 CHAPTER XIII. PART V. THE RECORDS OF OUR PAST The story that we have told in this report could not have been told if the government did not keep records that could be retrieved. By the same token, the story is often disturbingly fragmentary, seemingly contradictory statements of principle or policy abound, and the trail from policy to practice is often hard to discern. The story is complex, but it is also hard to reconstruct because notwithstanding considerable search efforts of the Human Radiation Interagency Working Group, many documents appear to have been long since lost or destroyed. In each case, we emphasize any loss or destruction took place prior, most often many years prior, to the advisory committee's creation. Federal records management law provides for the routine destruction of older records, and in the great majority of cases it should be assumed that loss or destruction was a function of normal record-keeping practices. At the same time, however, the records that recorded the destruction of documents, including secret documents, have themselves often been lost or destroyed. Thus the circumstances of destruction, and indeed whether documents were destroyed or simply lost, is often hard to ascertain. As Shields Warren and Alan Gregg suggested, where human research is connected to secret programs, the public has a special interest in the adequacy of record-keeping needed to ensure the integrity of experimental activity. Regardless of whether documents that cannot now be retrieved contained further secrets, they would have provided more confidence in our understanding of the rules and practices that governed the boundary between openness and secrecy. In too many cases, however, documents are no longer available. A number of such examples follow. The CIA, virtually all of whose records are classified, reported that it was unable to retrieve any records of its participation in the mid-century DOD panels that met in secret to discuss, among other things, human experiments. In addition, the CIA's classified records of its secret MKUltra Human Experimentation Program were, as reported when the program became a public scandal in the 1970s, substantially destroyed at the direction of then Director of Central Intelligence Richard Helms in 1973. In 1995 the CIA concluded, following a search for remaining records and interviews of those involved, that it did not likely conduct or sponsor human radiation experiments as a part of MKUltra. The advisory committee, which was necessarily limited in its abilities to directly review CIA files, did not find evidence to the contrary. As a CIA report on its own inquiry, which was declassified at the advisory committee's request, concluded, the circumstances of the CIA's MKUltra record keeping will likely leave questions in the public's mind. The DOD provided many documents that shed light on the rules of secrecy. However, some important collections are incomplete, and other important collections, such as the records of the Naval Radiological Defense Laboratory, the Medical Division of the Defense Nuclear Agency, classified records of the Navy Bureau of Medicine relating to Operation Crossroads Physical Exams, and entire sections of records of the Army Surgeon General, here to have been substantially lost or destroyed. The DOE could locate only fragments of the records of the Insurance and Declassification Branches which reviewed human subject research for declassification. The entirety of the files of the AEC Intelligence Division, which likely contained information on intentional releases, research performed by the AEC for other agencies, and secret policy and practices, was subject to purge in the 1970s and as late as 1989. Many other significant collections were retrieved. However, there were often gaps, including, for example, multi-year gaps in the Division of Biology and Medicine Fallout Collection, gaps in the transcripts from the Meetings of the Advisory Committee on Biology and Medicine, and limited collections relating to the work of the Isotope Distribution Division's Human Use Subcommittee. The DHHS was able to locate sufficient information to confirm that it conducted classified research on behalf of the military mission, but could not locate information needed to determine the nature and extent of this research. The classified information it once maintained has been substantially destroyed or lost. The VA, similarly, was able to provide fragments of information that show that confidential files were kept in anticipation of potential radiation liability claims. However, neither the VA nor the DOE and DOD, who evidently were parties to this secret record keeping, have been able to determine exactly what secret records were kept and what rules governed their collection and availability. VA publications did contain lists of several thousand non-classified human experiments conducted at VA facilities. However, the information was quite fragmentary, and further information could not be readily retrieved, if it still exists, on the vast majority of these experiments. Thus, in looking for answers to questions about the secrecy of data on human experiments and intentional releases, we find record keeping practices that leave questions about both what secrets were kept and what rules governed the keeping of secrets. CONCLUSION Openness, the public sharing of all information necessary to govern, has long been an ideal in American democracy and politics. Governments also have traditionally embraced openness as the surest guarantee of continued progress. However, the ideal of openness has often competed, of necessity, with some measure of government imposed secrecy. This has been particularly the case in a time of national emergency, such as war. But secrecy existed even at the roots of our democracy. The constitutional convention itself was conducted out of the public eye. In the earliest part of this century, President Woodrow Wilson called for open covenants openly arrived at, seeking to shed light upon an area, international diplomacy, traditionally shrouded in secrecy. In the half-century since the end of World War II, with the growing importance of science and technology in our lives, the proper place of secrecy at the intersection of government, private enterprise, and research, has emerged as a question of central and continuing importance to society. We have focused upon only one of many Cold War settings where secrecy was often a routine consideration. But human radiation experiments and intentional releases of radiation were often closely related to, if not directly a part of, some of the most closely held of secrets, including, most notably, nuclear weapons design and testing. The episodes we reviewed revealed the tensions underlying the necessarily delicate balance between openness and secrecy. We found that from the onset leading government biomedical officials and advisors were aware of the costs of secrecy and proclaimed the need to limit its reach. In one important respect, these officials and researchers lived up to their publicly stated ideals. Since about mid-century there have been very few instances in which the very existence of human subject radiation research has been officially classified. Nonetheless, we also found that practices often fell short of the ideals that were publicly expressed. We found that decision making related to the secrecy of human subject research considered not only national security, but also other criteria. At its birth in 1947, the AEC determined to keep Manhattan Project Experiment secret on the basis of concern for adverse effects on public opinion and possible legal suits, even where national security itself was not expressly invoked. More generally, we also found that decisions to keep information secret were often accompanied by a concern that the public might not understand the information, and thus overreact, or that the public would understand the information, but that its immediate reaction could undermine support for programs deemed essential by policymakers. Significantly, we found that AEC and DOD discussions of Cold War human research policy were themselves conducted outside the realm of public debate. For example, the 1947 AEC declarations of requirements for human research involving patients were evidently given minimal distribution within the AEC research community itself. Recently retrieved documents now show that in 1947 the requirement of informed consent was itself invoked in secret by the AEC's Medical Board of Review, in response to the request for criteria that had to be met when secret experiments could be declassified, and evidently thereafter relied on to keep some experiments secret. Similarly, the discussions underlying the 1953 Memorandum by Secretary of Defense Charles Wilson concerning human experiments done under DOD auspices were themselves secret, as of course was the Wilson Memorandum itself. Even if there is clear and public consensus on what constitutes national security, its application to the classification of particular information may be a matter of disagreement. In addition, in some cases the boundary between protecting the nation's security and simply avoiding the potential of adverse public reaction may not be so clear. For example, in an intense national crisis, the release of information that might jeopardize successful resolution of the crisis should properly be proscribed. But it is also clear that the assertion that programs will be jeopardized because of embarrassment or potential legal liability, or worse, because of a lack of confidence in the American public's ability to understand, can be used to limit disclosure of precisely those matters that most affect us all, and that would most benefit from informed public discussion. If the boundary between openness and secrecy is inherently ambiguous, the public trust in those who define it on a daily basis requires a clear explanation of the principles that they will follow. However, we found that some of the basic principles and rules by which this boundary was defined were themselves kept secret from the public. AEC officials, in consultation with biomedical advisers, internally invoked public relations and legal liability as basis for keeping secrets, while publicly declaring that secrecy should be limited to national security requirements. As a corollary, we found that where formal criteria for classification were not established, secrecy was nonetheless achieved by other informal means. Thus, at mid-century, participants in discussions of defense-related biomedical research were told that, while the information in question was not itself classified, it should nonetheless be kept from the press and public. Since 1951, presidential executive orders have limited the use of classification stamps to matters of national security. Nonetheless, the keeping of secrets with reference to ill-defined reasons, such as public relations, continued. Indeed, as recently as the early 1970s, adverse public relations was reportedly invoked as a reason for keeping secret details of the plutonium injections of the 1940s. In some cases, as we look back, the public relations rationale for secrecy appears to be more clearly documented than any national security rationale. For example, we found that in the early 1950s, public relations was an express consideration in keeping secrets related to fallout-related human tissue sampling. But we found it more difficult to locate contemporaneous documentation of national security rationales, and in 1995, surviving participants found it hard to reconstruct one as well. We also found instances where the keeping of secrets was accompanied by deception. The shades of deception ranged from outright denials by the AEC that had engaged in human experimentation, to the use of cover stories in the collection of human tissue, to incomplete information deliberately given participants in government-sponsored biomedical research. In some such cases, such as the use of a cover story in collecting the bones of stillborn infants, those involved rationalized that since partial truths were being told, active deceit was not involved. In others, a rationalization for deception was a desire not to alarm exposed workers or the public. In yet others, such as the AEC's denial that it sponsored human experiments, when its isotopes division publicly advertised the success of human subject research, the rationale is hard to discern in retrospect. In many cases, of course, some degree of secrecy was merited. We found that where secrecy was initially justified by reasons relating to national security, the classifying authority often gave too little attention to the likelihood that there would come a time when such information was no longer sensitive. Immediately prior to the AEC's creation, the Tolman Committee pointed out that, in the long run, which that committee identified in terms of years, not decades, the nation's interest lies in the disclosure of information that needs to be kept secret over the shorter term. Yet the practical reality was that once information was born secret, it often simply remained that way. Similarly, we found that where a national security rationale for secrecy did exist, no doubt attention was often not paid to ensuring that sufficient records would be created and maintained so that all affected individuals, and the public at large, could later know the possible health and safety consequences. As a result, downwinders, as well as knowing participants in nuclear tests, today wonder whether the information given them represents the full story of these events. Indeed, as we reported in Chapter 11, the number of once secret intentional releases that are publicly known, burgeoned from the thirteen reported by the General Accounting Office in late 1993, to the far greater number reported by the DOD and DOE following their more recent search, when, as we reported in Chapter 10, there is evidence that government officials contemplated, and may have kept, secret records to evaluate potential claims from service personnel exposed to government-sponsored radiation risk, the public has a right to expect that the government can readily and unambiguously account for any record keeping that may have taken place. Its inability to do so is very troubling. Finally, we found that confusion, misunderstanding, and controversy still characterize public understanding of issues at the core of the committee's work. For example, what is the nature of the risk from radiation? And to what extent can government statements about human radiation experiments and intentional releases be trusted? It is important to reflect on the ways in which this state of affairs may, in part, be a consequence of past secret keeping. In testimony before the advisory committee, numerous witnesses expressed a common feeling that the government did not give adequate weight to the interests of an informed public. Secrets, some said, were kept from the American public, not the enemy. Even where information may have been rightly classified in the first instance, many pointed out that there is no longer any reason for the absence of documents that provide a clear and full accounting to all those who were put at risk. There are too many cases where we can give no comforting answer to these angry voices. However, by paying heed to these voices and by trying to understand the past they point to, we may more readily find our path into the future. Perhaps the first step in this direction is a simple recognition that the proper boundary between openness and secrecy will not be immediately obvious in all cases. Many cases will not only require judgment but also the will to avoid the temptation to keep secrets because the benefits of secrecy may be immediate while the costs are longer term. A second step is to understand that where secrecy is truly merited and citizens are put at risk there must also be precautions to ensure that a timely public accounting will be possible when the information need no longer be kept secret. As the Cold War recedes further into history the issues of secrecy and openness it posed will undoubtedly continue to present themselves although often in new settings. Our review of the past provides the basis for some specific recommendations about the future but it also points to a more fundamental understanding of the wisdom of those leaders of the day who identified the long term costs of secrecy and called for policies to minimize them. The shortcomings of past policies and actions confirm that even when principles are articulated by well-intentioned officials the translation of principles into practice is not automatic and warrants careful attention by the public. At the same time the present day legacy of distrust confirms that too much secrecy in the short term will in the long run erode the public's trusting government and the government's ability to keep the secrets that must be kept. End of Section 69. Section 70 of the final report of the advisory committee on human radiation experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer please visit LibriVox.org. Recording by Patrick McAfee Evanston. Final report of the advisory committee on human radiation experiments. Contemporary Projects Chapter 14 Part 1. Part 3 Contemporary Projects. Part 3 Overview. In Parts 1 and 2 of this report the advisory committee attempted to come to terms with the past. We told the history of standards for conducting human subject research in Part 1 and the history of human radiation experiments through representative case studies in Part 2. Here in Part 3 of our final report we attempt to assess whether the current protections for human subjects are better than the prevailing standards and practices during the 1944 to 1974 period to help recommend what changes, if any, ought to be instituted in current policies governing human subject research. The advisory committee's study of contemporary research ethics is three-pronged. It comprises a review of agency policies and oversight practices, a review of documents from recently funded research proposals, the Research Proposal Review Project or RPRP to examine the extent to which the rights and interests of the subjects of federally sponsored research appear to be protected and the subject interview study, SIS, in which the attitudes and beliefs of patients about medical research and their decisions and experiences regarding participation in research are examined. These projects together form the basis of the advisory committee's picture of the protections now afforded the subjects of biomedical research and, along with findings regarding radiation experiments during the 1944-1974 period, inform the forward-looking recommendations of the advisory committee found in Part 4. Chapter 14 reviews the current regulatory structure for human subjects research conducted or supported by federal departments and agencies, a structure that has been in place since 1991. This common rule has its roots in the Human Subject Protection Regulations promulgated by the then Department of Health Education and Welfare, DHEW, in 1974. The historical developments behind these regulations are described in Chapter 3. Following a summary of the essential features of the common rule, Chapter 14 discusses several subjects of particular relevance to the advisory committee's work, such as special review processes for ionizing radiation research, protection for human subjects in classified research, and audit procedures of institutions performing human subject research. Chapter 15 describes the Research Proposal Review Project, RPRP, the advisory committee's examination of documents from research projects conducted at institutions throughout the country, including both radiation and non-radiation proposals. Documents utilized in the RPRP were those available to the local institutional review boards, IRBs, at the institutions where the research was conducted. The goals of the RPRP were to gain an understanding of the ethics of radiation research as compared with non-radiation research. How well research proposals address central ethical considerations, such as risk, voluntariness, and subject selection, and whether informed consent procedures seem to be appropriate. The RPRP reviewed documents prepared by investigators and institutions and submitted in IRB applications. This study was complemented by a nationwide effort to learn about research from the perspective of patients themselves, including those who were and were not research subjects. The subject interview study, SIS, described in Chapter 16, was conducted through interviews with nearly 1,900 patients throughout the country. The SIS aimed to learn the perspectives of former, current, and prospective research subjects by asking about their attitudes and beliefs regarding the endeavor of human subject research generally and their participation specifically. The RPRP tried to understand the experience of human subjects research from the standpoint of the local oversight process, while the SIS tried to understand it from the standpoint of the participant. Although the two studies related to different research projects and different groups of patients and subjects, some common tensions in the human research experience emerge in both projects, and they are described in the discussion section of Part 3. For example, it has long been recognized that the physician who engages in research with patient subjects assumes two roles that could conflict—that of the caregiver and that of the researcher. The goals inherent in each role are different—direct benefit of the individual patient in the first case and the acquisition of general medical knowledge in the second case. The interviews with SIS participants suggest that at least some patient subjects are not aware of this distinction or of the potential for conflict. In our review of documents in the RPRP, we found that the written information provided to potential patient subjects sometimes obscured rather than highlighted the differences between research and medical care and thus likely contributed to the potential for patients to confuse the two. To help complete the picture of current human subject research and its regulation and oversight, the committee also gathered limited information in two areas. One, the Federal System of Human Subject Protection as viewed by those charged with implementing it at the local level, the chairs of IRBs, and two, the particular review process applied to human subject research involving radiation as viewed by those charged with implementing it at the local level, the chairs of radiation safety committees. A letter was written to 41 chairs of IRBs and 40 chairs of radiation safety committees at institutions throughout the country attempting to gain their perspectives on the current regulatory systems their committees seek to apply. Many of these letters are reproduced in a supplemental volume to this report. Most of the replies from IRB chairs indicated a general approval of the current system, but many also had useful observations and suggestions for improvement. For example, several expressed concern about what they believed to be a disparity in the procedures of IRBs from one institution to another. The chairs of radiation safety committees, on the other hand, reported a nearly universal confidence in and approval of the review process for human subject research involving the use of radiation. The committee's recommendations in Part 4 of this report address some of the concerns outlined in response to our queries. Because the committee's work in Part 3 shows in the discussion section, contemporary human subject research does not suffer from the same shortcomings witnessed in the 1940s and 1950s, but poses different issues that need to be addressed. With a system of human subjects protections comes issues related to implementation and interpretation of rules and regulations. And with a change in the culture of medicine comes a change in the relationship between researchers and subjects. In the historical period of the committee's review, we found that subjects needed protections to ensure their basic rights to consent to or to refuse participation in research. While this need to protect the right of consent continues, in the current period we found that subjects also need protections to ensure their interests are served in understanding the distinctions between research and therapy and the limits of the benefits research may offer. These findings and conclusions suggest the need for changes in an oversight system designed to address the concerns of an earlier time, and the committee makes recommendations for such change in Part 4 of this report. Footnote The committee also contacted a sample of institutions at which therapeutic human radiation research involving higher doses of radiation and therefore imposing substantial risk had recently been conducted according to reports in the medical literature. The committee was interested in learning whether the research projects reported in these journal articles had been reviewed by an IRB, and if IRB review had depended upon whether the research was supported by federal funds. Information was received from only nine of the sixteen institutions requested. Although the projects about which we were inquiring were sometimes described as clinical investigations in the journal reports, these institutions did not always view them as satisfying the definition of human subject research, and thus did not appear to require IRB review for these projects. 14. Current Federal Policies Governing Human Subjects Research Each year, many thousands of people participate in biomedical and behavioral research projects conducted, sponsored, or regulated by federal agencies. The federal government invests roughly $3.5 billion annually in research that involves human subjects. The committee wanted to establish what the federal government currently does to protect the rights and interests of these subjects. The answers to this question all emanate from a seminal event in the history of human subjects research, the adoption of what is widely known as the common rule. A single general set of regulatory provisions governing human subjects protections was adopted by sixteen federal departments and agencies in 1991. The common rule specifies how research that involves human subjects is to be conducted and reviewed, including specific rules for obtaining informed consent. The common rule was developed in response to recommendations made by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research in 1981, calling for the adoption by all federal agencies of Department of Health and Human Services Regulations, then in effect for the protection of human subjects of research. In mid-1982, the President's Science Advisor, the head of the Office of Science and Technology Policy, OSTP, appointed an ad hoc committee that included the federal departments and agencies engaged in research involving human subjects to address these recommendations. Nine years later the common rule was the result of this committee's efforts. Three of the common rule since 1974. 1974, Title II of the National Research Act, PL93-348, required codification of DHEW policy in regulations imposed a moratorium on federally funded fetal research and established requirements for IRB review of all human subjects' research at any institution receiving DHEW funding. DHEW regulations for the protection of human research subjects, 45 CFR 46, established IRB review procedures in accordance with Title II. Later in the same year, DHEW published regulations providing additional protections for pregnant women and fetuses. 1974, 1978, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, issued reports and recommendations on fetal research, on research involving prisoners, psychosurgery, children and the mentally infirm, on IRBs and informed consent, and in the Belmont report discussed criteria for distinguishing research from the practice of medicine and ethical principles underlying the protection of subjects. 1978, revised DHEW regulations governing protections for pregnant women, fetuses, in vitro fertilization, subpart B of 45 CFR 46, and prisoners, subpart C, published. 1983, President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, charged with, among other responsibilities, reviewing federal policies governing human subjects' research and determining how well those policies were being carried out. Recommended that all federal agencies adopt the DHHS, a successor agency to DHEW, regulations for the protection of human subjects, 1981. 1981, DHHS published a revision of 45 CFR 46, responding to recommendations of the National Commission. The revision set out in greater specificity IRB responsibilities and the procedures IRBs were to follow. FDA regulations at 21 CFR 50, governing informed consent procedures, and at 21 CFR 56, governing IRBs revised to correspond to DHHS regulations to the extent allowed by FDA's statute. 1982, President's Science Advisor, Office of Science and Technology Policy, OSTP, appointed an interagency committee to develop a common federal policy for the protection of human research subjects. 1983, DHHS regulation governing protections afforded children in research. Subpart D of 45 CFR 46 published. 1986, proposed common federal policy for the protection of human research subjects published. 1991, final common federal policy published on June 18, codified in the regulations of 15 federal agencies and adopted by the CIA under executive order. This common policy, known as the common rule, is identical to the basic DHHS policy for the protection of research subjects, 45 CFR 46, subpart A. Other sections of the DHHS regulation provide additional protections for pregnant women, fetuses, in vitro fertilization, subpart B, prisoners, subpart C, and children, subpart D. Several agencies have adopted these additional provisions as administrative guidelines. The FDA made conforming changes in its informed consent and IRB regulations. The promulgation of the common rule was a significant achievement. The ability of the common rule to protect the rights and interests of human subjects is, however, at least partially dependent on how the departments and agencies to which the common rule applies implement and oversee its provisions. As a foundation for the advisory committee's recommendations concerning contemporary policies and practices regarding human subjects, we ask the 16 federal agencies and departments that conduct human subjects research to provide us with information on the relevant policies and practices currently in place. In this brief descriptive overview, we focus on six agencies within the scope of the advisory committee's charter. The Department of Defense, DOD, Department of Energy, DOE, Department of Health and Human Services, DHHS, Department of Veterans Affairs, VA, National Aeronautics and Space Administration, NASA, and the Central Intelligence Agency, CIA. Information on the 10 other agencies covered by the common rule is provided in a supplemental volume to this report. The following sections briefly describe the institutional structures, review mechanisms, and policies prescribed by the common rule and the variety of ways in which federal agencies attempt to ensure that human subjects are adequately protected in the conduct of research. The chapter closes with a review of an issue of particular importance to the advisory committee, the status of protections for human subjects of classified research. Part 3. The Federal Policy for Human Subjects Protections, the Common Rule. The common rule applies to all federally funded research conducted both intra and extramurally. The rule directs a research institution to assure the federal government that it will provide and enforce protections for human subjects of research conducted under its auspices. These institutional assurances constitute the basic framework within which federal protections are affected. Local research institutions remain largely responsible for carrying out the specific directives of the common rule. They must assess research proposals in terms of their risks to subjects and their potential benefits and they must see that the common rules requirements for selecting subjects and obtaining informed consent are met. As discussed below, central to the process of ensuring that the rights and well-being of human subjects are protected are institutional review boards, IRBs. The common rule requires that a research institution as a condition for receiving federal research support establish and delegate to an IRB the authority to review, stipulate changes in, approve or disapprove, and oversee human subjects protections for all research conducted at the institution. IRBs are generally composed of some combination of physicians, scientists, administrators, and community representatives, usually at the local research institution but sometimes at an agency that conducts intramural research. IRBs have the authority to suspend the conduct of any research found to entail unexpected or undue risk to subjects or research that does not conform to the common rule or the institution's additional protections. A prominent feature of the common rule is the informed consent requirement. The informed consent of a competent subject along with adequate safeguards to protect the interests of a subject who is unable to give consent is a cornerstone of modern research ethics reflecting respect for the subject's autonomy and for his or her capacity for choice. Informed consent is an ongoing process of communication between researchers and the subjects of their research. It is not simply a signed consent form and does not end at the moment a prospective subject agrees to participate in a research project. The required elements of informed consent stipulated by the common rule are summarized as follows. A statement that the study involves research, an explanation of the purposes of the research and a description of the procedures to be followed, a description of any reasonably foreseeable risks or discomforts to the subject, a description of any benefits to the subjects or to others that might reasonably be expected, a disclosure of alternative procedures or courses of treatment, a statement describing the extent to which confidentiality of records identifying the subject will be maintained, for research involving more than minimal risk and explanation of the availability and nature of any compensation or medical treatment if injury occurs, identification of whom to contact for further information about the research and about subjects' rights and whom to contact in the event of a research-related injury and a statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled and that the subject may discontinue participation at any time. The common rule includes several additional elements of consent that may be appropriate under particular circumstances and describes the conditions under which an IRB may modify or waive the informed consent requirement in particular research projects. When an IRB reviews and approves a research project, it must pay particular attention to the project's plan for obtaining subjects' informed consent and to the documentation of informed consent. The IRB may require changes in the investigator's procedure for obtaining informed consent and in the consent documents. The board also must be allowed to observe the informed consent process if the IRB considers such oversight important in ascertaining that subjects are being adequately protected by that process. Research involving ionizing radiation. Beyond the strictures of the common rule, research involving either external radiation or radioactive drugs usually undergoes additional reviews for safety and risk, including a review of radiation dose prior to IRB review at the local research institution. Most medical institutions have a radiation safety committee, RSC, responsible for evaluating the risks of medical activities involving radiation, whether for diagnostic, treatment or research purposes, and limiting the exposure of both employees and subjects to radiation. In addition, research and medical institutions that perform basic research involving human subjects and radioactive drugs must have such studies reviewed and approved by a radioactive drug research committee, RDRC, a local institutional committee approved by the Food and Drug Administration, FDA, to ensure that safeguards including limitations on radiation dose in the use of such drugs are met. Notwithstanding the prior review and approval of either or both of these radiation committees, the IRB must also assess the risks and potential benefits of the proposed research before approving it. Scope of programs of research involving human subjects. The six federal departments and agencies, DHHS, DOD, DOE, NASA, VA and CIA, all conduct or support research involving human subjects. Each agency's program is distinctive in terms of its scope, organization and focus, all of which reflect the primary mission of the agency. DHHS is the largest federal sponsor of research involving human subjects with approximately $367 million in intramural funding and $2.4 billion in extramural support for clinical research in fiscal year 1992, the latest year for which an estimate of extramural research funding is available. Intramural research is usually conducted by agency staff members at various field sites while extramural research is conducted outside the agency by contractors or grantees such as universities. Most of this research is biomedical and some involves the use of radiation in experimental diagnostic and therapeutic procedures or as tracers in basic biomedical research. The U.S. Public Health Service, PHS, is the operating division of DHHS and the principal health agency of the federal government. The DOD conducts biomedical and behavioral research involving human subjects within each of the military services and through several additional defense agencies, primarily in areas that support the mission of the department. In fiscal year 1994, DOD spent an estimated $77 million on intramural and $107 million on extramural human subjects research. The VA operates 171 inpatient medical centers including short-term hospitals, psychiatric and rehabilitation facilities, and nursing homes. The VA's larger intramural biomedical research program focuses on the healthcare needs of veterans. The VA spends approximately $114 million annually in appropriated research money on human subjects research along with another $110 million in staff clinicians time. Other federal agencies and private entities also support research in VA facilities. The DOE conducts and supports research both intramurally and extramurally involving human subjects that ranges from diagnostic and therapeutic applications in nuclear medicine to epidemiological and occupational health studies. DOE laboratories also receive funding from other federal agencies such as the NIH and from private sponsors of research. DOE spends $46 million annually on human subjects research, more than $20 million of which is devoted to the Radiation Effects Research Foundation, RERF in Japan, which is charged with studying the health effects of exposure to radiation from atomic weapons. Both intramurally and extramurally, NASA conducts ground-based and in-flight biomedical research involving human subjects related to space life. In fiscal year 1994, NASA spent approximately $25 million on ground-based human subjects research. The CIA supports or conducts a small number of intramurally and extramurally conducted studies involving human subjects each year. No figure for the annual dollar amount spent by the CIA was made available to the Advisory Committee. End of Section 70. Recording by Patrick McAfee, Evanston. Section 71 of final report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Recording by Patrick McAfee, Evanston. Final report of the Advisory Committee on Human Radiation Experiments. Contemporary Projects, Chapter 14, Part 2. Administrative Structures and Procedures for Research Oversight. The following is an overview of the administrative structures and procedures used by the six departments and agencies to ensure compliance with human subjects' ethics rules, particularly as they relate to the common rule. The Advisory Committee asked each of these agencies to provide the following information on its program of protections for human subjects involved in research. The scope of its human subjects' research programs, the organizational structure of its human subjects' protection efforts, and the resources devoted to such activities. The policy issuances and guidances pursuant to the common rule that the department or agency has prepared and provides to subsidiary agencies and research institutions engaged in human subjects' research. Recording and enforcement activities for ensuring that the provisions of the common rule are met. Sanctions available for non-compliance with human subjects' protections. The rules governing classified research involving human subjects and the use or potential use of waivers of any of the requirements of the common rule were the agency's human subjects' regulations. In a supplemental volume to this report, we provide greater detail on the department's and agency's responses. Each federal department structures its program of administrative oversight of human subjects' research somewhat differently, despite the fact that all operate under the requirements of the common rule. Some departments conduct reviews of research documentation out of one central departmental office, while others rely on local review. Some provide detailed interpretive guidance on human subjects' protections to subsidiary intramural research offices, contractors, and grantees, while others simply reference the common rule. And some departments audit or review IRB performance routinely, while others conduct investigations only when problems emerge. The Office for Protection from Research Risks OPRR at the National Institutes of Health within DHHS serves not only as the locus for that department's policies for the protection of research subjects, but also as the principal federal agent approving the assurances of research institutions to conduct human subjects' research sponsored by any of a number of departments. Scientific peer review of federally sponsored research is one layer of protection for research subjects. Most federal research programs require that committees of scientists, expert in the particular subject under consideration, and often from outside the agency, generally known as study sections, review both intramural and extramural research proposals for scientific merit and make recommendations regarding funding. When these committees of subject matter experts review research proposals, they also consider the risks that may be involved for subjects. They may recommend that the sponsoring agency more closely consider the potential risks or that the principal investigator make specific changes in the research protocol prior to any funding. Local review is a key component of the oversight system. The common rule requires IRB review and approval prior to the granting of federal funding for research on human subjects. Most all federal agencies that conduct human subjects' research within their own facilities have intramural IRBs, whose members include agency staff and at least one member who is not affiliated with the facility. Likewise, extramural research projects must undergo IRB review prior to agency funding, usually by an IRB at the site of the research activity. For example, a university, medical school, or hospital. The IRB is an administrative unit that must itself comply with certain requirements of the common rule in terms of its composition, review procedures, and substantive review criteria. It must also direct researchers to comply with other requirements of the rule, such as adequate informed consent and fair subject selection procedures. A research institution that has assured either OPRR or the federal agency sponsoring the research that it conducts human subjects' research in compliance with the common rule must delegate to its IRB the authority to preclude or halt the conduct of any federally funded research project that does not conform with federal human subjects' protections. This delegation of authority applies to IRBs within federal research institutions for intramural research and to those at non-federal research institutions as well. This authority extends even to research performed by military organizations where unit commanders cannot overrule safeguards adopted by military IRBs. Thus the IRB is the enforcing agent of federal protections that is situated closest to the conduct of research. Much of the success or failure of the federal regulations governing human subjects' research depends on the effectiveness of IRBs in carrying out their responsibilities, assessing research proposals prior to their funding, stipulating any changes in the research protocol or informed consent procedure that strengthen the protections afforded the subjects, disapproving inadequate or excessively risky research proposals, minimizing risks to subjects, reviewing ongoing research at least every 12 months to ascertain that the research poses no undue risks to subjects, and taking action quickly to correct any failings in safeguarding subjects' rights and welfare. In overseeing human subjects' research conducted in-house or supported extramurally, federal agencies acquire the following responsibilities. One, communication of practice guidelines to research institutions and IRBs based on the policies of the common rule. Two, establishment of a structure whereby research proposals involving human subjects are peer-reviewed for scientific merit as well as for IRB approval and the adequacy of subject protections. Three, negotiation of assurances with research institutions that ensure that adequate protections will be in place for research subjects. Four, verification that institutions, their IRBs, and researchers are complying with the federal human subjects' regulations. And five, investigation of complaints of non-compliance and adverse outcomes for subjects of research. Table one, quote, human subjects' research and protections in seven departments and agencies, end quote. At the end of this chapter, summarizes information received by the Advisory Committee about Human Subjects Research Programs in DHHS, DOD, DOE, VA, NASA, CIA, and FDA, a sub-agency of DHHS. This chart shows each department's or agency's staffing levels for human subjects' protection activities. Both the size of the department's research programs and their investment of staff resources in oversight activities vary widely. A particularly important distinction in oversight programs is the extent to which they investigate the performance of research institutions and IRBs in carrying out their responsibilities under the common rule. Some departments rely heavily on the prospective assurances that research institutions make to the funding agency or to OPRR, while others audit research institutions and IRB records periodically. The method, intensity, and frequency of research oversight and inspection activities depend entirely on how much staff and budget an agency allots them. OPRR negotiates multiple project assurances, MPAs, with large research institutions that perform a significant amount of research funded by DHHS. If an institution is awarded an MPA by OPRR, the federal agency funding the research must accept that institution's assurance of compliance with federal requirements and may not impose additional assurance requirements on the institution. This provision is intended to avoid duplicative and potentially contradictory enforcement of the federal protections. OPRR, in overseeing human subjects protections for DHHS funded research, and for all institutions to which it has issued an assurance, generally investigates the conduct of research only in cases where a complaint has been filed, where an institution, IRB or researcher has reported a problem or adverse outcome, or where a problematic audit finding has been referred to it by the FDA. Principal investigators are required to report to the IRB any adverse outcomes to subjects in the course of their research, and the IRB must have procedures to ensure that the appropriate institutional officials and the funding agency are informed as well. The FDA in its role regulating new drugs, biologics, and devices for marketing enforces the somewhat different requirements for human subjects protection of the Food, Drug and Cosmetic Act through periodic on-site investigations of research institutions, e.g. pharmaceutical firms, university-based research facilities funded by pharmaceutical firms, independent testing laboratories, and their IRBs. The DOD conducts on-site audits of its intramural research programs in addition to negotiating assurances. The DOD also reports that it is common practice in DOD-funded research to appoint independent medical monitors, healthcare providers qualified by training, experience, or both, to monitor human subjects during the conduct of research as advocates for safety of the subjects. The DOE is now planning to institute periodic audits of the research programs that it funds in addition to relying on assurances. Special Issues Arising in DOD Research Human subjects research conducted by military agencies and within military settings entails considerations for subject protections and research oversight that are unique to the military context. The activities of military research programs may be difficult to distinguish from innovative training programs and medical interventions undertaken for the protection of the troops. In addition to enforcing policies derived from the requirements of the common rule, the DOD has in place a parallel set of regulations for managing the risks to which military personnel are exposed in the course of these routine duties. Military leaders are responsible for determining whether human experimentation protections, in addition to the more general risk assessment requirements, apply to particular practices. A further distinction of the military context is the hierarchical and comprehensive nature of its authority structure, which poses special issues with respect to voluntariness in the recruitment of experimental subjects. In some cases, military researchers have excluded unit officers and senior non-commissioned officers from subject recruitment sessions, e.g. in vaccine trials conducted by Walter Reed Army Medical Center. DOD has regulations that require most more than minimal risk research proposals to be subjected to a second level of review by each military medical service at a central oversight office. The Army, for example, requires greater than minimal risk research protocols to undergo a second level of review at the Human Use Review and Regulatory Affairs Division, HURRAD, and the Human Subjects Research Review Board or the Clinical Investigation Regulatory Office, CIRO. General Responses to Violations of Human Subjects Protections In the event that the common rule is violated in the conduct of federally-sponsored research involving human subjects, there are various responses that can affect both investigators and grantee institutions, such as withdrawal or restriction of an institution's or project's assurance and, with that action, of research funding and suspension or termination of IRB approval for the research. In addition, an IRB is authorized by the common rule to suspend or terminate its approval of research that fails to comply with the IRB's requirements or when a research subject suffers an adverse event. No federal department or agency may continue to fund a project from which IRB approval has been withdrawn or at an institution whose assurance has been withdrawn. An institution's or investigator's prior performance with respect to human subjects protections may affect future federal funding as well. If human subjects protection regulations are willfully violated, the department secretary or agency head may bar the organization or individual from receiving funding from any federal source. Such debarment must be for a specified length of time and, in some extreme cases, may be permanent. Federal agencies may also take disciplinary action against employees involved in human subjects research for failure to follow human subjects protection rules. For example, DOD sanctions for noncompliance by intramural researchers include loss of investigator privileges. For military personnel, potential sanctions are letters of reprimand, non-judicial punishment, and sanctions under the Military Code of Justice. For civilian DOD personnel, sanctions include reprimands, suspension, or termination of employment. No requirement of the common rule can preempt state and local laws governing the conduct of human subjects research that are stricter or provide additional protections for subjects. Of those states with any laws governing research involving human subjects, only California authorizes sanctions for failure to obtain a subjects-informed consent. The California statute authorizes monetary awards for negligent failure to obtain a subjects-informed consent up to $1,000 for willful failure to obtain such consent up to $5,000 and if a subject is thereby exposed to, quote, a known substantial risk of serious injury, either bodily harm or psychological harm, end quote, jail terms of up to one year and or fines of up to $10,000. Protections for Human Subjects in Classified Research We were advised that the only classified studies involving human subjects currently conducted by the six federal agencies are a small number of projects sponsored by the DOD and the CIA. The common rule does not distinguish between classified and unclassified research in terms of the requirements or procedures it imposes to protect human subjects. The Department of Defense reported that it currently sponsors a small number of classified research studies involving human subjects. When such research is proposed, IRBs review classified protocols in one of two ways. The chair of the IRB may remove the classified portions of the protocol if he or she judges that those classified portions have no effect on the risks imposed on human subjects. Alternatively, the IRB may be composed of people with appropriate security clearances who then review the protocol in its entirety. A person not affiliated with the institution but with appropriate security clearance is included as a voting member of such IRBs. The CIA indicated that it is currently performing classified human research projects. The agency informed the advisory committee that all human subjects are informed of the CIA's sponsorship and of the specific nature of the study in which they are participating even if the general purposes of the research are classified. Although DOE has the authority to conduct or support classified human subjects research projects, it reports that it is not currently conducting such research. According to DOE guidelines, IRB review of classified research may take one of two forms. If the chair of the IRB determines that none of the classified information in a proposal is relevant to the protection of human subjects and that the research can be accurately and fully described to the IRB, the proposed research will be reviewed at a regular IRB meeting without disclosure of any classified information. If the proposed research cannot be reviewed in the foregoing manner, however, the IRB must meet in a secure environment. The advisory committee was advised that to date this has not occurred. To review classified research, each member of the IRB must have the appropriate security clearance. The member of the IRB who is not affiliated with the institution conducting the research must also have security clearance to participate in the review of classified research. DOE guidelines recommend that IRBs expecting to review classified research obtain clearance for their non-affiliated members so that they are not excluded from such reviews. DHHS neither conducts nor sponsors any classified research. Some FDA personnel hold security clearances so that they may review classified investigational new drug or device applications submitted by the DOD if the need to study or use these items in secret arises. The VA does not now conduct any classified research and does not have original classification authority. NASA currently conducts no classified research that involves human subjects and has not in the past. NASA does have classification authority, however, and conducts some classified research that does not involve human subjects. Research that involves human subjects and is classified for reasons of national security raises special issues for IRB review and for the process of obtaining informed consent, particularly with respect to the level of disclosure and waivers of informed consent. Specifically, the IRB must consider whether the prospective research subject will be adequately informed about the nature of classified research if some aspects of the research will not be disclosed in the informed consent process, whether security clearances are needed for IRB members, and whether information about classified studies must be partitioned from other IRB study reviews. Institutional review boards can determine that some aspect of a classified research project, if only the identity of the research sponsor, is irrelevant to the process of obtaining a subject's informed consent to participate. IRB members can decide that sponsorship information or complete disclosure of the purpose of the research need not be provided to potential subjects in contrast to information about physical risk. The common rule grants IRBs the authority to approve modifications in or to waive entirely informed consent requirements, but only for research involving no more than minimal risk. A separate provision grants an agency head the authority to waive any requirement of the common rule for any kind of human subject research as long as advanced notice is given to OPRR and the action is announced in the federal register. As indicated above, the rule makes no distinction between classified and unclassified research, so this latter route to an informed consent exception would appear to pose a tension between duties to disclose and the need to keep information secret. Conclusion, the common rule adopted by the 16 federal agencies and departments that conduct human subjects research is another step in the evolution of human subject research protections policies begun in the 1940s. While those protections are crucial, gaps still remain. With respect to classified research, the current requirement of informed consent is not absolute. If consent is waived, the research may proceed in ways that do not adequately protect the research subject. Also, military research involves special considerations because of the nature of the subject population whose voluntary participation must be especially guarded. In addition, non-fedrally funded research is not subject to the common rule except under the umbrella of an institution's multiple project assurance. Further, oversight mechanisms generally are limited to audits for cause and review of paperwork requirements. These offer little in the way of assurances that the prospective review process is working and do not give an indication of the quality or consistency of IRB review either among IRBs or within a single board. An effective system of oversight relies on the detection of violations of policies and the imposition of appropriate sanctions. The committee's recommendations for remedying these and other shortcomings are discussed in Chapter 18 of the final report. The remaining two chapters of Part 3 report what documents used by IRBs suggest about the protection of human subjects and what patients think about the enterprise of human subject research. End of Section 71, Recording by Patrick McAfee Evanston. Section 72 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments. Contemporary Projects. Chapter 15, Part 1. Research Proposal Review Project. Two of the biggest differences between research involving human subjects today and research involving human subjects as it was conducted in the 1940s, 1950s, and 1960s are the presence of applicable federal regulations and the articulation of rules of professional and research ethics. There is little question that these developments have had a significant effect on the protection of the rights and interests of human subjects. At the same time, however, there has been little systematic investigation of how much protection these developments have provided. As an advisory committee, charged both with looking at the past and making recommendations about the future, we hoped to learn as much as we could about the state of contemporary human subjects' research. We were particularly interested in exploring the extent to which the rights and interests of people currently involved as subjects of radiation research, conducted or supported by the federal government, appear to be adequately protected, and whether the level of protection afforded these subjects was the same as that afforded the subjects of non-radiation research. The advisory committee's research proposal review project, RPRP, was designed to address these questions. By examining documents from a wide variety of research projects funded by many agencies of the federal government, we hoped to offer insight into the general state of the protection of the rights and interests of human subjects. During the course of the RPRP, the committee reviewed documents from a random sample of research proposals involving human subjects and ionizing radiation that were approved and funded in fiscal years 1990 through 1993 by the Departments of Health and Human Services, DHHS, Defense, DOD, Energy, DOE, Veterans Affairs, VA, and the National Aeronautics and Space Administration, NASA. These are the only federal agencies that currently conduct human subjects' research involving ionizing radiation. We also reviewed a comparison sample of studies that did not involve ionizing radiation funded by the same agencies during the same period. In this chapter we first present the methodology and findings of the research proposal review project. We then report the results of an independent review of research proposals and documents conducted by one member of the committee who also acted as a reviewer in the RPRP. The chapter closes with a discussion of our results in the context of current policies and practices in research involving human subjects. Methodology of the RPRP Obtaining research proposal artifacts to identify studies of interest. The RPRP involved the collection and review of documents related to recently funded, federally supported human radiation research. This included research supported or performed by the DOD, DOE, DHHS, NASA, and VA. Each agency funds intramural research conducted by agency staff members at various field sites, and extramural research conducted outside the agency by contractors or grantees. The advisory committee requested and received abstracts or similar descriptions from these agencies for all intramural and extramural studies newly approved and funded between fiscal years 1990 and 1993, that is, new starts in those fiscal years, that fell within two general categories. One, studies involving the exposure of human subjects to research applications of ionizing radiation, or follow-up studies of such exposures, and two, non-radiation research involving human subjects. These abstracts represented the universe of federally funded contemporary human research from which studies were then selected for review. Selection of studies involving ionizing radiation. For purposes of the RPRP, a radiation experiment was defined as any federally funded or performed investigation where the exposure of human subjects to ionizing radiation is an element of the research design. In addition, we included follow-up or epidemiological studies of exposures of humans to ionizing radiation. Any procedures involving radiation incidental to a subject's enrollment in a study, for example, a diagnostic x-ray in research involving chemotherapy, were not considered experimental for purposes of the review. To select studies to review from the many abstracts we received, nuclear medicine experts on the advisory committee staff first reviewed and stratified the study abstracts obtained according to the biomedical categories that the advisory committee established for radiation research. Tracer bio-distribution studies, studies involving potential therapeutics, studies involving potential diagnostics, and epidemiological observational studies. These categories were intended to roughly parallel the various types of past radiation experiments identified by the advisory committee. We recognized that placing radiation experiments into discrete categories was a difficult task. The purpose of the categorization, however, was to sample proposals across the range of radiation research conducted on human subjects, rather than to identify specific research as falling into strict categories. Definitions of the biomedical categories used in the research proposal review project are listed in the accompanying box. Note box, definitions of biomedical categories. Tracer bio-distribution studies, studies involving the measurement of administered radioactive chemicals within the body, in vivo, using radiation detectors directed at the body from outside, or in body fluids such as blood and urine in the test tube, in vitro. Bio-distribution studies are distinct from tracer studies in that their object of study is radioactive contaminants themselves in order to understand their distribution and metabolism within the body. By contrast, tracer studies employ radio-labeled variants of ordinary biological chemicals to provide information on natural metabolic processes involving those chemicals. Tracer bio-distribution studies differ from research involving external sources of radiation such as x-rays because tracer bio-distribution studies involve the administration of radioactive chemicals into a subject's body. Studies involving potential therapeutics, studies that involve novel or non-validated uses of radiation for therapeutic purposes on sick individuals, studies involving potential diagnostics, studies that involve experimental uses of radiological or nuclear medicine diagnostics for imaging that are experimental in that their efficacy has not been established. This includes research involving different types of radiation exposure as well as applications of established radiation imaging techniques such as diagnostic x-rays or CAT scans for new diagnostic purposes. Epidemiological observational studies of health effects in people who have experienced exposures to ionizing radiation. This research does not employ radiation but attempts to understand health effects on humans exposed to ionizing radiation using follow-up studies, medical monitoring, and retrospective records reviews. End note. We then selected studies to ensure that each funding agency and each biomedical category of human radiation research, tracer bio-distribution, therapeutic, diagnostic, and epidemiological observational, were adequately represented in the random sample of studies to be reviewed. 84 radiation studies were selected from the proposal abstracts provided by the agencies. These included 31 extramural proposals representing non-federal research institutions, primarily universities, and 53 intramural proposals from the DHHS, DOE, DOD, NASA, and VA. Selection of a comparison group of non-radiation studies. For purposes of selecting a comparison sample of non-radiation studies, the 84 radiation studies were reclassified according to the following categories. One, federal funding agency. Two, extramural intramural. And three, cardiology, cancer, or neither cardiology nor cancer. Approximately half as many studies, 41, were selected for the comparison sample and were distributed in each of these three categories in comparable proportion to the distribution of radiation studies. We drew our sample of non-radiation studies from the same grantee institutions that were included in the radiation sample. Data sources. In total the advisory committee identified for review 125 research proposals involving human subjects, 84 involving ionizing radiation, and 41 not involving radiation, that were approved and funded by DHHS, DOE, DOD, NASA, or VA between fiscal year 1990 and fiscal year 1993. Long-term epidemiological studies that were initiated before fiscal year 1990 and continued through this period were included in the review in cases where the methodology and or consent procedures for such studies were found to have been updated in recent proposal renewals. The advisory committee requested the following documents for each of the 125 studies it identified for review. One, grant proposal submitted by investigator to federal agency. Two, institutional review board IRB application. Three, original consent form submitted to the IRB. Four, consent form as approved by the IRB. Five, the IRB's final disposition letter. Six, documentation concerning any changes to the research design, methods, or consent form approved by the IRB after the IRB's initial approval of the study. Seven, if relevant, the application submitted to and the official letter of approval from the Radioactive Drug Research Committee, RDRC. Eight, if relevant, the application submitted to and the official letter of approval from any institutional human use committee other than the IRB or RDRC. All of the relevant federal agencies and the 47 extramural grantee institutions to which the advisory committee submitted a request, complied with this request. The willingness of institutions to voluntarily make available documents for review indicates their commitment to research ethics, which the committee very much appreciates. The openness shown by the biomedical research community is important evidence of improvement in the ethics of human subjects research over the 50-year history reviewed by the committee. Review process. Three basic elements were considered in developing a system to review the research materials supplied to the advisory committee. The procedures for obtaining informed consent, the balance of risks to potential benefits for the subject, and the selection and recruitment of subjects. An evaluation form was developed by a subcommittee of committee members and staff to assist reviewers in organizing their assessments of the research documents, grant proposal IRB application, RDRC application, and the consent forms. The documents for each proposal were reviewed by a team of two individuals, with at least one member of the advisory committee placed on each team, so that documents from every proposal were reviewed by at least one member of the committee. Review teams consisted of either two advisory committee members or one committee member and one staff member. One member of each team had expertise in research ethics, while the other had expertise in radiation science, radiation medicine, another branch of medicine, or epidemiology. Reviewers were never assigned documents from their own institution. They were also required to recuse themselves if they were well acquainted with the principal investigator of a proposal. Documents were first reviewed independently by each reviewer and then by the reviewers together as a team. At the end of this process each team completed a single evaluation form representing a joint assessment. Limitations The research proposal review project was designed to provide insight on an exploratory basis into the current practice of human subjects research conducted or supported by the U.S. government. The project was not undertaken with the expectation that our results would be generalizable to all research involving human subjects or to research sponsored by nongovernmental agencies. Of necessity we reviewed documents from only a small sample of proposals for human subjects research funded in fiscal years 1990 through 1993. In a given year DHHS supported 16,972 projects and sub-projects involving human subjects research. At the same time, however, our sample includes examples of both radiation and non-radiation research funded or sponsored by five different federal agencies across a variety of biomedical categories and medical specialties. Moreover, the proposals whose documents we received and reviewed were selected at random. There was no attempt to identify proposals that appeared from the outset to pose human subjects problems or high levels of risk, and therefore no reason to suspect that the sample chosen was biased in favor of more problematic or higher risk studies. Within the committee reviewers rarely disagreed in their reviews. Although these reviews are based on interpretation and opinion in the context of committee deliberation, it should be noted that so too are the evaluations of IRBs on which the protection of human subjects now rests. Perhaps the most significant limitation of this project is that the evaluation of each proposal was based only on the documents that were provided by the federal funding agency and grantee institution. The documentation we received was not always complete. Moreover, IRBs may have had access to sources of information not available to the committee. Some IRBs invite principal investigators to make presentations at IRB meetings. Others encourage reviewers to discuss proposals with principal investigators before IRB meetings. Thus in some cases IRBs may have reviewed the proposals evaluated by the committee with a fuller and more accurate understanding of the project than was available to the committee. It is therefore possible that some of the research projects that raised concerns for us based on the documents we reviewed would, with the provision of additional information, be deemed unproblematic from a human subject's perspective. Conversely, it is possible that some of the research projects whose documents raised no concerns may nevertheless have inadequacies affecting the rights and interests of human subjects that we could not detect. From the outset the committee neither desired nor thought it possible, because of our limited tenure and resources, to make judgments about the extent to which these 125 research projects were in fact being conducted in an ethically acceptable manner. This would have required a careful evaluation of far more than the documents that we received. Neither IRB interactions with principal investigators nor documents speak to what actually happens between investigators, their assistants, and potential subjects. What investigators in fact say to potential subjects, the tone with which they say it, and the conditions under which the interaction takes place, are pieces of information that were unavailable to the advisory committee in its review of the documents from contemporary human research proposals, just as they are generally unavailable to IRBs. The advisory committee's review of research proposal documents, thus, was not intended to evaluate the performance of particular IRBs, or the ethics of the conduct of particular investigators or specific institutions. Rather, by examining documents from a wide variety of research projects, funded by many agencies of the federal government, we hoped to offer insight into the general state of the protection of the rights and interests of human subjects. Findings of the RPRP In this section, we present the results of the RPRP. We begin with a general characterization of our overall assessment of the research documents. We also provide additional analysis of the impact of the level of risk and the kind of experiment, non-radiation versus radiation, on our evaluations. Next, we turn to a discussion of what the committee found most troubling in these documents, organized around issues of understanding, voluntariness, and decisional capacity. Finally, we look at problems that were common in the sample as a whole, including the readability of consent forms and deficiencies in documentation. Overall Assessment Reviewer teams registered their overall assessment of each set of documents using a scale from one to five, where one was taken to indicate no ethical concerns, and five was taken to indicate serious ethical concerns. This scoring scale was used to assist reviewers in organizing their overall evaluations of the set of documents for each research proposal. These ratings were made in concert by the two reviewers after each had completed his or her own independent review. Ratings of four and five are grouped together in the discussion that follows, because reviewers generally did not differentiate between the two. Both ratings were used when documents raised serious ethical concerns for the reviewers. For the total sample of documents from 125 radiation and non-radiation research proposals, two-thirds received ratings of either one, 34 percent, or two, 34 percent. While 18 percent received a rating of three, and 14 percent received a rating of four or five. Level of risk Reviewers identified whether the research proposals, as described in the documents, involved minimal risk or greater than minimal risk of harm to subjects. 78 proposals were considered to involve greater than minimal risk, including 24 proposals that were evaluated as maybe greater than minimal risk, while 47 proposals were considered to involve minimal risk. There was a marked difference in the distribution of ratings between minimal risk and greater than minimal risk studies, although a substantial number of greater than minimal risk studies received ratings of one or two, all of the studies that received fours and fives were considered greater than minimal risk. Radiation versus non-radiation research While about 70 percent of both radiation and non-radiation proposals received ratings of one or two, a somewhat higher proportion of non-radiation studies than radiation studies received overall ratings of four or five. This difference could not be explained by differences in level of risk. The proportion of studies in the non-radiation subsample and the radiation subsample that involved greater than minimal risk were essentially the same. Perhaps the lower proportion of proposals in the radiation sample, whose documents were rated as ethically problematic, can be attributed to the second layer of scrutiny that is often afforded to radiation studies during the initial review process. It must be noted, however, that because there were few studies that received ratings of four or five, differences between radiation and non-radiation studies may not be significant.