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.     

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.     

Examining arts education policy development through policy frameworks

ABSTRACT

While policy formation frameworks are commonly used to understand public policy developments, scholars rarely have used them to reflect on arts education policies. Such analysis is important because it can assist both in identifying the genesis of past policies, including who the important actors are, how issues are framed and problematized, and how specific solutions are designed, as well as how to interpret unfolding policies. In this article, I review three prominent policy frameworks: Kingdon's “multiple streams framework,” Sabatier and Jenkins-Smith's “advocacy coalition framework,” and Baumgartner and Jones' “punctuated equilibrium framework.” After reviewing the frameworks, I address the following questions: (a) How would these conceptual frameworks predict arts education policy development to proceed? (b) How would these conceptual frameworks explain constituents and coalitions that affect the arts education policy sphere? (c) How would these conceptual frameworks illuminate precipitating events that drive the policy development process? I apply the frameworks to several instances of arts education policy development, including the formal designation of the arts as a core subjects under the Goals 2000: Educate America Act of 1994 (P.L. 103-227), the development of the 2014 National Core Arts Standards, and music's enumeration in the Every Student Succeeds Act of 2015. Because these three policy issues differ in important ways, they can help to illuminate the breadth of arts education policy.     

The policy context.

The final article in the series considers the ways in which the methods described previously are used in the formation of policy. When health authorities are making decisions about how to spend their money they have to draw on several sources of information about priorities: diktats from policy makers, opinions of consumers and of the professional bodies involved, and evidence gained from research. They must also consider the various methods of costing and select the right one for their circumstances. Some of these methods are still in the early stages of development, but more are being developed all the time and they have a valuable role in helping decision making throughout the NHS.     

Equipoise, knowledge and ethics in clinical research and practice

It is widely maintained that a clinical trial is ethical only if some form of equipoise between the treatments being compared obtains. To be in equipoise between two treatments A and B is to be cognitively indifferent between the statement 'A is strictly more effective than B' and its negation. It is natural to claim that equipoise regarding A and B is necessary for randomised assignment to treatments A and B to be beneficent and non-maleficent and is sufficient for such an assignment to be fair. Cashing this out precisely is difficult, and various forms of equipoise have been discussed which consider whose equipoise is relevant to the decision. This is to make judgement of equipoise something to be managed socially, while its prima facie significance is supposedly cognitive. Recent reconstructions of equipoise-like concepts in epistemology give clues about how to understand equipoise cognitively. In this paper I examine some of this work and discuss how successful it has been. I suggest that while this work is promising, it still has far to go, and that while equipoise remains the best theory we have of the cognitive justification for clinical trials, it is nonetheless incoherent.     

The face of equipoise - delivering a structured education programme within a randomized controlled trial: qualitative study

Background

In trials of behavioural interventions, the individuals who deliver the intervention are in a position of key influence on the success of the trial. Their fidelity to the intervention is crucial. Yet little is understood about the experiences of this group of trial personnel. This study aimed to investigate the views and experiences of educators who delivered a structured education intervention to people with type 2 diabetes, which incorporated training in self-monitoring of either blood glucose (SMBG) or urine glucose (SMUG) as part of a randomized controlled trial (RCT).

Methods

Educators’ views were explored through focus groups before and after training (N?=?18) and approximately 1 year into the trial (N?=?14), and semi-structured telephone interviews at approximately 2 years (N?=?7). Analysis was based on the constant comparative method.

Results

Educators held preferences regarding the intervention variants; thus, they were not in individual equipoise. Training raised awareness of preferences and their potential to impact on delivery. Educators were confident in their unbiased delivery, but acknowledged the challenges involved. Concealing their preferences was helped by a sense of professionalism, the patient-centred nature of the intervention, and concessions in the trial protocol (enabling participants to swap monitoring methods if needed). Commitment to unbiased delivery was explained through a desire for evidence-based knowledge in the contentious area of SMBG.

Conclusions

The findings provide insight into a previously unexplored group of trial personnel - intervention deliverers in trials of behavioural interventions - which will be useful to those designing and running similar trials. Rather than individual equipoise, it is intervention deliverers’ awareness of personal preferences and their potential impact on the trial outcome that facilitates unbiased delivery. Further, awareness of community equipoise, the need for evidence, and relevance to the individual enhance commitment to the RCT.

Trial registration

ISRCTN95696668     

Facing an unfortunate trade-off: policy responses,lessons and spill-overs during the COVID-19 pandemic

Although COVID-19 emerged as a global shock, governments adopted non-pharmaceutical policy responses that were rather heterogeneous, depending on cultural and institutional characteristics. At the country level, the stringency of ‘lockdown’-type policies should be set to achieve the best possible trade-off between economic and fatality dynamics, obviously accounting for possible cross-border influences. To allow for policy learning, I assume that the first country implementing a policy initiative that is worth emulating must either get the best possible health or the best possible economic outcome. I propose a combination of sign and magnitude restrictions, embedded in a global VAR model, to identify idiosyncratic policy shocks that spill over and influence policy responses abroad. Once policy shocks are identified, I run a comparison exercise between two model specifications, i.e. with and without policy emulation. Within a given a sample, this methodology can be used to find when and where policy lessons can be identified. I find that, among 17 developed and developing countries, few can offer lessons based on their policy initiatives, but several others might get better trade-offs through policy emulation, although in reality this outcome is not guaranteed to have occurred.     

A surplus of positive trials: weighing biases and reconsidering equipoise

In this issue, Fries and Krishnan raise provocative new ideas to explain the surfeit of positive industry sponsored trials evaluating new drugs. They suggest that these trials were designed after so much preliminary work that they were bound to be positive (design bias) and that this violates clinical equipoise, which they characterize as an antiquated concept that should be replaced by a focus on subject autonomy in decision making and expected value for all treatments in a trial. We contend that publication bias, more than design bias, could account for the remarkably high prevalence of positive presented trials. Furthermore, even if all new drugs were efficacious, given the likelihood of type 2 errors, not all trials would be positive. We also suggest that clinical equipoise is a nuanced concept dependent on the existence of controversy about the relative value of two treatments being compared. If there were no controversy, then trials would be both unnecessary and unethical. The proposed idea of positive expected value is intriguing, but in the real world such clearly determinable values do not exist. Neither is it clear how investigators and sponsors, who are invested in the success of a proposed therapy, would (or whether they should) develop such a formula.     

Moral philosophy and public policy: the case of NRTs

In this paper, I will express some reservations about the usefulness of moral philosophy for the analysis of public policy issues.... My question is whether taking morality seriously requires taking moral philosophy seriously. This paper focuses on one particular public policy context -- namely, government commissions into new reproductive technologies, such as Britain's Warnock Committee, Australia's Waller and Michael Committees, Canada's Baird Commission, and many others.... Moral philosophers are sometimes asked to participate in these commissions, either as Commissioners, staff, or expert advisers. How can moral philosophers contribute to the analysis of public policy recommendations on NRTs? A survey of the literature suggests that there are two main views on this question, one of which is ambitious, the other more modest. The ambitious view says that moral philosophers should attempt to persuade Commissioners to adopt the right comprehensive moral theory (e.g. adopt a deontological theory, rather than utilitarianism or contractarianism), and then apply this theory to particular policy questions. The more modest view shies away from promoting a particular moral theory, given that the relative merits of different moral theories are a subject of dispute even amongst moral philosophers. Instead, it says that moral philosophers should attempt to ensure that the Commission's arguments are clear and consistent. On this view, philosophers should focus on identifying conceptual confusions or logical inconsistencies within the Commission's arguments without seeking to influence its choice of the underlying theory.     

The Anna Karenina Principle Applied to Ecological Risk Assessments of Multiple Stressors

Successful ecological risk assessments are all alike; every unsuccessful ecological risk assessment fails in its own way. Tolstoy posited a similar analogy in his novel Anna Karenina: “Happy families are all alike; every unhappy family is unhappy in its own way.” By that, Tolstoy meant that for a marriage to be happy, it had to succeed in several key aspects. Failure on even one of these aspects, and the marriage is doomed. In this paper, I argue that the Anna Karenina principle also applies to ecological risk assessments involving multiple stressors. In particular, I argue that multiple stressors assessments and environmental decision making will not have a happy marriage unless the following can be achieved: (1) there must be societal and political buy-in to the assessment and decision-making process; (2) the assessment must have the latitude to consider a wide range of stressors and potential risk management options; (3) there must be a commitment to following a rigorous focusing of the assessment and to expending resources for model development and data collection; and (4) an adaptive management strategy must be adopted wherein risk management actions are undertaken, system response intensively observed and assessed, and revised management actions taken as appropriate. Failure to meet any of the above criteria for success will doom a multiple stressors assessment and prevent its use in effective decision-making.     

The molecular basis of I-R hybrid dysgenesis in Drosophila melanogaster: identification, cloning, and properties of the I factor

We have analyzed two mutations of the white-eye gene, which arose in flies subject to I-R hybrid dysgenesis. These mutations are associated with insertions of apparently identical 5.4 kb sequences, which we have cloned. We believe that these insertions are copies of the I factor controlling I-R hybrid dysgenesis. The I factor is not a member of the copia-like or fold-back classes of transposable elements and has no sequence homology with the P factor that controls P-M dysgenesis. All strains of D. melanogaster contain I-factor sequences. Those present in reactive strains must represent inactive I elements. I elements have a remarkably similar sequence organization in all reactive strains and are located in peri-centromeric regions. Inducer strains appear to contain both I elements, located in peri-centromeric regions, and 10-15 copies of the complete I factor at sites on the chromosome arms.     

The statistical basis of public policy: a paradigm shift is overdue.

The recent controversy over the increased risk of venous thrombosis with third generation oral contraceptives illustrates the public policy dilemma that can be created by relying on conventional statistical tests and estimates: case-control studies showed a significant increase in risk and forced a decision either to warn or not to warn. Conventional statistical tests are an improper basis for such decisions because they dichotomise results according to whether they are or are not significant and do not allow decision makers to take explicit account of additional evidence--for example, of biological plausibility or of biases in the studies. A Bayesian approach overcomes both these problems. A Bayesian analysis starts with a "prior" probability distribution for the value of interest (for example, a true relative risk)--based on previous knowledge--and adds the new evidence (via a model) to produce a "posterior" probability distribution. Because different experts will have different prior beliefs sensitivity analyses are important to assess the effects on the posterior distributions of these differences. Sensitivity analyses should also examine the effects of different assumptions about biases and about the model which links the data with the value of interest. One advantage of this method is that it allows such assumptions to be handled openly and explicitly. Data presented as a series of posterior probability distributions would be a much better guide to policy, reflecting the reality that degrees of belief are often continuous, not dichotomous, and often vary from one person to another in the face of inconclusive evidence.     

Embryos,The Principle of Proportionality,and the Shaky Ground of Moral Respect

The debate concerning the moral permissibility of using human embryos in human embryonic stem cell (hESC) research has long centred on the question of the embryo's supposed right to life. However, in focussing only on this question, many opponents to hESC research have escaped rigorous scrutiny by making vague and unfounded appeals to the concept of moral respect in order to justify their opposition to certain hESC practices. In this paper, I offer a critical analysis of the concept of moral respect, and its use to support the intuitively appealing principle of proportionality in hESC research. I argue that if proponents of this principle are to justify its adoption by appealing to the concept of moral respect, they must explain two things concerning the nature of the moral respect owed to embryos. First, they must explain which particular aspect of the embryo is morally relevant, and why. Second, they must explain why some uses of embryos in research fail to acknowledge what is morally relevant about the embryo, and thereby involve a violation of the moral respect that they are due. I shall show that providing such explanations may be more difficult than it first appears.     

Research versus practice: The dilemmas of research ethics in the era of learning health‐care systems

In this article we attempt to answer the question of how the ethical and conceptual framework (ECF) for a learning health‐care system (LHS) affects some of the main controversies in research ethics by addressing five key problems of research ethics: (a) What is the difference between practice and research? (b) What is the relationship between research ethics and clinical ethics? (c) What is the ethical relevance of the principle of clinical equipoise? (d) Does participation in research require a higher standard of informed consent than the practice of medicine? and (e) What ethical principle should take precedence in medicine? These questions allow us to construct two opposite idealized positions on the distinction between research and practice: the integration model and the segregation model of research and practice. We then compare the ECF for an LHS with these two idealized positions. We argue that the ECF for a LHS does not, in fact, solve these problems, but that it is a third, separate position in the relationship between research ethics and clinical ethics. Moreover, we suggest that the ECF for a LHS raises new ethical problems that require additional ethical analysis and justification. Our article contributes to the discussion on the relationship between research ethics and clinical ethics, revealing that although a learning health‐care system may significantly change the landscape of health care, some ethical dilemmas still require resolving on both theoretical and policy‐making levels.     

The effect of farm policy on production strategies among French family farmers

French farm policy has created incentives for certain production strategies which theoretically require little or no land and which would therefore be particularly suited for small holders. Through credit and subsidies for the construction of pigsties, and through contractual arrangements for the production of hybrid seed corn and tobacco, the government has encouraged these activities. However, because of certain constraints, these activities are more successfully pursued by holders of larger farms. Small holders, because they are small, cannot fully benefit from these strategies which would compensate them for their smallness.Funds for fieldwork were provided by the National Science Foundation, the Social Science Research Council, the National Institute of Mental Health, and Columbia University, all of whom I thank. I owe special thanks to Henri Mendras for suggesting the village which I call Alunhac as the site for my fieldwork, and to Pierre Boisseau for introducing me to its inhabitants. Alunhac is one of the ten communities studied by theGroupe de Sociologie Rural du CNRS, and has been described in Boisseau (1966) and Jollivet and Mendras (1971, pp. 120–130). All proper names of people and places are pseudonyms. I want to thank Susan Carol Rogers for comments on an earlier version of this paper, and I am grateful to the editors and the anonymous readers ofHuman Ecology for helpful criticisms.     

The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential

The liver X receptors (LXRs) have been shown to affect lipoprotein plasma profile, lipid metabolism, and reverse cholesterol transport (RCT). In the present study, we investigated whether a short-term administration of the synthetic LXR agonist T0901317 (T0) to mice may affect RCT by modulating the capacity of plasma to promote cellular lipid efflux. Consistent with previous data, the pharmacological treatment of mice caused a significant increase of macrophage-derived [3H]cholesterol content in plasma, liver, and feces and resulted in improved capacity of plasma to promote cellular cholesterol release through passive diffusion and scavenger receptor class B type I (SR-BI)-mediated mechanisms. Differently, plasma from treated mice possessed similar or reduced capacity to drive lipid efflux via ABCA1. Consistent with these data, the analysis of plasma HDL fractions revealed that T0 caused the formation of larger, lipid-enriched particles. These results suggest that T0 promotes in vivo RCT from macrophages at least in part by inducing an enrichment of those HDL subclasses that increase plasma capacity to promote cholesterol efflux by passive diffusion and SR-BI-mediated mechanisms.     

The inner dynein arms I2 interact with a "dynein regulatory complex" in Chlamydomonas flagella.

We provide indirect evidence that six axonemal proteins here referred to as "dynein regulatory complex" (drc) are located in close proximity with the inner dynein arms I2 and I3. Subsets of drc subunits are missing from five second-site suppressors, pf2, pf3, suppf3, suppf4, and suppf5, that restore flagellar motility but not radial spoke structure of radial spoke mutants. The absence of drc components is correlated with a deficiency of all four heavy chains of inner arms I2 and I3 from axonemes of suppressors pf2, pf3, suppf3, and suppf5. Similarly, inner arm subunits actin, p28, and caltractin/centrin, or subsets of them, are deficient in pf2, pf3, and suppf5. Recombinant strains carrying one of the mutations pf2, pf3, or suppf5 and the inner arm mutation ida4 are more defective for I2 inner arm heavy chains than the parent strains. This evidence indicates that at least one subunit of the drc affects the assembly of and interacts with the inner arms I2.     

Back-to-the-future: a fresh policy initiative for fisheries and a restoration ecology for ocean ecosystems

'Back-to-the-future' (BTF) is an integrative approach to a restoration ecology of the oceans that attempts to solve the fisheries crisis. To this end, it harnesses the latest understanding of ecosystem processes developments in whole ecosystem simulation modelling, and insight into the human dimension of fisheries management. BTF includes new methods for describing past ecosystems, designing fisheries that meet criteria for sustainability and responsibility, and evaluating the costs and benefits of fisheries in restored ecosystems. Evaluation of alternative policy choices, involving trade-offs between conservation and economic values, employs a range of economic, social and ecological measures. Automated searches maximize values of objective functions, and the methodology includes analyses of model parameter uncertainty. Participatory workshops attempt to maximize compliance by fostering a sense of ownership among all stakeholders. Some challenges that have still to be met include improving methods for quantitatively describing the past, reducing uncertainty in ecosystem simulation techniques and in making policy choices robust against climate change. Critical issues include whether past ecosystems make viable policy goals, and whether desirable goals may be reached from today's ecosystem. Examples from case studies in British Columbia, Newfoundland and elsewhere are presented.     

“The Simulacra of Morality”: Islamic Veiling, Religious Politics and the Limits of Liberalism

On December 17, 2003, French President Jaques Chirac went on television to explain the immediate necessity of passing a law recently proposed by the Stasi commission. This commission had been empowered to explore the failures of the last thirty years of French immigration policy in terms of integration. It had also been specifically instructed to investigate threats to the concept of laicite, the rigorous French version of secularism and the separation of the Church and the State. Chirac explained that, following the commission’s advice as well as that of numerous experts, he had centered on a policy to deal with these issues: We shall do so by bringing to life the principle of secularism, which is a pillar of our constitution. It expresses our wish to live together in respect, dialogue and tolerance. Secularism guarantees freedom of conscience. It protects the freedom to believe or not to believe. He then expanded upon what this freedom requires: It is the neutrality of the public sphere which enables the harmonious existence side by side of different religions. Like all freedoms, the freedom to express one’s faith can only have limits in the freedom of others, and in the compliance with rules of life in society. Religious freedom, which our country respects and protects, must not be abused, it must not call general rules into question, and it must not infringe the freedom of belief of others. Finally, Chirac, building to a rhetorical climax, came to the essence of the new law which had provoked so much commentary around the world: In all conscience, it is my view that the wearing of clothes or of symbols which conspicuously demonstrate religious affiliations must be banned in state schools. The hypothesis which I wish to advance is that in the actual world in which we inhabit the language of morality is in the same state of grave disorder as the language of natural science is in the imaginary world which I described. What we possess are the fragments of a conceptual scheme... we posses indeed simulacra of morality... but we have lost our comprehension, both theoretical and practical, of morality.     

“Maybe I Made Up the Whole Thing”: Placebos and Patients’ Experiences in a Randomized Controlled Trial

Patients in the placebo arms of randomized controlled trials (RCT) often experience positive changes from baseline. While multiple theories concerning such “placebo effects” exist, peculiarly, none has been informed by actual interviews of patients undergoing placebo treatment. Here, we report on a qualitative study (n = 27) embedded within a RCT (n = 262) in patients with irritable bowel syndrome. Besides identical placebo acupuncture treatment in the RCT, the qualitative study patients also received an additional set of interviews at the beginning, midpoint, and end of the trial. Interviews of the 12 qualitative subjects who underwent and completed placebo treatment were transcribed. We found that patients (1) were persistently concerned with whether they were receiving placebo or genuine treatment; (2) almost never endorsed “expectation” of improvement but spoke of “hope” instead and frequently reported despair; (3) almost all reported improvement ranging from dramatic psychosocial changes to unambiguous, progressive symptom improvement to tentative impressions of benefit; and (4) often worried whether their improvement was due to normal fluctuations or placebo effects. The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo—e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment—provides an inadequate model to explain its salubrious benefits. T.K., E.J., L.C., C.K., J.K. and A.L. initiated the RCT and obtained funding. E.J., T.K., C.K. and L.C. designed the qualitative study. Interviews were performed by E.J., and L.C., T.K., J.S., E.J., L.C., C.K., T.C., A.L. and J.K. performed the initial analysis and interpretation. J.S. devised the coding framework in consultation with all authors. T.K., E.J. and J.S. wrote the first draft. All authors commented on subsequent drafts. T.K. is the guarantor and accepts full responsibility for the conduct of the study and the contents of the paper.