Federal regulators shut down Johns Hopkins University's human medical-research program last week following the June death of a healthy woman in an asthma study. What regulations govern federally funded medical research involving human subjects, and what did Johns Hopkins do wrong?
Sixteen federal departments and agencies, ranging from the National Science Foundation and the Department of Health and Human Services to the Department of Defense and the Central Intelligence Agency, adopted a common federal policy in 1991 for the protection of human research subjects. (The Food and Drug Administration has its own policy.) A human subject is defined as any "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." Even mundane research conducted with paper-and-pencil questionnaires qualifies as human experimentation. (Though some research involving surveys or interviews is exempt from federal regulations.)
The regulations authorize Institutional Review Boards, local review panels at research institutions, with overseeing human research. IRBs can approve, modify, or reject all research within their jurisdiction. Some institutions, including Johns Hopkins, have more than one IRB. Many IRBs also review research exempt from federal regulations.
IRBs draw their members from such professions as the clergy, the law, education, and home-keeping, in addition to the sciences. One member's primary concern must be scientific, and one member's primary concern must be nonscientific, to ensure that the IRB is competent to review both science and ethics. The members must be free of any conflicts of interest regarding the research when they vote. Strict documentation is also required, including the recording of IRB minutes. IRB records must be retained for at least three years. As one guide to the requirements puts it, "If it isn't documented, it didn't happen."
Institutions that conduct human research must provide a written Assurance that they will meet federal standards. Johns Hopkins' agreement was called a Multiple Project Assurance, or MPA, which is approved for five-year periods for institutions that generally have several federally funded research projects going on at the same time.
The Assurance must contain a statement of principles. In the United States, most Assurances cite the Belmont Report, a 1978 study by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The report sets forth three basic ethical principles governing medical research on human subjects: respect for persons, beneficence, and justice. Respect for persons requires informed consent, beneficence requires the minimization of risks and a risk/benefit analysis, and justice requires the fair and equitable selection of subjects, in order to prevent the burden of research from falling on the poor or the disadvantaged, as it did in the Tuskegee syphilis study. The Belmont Report also states that brutal or inhumane treatment is never morally justified, that research must be conducted by qualified investigators using appropriate designs, and that subjects must be free to withdraw at any time.
Children who cannot consent legally must still provide assent to participate, and their parents or guardians must grant permission. The need for informed consent is why some researchers prefer the term "participants" to "subjects." Because of informed consent requirements, there are specific regulations for research involving prisoners, children, and fetuses and pregnant women.
Where did Johns Hopkins fail? According to the federal Office for Human Research Protections, Hopkins IRBs "failed to ensure that risks to subjects were minimized and reasonable" (by not examining published research about the dangers of the asthma drug) and failed to review research at officially convened meetings. OHRP also found that Hopkins researchers made changes to their research designs without IRB approval, and that they failed to obtain informed consent (by not adequately describing research procedures to subjects and not adequately describing foreseeable risks and discomforts).
This week, OHRP authorized Hopkins to continue "minimal risk" research, defined as research in which the probability of harm is no greater than that encountered in day-to-day life. All other research projects involving human subjects must provide documentation that they were reviewed according to the correct procedures. If they weren't, each project will have to be re-reviewed one at a time.