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Stepped-wedge cluster randomized trial (SW-CRT) designs are increasingly employed in pragmatic research; they differ from traditional parallel cluster randomized trials in which an intervention is delivered to a subset of clusters, but not to all. In a SW-CRT, all clusters receive the intervention under investigation by the end of the study. This approach is thought to avoid ethical concerns about the denial of a desired intervention to participants in control groups. Such concerns have been cited in the literature as a primary motivation for choosing SW-CRT design, however SW-CRTs raise additional ethical concerns related to the delayed implementation of an intervention and consent. Yet, PCT investigators may choose SW-CRT designs simply because they are concerned that other study designs are infeasible. In this paper, we examine justifications for the use of SW-CRT study design, over other designs, by drawing on the experience of the National Institutes of Health's Health Care Systems Research Collaboratory (NIH Collaboratory) with five pragmatic SW-CRTs. We found that decisions to use SW-CRT design were justified by practical and epistemic reasons rather than ethical ones. These include concerns about feasibility, the heterogeneity of cluster characteristics, and the desire for simultaneous clinical evaluation and implementation. In this paper we compare the potential benefits of SW-CRTs against the ethical and epistemic challenges brought forth by the design and suggest that the choice of SW-CRT design must balance epistemic, feasibility and ethical justifications. Moreover, given their complexity, such studies need rigorous and informed ethical oversight.

Rapid whole genome sequencing (WGS) and whole exome sequencing (WES), sometimes referred to as "next generation sequencing" (NGS) are now recommended by some experts as a first-line diagnostic test to diagnose infants with suspected monogenic conditions. Estimates of how often NGS leads to diagnoses or changes in management vary widely depending on the population being studied and the indications for testing. Finding a genetic variant that is classified as pathogenic may not necessarily equate with being able to predict the resultant phenotype or to give a reliable prognosis. Molecular diagnoses do not usually lead to changes in clinical management but they often end a family's diagnostic Odyssey and allow informed decisions about future reproductive choices. The likelihood that NGS will be beneficial for patients and families in the NICU remains uncertain. The goal of this paper is to highlight the implications of these ambiguities in interpreting the results of NGS. To do that, we will first review the types of cases that are admitted to NICUs and show why, at least in theory, NGS is unlikely to be useful for most NICU patients and families and may even be harmful for some, although it can help families in some cases. We then present a number of real cases in which NGS results were obtained and show that they often lead to unforeseen and unpredictable consequences. Finally, we will suggest ways to communicate with families about NGS testing and results in order to help them understand the meaning of NGS results and the uncertainty that surrounds them.

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

It has become increasingly difficult to place a value on the work that doctors do. Yet fiscal pressures have lead to economic incentives for performing certain kinds work instead of others. So the question arises: what are the ethics and consequences of trying to objectively compare the many services physicians offer?

Madam: The two articles on "Experts in Ethics" (HCR, November-December 1998) present an interesting view on the nature of expertise in the field of clinical ethics. The first article (David J. Casarett, Frona Daskal, and John Lantos, "The Authority of the Clinical Ethicist") stresses the importance of communication and consensus. The second (Scot D. Yoder, "The Nature of Ethical Expertise") defines expertise in terms of reasoning and providing justifications. As such, they make explicit some central aspects of clinical ethics work. Both articles try to give a foundation for clinical ethics by referring, respectively, to Habermas and Aristotle. Although the two contributions are certainly relevant, they also tend to be onesided, both in their view of clinical ethics practice and in their interpretation of philosophical theory. They tend to underestimate the fact that clinical ethics is highly contextual, and that its most important feature is the ethical assessment of concrete situations-an issue that makes the ethical theories of Habermas and Aristotle relevant for clinical ethics in ways the authors seem to overlook. According to Aristotle ethics is always about concrete situations. Clinical ethics is a splendid example of practical philosophy in the Aristotelian sense-that is, of a discipline that requires knowledge about particulars as well as knowledge about general rules and principles. The essence of expertise in this field is to apply general rules to the concrete situation, to see how general principles fit to specific circumstances. This means that an expert in clinical ethics is not only able to establish relevant general rules, but also to see to it that they are applied in the right manner. This expertise can be called hermeneutic competence. The Aristotelian perspective presupposes that ethics deals with truth. In this respect it is at odds with Yoder's suggestion that it is sufficient to provide a coherent justification for one's judgment. For Aristotle, coherence is not good enough; a recommendation is valid only if it is the best policy, given the concrete situation. It is, however, not easy to establish this. People need experience to apply rules and principles. Even experienced persons will have to know a lot about the details of the situation before they can give a sound judgment. This may explain the divergence in outcome when ethics consultants are asked to respond to hypothetical cases: such cases are probably too abstract and too thin for concrete recommendations. Habermas shares with Aristotle the presupposition that ethics is about truth. He claims that moral judgments can be right or wrong. He also agrees with Aristotle that ethics deals both with principles and with their application to concrete circumstances. Habermas gives ethics an intersubjective twist, however. Both the validity of general principles and the adequacy of their application to specific situations are not to be established through individual reasoning, but through dialogue and discussion. Habermas distinguishes between two kinds of institutionalized discussions regarding ethical issues: practical discourse and application discourse. Practical discourse is about the general validity of norms and principles; application discourse is about their application to a specific situation. Practical discourse aims at universalization, whereas application discourse aims at contextualization. In his theory of discourse ethics, Habermas puts most emphasis on the concept of practical discourse. This has given rise to the criticism that he tends to overlook the im

Randomized controlled trials raise a number of ethical issues. Physicians who participate in such trials must be in a state of "equipoise," or genuine uncertainty about the relative merits of the two arms of the trial. Otherwise, they would be ethically compelled to recommend the treatment they preferred. However, an agreement to participate in a masked trial is an agreement to deny oneself access to the knowledge that might allow one to judge which therapy is better. Physicians may dodge this dilemma in a number of ways. First, they may refuse to participate in randomized control trials. However, this does not allow assumptions about treatment to be tested. Second, they may judge participation ethically acceptable if other clinicians believe that an alternative treatment is better. By this formulation, individuals do not need to be in a state of equipoise, as long as the expert medical community is. Finally, they may use alternative methodologies, such as retrospective studies; crossover studies; or nonmasked, nonrandomized selection of alternative treatments with careful risk stratification and data collection. All of these solutions may be valid ways of dealing with the ethical dilemmas associated with randomized controlled trials.