Module 2

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Module 2: Introduction to Human Subjects Research

Institutional Training for Research Involving Human Subjects

KWU is committed to assuring that all of its research activities involving human subjects are conducted in a way that promotes their rights and welfare. In accordance with sound ethical principles and federal legal requirements, KWU has policies and procedures to help you fulfill your responsibilities when you conduct or collaborate in research involving human subjects at KWU or elsewhere. KWU designed its policies based on well-established ethical principles for conducting research with humans, as well as in compliance with the Federal Regulations for the Protection of Human Subjects, Title 45 Part 46 of the Code of Federal regulations (45 CFR 46).

Sometimes it isn’t easy to see how the policies apply to particular cases, for instance when research deals only with surveys, students or with volunteers. This course is designed to help you identify those research activities that involve human subjects, and to help you understand how to protect the rights and welfare of all human subjects involved in your research activities.

Hypothetical Research Collaboration Project

Let’s begin with a hypothetical collaborative research project involving receipt and analysis of human blood samples in your laboratory. Dr. Bronson is an oncologist in an economically-poor, third world country, and has been conducting a trial to develop a vaccine against stomach cancer, a condition highly prevalent in his country. Before he began his study, Dr. Bronson called you and asked if you would collaborate with him by performing some research analysis of blood samples to be drawn from subjects in the proposed vaccine trial, and to help with the subsequent data evaluation. He also suggested that you be identified as a co-author on any relevant publications. You have had professional association with Dr. Bronson, have co-authored several papers with him, and have confidence in his abilities. You judged that your role in the project was peripheral since you would personally have no contact with human subjects. You agreed to help, and have been receiving and analyzing blood samples monthly for over a year. During a recent interview, Dr. Bronson said that without the valuable collaboration of his colleague at KWU, the vaccine trial would not have been possible.

You are surprised to learn during the interview that a clinical trial with the same vaccine had been planned in the U.S., but was not conducted because of unresolvable concern over scientific validity and ethical permissibility. A month later, a journalist’s interest is aroused when she learns that 4 of 10 persons in Dr. Bronson’s vaccine trial died, allegedly from adverse reactions to the vaccine. When Dr. Bronson notifies you that 4 subjects died, you become concerned, and begin to question whether you have followed KWU’s procedures and policies related to collaborations. You become more concerned when the journalist calls you to request information on the vaccine trial related deaths, and inquires about your role in the study. The journalist asks you for a copy of the research protocol and for the Institutional Review Board (IRB) minutes for the meeting that approved the research proposal.

You feel that very distinct tightening in the pit of your stomach. You know that the KWU IRB is responsible for reviewing and approving research with human subjects, but you did not think that KWU IRB approval of the this study was necessary because you were only analyzing blood samples, and would have no direct contact with the human subjects involved in the research. The collaborative research that you performed on this hypothetical case -- samples drawn specifically for research, and analysis of research data -- are considered research with human subjects.

Therefore, before starting this research collaboration, you should have adhered to the relevant policies and procedures of the Human Subjects Committee, which requires review and approval by the KWU IRB.

A true example of a problem with human subjects research that happened here in Kansas

A faculty member and his graduate student decided to perform a survey of middle school aged children in areas of western Kansas. Part of the survey involved questions about specific sexual practices, preferences, and attitudes of the children surveyed. Several parents of children surveyed took exception to the survey that their children were asked to fill out at school, and were angry enough to call the Governor’s Office to complain. Predictably, the Governor called the President of the University and pointedly asked, “What’s going on down there?” The administration discovered that the graduate student had not submitted his project for IRB approval, and the University was acutely embarrassed.

This was a serious problem caused by a relatively simple project. The episode could have been prevented if the graduate student and his advisor had reviewed and understood their IRB policies, and complied with the applicable requirements for conducting research involving human subjects.

A Review

In order to better understand the reasons for your responsibilities when performing research using human subjects, let’s review a brief history of the ethical guidelines and the Federal regulations

In 1946, 23 Nazi physicians went on trial because of research atrocities performed on prisoners of war. Subsequently, the Nazi War Crimes Tribunal issued the Nuremberg Code, which was the first internationally recognized code of research ethics.

The formal codification of the ethical guidelines for the conduct of research involving humans began in the late 1940’s. While the Nuremberg Code and subsequent ethical guidelines represented the most enlightened thinking of the time, many well-intentioned researchers did not know about them or did not apply this guidance to their research activities. A series of abuses of research subjects came to public attention in the U.S. between 1953 and 1972, including the infamous

Tuskegee Study on the natural history of syphilis conducted by Public Health Service Employees. These studies have led some to conclude that researchers could not be trusted to perform research on humans without oversight. In the 50’s and 60’s, when Federal funding for biomedical research increased dramatically, ethical safeguards and legal requirements were imposed on research activities involving human subjects.

The U.S. government, in dialogue with the research community, gradually designed one of the most comprehensive systems in the world for the protection of human research subjects. Laws, regulations, and public opinion challenged the research community to make the system accountable and operable. By congressional mandate, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established in 1974 to make recommendations for the conduct of research involving humans. Oversight of the system was assigned to the Secretary of the Department of Health and Human Services, (DHHS). DHHS set as a goal: “High quality research accompanied by high standards of research ethics.” The primary task of the Commission was to identify the ethical principles that would guide all research involving humans. The Belmont Report -- Ethical Guidelines for the Protection of Human Subjects was published in 1979.The principles of the Belmont Report govern all research supported by the U.S. government.

There are three guiding principles that are the cornerstones of the Belmont Report: Respect for Persons, Beneficence, and Justice. The Respect for Persons principle acknowledges the dignity and freedom of every person. It requires obtaining informed consent of all potential research subjects (or their legally authorized representative). The principle of Beneficence requires that researchers maximize benefits and minimize harm associated with research. Research-related risks must be reasonable in light of expected benefits. The principle of Justice requires equitable selection and recruitment, and fair treatment of research subjects.

In the early 1980’s, revised regulations for the conduct of research involving humans were published, entitled Title 45 Code of Federal Regulations Part 46, Protection of Human Subjects (45 CFR 46). The Ethical principles of the Belmont Report are embodied in these regulations. Taken together, The Belmont Report and 45 CFR 46 articulate the minimal ethical and legal obligations of those who perform or support research involving human subjects.

Among other things, these regulations require that each institution conducting federally funded research adheres to the principles of the Belmont Report, and sets forth in writing ethical policies, procedures, and guidelines for protecting the rights and welfare of human subjects research. At KWU, this written assurance is done on a project-by-project basis, known as a Single Project Assurance (SPA). A sample SPA can be found online at

http://ohrp.osophs.dhhs.gov/humansubjects/assurance/spa.htm

The SPA places responsibility for protecting the rights of human subjects directly on you, the research investigator, and on KWU as an institution.

KWU feels it is important to comply with the federal guidelines regardless of whether your research is federally funded or not, as a protection for you and for the University. The KWU policies have been designed to help you do that. If you don’t understand the requirements of the KWU policy, ask the Dean or the Chair of the IRB for assistance. Not knowing or not understanding the proper procedures is not an acceptable reason for non-compliance with applicable requirements. Failure to comply with the policies may constitute unethical behavior and a violation of the law, and it can lead to loss of research privileges for an individual, a laboratory, or for an entire research program.

Federal regulations and the KWU Human Subjects Committee policies apply to all research involving human subjects. By federal definition, research means a systematic investigation designed to produce generalizable knowledge. Research may involve direct interactions or interventions with subjects, such as obtaining data by taking medical histories, obtaining blood samples, diagnostic procedures, or performing surveys, at least in part for the purpose of gaining generalizable information. Research may also involve indirect activities, such as the analysis of specimens or data from people. Participation in these indirect activities, especially if you plan to publish (or co-author) the results, constitutes human subjects research. Federal policies define a human subject as a living individual about whom an investigator obtains either: data through interaction or intervention with the individual, or identifiable private information.

Research investigators have the fundamental responsibility to safeguard the rights and welfare of those participating in their research activities. In addition, our society has decided by law that that an objective review of human subjects research by a group of diverse individuals is most likely to protect human subjects and promote sound and ethical research. Therefore, when conducting research involving humans, Federal regulations and the KWU policies require prospective and continuing review and approval of the research by a committee called the Institutional Review Board (IRB).

The Committee on Research Involving Human Subjects (IRB) is fundamental to the conduct of human subjects research at KWU, and at other research institutions both inside and outside the U.S.

One reason IRBs are necessary is because research investigators have an inherent conflict of interest. They should be dedicated to promoting the welfare of individuals, but as researchers, they seek to generalize knowledge applicable to persons or groups other than the individuals in their studies. The second goal may be in conflict with the first.

IRBs, on the other hand, have one paramount responsibility: To protect the rights and welfare of human subjects. IRBs take into account national, and when appropriate, international ethical standards of research on a protocol-by-protocol basis. Protecting human research subjects is their primary responsibility. Protection of the rights and welfare of research subjects is a high priority worldwide. It is reflected in the Nuremberg Code, the United Nations Charter of Human Rights, the Declarations of Helsinki, the guidelines of the World Health Organization, and the ethical codes of many professional societies. The KWU IRB infrequently disapproves proposed research activities. Instead, they strive to work interactively with research investigators to assure that research design is excellent, that risks are minimized and expected benefits are maximized, and that consequent procedures are adequate. IRB members bring diverse skills, insights, and perspectives to the responsibility of reviewing research activities involving humans. Although the IRB system is not perfect, conscientious IRBs reassure the American public that the rights and welfare of human subjects are seriously considered by people who do not have a vested interest in the outcome of research. By exercising their responsibility, IRBs promote the protection of human subjects. IRB approval provides a significant affirmation of the scientific and ethical quality of the research, and therefore offers important validation to the research investigator and the institution. Keep in mind that the application of ethical principles, the Federal regulations (45 CFR 46), and KWU’s policies are intended to balance society’s interest in advancing scientific knowledge with its mandate to protect the rights and welfare of human subjects. IRB review of proposed research helps achieve this balance. Experience has shown that sound ethics and good science are compatible. The system, though not perfect, has worked well in the U.S. for over 30 years.