Conducting research is one of VA’s core missions. VA researchers have been involved in a variety of important advances in medical research, including development of the cardiac pacemaker, kidney transplant technology, prosthetic devices, and drug treatments for high blood pressure and schizophrenia. For fiscal year 2000, Congress appropriated $321 million for VA’s research programs, which support a wide range of human, animal, and basic science studies. VA uses a competitive funding process in which its Office of Research and Development (ORD) allocates about $296 million of these funds to VA researchers, with awards based on scientific merit and potential contribution to knowledge of issues of particular concern to VA. VA allocates most of the remainder to indirect costs of research, which includes support for the human subjects protection system. Besides the appropriation for research, VA allocates funds from its medical care appropriation to support the research infrastructure at medical centers such as laboratory facilities and investigator salaries. In fiscal year 2000, this allocation amounted to $343 million. VA researchers receive additional grants and contracts from other federal agencies such as the National Institutes of Health (NIH), research foundations, and private industry sponsors, including pharmaceutical companies. In fiscal year 1999, these additional funds amounted to approximately $481 million. Nonprofit research foundations linked to VA medical centers control some of these non-VA research funds.In fiscal year 2000, biomedical or behavioral research involving human subjects is being conducted at about 70 percent of VA medical centers. VA is responsible for ensuring that all human research it conducts or supports meets the requirements of VA regulations, regardless of whether that research is funded by VA, the subjects are veterans, or the studies are conducted on VA grounds. Responsibility for administration and oversight of the research program has rested primarily with ORD. Recently, VA created the Office of Research Compliance and Assurance (ORCA), which has been charged with advising the Under Secretary for Health on all matters affecting the integrity of research protections for humans and animals, promoting the ethical conduct of research, and investigating allegations of research improprieties. Some VA research is also subject to oversight by two HHS components. The Food and Drug Administration (FDA) is responsible for protecting the rights of human subjects enrolled in research with products it regulates— drugs, medical devices, biologics, foods, and cosmetics. Research that involves human subjects and is funded by HHS is subject to oversight by its Office for Human Research Protections (OHRP).HHS requires institutions conducting human research with HHS funds to file a document with OHRP that indicates a commitment to comply with federal regulations. This document, called an assurance, may cover a single study (a single project assurance), or it may allow the institution to conduct multiple studies (a multiple project assurance).When an institution files a multiple project assurance with OHRP, all federally funded research involving human subjects at that institution must comply with HHS regulations. Both FDA and OHRP have the authority to monitor those studies conducted under their jurisdiction, and each can take action against investigators, IRBs, or institutions that fail to comply with applicable regulations. Research with human subjects conducted at VA facilities is governed by regulations designed to protect their rights and welfare. These regulations establish minimum standards for the conduct and review of research to ensure that research involving human subjects is conducted in accordance with the three ethical principles outlined by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.First, the principle of respect for persons requires acknowledgement of individual autonomy, and conversely, the need to protect those with diminished autonomy. In practice, this principle requires that subjects give informed consent to participate in research; that is, they must be given sufficient information about a study including its purpose, procedures, to decide whether to participate. They must also understand this information, and their consent must be voluntary. Second, the principle of beneficence requires that the expected benefits of research to the individual or to society outweigh its anticipated risks. Third, the principle of justice requires fair subject selection procedures, so that both the benefits and the burdens of research are distributed across a number of individuals in a just manner. In 1981, in response to the National Commission, both HHS and FDA promulgated revised regulations for the protection of human subjects. Seventeen federal departments and agencies, including HHS and VA, have adopted the core of HHS regulations.FDA’s regulations are slightly different from those adopted by HHS and VA. To safeguard the rights of subjects and promote ethical research, these federal regulations create a system in which the responsibility for the protection of human subjects is assigned to three groups. Investigators are responsible for conducting their research in accordance with applicable federal regulations and for ensuring that legally effective consent is obtained from each subject or his or her legally authorized representative. Institutions are responsible for establishing oversight mechanisms for research including establishing local committees known as institutional review boards (IRB), which are responsible for reviewing research proposals before studies are initiated and after they are under way to help ensure that research is conducted in accordance with the three principles described above. Agencies, including VA, are responsible for ensuring that their IRBs comply with applicable federal regulations and that they have sufficient space and staff to accomplish their obligations. VA requires each of its medical centers that engages in research with human subjects to establish its own IRBor secure the services of an IRB at an affiliated university. As of August 2000, approximately 40 percent of the medical centers conducting research with human subjects relied on an IRB at an affiliated university. The IRB sends its recommendations to the VA medical center’s research and development committee, which is responsible for maintaining standards of scientific quality, laboratory safety, and the safety of human and animal subjects. The research and development committee is charged with reviewing each study’s budget; assessing the availability of needed space, personnel, equipment, and supplies; and determining the effect of the planned research on the investigator’s other responsibilities, including the provision of clinical services. The committee can disapprove a study; however, VA regulations prevent the research and development committee (or any other institutional official or body) from overturning an IRB decision to disapprove a study. A VA investigator who wants to conduct research with human subjects must develop a research plan (called a protocol), supporting documents, and a consent form. The consent form is designed to provide potential subjects with sufficient information about the study, including its procedures, risks, and benefits, to allow the subject to make an informed decision about whether to participate in the study (see fig. 1). The investigator then submits these materials for review. The study is not to be initiated until both the IRB and the research and development committee have approved it, and these committees may insist on changes to the protocol or consent form. Once approval has been given, VA regulations prohibit any unapproved changes to the study’s procedures, unless doing so is absolutely necessary to ensure the safety of a subject. If an investigator wants to alter some aspect of the study, then the IRB must review and approve an amendment or modification to the protocol. In a process known as continuing review, each study is to be re-reviewed at least once per year, and more frequently if the degree of risk warrants it. We found variation across medical centers and their affiliated universities in the implementation of VA regulations and policies involving protections for human subjects. At the eight sites we visited, we found noncompliance with VA regulations in four areas: (1) informed consent; (2) IRB review; (3) IRB membership, staff, and space; and (4) IRB documentation. The problems we identified are similar to problems that OHRP noted in letters to universities and hospitals it has found to be out of compliance with federal regulations. As shown in fig. 2, some sites we visited had more problems than did others. Of the sites we visited, those with the most extensive violations of VA regulations relied on VA-run IRBs. We identified fewer problems at the IRBs in our sample that were run by universities. In particular, we observed fewer problems with IRB membership, staff, space, and documentation at university-run IRBs than at VA-run IRBs. University-run IRBs were also more likely to conduct thorough and timely continuing reviews than VA-run IRBs. University-run IRBs we visited were not without problems, however. We found that some IRB-approved consent forms at each site omitted required information and some investigators used nonapproved consent forms. We found problems with the content or use of informed consent forms at all of the medical centers we visited. We found that some informed consent documents that had been approved for use by IRBs provided incomplete or unclear information. In addition, we found some studies in which the investigators used nonapproved consent forms when enrolling subjects. We also found one instance in which research was conducted without consent. Informed consent is a primary ethical requirement of research with human subjects and reflects the principle of respect for persons. The ability of competent subjects to make informed decisions about whether to participate in research and the ability of legally authorized representatives to protect those who are unable to provide consent because they are incapacitated are undermined when IRBs fail to ensure that all required information is included in consent forms or when investigators fail to obtain consent using approved procedures. We found that 60 percent of the 138 IRB-approved consent forms that we randomly sampled from lists of active projects provided incomplete or unclear information about required elements of informed consent. (Fig. 3 lists the elements of informed consent required by VA regulations.) Each IRB we visited approved some consent forms that contained incomplete information. For example, IRB-approved consent forms did not indicate that blood would be drawn in a study on the effects of exposure mention possible risks of a biopsy in a study designed to test a treatment describe alternative treatment options in a study comparing two drug treatments for schizophrenia, and indicate who would have access to data obtained during a study on treatment for cirrhosis of the liver.