Recommendations 13-16

Chapter 18: Recommendations 7-12

Recommendation 7

The Advisory Committee recommends to the Human Radiation Interagency Working Group that it, together with Congress, give serious consideration to amending the provisions of the Radiation Exposure Compensation Act of 1990 relating to uranium miners in order to provide compensation to all miners who develop lung cancer after some minimal duration of employment underground (such as one year), without requiring a specific level of exposure. The act should also be reviewed to determine whether the documentation standards for compensation should be liberalized.

The uranium miners were exposed to extremely high levels of radon daughters, which were recognized at the time to be hazardous yet were not controlled by the government, despite the availability of feasible means to ventilate the mines. Furthermore, the government studied the miners without disclosing the purposes of the examinations or warning them of the hazards to which they were exposed. As a result of their continued exposure, hundreds of miners developed lung cancer or nonmalignant respiratory diseases that could have been prevented, and many of them have died.

In recognition of this tragedy, Congress included provisions for compensating certain uranium miners in the Radiation Exposure Compensation Act of 1990 (RECA). However, the criteria for compensation set in this act were far more stringent than for the two other groups (atomic veterans and downwinders of the Nevada Test Site) for which compensation was provided, despite the fact that the risks were far higher for the uranium miners.

Since 1990, additional scientific information has become available to support the view that radon exposure is responsible for a much higher proportion of the lung cancer cases among the miners than had been previously thought. In particular, the act's current requirement of a minimum of 200 WLM (working level months) exposure for nonsmokers or 300 to 500 WLM (depending on age) for smokers translates to quite large probabilities of causation, according to a recent report by the National Cancer Institute.[5] That analysis finds little evidence to support a distinction between smokers and nonsmokers and suggests that a majority of lung cancer deaths among Colorado white miners and New Mexico Navajo miners are attributable to radon exposure. Furthermore, it finds that the lung cancer risk is strongly modified by a number of factors and uncertainties that are not accounted for in the total dose; thus, for many miners, the level of exposure that would merit compensation on the basis of the principle of "balance of probabilities" might be far lower than the present criteria. In particular, no exposure measurements are available for 90 percent of the years in most mines, so that any requirement to reconstruct exposure histories is likely to require some degree of extrapolation or estimation and be quite uncertain. Furthermore, many mines have since gone out of business, so that records needed to establish an exposure history are simply unavailable.

Also since 1990, there has been considerable experience with the administration of the act, and apparently much of it has been negative. The Advisory Committee took extensive testimony regarding the difficulties faced by miners in meeting the documentation requirements, particularly those related to the requirement to provide a reconstruction of their radon dose. For these practical reasons, and in light of the additional information, we suggest that the requirement that a miner demonstrate that he had been exposed to a certain minimum cumulative dose be replaced by a simple requirement that he worked underground for a certain minimum length of time. Since more than half the lung cancer deaths in the cohort who worked at least one month underground appear to be attributable to radon, we suggest that minimum length of service be set quite low, preferably not more than a year. At most this should then lead to compensation being awarded to twice as many miners as would be entitled to it under the balance of probabilities principle, while not denying it to any who are entitled to it.

The grave injustice that the government did to the uranium miners, by failing to take action to control the hazard and by failing to warn the miners of the hazard, should not be compounded by unreasonable barriers to receiving the compensation the miners deserve for the wrongs and harms inflicted upon them as they served their country.

Recommendation 8

The Advisory Committee supports the Department of Energy's program of medical monitoring and treatment for the exposed inhabitants of the Marshall Islands atolls of Rongelap and Utirik and recommends that this program be continued as long as any member of the exposed population remains alive. Furthermore, the Advisory Committee recommends that the program be reviewed to determine if it is appropriate to add to the program the populations of other atolls to the south and east of the blast whose inhabitants may have received exposures sufficient to cause excess thyroid abnormalities. The Advisory Committee also recommends that consideration be given to the involvement of the Marshall Islanders in the design of any further medical research to be conducted upon them and the Advisory Committee recommends that the Human Radiation Interagency Working Group consider establishing an independent panel to review the status and adequacy of the current program of medical monitoring and medical care provided by the United States to the exposed population of the Marshall Islands.

The 1954 Bravo hydrogen bomb test caused the populations of several Marshall Islands atolls to be exposed to hazardous levels of radiation. The United States has provided a medical follow-up program that combines research on radiation effects with treatment for radiation-related illnesses. It is noteworthy that as a result of the ongoing program to study radiation effects, many cases of thyroid disease were detected and treated, but not all exposed Marshallese received the benefits of the program. The people of Ailuk, for example, who according to early reports received about the same exposure as the people of Utirik, were never evacuated from their atoll and were not followed up medically, even though they received a radiation dose of more than six roentgens. Moreover, an epidemiological study reported in the Journal of the American Medical Association in 1987 demonstrated that inhabitants of several atolls to the east and south of Bikini had elevated levels of thyroid disease and that there was a "strong inverse linear relationship" between incidence of thyroid nodules and distance from the blast. It should also be noted that the exposed populations received additional doses of radiation over the years from later bomb tests and residual radiation on the atolls. The medical program is ongoing, but Congress has the authority to reduce or eliminate funding.

Available evidence indicates that many Marshallese--it is impossible to identify specific individuals--were not adequately informed about the purposes of the medical tests to which they were subjected. There is also evidence in the documentary record that the Marshallese often did not understand the relationship between the research and medical care components of the medical follow-up program. For example, Dr. Robert A. Conard headed the program, and according to his report on twenty years of medical treatment and monitoring, "the people did not always understand the need for the examinations, or their results." Although this situation has improved in recent years, it would nevertheless be appropriate to consult with the Marshallese in the design and implementation of further medical research so as to minimize any possibility of misunderstanding and to ensure that the priorities of the Marshallese are a consideration in the planning of such research.

The Advisory Committee supports the continuation of the Department of Energy's program of medical monitoring and medical care for the exposed inhabitants of the Marshall Islands. Questions have been raised during the course of our deliberations as to whether this program is running as well as it should, both with respect to the research and monitoring activities conducted by Brookhaven National Laboratory (BNL) and with respect to the medical care provided. In particular, the issue has emerged whether the medical care ought to be expanded to include treatment for conditions that are not radiogenic as a further remedy to Marshallese people who were exposed, however inadvertently, as a result of weapons tests. The Advisory Committee did not have the resources to pursue these issues, but we believe that they deserve serious consideration. One mechanism through which this could be accomplished is the establishment of an independent panel to review the program with input from the Marshallese as to the panel's composition.

Recommendations for the Protection of the Rights and Interests of Human Subjects in the Future

While we were constituted to consider issues related to human radiation experiments, in critical (but not all) respects, the government regulations that apply to human radiation research do not differ from those that govern other kinds of research. In comparison with the practices and policies of the 1940s and 1950s, there have been significant advances in the protection of the rights and interests of human subjects. These advances, initiated primarily in the 1970s and 1980s, culminated in the adoption of the Common Rule throughout the federal government in 1991. Although the Common Rule now affords all human subjects of research funded or conducted by the federal government the same basic regulatory protections, the work of the Advisory Committee suggests that there are serious deficiencies in some parts of the current system. These deficiencies are of a magnitude warranting immediate attention.

The Committee was not able to address the extent to which these deficiencies are a function of inadequacies in the Common Rule, inadequacies in the implementation and oversight of the Common Rule, or inadequacies in the awareness of and commitment to the ethics of human subject research on the part of physician-investigators and other scientists. We urge that in formulating responses to the recommendations that follow, the Human Radiation Interagency Working Group consider each of these factors and subject them to careful review.

Recommendation 9

The Advisory Committee recommends to the Human Radiation Interagency Working Group that efforts be undertaken on a national scale to ensure the centrality of ethics in the conduct of scientists whose research involves human subjects.

A national understanding of the ethical principles underlying research and agreement about their importance is essential to the research enterprise and the advancement of the health of the nation. The historical record makes clear that the rights and interests of research subjects cannot be protected if researchers fail to appreciate sufficiently the moral aspects of human subject research and the value of institutional oversight.

It is not clear to the Advisory Committee that scientists whose research involves human subjects are any more familiar with the Belmont Report[6] today than their colleagues were with the Nuremberg Code forty years ago. The historical record and the results of our contemporary projects indicate that the distinction between the ethics of research and the ethics of clinical medicine was, and is, unclear. It is possible that many of the problems of the past and some of the issues identified in the present stem from this failure to distinguish between the two.

The necessary changes are unlikely to occur solely through the strengthening of federal rules and regulations or the development of harsher penalties. The experience of the Advisory Committee illustrates that rules and regulations are no guarantee of ethical conduct. The Advisory Committee has also learned, in responses to our query of institutional review board (IRB) chairs, that many of them perceive researchers and administrators as having an insufficient appreciation for the ethical dimensions of research involving human subjects and the importance of the work of IRBs. The federal government must work in concert with the biomedical research community to exert leadership that alters the way in which research with human subjects is conceived and conducted so that no one in the scientific community should be able to say "I didn't know" or "nobody told me" about the substance or importance of research ethics.

The Advisory Committee recommends that the Human Radiation Interagency Working Group institute, in conjunction with the biomedical community, a commitment to the centrality of ethics in the conduct of research involving human subjects. We urge that careful consideration be given to the development of effective strategies for achieving this change in the culture of human subjects research, including, specifically, how best to balance policies that mandate the teaching of research ethics with policies that encourage and support private sector initiatives. It may be useful to commission a study or convene an advisory panel charged with developing and perhaps implementing recommendations on how best to approach this challenge for the research community.[7]

The Committee suggests that such an examination include consideration of the following:

• Extending to all federal grant recipient institutions and all students and trainees involved or likely to be involved in human subject research the current federal requirement that institutions receiving NIH National Research Service Award training grants offer programs in the responsible conduct of research.
• The role of accrediting bodies such as the Joint Commission on Accreditation of Healthcare Organizations (JCAHO).
• Establishing competency in research ethics as a condition of receipt of federal research grants, both for institutions and individual investigators.
• Incorporating of research ethics, and the differences between the ethics of research involving human subjects and the ethics of clinical medical care, into curricula for medical students, house staff, and fellows.
• Encouraging the nation's leaders in biomedical research to spearhead efforts to elevate the importance of research ethics in science.

Recommendation 10

The Advisory Committee recommends to the Human Radiation Interagency Working Group that the IRB component of the federal system for the protection of human subjects be changed in at least the five critical areas described below.

1. Mechanisms for ensuring that IRBs appropriately allocate their time so they can adequately review studies that pose more than minimal risk to human subjects. This may include the creation of alternative mechanisms for review and approval of minimal-risk studies.

The majority of the Advisory Committee's concerns in its Research Proposal Review Project centered on research that exposed subjects to greater than minimal risk of harm. If human subjects are to be adequately protected, such research must be carefully scrutinized. However, higher risk research is often complex, and careful review is time-consuming and difficult. The Advisory Committee heard from several chairs of IRBs who underscored the difficulties their committees experience in finding the time to adequately review such research. Members of IRBs have only so many hours they can devote to review of proposals. This problem of inadequate time appears to have worsened in recent years. Institutional review boards are required to review research proposals prior to their review for funding by the National Institutes of Health. As the probability that a proposal will be approved for funding has decreased over time, due to increasing competition for limited research monies, the number of proposals being submitted to NIH from many institutions has significantly increased. This has resulted in a substantial increase in the workload of some IRBs, whose members are spending considerable time reviewing proposals that are never implemented. Without guidance from the federal government, and perhaps regulatory relief, IRBs may not have the flexibility necessary to concentrate their efforts where subjects are in greatest need of protection--on the proposals that pose the greatest risks to subjects and that are actually implemented.

2. Mechanisms for ensuring that the information provided to potential subjects (1) clearly distinguishes research from treatment, (2) realistically portrays the likelihood that subjects may benefit medically from their participation and the nature of the potential benefit, and (3) clearly explains the potential for discomfort and pain that may accompany participation in the research.

The Advisory Committee's empirical studies and public testimony suggests that there may be considerable confusion in the minds of many members of the public concerning what is "research" or "experimentation," and what is simply an application of a new technology or even standard medical care. There is reason to worry that participants in research may have unrealistic expectations both about the possibility that they will personally benefit from participation and about the discomfort, pain, and suffering that sometimes accompany some research. This seemed particularly to be the case in Phase I and Phase II drug trials. It is important that in the informed consent process it is clearly communicated to the potential subject, particularly the potential patient-subject, that the primary intent of "research" is to advance medical knowledge and not to advance the welfare of particular subjects. Inadequate and potentially misleading information about potential benefits and harms, and about the trade-offs between enrollment in research and standard or conventional treatment, was one of the major problems identified by the Advisory Committee in our Research Proposal Review Project.

3. Mechanisms for ensuring that the information provided to potential subjects clearly identifies the federal agency or agencies sponsoring or supporting the research project in whole or in part and all purposes for which the research is being conducted or supported.

A morally complicating factor in several of the human radiation experiments the Advisory Committee has studied is the tendency to disclose to subjects only the medical purpose of the research (if that) and not those purposes of the research that advance interests other than medical science or the sponsorship of agencies other than DHEW/DHHS. For example, in the case of the total-body irradiation experiments, the data gathered from the research had a military purpose quite distinct from questions of cancer therapy. The purpose and funding source may be relevant to a person's decision to participate in human subject research and should be disclosed.

4. Mechanisms for ensuring that the information provided to potential subjects clearly identifies the financial implications of deciding to consent to or refuse participation in research.

Many of the consent forms that the Committee reviewed as part of the Research Proposal Review Project were silent on the subject of financial costs. However, knowing whether being in research costs or saves them money may be necessary for potential subjects to make an informed decision about whether to participate. Potential subjects need to know whether the interventions that are part of the research are free or must be paid for and--if there are any financial costs--what they are, the likelihood that third-party payers will pay for these research-related medical services, and the extent to which the research institution will assist patient-subjects in securing third-party payment or reimbursement.

5. Recognition that if IRBs are to adequately protect the interests of human subjects, they must have the responsibility to determine that the science is of a quality to warrant the imposition of risk or inconvenience on human subjects and, in the case of research that purports to offer a prospect of medical benefit to subjects, to determine that participating in the research affords patient-subjects at least as good an opportunity of securing this medical benefit as would be available to them without participating in research.

In research involving human subjects, good ethics begins with good science. In our Research Proposal Review Project, the Advisory Committee was unable to evaluate the scientific merit of a significant number of proposals based on the documents provided by institutions. We suspect that this occurred in part because there is ambiguity about the role that IRBs should play with respect to evaluation of scientific merit and, thus, that documents submitted to IRBs may be inadequate in this area. The Advisory Committee also heard dissatisfaction with this ambiguity in our interviews and oral histories of researchers and from chairs of IRBs. If the science is poor, it is unethical to impose even minimal risk or inconvenience on human subjects. Although the fine points of the relative merit of research proposals are best left to study sections and other review mechanisms specially constituted to make such judgments, IRBs must be situated to assure themselves that the science they approve to go forward with human subjects satisfies some minimal threshold of scientific merit. In some cases, the IRB may be the only opportunity for this kind of scientific review.

In our Subject Interview Study interviews with patient-subjects, we confirmed that patient-subjects often base their decisions to participate in research on the belief that physicians, and research institutions generally, would not ask them to enter research projects if becoming a research subject was not in their medical best interests. For these patients, even the most candid, clearly written consent form affords little protection, for both the consent form and the consent process are of little interest to them. For patient-subjects whose decisions to participate in research are based on trust, and not on an assessment of disclosed information, the IRB review is of special importance. It is the only source of protection in the federal system for regulating human research positioned to ensure that their participation in research does not compromise their medical interests. Such a determination, however, often requires more specialized clinical expertise than any one IRB can possess. Federal policy must make it clear that IRBs have the responsibility to make this determination, but it must also allow mechanisms to be devised at the local level that permit this responsibility to be satisfied in an efficient and effective manner.

Recommendation 11

The Advisory Committee recommends to the Human Radiation Interagency Working Group that a mechanism be established to provide for the continuing interpretation and application of ethics rules and principles for the conduct of human subject research in an open and public forum. This mechanism is not provided for in the Common Rule.

Issues in research ethics are no more static than issues in science. Advances in biomedical research bring new twists to old questions in ethics and sometimes raise new questions altogether. No structure is currently in place for interpreting and elaborating the rules of research ethics, a process that is essential if research involving human subjects is to have an ethical framework responsive to changing times. Also, for this framework to be effective, any changes or refinements to it must be debated and adopted in public; otherwise, the framework will fail to have the respect and support of the scientific community and the American people, so necessary to its success.

Three examples of outstanding policy issues in need of public resolution that the Advisory Committee confronted in our work are presented below:

1. Clarification of the meaning of minimal risk in research with healthy children, including, but not limited to, exposure to radiation.

2. Regulations to cover the conduct of research with institutionalized children.

3. Guidelines for research with adults of questionable competence. Of particular concern is more-than-minimal-risk research that offers adults of questionable competence no prospect of offsetting medical benefit.

Current regulations permit the involvement of children as subjects in research that offers no prospect of medical benefit to participants when the research poses no more than minimal risk. An important question that has come to the Advisory Committee's attention, both in the literature and in our Research Proposal Review Project, is whether research proposing to expose healthy children to tracer doses of radiation constitutes minimal risk. The uncertainty surrounding this issue calls into question the adequacy of the federal regulations, as currently formulated, in providing guidance for this category of research. This is a policy question that ought to be discussed and resolved in a public forum at the national level, not left to the deliberations of individual IRBs.

Current regulations do not provide any special protections for children who are institutionalized unless they are also wards of the state. Thus, researchers and IRBs have no more guidance from the federal government on the ethics of conducting such research than was available at the time of the Fernald and Wrentham experiments, decades ago.

The Advisory Committee also confronted in its Research Proposal Review Project another issue of research policy deserving public debate and resolution in a public forum. This is the issue of whether and under what conditions adults of questionable capacity can be used as subjects in research that puts them at more than minimal risk of harm and from which they cannot realize direct medical benefit. It is important that the nation decide together whether or under what conditions it is ever permissible to use a person toward a valued social end in an activity that puts him or her at risk but from which the person cannot possibly benefit medically.

Recommendation 12

The Advisory Committee recommends to the Human Radiation Interagency Working Group that at least the following four steps be taken to improve existing protections of the rights and interests of military personnel with respect to human subject research.

1. Review of policies and procedures: Policies and procedures governing research involving human subjects should be reviewed to ensure that they (1) clearly state that participation as research subjects by members of the armed services is voluntary and without repercussions for those who choose not to participate; and (2) clearly distinguish those activities that are research and therefore discretionary on the part of members of the armed services from other activities that are obligatory, such as training maneuvers and medical interventions intended to protect the troops.

2. Appreciation of regulations: Education in applicable human subjects regulations should be a component of the training of all officers and investigators who may be involved in decisions regarding research on human subjects. Mechanisms are needed to ensure that officers expected to have command responsibilities and all officers engaged in research, development, testing, and evaluation have an adequate appreciation of the regulations (including DOD regulations and directives, and service regulations) that bear on the conduct of research involving human subjects, including an appreciation of the conditions under which such regulations apply, the role of officers in interpreting such regulations, and how such regulations are to be implemented.

3. Maximizing voluntariness: The service secretaries should consider the situations under which it would be appropriate to make obligatory two practices for maximizing voluntariness that have been employed on an ad hoc basis in some military research: first, that unit officers and senior noncommissioned officers (NCOs) who are not essential as volunteers in the research be excluded from recruitment sessions in which members of units are informed of the opportunity and asked to participate in research by investigators; and second, that an ombudsman not connected in any way with the proposed research be present at all such recruitment sessions to monitor that the voluntariness of participation is adequately stressed and that the information provided about the research is adequate and accurate.

The Advisory Committee recommends consideration of steps 1 through 3 above in light of our examination of history that makes plain how difficult it often is in a military context to distinguish an order from a request for voluntary participation and to distinguish research from training. (These tensions are similar in many respects to tensions in the clinical context between research and treatment.) Although the military has a long tradition of commitment to the use of volunteers in research and has introduced significant advances in the military's system of protection for human subjects since the 1940s and 1950s, without constant attention to these inherent tensions, the potential for confusion and inappropriate practice continues.

The military setting, with its strict hierarchical authority structure and pervasive presence in the lives of its members, poses special problems for ensuring the voluntariness of participation in research activities. Thus, although the DOD has adopted and implemented the consent requirements of the Common Rule, additional procedural safeguards and educational activities for officers may be warranted to counteract the generalized deference to authority inherent in military culture. Also, because the opportunity to serve the nation as subjects in defense-oriented research projects is closely akin to the demands placed on members of the military in their routine duties, it is desirable to emphasize the distinction between research and course-of-duty risks both in consent procedures and in officer training programs.

The Advisory Committee recognizes that additional procedural requirements in soliciting research volunteers and augmenting already demanding training curricula would have administrative costs and, to a limited extent, would shift organizational priorities. It is the Advisory Committee's understanding that the DOD is preparing to revise its directive implementing the Common Rule and that the Advisory Committee's recommendations with respect to steps 1 through 3 above are a timely contribution to the department's deliberations.

Military personnel are exposed to both short- and long-term risks in the course of training and regular duty activities as well as when they participate in biomedical or behavioral experiments. The demarcation of those activities that are research in contrast with those that constitute routine duty assignments and medical care in the military context is not always easy to discern from the standpoint of the potential subject-member of the military. Indeed, except in medical settings where research studies are regularly performed and military testing sites that conduct weapons, matériel, and performance trials routinely, officers as well as their troops may be uncertain as to whether the status of particular exercises is research or training. Greater clarity in communications to potential subjects about the genuinely voluntary nature of participation in research projects and procedural safeguards in recruiting volunteers could improve their understanding of what they are being asked (rather than required) to do. Likewise, educating officers throughout the military services who may be in a position to solicit volunteers for research studies as to the distinctive rights of research subjects and the particular duties to protect subjects of research from both harm and violations of rights would make the Common Rule protections of subjects more effective.

4. Maintenance of a registry: The secretaries of the Navy and the Air Force should be directed to adopt the policy of the Army, as detailed in Army Regulation 70-25, to maintain a registry of all volunteers in human studies and experiments conducted under research and development programs. Such registries make it easier to confirm participation in research by subjects and facilitates their long-term follow-up.

In analyzing the record of atomic bomb testing, the Advisory Committee has found that military personnel were exposed to radiation and nonradiation risks as participants in experiments that were conducted in conjunction with the tests, and as participants in other activities connected to the testing. While these activities were not intended to measure biological effects of ionizing radiation, the exposure to radiation risk was incurred without adequate provision for the maintenance of records to document exposures or in order to allow for monitoring and follow-up of those who were exposed. Army regulations now provide for a registry of participants in experiments conducted under the authority of the Army's research and development program. This tool for long-term monitoring and follow-up in the case of exposures to risks unknown at the time of participation should be employed by the other services as well.