Environmental sustainability and the carbon emissions of pharmaceuticals.

The US healthcare industry emits an estimated 479 million tonnes of carbon dioxide each year; nearly 8% of the country's total emissions. When assessed by sector, hospital care, clinical services, medical structures, and pharmaceuticals are the top emitters. For 15 years, research has been dedicated to the medical structures and equipment that contribute to carbon emissions. More recently, hospital care and clinical services have been examined. However, the carbon of pharmaceuticals is understudied. This article will focus on the carbon emissions of pharmaceuticals since they are consistently calculated to be among the top contributors to healthcare carbon and assess the factors that contribute to pharmaceutical carbon emissions. Specifically, overprescription, pharmaceutical waste, antibiotic resistance, routine prescriptions, non-adherence, drug dependency, lifestyle prescriptions, and drugs given due to a lack of preventive healthcare will be identified. Prescribing practices have environmental ramifications. Carbon reduction, when focused on pharmaceuticals, can lead to cleaner, more sustainable healthcare.

Accessing unproven interventions in the COVID-19 pandemic: discussion on the ethics of 'compassionate therapies' in times of catastrophic pandemics.

Since the onset of the SARS-CoV-2 pandemic, an array of off-label interventions has been used to treat patients, either provided as compassionate care or tested in clinical trials. There is a challenge in determining the justification for conducting randomised controlled trials over providing compassionate use in an emergency setting. A rapid and more accurate evaluation tool is needed to assess the effect of these treatments. Given the similarity to the Ebola Virus Disease (EVD) pandemic in Africa in 2014, we suggest using a tool designed by the WHO committee in the aftermath of the EVD pandemic: Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI). Considering the uncertainty around SARS-CoV-2, we propose using an improved MEURI including the Plan-Do-Study-Act tool. This combined tool may facilitate dynamic monitoring, analysing, re-evaluating and re-authorising emergency use of unproven treatments and repeat it in cycles. It will enable adjustment and application of outcomes to clinical practice according to changing circumstances and increase the production of valuable data to promote the best standard of care and high-quality research-even during a pandemic.

Institutional conflict of interest: attempting to crack the deferiprone mystery.

A recent study by Olivieri et al, published in PLOS ONE, reports that between 2009 and 2015 a third of patients with thalassaemia in Canada's largest hospital were switched from first-line licensed drugs to regimens of deferiprone, an unlicensed drug of unproven safety and efficacy. Based on retrospective data from patient records, the PLOS Study reports that patients treated with deferiprone, either as monotherapy or in combination with first-line drugs, suffered serious (and often irreversible) adverse effects. The data reported by Olivieri et al give rise to a number of ethical issues. These ethical issues are identified, placed in historical context and analysed. For purposes of this analysis, reliance is placed on two core principles of research ethics, harm minimisation and informed consent, and also on the hospital's mission statement. Then a mystery is explored: How and why did it happen that Toronto's University Health Network treated large numbers of patients with an unlicensed drug over a period of many years? 'Institutional conflict of interest' is considered as a possible explanatory hypothesis.

Novel drug candidates targeting Alzheimer's disease: ethical challenges with identifying the relevant patient population.

Intensive research is carried out to develop a disease-modifying drug for Alzheimer's disease (AD). The development of drug candidates that reduce Aß or tau in the brain seems particularly promising. However, these drugs target people at risk for AD, who must be identified before they have any, or only moderate, symptoms associated with the disease. There are different strategies that may be used to identify these individuals (eg, population screening, cascade screening, etc). Each of these strategies raises different ethical challenges. In this paper, we analyse these challenges in relation to the risk stratification for AD necessary for using these drugs. We conclude that the new drugs must generate large health benefits for people at risk of developing AD to justify the ethical costs associated with current risk stratification methods, benefits much larger than current drug candidates have. This conclusion raises a new set of ethical questions that should be further discussed.

Do we really know how many clinical trials are conducted ethically? Why research ethics committee review practices need to be strengthened and initial steps we could take to strengthen them.

Research Ethics Committees (RECs) play a critical gatekeeping role in clinical trials. This role is meant to ensure that only those trials that meet certain ethical thresholds proceed through their gate. Two of these thresholds are that the potential benefits of trials are reasonable in relation to risks and that trials are capable of producing a requisite amount of social value. While one ought not expect perfect execution by RECs of their gatekeeping role, one should expect routine success in it. This article reviews a range of evidence showing that substantial numbers of ethically tainted trials are receiving REC approvals. Many of the trials are early phase trials that evidence shows have benefits that may not be reasonable compared with their risks and many others are later trials that evidence shows may lack sufficient social value. The evidence pertains to such matters as methodologically inadequate preclinical studies incapable of supporting the inferences that REC members must make about the prospects for potential benefit needed to offset the risks in early phase trials and sponsorship bias that can cause improperly designed, conducted, analysed and reported later phase trials. The analysis of the evidence makes clear that REC practices need to be strengthened if they are to adequately fulfil their gatekeeping role. The article also explores options that RECs could use in order to improve their gatekeeping function.

Respect women, promote health and reduce stigma: ethical arguments for universal hepatitis C screening in pregnancy.

In the USA, there are missed opportunities to diagnose hepatitis C virus (HCV) in pregnancy because screening is currently risk-stratified and thus primarily limited to individuals who disclose history of injection drug use or sexually transmitted infection risks. Over the past decade, the opioid epidemic has dramatically increased incidence of HCV and a feasible, well-tolerated cure was introduced. Considering these developments, recent evidence suggests universal HCV screening in pregnancy would be cost-effective and several professional organisations have called for updated national policy. Historically, universal screening has been financially disincentivised on the healthcare system level, particularly since new diagnoses may generate an obligation to provide expensive treatments to a population largely reliant on public health resources. Here, we provide ethical arguments supporting universal HCV screening in pregnancy grounded in obligations to respect for persons, beneficence and justice. First, universal prenatal HCV screening respects pregnant women as persons by promoting their long-term health outside of pregnancy. Additionally, universal screening would optimise health outcomes within current treatment guidelines and may support research on treatment during pregnancy. Finally, universal screening would avoid potential harms of risk-stratifying pregnant women by highly stigmatised substance use and sexual behaviours.

'I just need an opiate refill to get me through the weekend'.

In this article, we discuss the ethical dimensions for the prescribing behaviours of opioids for a chronic pain patient, a scenario commonly witnessed by many physicians. The opioid epidemic in the USA and Canada is well known, existing since the late 1990s, and individuals are suffering and dying as a result of the easy availability of prescription opioids. More recently, this problem has been seen outside of North America affecting individuals at similar rates in Australia and Europe. We argue that physicians are also confronted with an ethical crisis where a capitalist-consumerist society is contributing to this opioid crisis in which societal, legal and business interests push physicians to overprescribe opioids. Individual physicians often find themselves unequipped and unsupported in attempts to curb the prescribing of opioid medications and balance competing goals of alleviating pain against the judicious use of pain medications. Physicians, individually and as a community, must reclaim the ethical mantle of our profession, through a more nuanced understanding of autonomy and beneficence. Furthermore, physicians and the medical community at large have a fiduciary duty to patients and society to play a more active role in curbing the widespread distribution of opioids in our communities.

Donor-funded research: permissible, not perfect.

Donor-funded research is research funded by private donors in exchange for research-related benefits, such as trial participation or access to the trial intervention. This has been pejoratively referred to as 'pay to play' research, and criticised as unethical. We outline three models of donor-funded research, and argue for their permissibility on the grounds of personal liberty, their capacity to facilitate otherwise unfunded health research and their consistency with current ethical standards for research. We defend this argument against objections that donor-funded research is wrongly exploitative, unfair and undermines the public good of medical research. Our conclusion is that, like all human subjects research, donor-funded research should be regulated via standard health research legislation/guidelines and undergo Research Ethics Committee/Institutional Review Board and scientific peer-review. We expect that, measured against these standards, some donor-funded research would be acceptable.

Is there a nocebo response that results from disease awareness campaigns and advertising in Australia, and can this effect be mitigated?

Direct-to-consumer advertising is banned in Australia, and instead pharmaceutical companies use disease awareness campaigns as a strategy to raise public awareness of conditions for which the company produces a treatment. This practice has been justified by promoting individual autonomy and public health, but it has attracted criticism regarding medicalisation of normal health and ageing, and exaggeration of the severity of the condition in question, imbalanced reporting of risks and benefits, and damaging the patient-clinician relationship. While there are benefits of disease awareness promotion, there is another possible adverse consequence that has not yet been rigorously considered: the possibility of inducing a nocebo response via the campaign. We will discuss the creation of a nocebo response in this context.

What makes clinical labour different? The case of human guinea pigging.

Each year thousands of individuals enrol in clinical trials as healthy volunteers to earn money. Some of them pursue research participation as a full-time or at least a part-time job. They call themselves professional or semiprofessional guinea pigs. The practice of paying healthy volunteers raises numerous ethical concerns. Different payment models have been discussed in literature. Dickert and Grady argue for a wage-payment model. This model gives research subjects a standardised hourly wage, and it is based on an assumption that research participation is morally indistinguishable from other forms of unskilled labour. In this paper, I will challenge this assumption. I will argue that human guinea pigging has particular characteristics which taken together make it significantly different from other forms of labour. (1) Participation in research is skill-independent. Healthy volunteers are valuable not because they are skilful persons, but because they are human bodies. (2) The role of research volunteers is mainly passive. They are not asked to produce goods or deliver services. They are paid for enduring unpleasant, painful and risky interventions performed by investigators. (3) Research volunteering involves inherent risks and uncertainties, and subjects have little or no control over their minimisation and materialisation. I conclude that participation in clinical research is a specific kind of activity. It is more like renting out one's body to strangers, than working. Thus, research participation should not be treated on par with other forms of employment.

Distress, disease, desire: perspectives on the medicalisation of premature ejaculation.

The discovery that certain selective serotonin reuptake inhibitors delay ejaculation and the later development and approval of dapoxetine as an on-demand treatment option has led to a dramatic increase in medical interest in premature ejaculation. This paper analyses the diagnostic criteria and the discussion within the medical community about suitable treatments against the backdrop of theories of science, sex and gender. Our conclusion is that the diagnosis itself and the suggested treatments contribute to normative models of sexual conduct and therefore reinforce the norms that cause patients' distress over ejaculating 'too soon'.

Ethics of a relaxed antidoping rule accompanied by harm-reduction measures.

Harm-reduction approaches are used to reduce the burden of risky human behaviour without necessarily aiming to stop the behaviour. We discuss what an introduction of harm reduction for doping in sports would mean in parallel with a relaxation of the antidoping rule. We analyse what is ethically at stake in the following five levels: (1) What would it mean for the athlete (the self)? (2) How would it impact other athletes (the other)? (3) How would it affect the phenomenon of sport as a game and its fair play basis (the play)? (4) What would be the consequences for the spectator and the role of sports in society (the display)? and (5) What would it mean for what some consider as essential to being human (humanity)? For each level, we present arguments for and against doping and then discuss what a harm-reduction approach, within a dynamic regime of a partially relaxed antidoping rule, could imply. We find that a harm-reduction approach is morally defensible and potentially provides a viable escape out of the impasse resulting from the impossibility of attaining the eradication of doping. The following question remains to be answered: Would a more relaxed position, when combined with harm-reduction measures, indeed have less negative consequences for society than today's all-out antidoping efforts that aim for abstinence? We provide an outline of an alternative policy, allowing a cautious step-wise change to answer this question and then discuss the ethical aspects of such a policy change.

Prescription preferences in antipsychotics and attitude towards the pharmaceutical industry in Belgium.

OBJECTIVES: The number of antipsychotic prescriptions are increasing rapidly worldwide, a trend which is mainly driven by the steep rise in second-generation antipsychotic (SGA) prescriptions. However, the success of SGA, compared with the older first-generation antipsychotics (FGAs), cannot be explained by evidence. Several studies concluded on equal efficacy of FGA and SGA on positive, negative and cognitive symptoms of schizophrenia. Next to that, the influence of the pharmaceutical industry on prescription behaviour has drawn considerable interest. Therefore, the relationship between antipsychotic prescription patterns and exposure to information directly provided by pharmaceutical companies was studied. METHODS: A cross-sectional online survey, addressing psychiatrists, general practitioners (GPs) and trainees in Flanders, was carried out. Respondents were questioned about their prescription behaviour, opinion about efficacy of SGA versus FGA and the nature and frequency of their contact with the pharmaceutical industry. Using Spearman's rank correlations and χ2 tests, the relationship between different variables and group differences were examined. RESULTS: Psychiatrists, GPs and trainees in Flanders clearly favour olanzapine and risperidone, followed by quetiapine and aripiprazole above all other agents. This behaviour is supported by the conviction that SGAs have superior efficacy and a more benign side effect profile, compared with FGA. Frequent contact with drug representatives is correlated with a preference of SGA over FGA. 41% of the respondents acknowledge to be influenced by the pharmaceutical industry, which is more than that previously reported.

From protection to entitlement: selecting research subjects for early phase clinical trials involving breakthrough therapies.

Our goals are to (1) set forth and defend a multiprinciple system for selecting individuals who meet trial eligibility criteria to participate in early phase clinical trials testing chimeric antigen receptor (CAR T-cell) for acute lymphoblastic leukaemia when demand for participation exceeds spaces available in a trial; (2) show the relevance of these selection criteria to other breakthrough experimental therapies; (3) argue that distinct distributive justice criteria apply to breakthrough experimental therapies, standard research and healthcare and (4) argue that as evidence of benefit increases, the emphasis of justice in research shifts from protecting subjects from harm to ensuring fair access to benefits.

The unethical use of ethical rhetoric: the case of flibanserin and pharmacologisation of female sexual desire.

The current debate around sexual dysfunctions focuses mostly on the pharmacological regulation of lowered sexual desire in women. The Food and Drug Administration approval of the first drug-Addyi-to treat this condition was preceded by a campaign, in which ethically saturated arguments were used to lobby policy makers. This article provides a critical evaluation of these arguments. In particular, we focus our attention on deceitful and unethical use of moral arguments and concepts. First, we present the context in which hypoactive sexual desire disorder is defined as a serious medical condition, showing how non-medical and non-scientific influences shaped the understanding of the problem. Further, we demonstrate how in current discussions regarding lower sexual interest attention has been shifted from psychosocial to pharmacological solutions and we trace the ethical consequences of such a change. We argue that, in addition to typical detrimental effects of overmedicalisation, there are new serious perils. In particular, we demonstrate that it is highly probable that pharmacologisation of female desire-contrary to the emancipatory declarations of the drug proponents-exerts pressure on women and narrows the range of potential choices they can make. As a result, it is inconsistent with the very idea of free choice.

Ethics of tobacco harm reduction from a liberal perspective.

Mixed evidence on the possible harms, benefits and usage patterns of electronic nicotine delivery systems (ENDS, or 'e-cigarettes'), has led to vigorous and ongoing debates on the issue. The ethical trade-off often represented is that, though smokers should be permitted access to ENDS as a less harmful alternative to smoking, this comes at the expense of non-smokers and children who may experiment with ENDS, become addicted to them, or experience health issues from long-term exposure to passive ENDS vapour. Lacking from many debates is a balanced analysis based on sound ethical reasoning, so this paper aims to examine the issue from a liberal perspective. More specifically, focus is on how ENDS policy can help to promote freedom in a broader sense, with 'freedom' considered as originating from having options and the necessary information and ability to autonomously choose between these options.

Deciphering assumptions about stepped wedge designs: the case of Ebola vaccine research.

Ethical concerns about randomising persons to a no-treatment arm in the context of Ebola epidemic led to consideration of alternative designs. The stepped wedge (SW) design, in which participants or clusters are randomised to receive an intervention at different time points, gained popularity. Common arguments in favour of using this design are (1) when an intervention is likely to do more good than harm, (2) all participants should receive the experimental intervention at some time point during the study and (3) the design might be preferable for practical reasons. We examine these assumptions when considering Ebola vaccine research. First, based on the claim that a stepped wedge design is indicated when it is likely that the intervention will do more good than harm, we reviewed published and ongoing SW trials to explore previous use of this design to test experimental drugs or vaccines, and found that SW design has never been used for trials of experimental drugs or vaccines. Given that Ebola vaccines were all experimental with no prior efficacy data, the use of a stepped wedge design would have been unprecedented. Second, we show that it is rarely true that all participants receive the intervention in SW studies, but rather, depending on certain design features, all clusters receive the intervention. Third, we explore whether the SW design is appealing for feasibility reasons and point out that there is significant complexity. In the setting of the Ebola epidemic, spatiotemporal variation may have posed problematic challenges to a stepped wedge design for vaccine research. Finally, we propose a set of points to consider for scientific reviewers and ethics committees regarding proposals for SW designs.

Innovation in medicine: Ignaz the reviled and Egas the regaled.

In our current climate of rapid technological progress, it seems counterintuitive to think that modern science can learn anything of ethical value from the dark recesses of the nineteenth century or earlier. However, this happens to be quite true, with plenty of knowledge and wisdom to be gleaned by studying our scientific predecessors. Presently, our journals are flooded with original concepts and potential breakthroughs, a continuous stream of ideas pushing the frontiers of knowledge ever forward. Some ideas flourish while others flounder; but what sets the two apart? The distinguishing feature between success and failure within this context is the ability to discern the appropriate time to accept an innovation with open arms, versus when to take a more cautious approach. And the primary arbiters for whether an idea will catch on or not are the professional audience. I illustrate this concept by comparing the initial reception of two innovative ideas from Medicine's past: sterile technique, and prefrontal lobotomy. Sterile technique was first introduced by Dr. Ignaz Semmelweis and was initially ridiculed and rejected, with Semmelweis eventually dying in exile. Conversely, lobotomy was accepted and lauded and its inventor, Dr. Egas Moniz, won the Nobel Prize for his "discovery". This begs the question: why was a technique with the potential to save millions of lives initially rejected, whereas paradoxically, one that compromised and sometimes destroyed lives, accepted? Here I explore and analyze the potential reasons why, suggest how we can learn from these mistakes of the past and apply new insight to some current ethical dilemmas.

Testing ground GDR: Western pharmaceutical firms conducting clinical trials behind the Iron Curtain.

Western pharmaceutical companies conducted clinical trials in the Eastern Bloc during the Cold War. Recently, media reports about alleged human experimentation provoked a wave of indignation. However, a scientific and objective account of these trials is lacking. The aim of this study was to describe and evaluate the clinical trials performed in the German Democratic Republic (GDR) based on archival material from the health system and the secret service. We found documents relating to 220 trials involving more than 14,000 patients and 68 Western companies. However, no record of patient information forms or systematic documentation regarding the provision of patient consent was discovered. There was no evidence to suggest that the trials systematically and intentionally damaged patients. The trials were conducted without the knowledge of the public. GDR legislation stipulated that patients must consent to the trials, but no evidence was found to suggest that patients were systematically informed. Documents suggest that at least some of the trials were carried out without patients having a comprehensive understanding of what the trial involved. The GDR agreed to the trials due to impending bankruptcy and Western pharmaceutical companies capitalised on this situation.

The evaluation of complex clinical trial protocols: resources available to research ethics committees and the use of clinical trial registries--a case study.

OBJECTIVES: To assess the potential role of clinical trial (CT) registries and other resources available to research ethics committees (RECs) in the evaluation of complex CT protocols in low-income and middle-income countries. METHODOLOGY: Using a case study approach, the authors examined the decision-making process of a REC in Argentina and its efforts to use available resources to decide on a complex protocol. We also analysed the information in the USA and other CT registries and consulted 24 CT experts in seven countries. FINDINGS: Information requested by the Argentinean REC from other national RECs and ethics' experts was not useful to verify the adequacy of the REC's decision whether or not to approve the CT. The responses from the national regulatory agency and the sponsor were not helpful either. The identification of international resources that could assist was beyond the REC's capability. The information in the USA and other CT registries is limited, and at times misleading; and its accuracy is not verified by register keepers. DISCUSSION AND CONCLUSION: RECs have limited access to experts and institutions that could assist them in their deliberations. Sponsors do not always answer RECs' request for information to properly conduct the ethical and methodological assessment of CT protocols. The usefulness of the CT registries is curtailed by the lack of appropriate codes and by data errors. Information about reasons for rejection, withdrawal or suspension of the trial should be included in the registries. Establishing formal channels of communication among national and foreign RECs and with independent international reference centres could strengthen the ethical review of CT protocols.