Why is revitalizing clinical research so important, yet so difficult?

We believe that support for academic clinical research has greatly declined in recent decades. Here we discuss our views on why this has happened. We define clinical or patient-oriented research as limited to the study of human beings or populations of individuals, and argue that its eclipse in favor of basic and "translational" research is the result of inappropriate conceptual paradigms or "models" for medical advances. We believe that medical history shows that the "bench-to-bedside" model is inadequate to explain most recent progress and that clinical advances themselves often lead to new basic research. Discussion of alternate conceptual frameworks for biomedical research should help lead to changes in funding and organizational structures that might finally revitalize clinical research.     

Evidence-based alternative medicine?

The validity of evidence-based medicine (EBM) is the subject of ongoing controversy. The EBM movement has proposed a "hierarchy of evidence," according to which randomized controlled trials (RCTs) and meta-analyses of RCTs provide the most reliable evidence concerning the efficacy of medical interventions. The evaluation of alternative medicine therapies highlights problems with the EBM hierarchy. Alternative medical researchers-like those in mainstream medicine-wish to evaluate their therapies using methods that are rigorous and that are consistent with their philosophies of medicine and healing. These investigators have three ways to relate their work to EBM. They can accept the EBM hierarchy and carry out RCTs when possible; they can accept the EBM standards but argue that the special characteristics of alternative medicine warrant the acceptance of "lower" forms of evidence; or they can challenge the EBM approach and work to develop new research designs and new standards of evidence that reflect their approach to medical care. For several reasons, this last option is preferable. First, it will best meet the needs of alternative medicine practitioners. Moreover, because similar problems beset the evaluation of mainstream medical therapies, reevaluation of standards of evidence will benefit everyone in the medical community--including, most importantly, patients.     

EQUALITY AND THE TREATMENT‐ENHANCEMENT DISTINCTION

In From Chance to Choice, Allen Buchanan, Dan Brock, Norman Daniels and Daniel Wikler propose a new way of defending the moral significance of the distinction between genetic treatments and enhancements. They develop what they call a ‘normal function model’ of equality of opportunity and argue that it offers a ‘limited’ defence of this distinction. In this article, I critically assess their model and the support it (allegedly) provides for the treatment‐enhancement distinction. First, I argue that there is a troubling tension in the normal function model. Secondly, I argue that neither of the rationales invoked by Buchanan et al. really serves to justify this model or the results they seek to derive from it with respect to the significance of the distinction between treatments and enhancements.     

Prisoner's dilemma posed by fitness-associated recombination strategies

Genetic recombination is a central and repeated topic of study in the evolution of life. However, along with the influence of recombination on evolution, we understand surprisingly little of how selection shapes the nature of recombination. One explanation for recombination is that it allows organisms to escape from perilous situations where they experience very low fitness. As a corollary, it has been suggested that selection should favor recombination at low fitness and not at high fitness (fitness-associated recombination, FAR), and theory suggests that such strategies can indeed be selected. Here we develop models to further investigate the evolution of FAR. Consistent with previous works, we find that FAR can invade and dominate over a strategy of uniform recombination that is independent of fitness. However, our simulation results suggest that extreme FAR strategies, known as group-elitism, are not necessarily superior to other FAR strategies. Moreover, we argue that FAR domination will often occur with a net loss of mean population fitness. Interestingly, this suggests that the strategy of not recombining at high fitness will sometimes be analogous to a defector strategy from the famous "prisoner's dilemma" game: a selfish strategy that is selected but leads to a loss of mean fitness for all players.     

The ethics of public policy RCTs: The principle of policy equipoise

In this article, I ask whether a principle analogous to the principle of clinical equipoise should govern the design and conduct of RCTs evaluating the effectiveness of policy interventions. I answer this question affirmatively, and introduce and defend the principle of policy equipoise. According to this principle, all arms of a policy RCT must be, at minimum, in a state of equipoise with the best proven policy that is also morally and practically attainable and sustainable. For all arms of a policy RCT, policy experts must either (1) reasonably disagree about whether the trial arms are more effective than this policy, or (2) know that they are.     

Human genetic banking: altruism, benefit and consent

This article considers how we should frame the ethical issues raised by current proposals for large-scale genebanks with on-going links to medical and lifestyle data, such as the Wellcome Trust and Medical Research Council's 'UK Biobank'. As recent scandals such as Alder Hey have emphasised, there are complex issues concerning the informed consent of donors that need to be carefully considered. However, we believe that a preoccupation with informed consent obscures important questions about the purposes to which such collections are put, not least that they may be only haphazardly used for research (especially that of commercial interest)--an end that would not fairly reflect the original altruistic motivation of donors, and the trust they must invest. We therefore argue that custodians of such databases take on a weighty pro-active duty, to encourage public debate about the ends of such collections and to sponsor research that reflects publicly agreed priorities and provides public benefits.     

Ethics and HIV prevention research: An analysis of the early tenofovir PrEP trial in Nigeria

In 2004, the first ever multi‐sited clinical trials studied the prospect of HIV biomedical prevention (referred to as pre‐exposure prophylaxis—‘PrEP’). The trials were implemented at several international sites, but many officially closed down before they completed. At most sites, both scientists and community AIDS advocates raised concerns over the ethics and scientific rationales of the trial. Focusing on the Nigerian trial site, we detail the controversy that emerged among mostly Nigerian research scientists who scrutinized the research design and protocol. While some of the disputes, especially those pertaining to community engagement mechanisms, were ultimately resolved in international fora and implemented in later PrEP trials, concerns over science rationales and assumptions were never addressed. We argue that scientific rationales should be treated as ethical concerns and suggest that such concerns should be deliberated at host sites before the trial protocol is finalized.     

Human genetic banking: altruism,benefit and consent

This article considers how we should frame the ethical issues raised by current proposals for large‐scale genebanks with on‐going links to medical and lifestyle data, such as the Wellcome Trust and Medical Research Council's ‘UK Biobank’. As recent scandals such as Alder Hey have emphasised, there are complex issues concerning the informed consent of donors that need to be carefully considered. However, we believe that a preoccupation with informed consent obscures important questions about the purposes to which such collections are put, not least that they may be only haphazardly used for research (especially that of commercial interest)—an end that would not fairly reflect the original altruistic motivation of donors, and the trust they must invest. We therefore argue that custodians of such databases take on a weighty pro‐active duty, to encourage public debate about the ends of such collections and to sponsor research that reflects publicly agreed priorities and provides public benefits.     

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.     

The roles of harsh and fluctuating conditions in the dynamics of ecological communities

Harsh conditions (e.g., mortality and stress) reduce population growth rates directly; secondarily, they may reduce the intensity of interactions between organisms. Near-exclusive focus on the secondary effect of these forms of harshness has led ecologists to believe that they reduce the importance of ecological interactions, such as competition, and favor coexistence of even ecologically very similar species. By examining both the costs and the benefits, we show that harshness alone does not lessen the importance of species interactions or limit their role in community structure. Species coexistence requires niche differences, and harshness does not in itself make coexistence more likely. Fluctuations in environmental conditions (e.g., disturbance, seasonal change, and weather variation) also have been regarded as decreasing species interactions and favoring coexistence, but we argue that coexistence can only be favored when fluctuations create spatial or temporal niche opportunities. We argue that important diversity-promoting roles for harsh and fluctuating conditions depend on deviations from the assumptions of additive effects and linear dependencies most commonly found in ecological models. Such considerations imply strong roles for species interactions in the diversity of a community.     

Cost-Effectiveness of Chagas Disease Vector Control Strategies in Northwestern Argentina

Background

Control and prevention of Chagas disease rely mostly on residual spraying of insecticides. In Argentina, vector control shifted from a vertical to a fully horizontal strategy based on community participation between 1992 and 2004. The effects of such strategy on Triatoma infestans, the main domestic vector, and on disease transmission have not been assessed.

Methods and Findings

Based on retrospective (1993–2004) records from the Argentinean Ministry of Health for the Moreno Department, Northwestern Argentina, we performed a cost-effectiveness (CE) analysis and compared the observed CE of the fully horizontal vector control strategy with the expected CE for a vertical or a mixed (i.e., vertical attack phase followed by horizontal surveillance) strategy. Total direct costs (in 2004 US$) of the horizontal and mixed strategies were, respectively, 3.3 and 1.7 times lower than the costs of the vertical strategy, due to reductions in personnel costs. The estimated CE ratios for the vertical, mixed and horizontal strategies were US$132, US$82 and US$45 per averted human case, respectively. When per diems were excluded from the costs (i.e., simulating the decentralization of control activities), the CE of vertical, mixed and horizontal strategies was reduced to US$60, US$42 and US$32 per averted case, respectively.

Conclusions and Significance

The mixed strategy would have averted between 1.6 and 4.0 times more human cases than the fully horizontal strategy, and would have been the most cost-effective option to interrupt parasite transmission in the Department. In rural and dispersed areas where waning vertical vector programs cannot accomplish full insecticide coverage, alternative strategies need to be developed. If properly implemented, community participation represents not only the most appealing but also the most cost-effective alternative to accomplish such objectives.     

HUMAN NATURE AND ENHANCEMENT

Appeals to the idea of human nature are frequent in the voluminous literature on the ethics of enhancing human beings through biotechnology. Two chief concerns about the impact of enhancements on human nature have been voiced. The first is that enhancement may alter or destroy human nature. The second is that if enhancement alters or destroys human nature, this will undercut our ability to ascertain the good because, for us, the good is determined by our nature. The first concern assumes that altering or destroying human nature is in itself a bad thing. The second concern assumes that human nature provides a standard without which we cannot make coherent, defensible judgments about what is good.
I will argue (1) that there is nothing wrong, per se, with altering or destroying human nature, because, on a plausible understanding of what human nature is, it contains bad as well as good characteristics and there is no reason to believe that eliminating some of the bad would so imperil the good as to make the elimination of the bad impermissible, and (2) that altering or destroying human nature need not result in the loss of our ability to make judgments about the good, because we possess a conception of the good by which we can and do evaluate human nature. I will argue that appeals to human nature tend to obscure rather than illuminate the debate over the ethics of enhancement and can be eliminated in favor of more cogent considerations.     

The importance of subjectivity in perceptual errors on the emergence of indirect reciprocity

Indirect reciprocity is one mechanism that allows for unilateral resource giving among n-persons. Using analytical methods and computer simulations, previous studies have examined a number of strategies that make indirect reciprocity possible. In particular, previous investigations have concentrated on whether differentiating between justified and unjustified not-giving is important. However, whether or not a given strategy is ESS depends on the type of perceptual errors that are assumed. When errors are objective, regarding those who do not give to "bad" as "good" is critical. When perceptual errors are subjective, however, regarding those who give to "bad" as "bad" is critical. Since we believe that there is no guarantee that perceptual errors are shared among all individuals in a society, we argue that the latter moral principle may play a more important role in human interactions.     

Pioneer-Follower dilemma game in <Emphasis Type="Italic">Acanthoscelides obtectus</Emphasis> (Coleoptera: Bruchidae)

Larvae of Acanthoscelides obtectus show two contrasting behaviors when entering a bean. One is pioneer behavior in which a larva enters the bean through an entrance hole made by itself; the other is follower behavior in which a larva enters the bean through an entrance hole made by a pioneer. Previous studies have shown that the number of followers is much greater than that of pioneers. If there is a cost to being a pioneer, and if larvae can choose either of the two strategies, there is a dilemma: to be a pioneer or not. This dilemma is similar to the chicken game because if all larvae avoid choosing the risky pioneer strategy in favor of the follower strategy, none of the larvae can enter a bean, and they will die. In the present study, in order to investigate whether the larvae of A. obtectus are facing a dilemma of entry order, we experimentally measured the cost to pioneers and tested the flexibility of larval entering strategies. Pioneers’ costs were measured by entrance success rate, and the flexibility of larval strategies was tested by gauging the proportion of pioneers at various larval densities. The entrance success of pioneers was lower than that of followers, and the proportion of pioneers decreased as the number of competing larvae increased. These results suggest that the Pioneer-Follower interaction in A. obtectus satisfies the conditions for a dilemma game: the larvae of A. obtectus are in a dilemma of entry order.     

Mistakes allow evolutionary stability in the repeated prisoner's dilemma game

The repeated prisoner's dilemma game has been widely used in analyses of the evolution of reciprocal altruism. Recently it was shown that no pure strategy could be evolutionarily stable in the repeated prisoner's dilemma. Here I show that if there is always some probability that individuals will make a mistake, then a pure strategy can be evolutionarily stable provided that it is "strong perfect equilibria" against itself. To be a strong perfect equilibrium against itself, a strategy must be the best response to itself after every possible sequence of behavior. I show that both unconditional defection and a modified version of tit-for-tat have this property.     

An ontological crisis? A review of large felid conservation in India

The need for a solid knowledge base to inform conservation activity is now universally recognised. We critically scrutinised the scientific knowledge of large felids in India located in peer-reviewed research papers to assess the information available to make landscape-level management decisions that aid conservation, which is a stated goal of both the Indian government and the international community. We found two striking patterns: the biological sciences dominate in the published literature, and nearly all the research has been carried out in protected areas, though a substantial number of large felids also live outside protected areas. We argue that these patterns are not incidental, but the result of the dualistic ontology of science that uses processes of ‘purification’ and ‘translation’ to fit complex realities into disciplinary prerogatives organised around creating dichotomies (like nature–culture). In addition, since this body of scientific knowledge locates large felids in ‘pure’ biological landscapes, there is little or no insight from multi-use landscapes. These findings, we believe, highlight important knowledge gaps in our present research-based knowledge of large felids in India, which urgently need to be addressed if progress is to be made in conservation.     

Randomized Controlled Trials of Maternal‐Fetal Surgery: A Challenge to Clinical Equipoise

This article focuses on maternal‐fetal surgery (MFS) and on the concept of clinical equipoise that is a widely accepted requirement for conducting randomized controlled trials (RCT). There are at least three reasons why equipoise is unsuitable for MFS. First, the concept is based on a misconception about the nature of clinical research and the status of research subjects. Second, given that it is not clear who the research subject/s in MFS is/are, if clinical equipoise is to be used as a criterion to test the ethical appropriateness of RCT, its meaning should be unambiguous. Third, because of the multidisciplinary character of MFS, it is not clear who should be in equipoise. As a result, we lack an adequate criterion for the ethical review of MFS protocols. In our account, which is based on Chervenak and McCullough's seminal work in the field of obstetric ethics, equipoise is abandoned. and RCT involving MFS can be ethically initiated when a multidisciplinary ethics review board (ERB), having an evidence‐based assessment of the risks involved, is convinced that the value of answering the research hypothesis, for the sake of the health interests of future pregnant women carrying fetuses with certain congenital birth defects, justifies the actual risks research participants might suffer within a set limit of low/manageable.     

Assessment of the Quality of Reporting of Randomised Controlled Trials in Otorhinolaryngologic Literature – Adherence to the CONSORT Statement

Background

Randomised Controlled Trials (RCTs) are the preferred study design when comparing therapeutical interventions in medicine. To improve clarity, consistency and transparency of reporting RCTs, the Consolidated Standards of Reporting Trials (CONSORT) statement was developed.

Objectives

(1) To assess the quality of reports and abstracts of RCTs in otorhinolaryngologic literature by using CONSORT checklists, (2) to compare the quality of reports and abstracts of otorhinolaryngologic RCTs between the top 5 general medical journals and top 5 otorhinolaryngologic journals, and (3) to formulate recommendations for authors and editors of otorhinolaryngologic (‘ENT’) journals.

Methods

Based on 2012 ISI Web of Knowledge impact factors, the top 5 general medical and ENT journals were selected. On 25 June 2014, using a highly sensitive Cochrane RCT filter and ENT filter, possibly relevant articles since January 1st, 2010 were retrieved and relevant RCTs were selected. We assessed how many CONSORT items were reported adequately in reports and abstracts and compared the two journal types.

Results

Otorhinolaryngologic RCTs (n = 15) published in general medical journals reported a mean of 92.1% (95% confidence interval: 89.5%–94.7%) of CONSORT items adequately, whereas RCTs (n = 18) published in ENT journals reported a mean of 71.8% (66.7%–76.8%) adequately (p < 0.001). For abstracts, means of 70.0% (63.7%–76.3%) and 32.3% (26.6–38.0%) were found respectively (p < 0.001). Large differences for specific items exist between the two journal types.

Conclusion

The quality of reporting of RCTs in otorhinolaryngologic journals is suboptimal. RCTs published in general medical journals have a higher quality of reporting than RCTs published in ENT journals. We recommend authors to report their trial according to the CONSORT Statement and advise editors to endorse the CONSORT Statement and implement the CONSORT Statement in the editorial process to ensure more adequate reporting of RCTs and their abstracts.     

Debates, divisions, and decisions: recombinant DNA advisory committee (RAC) authorization of the first human gene transfer experiments.

Possibly the most far-reaching, controversial research currently being conducted in the international biological science community involves human gene therapy experimentation. In this paper, I report the dynamics of the political process which ultimately found the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health approving for the first time protocols of this genre. A full appreciation of the policy-making dialogue shows that significant participants perceived the process from very different vantage points regarding the way in which the American political system works and the way in which it ought to work. I argue that, if we are to understand how the RAC should proceed in orchestrating a human gene therapy policy agenda, then we must flesh out and critically analyze these competing vantage points. To that end, I postulate seven possible "action models" for characterizing how protocol assessments of the type at issue might be developed given the nature of our politics, reaching the conclusion that one of these models holds out the most promise for synthesizing efficaciously the key factors involved. In conclusion, I discuss how the RAC might profitably employ this preferred strategy in these and other cases.