Ethical Issues in the Use of Data from Testing of Human Subjects to Support Risk Assessment

The public understands and supports the ethical use of human subjects in medical research, recognizing the unique role for this type of study in the development of new drugs and therapeutic strategies for treatment of disease. The use of data from human subjects can also be of value in understanding the circumstances under which individuals exposed to chemicals in the food supply, in the workplace, or in the environment might experience toxicity, i.e., in support of risk assessment. However, questions have been raised as to whether this latter type of research is ethical, or can be performed in an ethical manner. Under what circumstances is it acceptable to intentionally expose human subjects to potentially toxic agents? This is an extremely important issue for the risk assessment community to address, because it affects in a fundamental way the types of information that will be available to conduct human health risk assessments. Four papers in this issue offer viewpoints on the value of human data, the circumstances under which human subjects might be exposed to toxic chemicals for research purposes, the ethical problems associated with this research, and the role of human vs. animal data in the development of toxicity values for human health risk assessment     

Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data

In longitudinal studies it is often of interest to investigate how a marker that is repeatedly measured in time is associated with a time to an event of interest. This type of research question has given rise to a rapidly developing field of biostatistics research that deals with the joint modeling of longitudinal and time-to-event data. In this article, we consider this modeling framework and focus particularly on the assessment of the predictive ability of the longitudinal marker for the time-to-event outcome. In particular, we start by presenting how survival probabilities can be estimated for future subjects based on their available longitudinal measurements and a fitted joint model. Following we derive accuracy measures under the joint modeling framework and assess how well the marker is capable of discriminating between subjects who experience the event within a medically meaningful time frame from subjects who do not. We illustrate our proposals on a real data set on human immunodeficiency virus infected patients for which we are interested in predicting the time-to-death using their longitudinal CD4 cell count measurements.     

Impact of Open Data Policies on Consent to Participate in Human Subjects Research: Discrepancies between Participant Action and Reported Concerns

Research outlets are increasingly adopting open data policies as a requisite for publication, including studies with human subjects data. We investigated whether open data policies influence participants’ rate of consent by randomly assigning participants to view consent forms with and without discussion of open data policies. No participants declined to participate, regardless of condition, nor did rates of drop-out vs. completion vary between conditions. Furthermore, no significant change in potential consent rates was reported when participants were openly asked about the influence of open data policies on their likelihood of consent. However, follow-up analyses indicated possible poor attention to consent forms, consistent with previous research. Moreover, thematic analysis of participants’ considerations of open data policy indicated multiple considerations such as concerns regarding confidentiality, anonymity, data security, and study sensitivity. The impact of open data policies on participation raises complex issues at the intersection of ethics and scientific innovation. We conclude by encouraging researchers to consider participants as stakeholders in open data policy and by providing recommendations for open data policies in human subjects research.     

The cross-cultural study of emotions

The problems encountered in cross-cultural research are detailed and the way they affect the study of emotions is discussed. They include: obtaining samples of subjects in developing countries that are comparable to samples studied in the West; constructing tasks and writing and translating questions that are meaningful for subjects from a variety of cultures; dealing with subjects to whom the experimental method appears strange; and attempting to eliminate ethnocentric bias from the design of studies, the perception of subjects' responses, and the interpretation of data. Psychiatric studies of emotional disorders and psychological studies of the perception of emotion across cultures are reviewed in relation to these problems. It is concluded that this area of study is in its infancy, and guidelines for future development are laid down.     

Certificates of confidentiality in research: rationale and usage

Certificates of confidentiality (COCs) are a tool to protect researchers from being compelled to release identifying information about their subjects. Whereas institutional review board (IRB) review and informed consent procedures are mandatory tools to protect human subjects, COCs are voluntary. There are limited data about who procures COCs and why, and whether they are useful. Three Institutes of the National Institutes of Health (NIH) provided data on 114 research projects that had received COCs. Eighty-three researchers had procured a single COC and 11 researchers had procured 31 COCs. One hundred and four (91%) of the COCs were obtained by researchers at academic sites, and 17 institutions collectively accounted for 82 COCs. The most commonly cited sources of information about COCs came from colleagues (n = 18, 35%) and previous experience (n = 17, 33%). The most common reasons for procuring a COC were that the research involved genetics (n = 28, 54%), the research could lead to social stigmatization or discrimination (n = 22, 42%), or the research could damage an individual's financial standing, employability, or reputation (n = 21, 40%). These findings show that COCs are often congregated within institutions and by particular individuals. This may be because others are unaware of COCs or because others do not believe they are necessary or useful.     

Consent and confidentiality in the light of recent demands for data sharing

Many attempts have been made to formalize ethical requirements for research. Among the most prominent mechanisms are informed consent requirements and data protection regimes. These mechanisms, however, sometimes appear as obstacles to research. In this opinion paper, we critically discuss conventional approaches to research ethics that emphasize consent and data protection. Several recent debates have highlighted other important ethical issues and underlined the need for greater openness in order to uphold the integrity of health‐related research. Some of these measures, such as the sharing of individual‐level data, pose problems for standard understandings of consent and privacy. Here, we argue that these interpretations tend to be overdemanding: They do not really protect research subjects and they hinder the research process. Accordingly, we suggest another way of framing these requirements. Individual consent must be situated alongside the wider distribution of knowledge created when the actions, commitments, and procedures of researchers and their institutions are opened to scrutiny. And instead of simply emphasizing privacy or data protection, we should understand confidentiality as a principle that facilitates the sharing of information while upholding important safeguards. Consent and confidentiality belong to a broader set of safeguards and procedures to uphold the integrity of the research process.     

Comparison of research cost: man--primate animal--other animal models

The costs of research in human subjects are compared to those in primate animals and in other animal models on the basis of data available from a U.S. institution. The cost of experimentation in a chimpanzee is 3.59% of the per diem cost of clinical research in man. The cost for the dog is 37.1% of that of the chimpanzee, and the mouse costs 2.02% of the cost of the dog.     

On the Alleged Right to Participate in High‐Risk Research

Reigning regulatory frameworks for biomedical research impose on researchers and research ethics committees an obligation to protect research participants from risks that are unnecessary, disproportionate to potential research benefits, and non‐minimized. Where the research has no potential to produce results of direct benefit to the subjects and the subjects are unable to give consent, these requirements are strengthened by an additional condition, that risks should not exceed a certain minimal threshold. In this article, I address the question of whether there should be limits of permissible risks in non‐therapeutic research involving competent and healthy subjects. Some commentators argue that competent and informed individuals should have a right to participate even in extremely risky research and that research ethics committees should never reject studies because they are too dangerous. To use David Shaw's expression, competent volunteers should have ‘a right to participate in high‐risk research’. I argue that this idea is ill‐founded, as it does not take into account the social mission and complex collaborative nature of research practice as well as the inequity of power between researchers and subjects. Imposition of limits on permissible risks for healthy volunteers is justified by the need to protect research enterprise and the need to protect the weaker party, namely the subjects. Also, I suggest that the best way to set boundaries on research risks is to leave the judgment of risk acceptability to research ethics committees.     

A bar code scoring system for behavioral research

A data collection method using lap-top computers and bar codes was developed and used in behavioral research. The studies involved several common sampling methods and a variety of study subjects. Advantages and restrictions of the system are discussed. Overall, we found bar code technology to increase both efficiency and accuracy of behavioral data collection.     

Certificates of confidentiality: a valuable tool for protecting genetic data.

Protecting the confidentiality of genetic research data is an important aspect of genetic research that has been discussed in various forums. Research data must be protected to prevent discrimination and its use in litigation. The certificate of confidentiality was created to protect the subjects of alcohol- and drug-abuse studies, who may be engaging in illegal activities. As revised in 1988, the certificate protects investigators engaging in other kinds of studies from being compelled to reveal information about subjects. Because the certificate protects information that could damage a subject's financial or social standing or employability, it is an appropriate tool to use to maintain the confidentiality of genetic data. The Department of Health and Human Services issues the certificates; the procedure for applying for a certificate of confidentiality is presented.     

Adjusting the focus: A public health ethics approach to data research

This paper contends that a research ethics approach to the regulation of health data research is unhelpful in the era of population‐level research and big data because it results in a primary focus on consent (meta‐, broad, dynamic and/or specific consent). Two recent guidelines – the 2016 WMA Declaration of Taipei on ethical considerations regarding health databases and biobanks and the revised CIOMS International ethical guidelines for health‐related research involving humans – both focus on the growing reliance on health data for research. But as research ethics documents, they remain (to varying degrees) focused on consent and individual control of data use. Many current and future uses of health data make individual consent impractical, if not impossible. Many of the risks of secondary data use apply to communities and stakeholders rather than individual data subjects. Shifting from a research ethics perspective to a public health lens brings a different set of issues into view: how are the benefits and burdens of data use distributed, how can data research empower communities, who has legitimate decision‐making capacity? I propose that a public health ethics framework – based on public benefit, proportionality, equity, trust and accountability – provides more appropriate tools for assessing the ethical uses of health data. The main advantage of a public health approach for data research is that it is more likely to foster debate about power, justice and equity and to highlight the complexity of deciding when data use is in the public interest.     

Sleep and pregnancy

Sleep disturbances are frequent during pregnancy and are currently regarded as one of the most important factors determining pregnancy outcome. Detailed research of sleep features during pregnancy is obviously essential. In the present review recent data concerning changes in sleep structure and regulation in pregnant women and rats - main subjects of experimental sleep research, are given, including surmised mechanisms underlying such changes. The importance of women's sleep integrity preservation during pregnancy for the viability and normal development of the fetus is emphasized and possible ways of pathological influence of sleep disorders during this period are discussed.     

Erosion of informed consent in U.S. research

This paper evaluates four recent randomized clinical trials in which the informed consent of participants was either not sought at all, or else was conducted with critical information missing from the consent documents. As these studies have been taking place, various proposals to conduct randomized clinical trials without consent have been appearing in the medical literature. Some of the explanations offered for why it is appropriate to bypass consent or disclosure requirements appear to represent a fundamental misunderstanding of applicable government regulations and even the research enterprise. Others are the result of conceptual disagreements about the importance and application of traditional research ethics norms to ‘comparative effectiveness research’ and modern research environments. Common among these explanations, however, is a failure to appreciate when a research intervention, rather than merely an observation or review of data, is taking place. Review committees and investigators are failing to see, or choosing to ignore, interventions in the lives of research subjects. When these studies have come to light, government agencies with oversight authority have done little or backed down. Prestigious medical journals have published research results knowing that the required consent was not obtained, or they have stood by the published studies even after the inadequacy of consent is discovered. This article critically examines this erosion of consent in theory and practice and calls for restoring the requirement of informed consent to its proper place as a priority in human subjects research.     

Impairment of renal sodium excretion in tropical residents – phenomenological analysis

There is evidence of impaired renal sodium excretion in salt-sensitive African Blacks. A decreased rate of renal sodium chloride (NaCl) excretion, low plasma renin activity and a tendency to elevated blood pressure are the hallmarks of salt sensitivity. Recent evidence indicates that increased proximal and distal tubular fluid reabsorption in some tropical residents may explain the impaired sodium excretion in these people. In this study of a cohort population, we speculated that subjects selected from that population might be salt-sensitive. We therefore measured the sodium balance in 10 normotensive male subjects over 10 consecutive days, after they had ingested a normal or a high amount of sodium, as NaCl (salt) in their diet. We quantified their renal sodium excretion rate by phenomenological analysis of their sodium balance data. We also measured plasma renin activity for 7 consecutive days in a separate group of 6 male and 4 female subjects in order to assess the state of their renin/angiotensin system. We selected all our subjects from a cohort population of 269 subjects randomly selected from a community known to have a high prevalence of primary hypertension. Our data on two separate groups of subjects from the same cohort population revealed delayed renal sodium excretion with t _1/2 of about 5 days, compared to published data for normal individuals with t _1/2 of less than 24 h. Also, plasma renin activity levels were low. Hence, our subjects are salt-sensitive. Quantification of their renal impairment is important for various reasons: it heightens one’s appreciation of the problem of salt retention in African Blacks who are salt-sensitive and it also underlines the importance of the need for further research into the benefits of dietary salt restriction for reducing cardiovascular mortality in African populations, as has been done in some Western countries. Received: 4 March 1999 / Accepted: 12 May 1999     

Analysis of serial measurements in medical research.

In medical research data are often collected serially on subjects. The statistical analysis of such data is often inadequate in two ways: it may fail to settle clinically relevant questions and it may be statistically invalid. A commonly used method which compares groups at a series of time points, possibly with t tests, is flawed on both counts. There may, however, be a remedy, which takes the form of a two stage method that uses summary measures. In the first stage a suitable summary of the response in an individual, such as a rate of change or an area under a curve, is identified and calculated for each subject. In the second stage these summary measures are analysed by simple statistical techniques as though they were raw data. The method is statistically valid and likely to be more relevant to the study questions. If this method is borne in mind when the experiment is being planned it should promote studies with enough subjects and sufficient observations at critical times to enable useful conclusions to be drawn. Use of summary measures to analyse serial measurements, though not new, is potentially a useful and simple tool in medical research.     

Environmental health research on hazards in the home and the duty to warn

When environmental health researchers study hazards in the home, they often discover information that may be relevant to protecting the health and safety of the research subjects and occupants. This article describes the ethical and legal basis for a duty to warn research subjects and occupants about hazards in the home and explores the extent of this duty. Investigators should inform research subjects and occupants about the results of tests conducted as part of the research protocol only if the information is likely to be accurate, reliable, and medically useful. Investigators should warn subjects and occupants about hazards they happen to discover while they are in the home, if a reasonable person would warn the subjects and occupants about those hazards. Investigators should not report illegal hazards discovered in the home to the authorities, unless those hazards constitute abuse or neglect of children or mentally disabled people living in the home. When investigators decide to warn research subjects and occupants about hazards in the home, they should take some steps to help them make effective use of this information, such as providing additional counselling or making a referral for remediation or medical treatment. Investigators should discuss these issues with research subjects during the informed consent process.     

Overview of FEED, the feeding experiments end-user database

The Feeding Experiments End-user Database (FEED) is a research tool developed by the Mammalian Feeding Working Group at the National Evolutionary Synthesis Center that permits synthetic, evolutionary analyses of the physiology of mammalian feeding. The tasks of the Working Group are to compile physiologic data sets into a uniform digital format stored at a central source, develop a standardized terminology for describing and organizing the data, and carry out a set of novel analyses using FEED. FEED contains raw physiologic data linked to extensive metadata. It serves as an archive for a large number of existing data sets and a repository for future data sets. The metadata are stored as text and images that describe experimental protocols, research subjects, and anatomical information. The metadata incorporate controlled vocabularies to allow consistent use of the terms used to describe and organize the physiologic data. The planned analyses address long-standing questions concerning the phylogenetic distribution of phenotypes involving muscle anatomy and feeding physiology among mammals, the presence and nature of motor pattern conservation in the mammalian feeding muscles, and the extent to which suckling constrains the evolution of feeding behavior in adult mammals. We expect FEED to be a growing digital archive that will facilitate new research into understanding the evolution of feeding anatomy.     

Common husbandry-related variables in biomedical research with animals

Common, often overlooked, variables in biomedical research with animals are reviewed. The barren primary enclosure is an abnormal living environment for laboratory animals. Species-appropriate enrichment attenuates some of the distress resulting from chronic understimulation. Social deprivation distress of individually-caged social animals is best mitigated by the provision of compatible companionship. Biotelemetry and positive reinforcement training avoid or minimize stress reactions that typically occur when animals are forcibly restrained during procedures. The variables, 'light' and 'position of living quarters' are inherent in the multi-tier caging system. To date there is no satisfactory alternative other than the single-tier cage arrangement that eliminates both variables. Removing test animals from their familiar home environment and from their cage mates for procedures introduces stress as an avoidable influential variable. Music may become an important variable if not all subjects are exposed to it. Disturbance time cannot be controlled as an extraneous variable but it should at least be mentioned to explain possible incongruities of data. A positive relationship between animal care personnel and research subjects is a key requisite to minimize stress as a data-confounding variable.     

Effects of brief rest periods upon heart rate in multiple baseline studies of heart rate reactivity

Although there has been some discussion regarding the appropriate length of time necessary for subjects to reach true resting heart rate prior to experimentation, the relevance of conclusions from that discussion for multiple baseline studies of heart rate has not been demonstrated. To investigate this issue, data were collected from 39 males and 33 females following a standard 15-minute adaptation period and then during a series of two-minute experimental phases including stressor tasks and rest periods. Results indicated that, while the group's heart rate during brief rest periods returned to postadaptation levels, there was a substantial subgroup of subjects for whom this was not the case. Implications for the use of multiple baseline procedures in research where heart rate is the dependent variable are discussed.