntary and un-coerced decision. Requires additional membership on the IRB to serve as an advocate for the prisoners. Identifies the areas of permitted research involving prisoners. 16

What does 45 CFR 46 say? (continued) SUBPART D – Additional Protections for Children Involved as Subjects in Research Allows for research with children if the IRB finds that no greater than minimal risk to children is presented. Additional requirements for research that involves greater than minimal risk but presents a direct benefit to the child. Additional requirements for research that involves greater than minimal risk and no direct benefit but is likely to yield generalizable knowledge about the subject’s disorder or condition. 17

Federalwide Assurance The Office for Human Research Protections (OHRP) defines a human subject assurance as, “a legally binding written document that commits a public or private entity to compliance with applicable federal minimum standards for the protection of human subjects prior to engagement in department or agency conducted or supported research.” 18

Ethical Considerations: IRB Review The following addresses each of the criteria for IRB approval, as specified in 45 CFR 46: SPECIFIC AIMS & BACKGROUNDS – Are the purposes and aims clearly specified? Is there adequate justification for this protocol? SCIENTIFIC DESIGN – Is the research design adequately described? Are the objectives achievable as proposed? INCLUSION/EXCLUSION CRITERIA – Are the criteria clearly specified and are they appropriate to the protocol? Is the choice of subjects appropriate for the question asked? Is subject selection equitable? RECRUITMENT – Are the methods for recruitment well defined? Are all recruiting materials included and appropriate? Are the location and timing of recruitment acceptable? 19

Ethical Considerations: IRB Review (continued) PROCEDURES – Are the research procedures adequately described? Are there plans to inform subjects about research results if appropriate? DATA AND STATISTICAL ANALYSIS – Is the rationale for the proposed number of subjects reasonable? Are there adequate provisions for monitoring data? POTENTIAL RISKS, DISCOMFORTS & BENEFITS – Are risks and benefits adequately identified, evaluated, and described? Are the risks/benefit ratio acceptable? Have sample questions been provided? COMPENSATION & COSTS – Is the amount of compensation or remuneration reasonable? If children or adolescents are involved, who receives the compensation? 20

Ethical Considerations: IRB Review (continued) PRIVACY & CONFIDENTIALITY – What are the provisions for protecting the privacy and confidentiality of the subjects? Are they reasonable? What are the plans for storage of data? Are identifiers to be included? INFORMED CONSENT/ASSENT – Are all required elements included in the consent form? Are all institutional requirements included? Is the process for obtaining consent well defined? Have the issues of subject comprehension been adequately considered and addressed? If minor subjects are included, are the children capable of providing assent? Is the method for obtaining assent appropriate? Assent: For potential participants who cannot give consent, investigators must obtain permission from a legally authorized representative of the potential participant. For children, this is usually the parent. For adults, it may be someone designated as health care proxy. 21

Ethical Considerations: IRB Review (continued) WAIVER/MODIFICATION OF INFORMED CONSENT – Is the investigator proposing a waiver or modification of informed consent? Does the request meet the federal regulations? OTHER ISSUES – When should the next continuing review occur? 22

Confidential v. Anonymous When the Principal Investigator (PI) is filling out the application and the informed consent document, he/she must select either confidential or anonymous. Confidential information is not the same as anonymous information. Anonymous means no identifiers are tied to any research subject and the identity of the subject can never be traced back. Confidential means you will protect identifiers tied to research subjects. 23

Informed Consent A process – not a single event or a piece of paper. Informed consent is an educational process that takes place between the investigator and the prospective subject. Informed consent must be presented in a manner that allows a subject to voluntarily agree to participate. 24

Informed Consent (continued) Documentation of consent must be in a language easily understood by all potential subjects. It is generally recommended that consent forms be written to a 6th grade reading level. The written document must include all elements established in the regulations as well as any institutional elements. The consent document should be revised when deficiencies are noted or when additional information will improve the consent process. 25

Tips on Informed Consent Use layman’s language. Describe the overall experience that will be encountered. Describe the benefits that subjects can reasonably expect to encounter. Describe any alternatives to participation. 26

Tips on Informed Consent (continued) Confidentiality. The regulations insist that subjects be told the extent to which their personally identifiable information will be held in confidence. The IRB will determine the adequate requirements for confidentiality. If research-related injury is possible in research that is greater than minimal risk, an explanation must be given of whatever voluntary compensation and treatment will be provided. Note that the regulations do not limit injury to “physical” injury. The regulations prohibit waiving or appearing to waive any legal rights of subjects. 27

Tips on Informed Consent (continued) The regulations provide for identification of contact persons who would be knowledgeable to answer questions of subjects about the research, rights as research subjects, and research- related injuries. It is important not to overlook the need to point out that no penalty or loss of benefits will occur as a result of both not participating or withdrawing at any time. 28

Waiver of Informed Consent The research involves no more than minimal risk to the subjects. The waiver will not adversely affect the rights and welfare of the subjects. The research could not practicably be carried out without the waiver. Whenever appropriate, the subjects will be provided with additional pertinent information after participation. CPHS requires you submit Appendix B “Waiver of Informed Consent” found on the Division of Research website. 29

Waiver of Documentation of Informed Consent The only record linking the subject and the research would be the consent form document and the principal risk would be potential harm resulting from a breach of confidentiality. The research presents no more than minimal risk of harm to subjects and involves no procedures for with written consent is required. 30

Human Subject Research Training Requirements All investigators submitting a grant application to the National Institutes of Health are required to show evidence of human subject’s education if the project includes the use of humans. All other investigators submitting a CPHS application are advised to complete the training program. The course recommended by CPHS is the web-based Course in the Protection of Human Research Subjects through the Collaborative IRB Training Initiative (CITI). The CPHS will also accept NIH Human Subject Research certificates. 31

Tips for Interactions with the IRB CPHS must review all research activities covered by the HHS regulations, including proposed changes in previously approved human subjects research, and have the authority to approve, require modifications to secure approval, or disapprove any research activity. CPHS must conduct continuing review of approved research at intervals appropriate to the degree of risk, but not less than once per year. *Exempt reviews are good for 5 years. CPHS has the authority to suspend or terminate approved research that is not being conducted in accordance with the committee’s requirements, or that has been associated with unexpected serious harm to subjects. 32

Any suspension or termination of approval must include a statement of the reason for CPHS action and must be reported promptly to the investigator, appropriate institutional officials, and HHS. Research approved by CPHS may be subject to further review and approval or disapproval by institutional officials. However, institutional officials may not approve the conduct of human subjects research covered by HHS regulations that has not been approved by CPHS. Human subject research conducted by UH faculty and students must be reviewed in a CPHS Full Committee, Expedited Committee or under Exempt Status. UH faculty and students may not begin human subject research before getting approval from the CPHS. 33 Tips for Interactions with the IRB

Investigators have the primary responsibility of protecting the rights and welfare of human research subjects and complying with all rules set by CPHS. Investigators must pay close attention to deadlines outlined by CPHS for review of applications. The deadline dates can be found on the Division of Research website. Investigators should submit research applications at least 2 months before anticipated start of the research. This will allow for due processing and review by the CPHS. If you plan on conducting human subject research at UH, please talk with your faculty sponsor prior to designing a research project. 34

The first item the PI will complete is the CPHS application. The application is in electronic form on the Division of Research website under Human Subjects. PI application must be typed and submitted in paper format to the CPHS office located at 316 E Cullen Building. The application must be filled out completely and signed by the faculty sponsor and the Chair/Dean of the Department. The second item the PI must complete and submit along with the application is the Informed Consent document. The Division of Research website has a template to follow. The PI may also request a Waiver of Consent or Waiver of Documentation of Consent if applicable. The third item is to submit all documents that will be used when conducting the research. This includes subject questionnaires, interview questions, educational documents backing up the research, recruiting scripts, recruiting flyers, etc. 35 Tips for Interactions with the IRB