Evolving values in ethics and global health research.

Over the past 25 years, the ethics of international health research have shifted from addressing narrow issues such as cultural differences in informed consent practices towards a greater emphasis on development and social justice. We anticipate that the next 'era' in international research ethics will involve an intensification of this focus on the role of research in achieving global justice. Three values, in particular, will shape how ethics considerations should evolve: solidarity; respect for Southern innovation; and commitment to action. We expect continuing debate on whether researchers and research sponsors should recognise more than a minimal set of obligations for the care and benefit of research participants and their communities. As the debate about the role of research in development intensifies, we expect to see new and more elaborate mechanisms for financing on-going access to beneficial interventions, ancillary care and other research-related benefits, as well as a greater involvement in research funding by developing country governments and private foundations. Ethics review and oversight need to reflect on these new values and on ways of operationalising them, or risk becoming marginalised in the research process.

Payment to healthy volunteers in clinical research: the research subject's perspective.

Although there is much discussion regarding the ethics of making payments to healthy volunteers for participating in clinical research, little data are available from the point of view of the volunteers as to what they would consider to be fair payment. The objectives of this study were to determine healthy volunteers' estimates of appropriate payments for participation in hypothetical clinical trials in order to explore the reasoning behind these estimates and to examine the association between volunteer demographics and payment expectations. Sixty participants with previous experience as healthy volunteers in research studies were presented with four hypothetical studies and interviewed about their impressions of burden and risks involved in the studies. They were also asked to estimate an appropriate payment to the volunteers for each of the studies. For each of the studies, the payment estimates made by the participants varied over a wide range. However, each individual tended to be consistent in estimate placement within this range. No demographic factor was significantly associated with the estimated study payment. Subjects frequently mentioned risk and logistical burden as factors that should determine payment levels. Healthy volunteer subjects appear to have individualized yet consistent methods of arriving at estimates of payments for participating in clinical studies. These estimates are based on each subject's perception of study burden and associated risk.

Understanding respect: learning from patients.

BACKGROUND: The importance of respecting patients and participants in clinical research is widely recognised. However, what it means to respect persons beyond recognising them as autonomous is unclear, and little is known about what patients find to be respectful. OBJECTIVE: To understand patients' conceptions of respect and what it means to be respected by medical providers. DESIGN: Qualitative study from an academic cardiology clinic, using semistructured interviews with 18 survivors of sudden cardiac death. RESULTS: Patients believed that respecting persons incorporates the following major elements: empathy, care, autonomy, provision of information, recognition of individuality, dignity and attention to needs. CONCLUSIONS: Making patients feel respected, or valued as a person, is a multi-faceted task that involves more than recognising autonomy. While patients' views of respect do not determine what respect means, these patients expressed important intuitions that may be of substantial conceptual relevance.

Balancing justice and autonomy in clinical research with healthy volunteers.

In clinical research, ethics review generally first examines whether study risks are reasonable in light of benefits provided. Through informed consent, then, prospective subjects consider whether the risk/benefit balance and procedures are reasonable for them. Unique ethics issues emerge in clinical research with healthy volunteers. Certain types of studies only recruit healthy volunteers as participants. Phase 1 studies, for example, including first time in human studies of investigational drugs and vaccines, generally are conducted in healthy volunteers. Although such research carries inherent and often unknown risks, healthy subjects provide the most efficient target population in which to conduct such research, as these volunteers generally are free of concurrent diseases or medications that could confound interpretation of toxicity. Other studies enrolling healthy volunteers often are simply looking for the most scientifically sound population for the study of normal human physiology.

Ethical review of health research: a perspective from developing country researchers.

BACKGROUND: Increasing collaboration between industrialised and developing countries in human research studies has led to concerns regarding the potential exploitation of resource deprived countries. This study, commissioned by the former National Bioethics Advisory Commission of the United States, surveyed developing country researchers about their concerns and opinions regarding ethical review processes and the performance of developing country and US international review boards (IRBs). METHODS: Contact lists from four international organisations were used to identify and survey 670 health researchers in developing countries. A questionnaire with 169 questions explored issues of IRB review, informed consent, and recommendations. RESULTS: The majority of the developing country researchers were middle aged males who were physicians and were employed by educational institutions, carrying out research on part time basis. Forty four percent of the respondents reported that their studies were not reviewed by a developing country IRB or Ministry of Health and one third of these studies were funded by the US. During the review process issues such as the need for local language consent forms and letters for approval, and confidentiality protection of participants were raised by US IRBs in significantly higher proportions than by host country IRBs. CONCLUSION: This survey indicates the need for the ethical review of collaborative research in both US and host countries. It also reflects a desire for focused capacity development in supporting ethical review of research.

An ethics framework for public health.

More than 100 years ago, public health began as an organized discipline, its purpose being to improve the health of populations rather than of individuals. Given its population-based focus, however, public health perennially faces dilemmas concerning the appropriate extent of its reach and whether its activities infringe on individual liberties in ethically troublesome ways. In this article a framework for ethics analysis of public health programs is proposed. To advance traditional public health goals while maximizing individual liberties and furthering social justice, public health interventions should reduce morbidity or mortality; data must substantiate that a program (or the series of programs of which a program is a part) will reduce morbidity or mortality; burdens of the program must be identified and minimized; the program must be implemented fairly and must, at times, minimize preexisting social injustices; and fair procedures must be used to determine which burdens are acceptable to a community.

Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening.

Utilizing the plasma very long chain fatty acid assay, supplemented by mutation analysis and immunofluorescence assay, we determined the number of X-linked adrenoleukodystrophy (X-ALD) hemizygotes from the United States identified each year in the two laboratories that perform most of the assays in this country: the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998. The minimum frequency of hemizygotes identified in the United States is estimated to be 1:42,000 and that of hemizygotes plus heterozygotes 1:16,800. Our studies involved 616 pedigrees with a total of 12,787 identified at-risk members. Diagnostic assays were performed in 4,169 at-risk persons (33%) and included members of the extended family. Only 5% of male probands and 1.7% of X-ALD hemizygotes were found to have new mutations. The extended family testing led to the identification of 594 hemizygotes and 1,270 heterozygotes. Two hundred fifty of the newly identified hemizygotes were asymptomatic and represent the group in which therapy has the greatest chance of success. Identification of heterozygotes provides the opportunity for disease prevention through genetic counseling. Diagnostic tests should be offered to all at-risk relatives of X-ALD patients and should include members of the extended family.

Health-related quality of life among people with HIV disease: results from the Multicenter AIDS Cohort Study.

To examine the effect of HIV status, symptomatology and CD4+ lymphocyte level on health-related quality of life, the Medical Outcomes Study Short-Form Health Survey (SF-36) was administered to 2,295 gay men enrolled in the Multicenter AIDS Cohort Study (MACS) in 1994. Distinct physical and mental health factors of the SF-36 were found. Seropositive asymptomatic individuals and seropositive individuals with CD4+ lymphocytes > or = 500/mm3 scored as well as seronegative participants on all of the mental health domain scales, but lower on the general health perceptions and physical health composite score. Seropositive individuals with at least one symptom or with CD4+ lymphocytes below 200/mm3 scored significantly lower on all of the SF-36 scales and summary scores than seronegative controls. The SF-36 was found to exhibit similar mental and physical health factors for an adult gay male population to that previously seen in general population samples and in patient groups with other diseases. In conclusion, HIV-positive men who are asymptomatic or have CD4+ lymphocytes above 500/mm3 have similar perceived mental health but worse perceived physical health than seronegative men. HIV-positive men who are symptomatic or have CD4+ lymphocytes below 200/mm3 have worse perceived mental and physical health than seronegative men.

Treatment of human immunodeficiency virus during pregnancy: the shift from an exclusive focus on fetal protection to a more balanced approach.

A review is presented of policy and treatment guidelines for human immunodeficiency virus infection in pregnancy. Interventions that serve the best interests of pregnant women and their fetuses are suggested. Reproductive studies with animals should be done routinely, and more research with pregnant women should be conducted. Women and their health care providers need to shift away from the "therapeutic nihilism" paradigm. All clinical decisions must be made cautiously and thoughtfully, with the understanding that the health needs of the pregnant woman are usually whatever is in the best interest of the developing fetus.

Trust, The fragile foundation of contemporary biomedical research.

It is widely assumed that informing prospective subjects about the risks and possible benefits of research not only protects their rights as autonomous decisionmakers, but also empowers them to protect their own interests. Yet interviews with patient-subjects conducted under the auspices of the Advisory Committee on Human Radiation Experiments suggest this is not always the case. Patient-subjects often trust their physician to guide them through decisions on research participation. Clinicians, investigators, and IRBs must assure that such trust is not misplaced.

Interpersonal conflict and physical violence during the childbearing year.

Reducing physical abuse directed at women by male partners is one of the nation's Year 2000 health objectives. An important target group for achieving this health objective is pregnant women. The present study examines the frequency, severity, perpetrators and psychosocial correlates of violence during the childbearing year. A panel of 275 women were interviewed 3 times during pregnancy and at 6 months postpartum. Moderate or severe violence was somewhat more common during the postpartum period than during the prenatal period--19% of women reported experiencing moderate or severe violence prenatally, compared to 25% in the postpartum period. For partner-perpetrated violence, being better educated was associated with increased risk of violence as was having had a sex partner who ever shot drugs; being older, having a confidant and having social support from friends were significant protective factors. For violence perpetrated by someone other than a male partner, having a confidant was a significant protective factor. Obstetric care providers who routinely come in contact with pregnant women, as well as emergency department staff, need to be systematically screening for violence against women. Efforts to enhance women's social support networks should be included in primary and secondary prevention programs.

Policy, ethics, and reproductive choice: pregnancy and childbearing among HIV-infected women.

As the numbers of women infected with HIV continue to increase, there are more calls for women who are HIV-infected not to have children, or for policies to be created that limit or try to influence the reproductive choices of HIV-infected women. Although motivated by legitimate concerns, such potential policies may be problematic in terms of their threats to the autonomy of women and considerations of justice. An alternative counseling approach is proposed that advocates encouraging HIV-infected women to make reasoned and considered decisions concerning childbearing. Such an approach would require providers to discuss with women not only the medical facts relevant to vertical transmission, but also many of the psychosocial issues relevant to the woman's interest in bearing a child. Moreover, the encounter would be contextualized to include discussion of issues unique to the woman's situation and other family considerations.

Impact of immunosuppression on health care use by men in the Multicenter AIDS Cohort Study (MACS).

The effects of human immunodeficiency virus type 1 (HIV-1) serostatus, AIDS, and level of immunosuppression on health service use were examined in the Multicenter AIDS Cohort Study. Data on self-reported hospitalizations, outpatient medical services (non-emergency room) and emergency room care during the preceding 6 months were collected for 3,447 homosexual/bisexual men returning for their 14th and/or 15th semiannual visits in Chicago, Baltimore, Los Angeles, and Pittsburgh. AIDS-free seropositive men with CD4+ cells < 200/microliters were more likely to be hospitalized [odds ratio (OR) = 2.3, 95% confidence limits (CL) = 1.4, 3.8] and use outpatient medical care (OR = 7.9, 95% CL = 4.9, 12.6), compared with seronegative men. Increased outpatient care was initiated at the earliest stages of HIV-1 infection, even when CD4+ cells were > 500/microliter. Dramatic increases in outpatient care for each level of immunosuppression were observed. HIV-1-related symptoms were associated with increased hospitalizations (OR = 4.8, 95% CL = 3.2, 7.3), use of outpatient medical services (OR = 3.3, 95% CL = 1.9, 5.6), and emergency room care (OR = 3.1, 95% CL = 2.1, 4.6). Persons with AIDS and < or = 50 CD4+ cells/microliter most likely to be hospitalized (OR = 8.1; 95% CL = 4.4, 14.9). No significant difference (p > 0.05) in emergency room use was observed according to HIV-1 serostatus, AIDS, or immunosuppression, after adjusting for insurance and clinical symptoms. To the extent that CD4+ cell counts are used as one of the criteria for an AIDS diagnosis and such a diagnosis broadens available benefits to persons with HIV disease, the pattern of health care services described here will be important for health care providers and planners.

Changes in employment, insurance, and income in relation to HIV status and disease progression. The Multicenter AIDS Cohort Study.

While patterns of health care financing for HIV have received considerable attention in the literature, the financial impact of disease on individuals living with HIV infection has been underexplored, particularly in relation to disease progression. Therefore, we sought to document changes in employment, income, and insurance coverage over time among HIV-negative, HIV-positive, and AIDS-diagnosed gay and bisexual men participating in the Multicenter AIDS Cohort Study (MACS) and to document measures of financial hardship. Persons with AIDS (PWAs) were 2.7 times more likely to lose full-time employment over a 6-month period than seronegative persons (p < 0.05), and loss of employment was strongly associated (p < 0.001) with both loss of private health insurance and loss of income. Twenty-seven percent of PWAs reported having financial difficulty meeting their basic expenses, compared with 10% of seronegative (p < 0.001), and 15% of PWAs, compared with only 9% of seronegative persons, said that, for financial reasons, they had not sought medical care that they thought they needed (p = 0.028). When 27% of PWAs in a cohort such as this report financial difficulty meeting their basic expenses, it is clear that the response of our public health and social welfare systems has not been adequate. Given that the problems experienced by most persons infected by HIV are considerably more severe than those experienced by MACS participants, the imperative for action is even greater.