Equipoise,design bias,and randomized controlled trials: the elusive ethics of new drug development

The concept of 'equipoise', or the 'uncertainty principle', has been represented as a central ethical principle, and holds that a subject may be enrolled in a randomized controlled trial (RCT) only if there is true uncertainty about which of the trial arms is most likely to benefit the patient. We sought to estimate the frequency with which equipoise conditions were met in industry-sponsored RCTs in rheumatology, to explore the reasons for any deviations from equipoise, to examine the concept of 'design bias', and to consider alternative ethical formulations that might improve subject safety and autonomy. We studied abstracts accepted for the 2001 American College of Rheumatology meetings that reported RCTs, acknowledged industry sponsorship, and had clinical end-points (n = 45), and examined the proportion of studies that favored the registration or marketing of the sponsor's drug. In every trial (45/45) results were favorable to the sponsor, indicating that results could have been predicted in advance solely by knowledge of sponsorship (P < 0.0001). Equipoise clearly was being systematically violated. Publication bias appeared to be an incomplete explanation for this dramatic result; this bias occurs after a study is completed. Rather, we hypothesize that 'design bias', in which extensive preliminary data are used to design studies with a high likelihood of being positive, is the major cause of the asymmetric results. Design 'bias' occurs before the trial is begun and is inconsistent with the equipoise principle. However, design bias increases scientific efficiency, decreases drug development costs, and limits the number of subjects required, probably reducing aggregate risks to participants. Conceptual and ethical issues were found with the equipoise principle, which encourages performance of negative studies; ignores patient values, patient autonomy, and social benefits; is applied at a conceptually inappropriate decision point (after randomization rather than before); and is in conflict with the Belmont, Nuremberg, and other sets of ethical principles, as well as with US Food and Drug Administration procedures. We propose a principle of 'positive expected outcomes', which informs the assessment that a trial is ethical, together with a restatement of the priority of personal autonomy.     

Gonorrhea and the beginnings of clinical research ethics

Research on ocular inflammation associated with gonorrhea began in conjunction with the entry of trachoma into Europe during the Napoleonic wars. The initial questions involved the cause of the contagiousness of gonorrhea and how the contagion spreads from the genitalia to other sites. Because efforts to infect animals with gonorrheal matter were unsuccessful, all experiments were conducted on human subjects. Once these two causes of blindness were tentatively differentiated, attempts to restore vision in an eye that had been blinded by a trachomatous membrane over the cornea by instilling gonorrheal pus began to be practiced. In 1841, Joseph Piringer described his use of this method to determine infectiousness decades before the discovery of pathogenic bacteria, as well as ethical concerns about the associated endangerment of patients. Beginning in the 1880s, research focused on the identification of the gonococcus and assessment of its pathogenicity.The ethical dilemma of inducing a disease with an unpredictable outcome persisted until the 1940s, when gonorrhea could be reliably cured by penicillin.     

Theory and practice of clinical ethics support services: narrative and hermeneutical perspectives

In this paper we introduce narrative and hermeneutical perspectives to clinical ethics support services (CESS). We propose a threefold consideration of 'theory' and show how it is interwoven with 'practice' as we go along. First, we look at theory in its foundational role: in our case 'narrative ethics' and 'philosophical hermeneutics' provide a theoretical base for clinical ethics by focusing on human identities entangled in stories and on moral understanding as a dialogical process. Second, we consider the role of theoretical notions in helping practitioners to understand their situation in clinical ethics practice, by using notions like 'story', 'responsibility', or 'vulnerability' to make explicit and explain their practical experience. Such theoretical notions help us to interpret clinical situations from an ethical perspective and to foster moral awareness of practitioners. And, thirdly, we examine how new theoretical concepts are developed by interpreting practice, using practice to form and improve our ethical theory. In this paper, we discuss this threefold use of theory in clinical ethics support services by reflecting on our own theoretical assumptions, methodological steps and practical experiences as ethicists, and by providing examples from our daily work. In doing so, we illustrate that theory and practice are interwoven, as theoretical understanding is dependent upon practical experience, and vice-versa.     

Neuroproteomics and microRNAs studies in multiple sclerosis: transforming research and clinical knowledge in biomarker research

Multiple sclerosis (MS) is a complex disease characterized by extensive phenotypic variability. Biomarkers to capture the different aspects of MS heterogeneity, and to help make a diagnosis and monitor disease progression, while providing insights into etiopathogenesis and response to treatment, are urgently needed. Omics technologies and research efforts with microRNAs have provide unparalleled opportunities for exploring altered protein profiles associated with molecular mechanisms of disease, substantially expanding the list of candidate biomarkers for MS. This review presents evidence from proteomic studies that have focused on identification of biomarkers released in biofluids as a result of the different pathophysiological processes of MS. Also discussed is the emerging role of miRNAs as complementary biomarkers related to cellular processes occurring in MS patients. Also provided is an overview of candidate biomarkers that have been proposed for elucidating pathophysiological processes and disease activity and for guiding clinical diagnosis and/or therapeutic interventions in MS.     

Abortion and neonaticide: ethics,practice, and policy in four nations

Abortion, particularly later-term abortion, and neonaticide, selective non-treatment of newborns, are feasible management strategies for fetuses or newborns diagnosed with severe abnormalities. However, policy varies considerably among developed nations. This article examines abortion and neonatal policy in four nations: Israel, the US, the UK and Denmark. In Israel, late-term abortion is permitted while non-treatment of newborns is prohibited. In the US, on the other hand, later-term abortion is severely restricted, while treatment to newborns may be withdrawn. Policy in the UK and Denmark bridges some of these gaps with liberal abortion and neonatal policy. Disparate policy within and between nations creates practical and ethical difficulties. Practice diverges from policy as many practitioners find it difficult to adhere to official policy. Ethically, it is difficult to entirely justify perinatal policy in these nations. In each nation, there are elements of ethically sound policy, while other aspects cannot be defended. Ethical policy hinges on two underlying normative issues: the question of fetal/newborn status and the morality of killing and letting die. While each issue has been the subject of extensive debate, there are firm ethical norms that should serve as the basis for coherent and consistent perinatal policy. These include 1) a grant of full moral and legal status to the newborn but only partial moral and legal status to the late-term fetus 2) a general prohibition against feticide unless to save the life of the mother or prevent the birth of a fetus facing certain death or severe pain or suffering and 3) a general endorsement of neonaticide subject to a parent's assessment of the newborn's interest broadly defined to consider physical harm as well as social, psychological and or financial harm to related third parties. Policies in each of the nations surveyed diverging from these norms should be the subject of public discourse and, where possible, legislative reform.     

Status of knowledge,ongoing research,and research needs in Amazonian wetlands

Exploitation and exploration of the Amazon basin by Europeans started in the 17th century, but only since about 1970 has the Brazilian government given priority to the connection of the Amazon basin to the industrialized southern part of the country. This new policy required scientific research on the natural resources of the area. Wetlands cover about 20% of the Amazon basin. Inland fishery, fertile floodplain soils, and hydroelectric energy offer a large potential for economic development. Research concentrates on major wetlands and water bodies near the large cities. The Amazon River floodplain belongs to the best studied tropical river floodplains in the world. However, studies in other areas suffer from lack of wetland inventory and classification. Accelerated economic development is not adequately accompanied by wetland research. Insufficient knowledge about distribution, size, structure and function of many wetlands leads to increasing degradation and loss of biodiversity, for instance, by the construction of hydroelectric power plants, large scale deforestation for cattle ranching and agro-industrial projects, mining activities, the construction of navigation channels (hidrovias), etc. The low number of scientists working in the area and lack of funding require close cooperation in problem-oriented multidisciplinary projects (scientific clustering) to optimize scientific outcome. Intensive, long-term cooperation and scientific exchange with institutions from southern Brazil and from abroad is recommended to improve the scientific infrastructure in Amazonian institutions, to accelerate the transfer of new scientific methods and technology, and to intensify the training program for local human resources.This revised version was published online in March 2005 with corrections to the issue cover date.     

On knowledge, policy, practice, and fate.

Knowledge of the nation's health and nutritional status is dated, uncertain, incomplete, and complex, whereas politicans demand simplicity and administrators, practicability, and everyone wants more and better information. Rational policy, the unicorn intellectuals hunt, should combine clarity, realism, and conviction, which calls for a touch of passion. Attempts to reconcile these contradictory elements can lead to dangerous political pressures on research; the simplification, exaggeration, and over-generalization of findings; and excessive expectations for humdrum programs that often bear little resemblance to their glorified goals. Inadequate knowledge can justify both action and inaction, which are merely different lays of meeting our fate. The ultimate goal of health and nutrition policy, it may be said, is a long and healthy life and a quick and happy death. That may be desirable, but is it attainable.     

Regenerative medicine research in China: from basic research to clinical practice

<正>I am very happy to write editorial for this Special Issue of Stem Cells and Regenerative Medicine in China in Science China Life Sciences.As we all know,stem cells and regenerative medicine research is the frontiers not only in China,but also in the world.In recent decades,rapid research progressing,strong governmental support and recruitment of highly trained scientists from abroad together with domestic outstanding researchers and clinicians have made it possible