Ethical approval for controlled human infectious model clinical trial protocols - A workshop report.

Controlled Human Infectious Model studies (CHIM) involve deliberately exposing volunteers to pathogens. To discuss ethical issues related to CHIM, the European Vaccine Initiative and the International Alliance for Biological Standardization organised the workshop "Ethical Approval for CHIM Clinical Trial Protocols", which took place on May 30-31, 2023, in Brussels, Belgium. The event allowed CHIM researchers, regulators, ethics committee (EC) members, and ethicists to examine the ethical criteria for CHIM and the role(s) of CHIM in pharmaceutical development. The discussions led to several recommendations, including continued assurance that routine ethical requirements are met, assurance that participants are well-informed, and that preparation of study documents must be both ethically and scientifically sound from an early stage. Study applications must clearly state the rationale for the challenge compared to alternative study designs. ECs need to have clear guidance and procedures for evaluating social value and assessing third-party risks. Among other things, public trust in research requires minimisation of harm to healthy volunteers and third-party risk. Other important considerations include appropriate stakeholder engagement, public education, and access to health care for participants after the study.

The Ethical Obligation for Research During Public Health Emergencies: Insights From the COVID-19 Pandemic.

In times of crises, public health leaders may claim that trials of public health interventions are unethical. One reason for this claim can be that equipoise-i.e. a situation of uncertainty and/or disagreement among experts about the evidence regarding an intervention-has been disturbed by a change of collective expert views. Some might claim that equipoise is disturbed if the majority of experts believe that emergency public health interventions are likely to be more beneficial than harmful. However, such beliefs are not always justified: where high quality research has not been conducted, there is often considerable residual uncertainty about whether interventions offer net benefits. In this essay we argue that high-quality research, namely by means of well-designed randomized trials, is ethically obligatory before, during, and after implementing policies in public health emergencies (PHEs). We contend that this standard applies to both pharmaceutical and non-pharmaceutical interventions, and we elaborate an account of equipoise that captures key features of debates in the recent pandemic. We build our case by analyzing research strategies employed during the COVID-19 pandemic regarding drugs, vaccines, and non-pharmaceutical interventions; and by providing responses to possible objections. Finally, we propose a public health policy reform: whenever a policy implemented during a PHE is not grounded in high-quality evidence that expected benefits outweigh harms, there should be a planned approach to generate high-quality evidence, with review of emerging data at preset time points. These preset timepoints guarantee that policymakers pause to review emerging evidence and consider ceasing ineffective or even harmful policies, thereby improving transparency and accountability, as well as permitting the redirection of resources to more effective or beneficial interventions.

A Systematic Review of Human Challenge Trials, Designs, and Safety.

BACKGROUND: Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. METHODS: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. RESULTS: Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. CONCLUSIONS: HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.

Herd immunity, vaccination and moral obligation.

The public health benefits of herd immunity are often used as the justification for coercive vaccine policies. Yet, 'herd immunity' as a term has multiple referents, which can result in ambiguity, including regarding its role in ethical arguments. The term 'herd immunity' can refer to (1) the herd immunity threshold, at which models predict the decline of an epidemic; (2) the percentage of a population with immunity, whether it exceeds a given threshold or not; and/or (3) the indirect benefit afforded by collective immunity to those who are less immune. Moreover, the accumulation of immune individuals in a population can lead to two different outcomes: elimination (for measles, smallpox, etc) or endemic equilibrium (for COVID-19, influenza, etc). We argue that the strength of a moral obligation for individuals to contribute to herd immunity through vaccination, and by extension the acceptability of coercion, will depend on how 'herd immunity' is interpreted as well as facts about a given disease or vaccine. Among other things, not all uses of 'herd immunity' are equally valid for all pathogens. The optimal conditions for herd immunity threshold effects, as illustrated by measles, notably do not apply to the many pathogens for which reinfections are ubiquitous (due to waning immunity and/or antigenic variation). For such pathogens, including SARS-CoV-2, mass vaccination can only be expected to delay rather than prevent new infections, in which case the obligation to contribute to herd immunity is much weaker, and coercive policies less justifiable.

Ethics of antibiotic allergy.

Antibiotic allergies are commonly reported among patients, but most do not experience reactions on rechallenge with the same agents. These reported allergies complicate management of infections in patients labelled as having penicillin allergy, including serious infections where penicillin-based antibiotics are the first-line (most effective and least toxic) treatment option. Allergy labels are rarely questioned in clinical practice, with many clinicians opting for inferior second-line antibiotics to avoid a perceived risk of allergy. Reported allergies thereby can have significant impacts on patients and public health, and present major ethical challenges. Antibiotic allergy testing has been described as a strategy to circumvent this dilemma, but it carries limitations that often make it less feasible in patients with acute infections or in community settings that lack access to allergy testing. This article provides an empirically informed ethical analysis of key considerations in this clinical dilemma, using Staphylococcus aureus bacteraemia in patients with penicillin allergies as a case study. We argue that prescribing first-line penicillin-based antibiotics to patients with reported allergies may often present a more favourable ratio of benefits to risks, and may therefore be more ethically appropriate than using second-line drugs. We recommend changes to policy-making, clinical research and medical education, in order to promote more ethically acceptable responses to antibiotic allergies than the status quo.

Ethical issues in Nipah virus control and research: addressing a neglected disease.

Nipah virus is a priority pathogen that is receiving increasing attention among scientists and in work on epidemic preparedness. Despite this trend, there has been almost no bioethical work examining ethical considerations surrounding the epidemiology, prevention, and treatment of Nipah virus or research that has already begun into animal and human vaccines. In this paper, we advance the case for further work on Nipah virus disease in public health ethics due to the distinct issues it raises concerning communication about the modes of transmission, the burdens of public health surveillance, the recent use of stringent public health measures during epidemics, and social or religious norms intersecting with preventive measures. We also advance the case for further work on Nipah virus disease in research ethics, given ethical issues surrounding potential vaccine trials for a high-fatality disease with sporadic spillover events, the different local contexts where trials may occur, and the potential use of unproven therapeutics during outbreaks. Further bioethics work may help to ensure that research and public health interventions for Nipah virus disease are ethically acceptable and more likely to be effective.

Ethics and antibiotic resistance.

INTRODUCTION OR BACKGROUND: Antibiotic resistance raises ethical issues due to the severe and inequitably distributed consequences caused by individual actions and policies. SOURCES OF DATA: Synthesis of ethical, scientific and clinical literature. AREAS OF AGREEMENT: Ethical analyses have focused on the moral responsibilities of patients to complete antibiotic courses, resistance as a tragedy of the commons and attempts to limit use through antibiotic stewardship. AREAS OF CONTROVERSY: Each of these analyses has significant limitations and can result in self-defeating or overly narrow implications for policy. GROWING POINTS: More complex analyses focus on ethical implications of ubiquitous asymptomatic carriage of resistant bacteria, non-linear outcomes within and between patients over time and global variation in resistant disease burdens. AREAS TIMELY FOR DEVELOPING RESEARCH: Neglected topics include the harms of antibiotic use, including off-target effects on the human microbiome, and the lack of evidence guiding most antibiotic prescription decisions.

COVID-19 vaccine boosters for young adults: a risk benefit assessment and ethical analysis of mandate policies at universities.

In 2022, students at North American universities with third-dose COVID-19 vaccine mandates risk disenrolment if unvaccinated. To assess the appropriateness of booster mandates in this age group, we combine empirical risk-benefit assessment and ethical analysis. To prevent one COVID-19 hospitalisation over a 6-month period, we estimate that 31 207-42 836 young adults aged 18-29 years must receive a third mRNA vaccine. Booster mandates in young adults are expected to cause a net harm: per COVID-19 hospitalisation prevented, we anticipate at least 18.5 serious adverse events from mRNA vaccines, including 1.5-4.6 booster-associated myopericarditis cases in males (typically requiring hospitalisation). We also anticipate 1430-4626 cases of grade ≥3 reactogenicity interfering with daily activities (although typically not requiring hospitalisation). University booster mandates are unethical because they: (1) are not based on an updated (Omicron era) stratified risk-benefit assessment for this age group; (2) may result in a net harm to healthy young adults; (3) are not proportionate: expected harms are not outweighed by public health benefits given modest and transient effectiveness of vaccines against transmission; (4) violate the reciprocity principle because serious vaccine-related harms are not reliably compensated due to gaps in vaccine injury schemes; and (5) may result in wider social harms. We consider counterarguments including efforts to increase safety on campus but find these are fraught with limitations and little scientific support. Finally, we discuss the policy relevance of our analysis for primary series COVID-19 vaccine mandates.

Against COVID-19 vaccination of healthy children.

COVID-19 vaccination of children has begun in a number of countries with provisional regulatory approval and public support. This article provides an ethical analysis of COVID-19 vaccination of healthy children. Specifically, we present three of the strongest arguments that might justify COVID-19 vaccination of children: (a) an argument from paternalism, (b) an argument from indirect protection and altruism, and (c) an argument from global eradication. We offer a series of objections to each of these arguments to show that none of them is currently tenable. Given the minimal direct benefit of COVID-19 vaccination for healthy children, the potential for rare risks to outweigh these benefits and to undermine vaccine confidence, the substantial evidence that COVID-19 vaccination confers adequate protection to risk groups whether or not healthy children are vaccinated and that current vaccines do not provide sterilizing immunity, and given that eradication of the virus is neither feasible nor a high priority for global health, we argue that routine COVID-19 vaccination of healthy children is currently ethically unjustified. Since mandates for children have already been implemented in some places (e.g., California) and may be considered elsewhere, we also present two additional arguments explicitly against making COVID-19 vaccination mandatory for children.

Moralization and Mismoralization in Public Health.

Moralization is a social-psychological process through which morally neutral issues take on moral significance. Often linked to health and disease, moralization may sometimes lead to good outcomes; yet moralization is often detrimental to individuals and to society as a whole. It is therefore important to be able to identify when moralization is inappropriate. In this paper, we offer a systematic normative approach to the evaluation of moralization. We introduce and develop the concept of 'mismoralization', which is when moralization is metaethically unjustified. In order to identify mismoralization, we argue that one must engage in metaethical analysis of moralization processes while paying close attention to the relevant facts. We briefly discuss one historical example (tuberculosis) and two contemporary cases related to COVID-19 (infection and vaccination status) that we contend to have been mismoralized in public health. We propose a remedy of de-moralization that begins by identifying mismoralization and that proceeds by neutralizing inapt moral content. De-moralization calls for epistemic and moral humility. It should lead us to pull away from our tendency to moralize-as individuals and as social groups-whenever and wherever moralization is unjustified.

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers.

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Transparency in clinical practice guidelines: the problem of consensus-based recommendations and practice points.

Clinical practice guidelines often provide 'consensus-based recommendations' for issues where there is a lack of evidence to support an evidence-based recommendation, and 'practice points' to assist clinicians in various aspects of everyday clinical care. However, Australian clinical practice guidelines often fail to define these terms clearly, and there is significant inconsistency in how they are used. This lack of clarity presents an impediment to the effective practice of evidence-based medicine and an opportunity for reform in Australian clinical guideline development.

Imagination and remembrance: what role should historical epidemiology play in a world bewitched by mathematical modelling of COVID-19 and other epidemics?

Although every emerging infectious disease occurs in a unique context, the behaviour of previous pandemics offers an insight into the medium- and long-term outcomes of the current threat. Where an informative historical analogue exists, epidemiologists and policymakers should consider how the insights of the past can inform current forecasts and responses.

Human infection challenge studies in endemic settings and/or low-income and middle-income countries: key points of ethical consensus and controversy.

Human infection challenge studies (HCS) involve intentionally infecting research participants with pathogens (or other micro-organisms). There have been recent calls for more HCS to be conducted in low-income and middle-income countries (LMICs), where many relevant diseases are endemic. HCS in general, and HCS in LMICs in particular, raise numerous ethical issues. This paper summarises the findings of a project that explored ethical and regulatory issues related to LMIC HCS via (i) a review of relevant literature and (ii) 45 qualitative interviews with scientists and ethicists. Among other areas of consensus, we found that there was widespread agreement that LMIC HCS can be ethically acceptable, provided that they have a sound scientific rationale, are accepted by local communities and meet usual research ethics requirements. Unresolved issues include those related to (i) acceptable approaches to trade-offs between the scientific aim to produce generalisable results and the protection of participants, (iii) the sharing of benefits with LMIC populations, (iii) the acceptable limits to risks and burdens for participants, (iv) the potential for third-party risk and whether the degree of acceptable third-party risk is different in endemic settings, (v) the conditions under which (if any) it would be appropriate to recruit children for disease-causing HCS, (v) appropriate levels of payment to participants and (vi) appropriate governance of (LMIC) HCS. This paper provides preliminary analyses of these ethical considerations in order to (i) inform scientists and policymakers involved in the planning, conduct and/or governance of LMIC HCS and (ii) highlight areas warranting future research. Insofar as this article focuses on HCS in (endemic) settings where diseases are present and/or widespread, much of the analysis provided is relevant to HCS (in HICs or LMICs) involving pandemic diseases including COVID19.

SARS-CoV-2 challenge studies: ethics and risk minimisation.

COVID-19 poses an exceptional threat to global public health and well-being. Recognition of the need to develop effective vaccines at unprecedented speed has led to calls to accelerate research pathways ethically, including by conducting challenge studies (also known as controlled human infection studies (CHIs)) with SARS-CoV-2 (the virus which causes COVID-19). Such research is controversial, with concerns being raised about the social, legal, ethical and clinical implications of infecting healthy volunteers with SARS-CoV-2 for research purposes. Systematic risk evaluations are critical to inform assessments of the ethics of any proposed SARS-CoV-2 CHIs. Such evaluations will necessarily take place within a rapidly changing and at times contested epidemiological landscape, in which differing criteria for the ethical acceptability of research risks have been proposed. This paper critically reviews two such criteria and evaluates whether the use of effective treatment should be a necessary condition for the ethical acceptability of SARS-CoV-2 CHIs, and whether the choice of study sites should be influenced by COVID-19 incidence levels. The paper concludes that ethical evaluations of proposed SARS-CoV-2 CHIs should be informed by rigorous, consultative and holistic approaches to systematic risk assessment.

Evidence-poor medicine: just how evidence-based are Australian clinical practice guidelines?

BACKGROUND: Clinical practice guidelines aim to assist medical practitioners in making efficient evidence-based decisions in daily practice. However, international studies have shown that the majority of recommendations in American and European guidelines are not based on strong evidence. AIMS: To review Australian clinical practice guidelines across a broad range of high-impact conditions and determine how evidence-based they are. METHODS: Australian guidelines published from January 2010 to May 2018 relating to the top 10 causes of death in Australia were identified from the National Health and Medical Research Council (NHMRC) clinical practice guideline database and other relevant sources. The graded recommendations in these guidelines were extracted for analysis and the systems used for grading the recommendations were recorded. RESULTS: Ten relevant Australian guidelines were identified, containing a total of 748 graded recommendations. All 10 guidelines used either the Grading of Recommendations Assessment, Development and Evaluation (GRADE) or NHMRC systems to assess recommendations. However, only 18% (n = 136) of these recommendations were based on Level I (or equivalent) evidence; 25% (n = 185) were based on Level II evidence, 29% (n = 218) on Level III, and 9% (n = 66) on Level IV. Consensus-based recommendations accounted for 19% (n = 143) of all recommendations. CONCLUSIONS: Despite the enthusiasm of the evidence-based medicine movement and its documented successes, contemporary medicine appears to remain largely evidence-poor, not evidence-based. Future research should aim to provide reliable descriptions of what constitutes valid clinical reasoning in evidence-poor situations.

Ethical issues surrounding controlled human infection challenge studies in endemic low-and middle-income countries.

Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro-organisms. There have been increased calls for more CHIs to be conducted in low- and middle-income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third-party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well-designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly.

Surveillance and control of asymptomatic carriers of drug-resistant bacteria.

Drug-resistant bacterial infections constitute a major threat to global public health. Several key bacteria that are becoming increasingly resistant are among those that are ubiquitously carried by human beings and usually cause no symptoms (i.e. individuals are asymptomatic carriers) until and/or unless a precipitating event leads to symptomatic infection (and thus disease). Carriers of drug-resistant bacteria can also transmit resistant pathogens to others, thus putting the latter at risk of resistant infections. Accumulating evidence suggests that such transmission occurs not only in hospital settings but also in the general community, although considerably more data are needed to assess the extent of this problem. Asymptomatic carriage of drug-resistant bacteria raises important ethical questions regarding the appropriate public health response, including the degree to which it would be justified to impose burdens on asymptomatic carriers (and others) in order to prevent transmission. In this paper, we (i) summarize current evidence regarding the carriage of key drug-resistant bacteria, noting important knowledge gaps; and (ii) explore the particular implications of existing public health ethics frameworks for policy-making regarding asymptomatic carriers. Inter alia, we argue that the relative burdens imposed by public health measures on healthy carriers (as opposed to sick individuals) warrant careful consideration and should be proportionate to the expected public health benefits in terms of risks averted. We conclude that more surveillance and research regarding community transmission will be needed in order to clarify relevant risks and design proportionate policies, although extensive community surveillance itself would also require careful ethical consideration.

How to hold an ethical pox party.

Pox parties are a controversial alternative to vaccination for diseases such as chickenpox. Such parties involve parents infecting non-immune children by exposing them to a contagious child. If successful, infection will usually lead to immunity, thus preventing infection later in life, which, for several vaccine-preventable diseases, is more severe than childhood infection. Some may consider pox parties more morally objectionable than opting out of vaccination through non-medical exemptions. In this paper, I argue that this is not the case. Pox parties involve immediate risk of harm for children and reduce future harms, whereas opting out of vaccination places children at long-term risk of harms that increase with time, at least for some pathogens. Regarding harm to others through onward transmission of infection, this can be easily prevented in the case of pox parties-given the relatively controlled timing of infection-by quarantining attendees after the party, whereas opting out of vaccination involves risks to others that are more difficult to control. I defend three criteria for an ethical pox party: (1) that the disease is sufficiently low risk, (2) that parents consent to their child's attendance and (3) that children exposed to infection are quarantined and isolated appropriately. I argue that, if these criteria are met, pox parties are morally preferable to non-vaccination; such parties involve less risk to non-consenting others and, for some pathogens in some cases, even involve less risk for the children who participate. Thus, policies that permit non-medical exemption to vaccination should also permit ethical pox parties. Alternatively, if pox parties are not permitted, then vaccination should be mandated for those without medical contraindication.