Research Quality and Dissemination

Abstract

This chapter focuses on issues relating to the rigour and quality of research in pandemic contexts, and the dissemination and publication of research findings. Research is indispensable to inform pandemic responses, including the development of new vaccines and therapeutic possibilities. While these studies are badly needed, public health emergencies present profound ethical challenges for the conduct of research. Key questions arise about whether and to what extent research designs should be adapted to pandemic contexts, including which adaptions may be necessary and which are unjustifiable. Where adaptions are needed, their implications for multiple aspects of research require careful consideration, including the quality of research, participant protections, and potential barriers to recruitment and participation. Challenges may also arise with ensuring that consent to research is informed, and that participants can distinguish between research and the early rollout of interventions in rapidly evolving pandemic contexts. Questions also arise about appropriate responses to studies with smaller sample sizes or other methodological flaws, which are proposed to address urgently pandemic priorities. Pressures to urgently contribute to pandemic evidence bases, including issuing pre-publications and press releases about research results prior to peer review, and dramatically accelerating peer-review processes, raise ethical issues about the dissemination and responses to research findings. The publication of poor quality research, including fraudulent research, contributed to the infodemic in COVID-19, and posed significant challenges for researchers, regulators, and policy makers seeking to develop evidence-informed pandemic responses. Accelerated dissemination of research findings prompts consideration of how to promote research integrity and detect research misconduct, and responsibilities to uphold research quality standards and ensure that publications make constructive contributions in challenging pandemic contexts. The five cases in this chapter promote reflection on citizen-scientists undertaking self-experimentation to develop COVID-19 vaccines outside frameworks for ethical and regulatory review of research; researchers proposing and undertaking research of questionable value and quality with vulnerable populations; and responsibilities of researchers, reviewers, journals and other research during accelerated pre-publication and peer-review processes.

3.1 Introduction

In a pandemic, it is necessary to conduct research and generate evidence rapidly in order to inform effective responses. As the World Health Organization states, “there is an ethical imperative to conduct research during public health emergencies, as some research questions can be adequately investigated only in emergency contexts” (WHO 2020). Such research is indispensable for developing vaccines as well as new therapeutic possibilities. While these studies are badly needed, biomedical research carried out during public health emergencies presents ethical challenges. The five cases in this chapter focus on issues relating to the quality of research, and the dissemination and publication of its findings.

3.2 Research Quality

Research quality standards address the entire research process, including the identification of a research question, the selection of a study approach, data collection and analysis, and the presentation and publication of results (Jacobsen 2016). Research quality considerations are relevant to all aspects of research study design, specifically:

• the match between the research questions and the methods

• participant selection

• outcome measurement

• protection against bias and error (Boaz and Ashby 2003; Shavelson and Towne 2002).

Biomedical research is subject to ethical frameworks based on international consensus standards within the global health community (CIOMS 2016). International guidelines set out ethical principles for the design, aims, revision and follow-up of any research involving human participants, and most countries have integrated some or all these principles into their local regulatory research frameworks as safeguards.

International standards for research ethics seek to protect the interests of human participants and include requirements for research to be reviewed by independent research ethics committees (RECs) (see Chap. 6). Such review includes consideration of the research protocol, including the social and scientific value of the study, and the consent process. Safeguards address the fairness of the recruitment process and the balance of potential benefits and risks for research participants. These safeguards are important to ensure research is ethical and of appropriate quality.

Research quality is a fundamental ethical issue, as the evidence informing responses, practices and policies must be valid and trustworthy. Safeguarding the quality of research is integral to justifying its conduct and ensuring that the anticipated benefits outweigh potential risks and burdens. Research integrity, as a subset of research ethics, urges investigators to possess and steadfastly adhere to “professional standards as outlined by professional organizations, research institutions, and, when relevant, the government and the public” (CIOMS 2016). Research ethics and research integrity are both necessary to ensure research quality during a global health emergency.

A range of pandemic-specific considerations can impact research quality. Concerns related to the value and quality of research during the COVID-19 pandemic have included the following (Glasziou et al. 2020; Lidz and Appelbaum 2002; Luxembourg Agency for Research Integrity n.d.):

• studies being conducted with inadequate scientific background and justification

• studies being conducted with very small sample sizes and limited statistical power

• effective evaluation of the social value of proposed research (pandemic priorities may be a significant multiplier in evaluations of social value)

• an abundance of COVID-19-specific funding resulting in the unnecessary conduct and duplication of studies

• appropriate oversight and conduct of research given gaps in expertise in RECs, on editorial boards, and amongst research teams pivoting to address pandemic priorities

These concerns can all occur in research during pandemics because of the urgency, stress, hype, potential for fame and career progression, and overwhelming need for reliable treatment and prevention of the disease in question.

Additional pandemic-specific study limitations can occur: for example, research quality may be impacted and results biased when specific populations, including vulnerable populations facing increased barriers to accessing health care, are under- or over-represented in research cohorts (Etowa et al. 2021). Additional challenges arise when research is conducted in hospitals which fail to collect high-quality data because their health workers are overburdened and their systems overwhelmed (Rojek et al. 2020). Furthermore, the urgency created by the pandemic could decrease the scientific rigour required to ensure that research is robust and generates reliable conclusions. This urgency, combined with lapses in research ethics, integrity and study design, have resulted in “a carnage of substandard research” during the pandemic (Bramstedt 2020). To better develop a robust evidence base going forward, researchers, REC members and journal editors, as well as academic and research organizations, should be vigilant about the specific considerations which can impact research quality during public health emergencies (ENRIO 2020).

Suggestions that the urgency generated by a pandemic justifies making changes to research standards (pandemic exceptionalism) must be treated with caution. Should we change research standards during a pandemic because of the magnitude of health burdens and urgent need for evidence to inform responses? Concerns have arisen that in practice, the impact of COVID-19 and a scarcity of qualified peer reviewers may result in a proliferation of studies with small sample sizes and other methodological flaws (London and Kimmelman 2020). Two cases in this chapter (Cases 3.1 and 3.2) highlight issues that arise when research standards are bypassed entirely in the context of a pandemic. When the economic crises and losses of human life are devastating, researchers may be tempted to forge ahead with pandemic priorities without adhering to research governance processes, which can be seen to obstruct progress. Case 3.1 addresses issues related to self-experimentation and citizen science, in a situation where researchers self-administered inoculations with the aim of developing a new COVID-19 vaccine and actively sought to work outside standard research ethics and governance processes. In Case 3.2 the ethics of research on a group of incarcerated subjects using an unproven therapeutic alternative are considered in a situation where the research does not comply with international research ethics standards.

Research ethics guidelines stipulate that researchers can only invite participants to consent to research which meets substantive ethical standards, as discussed further in Chap. 6. If a research study’s intrinsic value and scientific validity have not been established, and the research participant selection process is not fair, the risk–benefit ratio is not favourable and independent review has not taken place, the study must not be conducted and the participants’ consent is ethically irrelevant (Emanuel et al. 2000). Research ethics guidelines prompt researchers to review whether participants understand that they are taking part in research, and that the intervention being tested may not prevent infection or lessen the symptoms of the disease. When the people enrolled in the study are not aware of the difference between being a participant in a clinical trial and being a patient, a situation known as “therapeutic misconception” arises, in which a trial’s participants incorrectly believe that they are receiving routine clinical care (Lidz and Appelbaum 2002). Research quality issues specific to the pandemic and which relate to scientific validity, therapeutic misconception and informed consent are further explored in Cases 3.2 and 3.3.

3.3 Disseminating and Publishing Research

Since the start of the COVID-19 pandemic, there have been an unprecedented number of research publications, leading to a new term: infodemic. The World Health Organization describes an infodemic as a time during a disease outbreak when there is too much information, including false or misleading information, in digital and physical environments. It causes confusion and encourages risk-taking behaviours that can harm health, and also leads to mistrust in health authorities and undermines the public health response (WHO n.d.). Social media networks, the mainstream media and scientific journals have highlighted or published studies that lack scientific validity, which have at times influenced clinical decision-making and behaviour. As a result, many educators now recommend a new pedagogy which will enable students to assess the validity of research better and will develop competent consumers and communicators of science information (Nasr 2021).

Peer-reviewed journals have been under pressure to contribute to the pandemic evidence base and have faced many challenges when they have sought to do so. Publication platforms have sought to make research results available quickly, while also promoting review and research quality, which takes time. The peer-review process is considered a fundamental step for assuring methodological rigour and accurate interpretation of research findings; however, weaknesses in the process have become manifest during the pandemic. The increasing complexity of the scientific and research enterprise, coupled with the multidisciplinary nature of many research collaborations, has meant that the reviewer’s role has sometimes proved insufficient for analysing every detail of the scientific quality and legitimacy of a research paper.

The pandemic peer-review process was ineffective in many instances, and the scientific community is now debating which actors have which responsibilities to ensure the rigour of publications. Going forward, how can journal editors guarantee that peer review will ensure methodological rigour during global health emergencies? Publication codes of conduct promote integrity, accuracy and rigour, which assist journal editors to make the tough decisions which will assure the quality of the material they publish (Smith et al. 2020; Committee on Publication Ethics 2011). Alternative and creative methods of peer review are also under consideration (Rojek et al. 2020). Examples of challenges arising in processes related to peer review and publication ethics during the pandemic are highlighted in Case 3.4.

Case 3.5 highlights the impact that inadequate peer review can have on the conduct of research. Two articles, accepted in The Lancet and The New England Journal of Medicine respectively, show that even highly respected journals sometimes lacked the necessary scrutiny for assuring the soundness of the studies they published. One of the papers, the now infamous Surgisphere study, concerned a multinational registry analysis of the use of hydroxychloroquine for treating COVID-19 patients (Mehra et al. 2020a). Almost simultaneously, the same authors published another paper in the New England Journal, about cardiovascular disease, mortality and the effect of angiotensin-receptors blockers on COVID-19 patients (Mehra et al. 2020b). In both cases, the articles withstood the peer reviewers’ scrutiny, but when they were published, many scientists wondered how it was possible that hospitals from around the world could so easily and expeditiously share the data of thousands of their COVID-19 patients. There was “skepticism as to the integrity and validity of the dataset, statistical analysis, and conclusions” (Lipworth et al. 2020). The authors could not respond to the journal editors’ “expression of concern” and request for access to the raw data, so they retracted both articles. It is not clear how fraudulent or other poor-quality research got through the peer-review quality control process used by some high-impact journals during the pandemic. Ineffective peer review processes are further explored in Cases 3.4 and 3.5 in this chapter and are followed by questions that encourage reflection on the roles of researchers, research ethics committees and journal editors during pandemics.

Disseminating poor-quality research can damage both individuals and entire populations. In 1998, a physician, Andrew Wakefield, and some of his colleagues published a paper in The Lancet claiming that the measles, mumps and rubella vaccine was associated with the onset of autism in children. The article proved to be fraudulent, but it took 12 years for it to be retracted (Eggertson 2010), and despite the retraction, it is still cited frequently (Suelzer et al. 2019). Wakefield was subsequently stripped of his medical licence, however, the damage he did remains, as measles and its complications have resurged in unvaccinated communities.

The Retraction Watch database, a blog that tracks retractions from scientific journals, showed that between January 2020 and February 2022, 181 articles were retracted or withdrawn by authors, owing to undisclosed conflicts of interests, concerns about data validity or data analysis errors, misleading conclusions, fake peer reviews or duplicative publications (Retraction Watch Database n.d.). The US Office of Research Integrity gives fabrication, falsification and plagiarism as examples of research misconduct. Other regulatory bodies and international agencies now include many other types of behaviour in their lists of detrimental research practices. These practices fall short of being considered misconduct but affect the integrity, reliability and quality of research. They include inadequate research records, neglectful or exploitative research supervision, misleading statistical analysis and, for institutions, a lack of policies for addressing research misconduct allegations (NASEM 2017). The All-European Academies (ALLEA) issued the revised edition of the European Code of Conduct for Research Integrity in 2017. This code delineates a series of principles for good research practices, such as reliability, honesty, respect and accountability, and also characterizes falsification, fabrication and plagiarism as research misconduct. It also addresses emerging challenges emanating from technological developments, open science, citizen science and social media, among other areas, and adds new areas of unacceptable research practice such as manipulating authorship, unnecessarily expanding the study bibliography and misrepresenting research achievements (ALLEA n.d.). Regulatory bodies in many other countries, including Australia, New Zealand, Canada, and some Asian countries, have adopted similar codes of conduct.

In the Symposium on the COVID-19 Pandemic held by the Journal of Bioethical Inquiry, scholars offered their pandemic recommendations, which included establishing independent review panels with oversight over the whole research lifecycle, from the methodological study design to the publication stage, outlining clear data-sharing processes, and increasing funding for research facilities and oversight overall. The authors also recommend stricter penalties for research misconduct, more than just the shame of article retraction, and perhaps penalties for complacent research supervision too (Lipworth et al. 2020). In this way the research governance system can be streamlined and adequately funded and respected to facilitate rapid research, while remaining attentive to scientific quality and integrity.

The unprecedented number of COVID-19-related papers submitted as preprints – articles posted online before formal peer review – has been overwhelming. Scientific manuscripts, before going through peer-review processes, were uploaded at an unprecedented pace to preprint sites and widely shared. While open-access preprints represent a way to increase the knowledge of researchers from all around the world and provide opportunities for sharing efforts, the sites that present them risk becoming platforms for the dissemination of poor-quality research and misinformation, and supporting questionable research practices (Bramstedt 2020). Preprints contributed substantially to the COVID-19 infodemic.

A prominent preprint site for health sciences, MedRxiv, was launched in 2019. Founded by Cold Spring Harbour Laboratory, Yale University, and the British Medical Journal, MedRxiv aims “to improve the openness and accessibility of scientific findings, enhance collaboration among researchers, document provenance of ideas, and inform ongoing and planned research through more timely reporting of completed research” (MedRxiv n.d.). A search of articles uploaded between 15 January 2020 and 15 February 2022 to the MedRxiv database, using the term “COVID-19”, found 15,383 related articles – many of which had not passed peer review – which exacerbated an already confused evidentiary COVID-19 situation. Issues with preprints can be further debated as readers reflect on Case 3.4, which outlines the need for increased research support and improved infrastructure to inform evidence-based responses during pandemics.

However, with proper precautions and oversight, preprints can be a valuable source of information and provide a timely reference hub for the global scientific community during pandemics, as discussed in Case 5.4 of Chap. 5. For example, a frequently cited and shared March 2020 preprint, from researchers at Imperial College London, estimated the effectiveness of lockdown and social distancing measures and played a significant role in informing policy in the United Kingdom at the beginning of the pandemic (Else 2020). Additionally, preprints are a tool for scrutinizing published data and allow readers to alert the authors to methodological inaccuracies that could have led to incorrect conclusions. In one such case, an article about a clinical trial for a COVID-19 vaccine, Epi-Vac Corona published in the Russian Journal of Infection and Immunity reported that in a double-blind placebo-controlled trial, the vaccine had developed 100% immunogenicity against the SARS-CoV-2 virus (Ryzhikov et al. 2021). Several scientists who were not involved in that study subsequently communicated in a preprint that the “true immunogenicity of Epi-Vac is lower than claimed” and that furthermore, “it did not lead to the emergence of neutralizing antibodies in healthy volunteers”, while two other preprints mentioned the small cohort size of the study, as well as other inaccuracies that rendered the results dubious (Loseva 2022). These preprints quickly alerted the scientific community to the methodological inaccuracies of research that had already been published.

Noting the time-consuming peer-review process for publication in journals, scientific communities are using alternative methods to share information needed to influence practice rapidly during pandemics. Are preprints a channel that meets the urgent need of the scientific community to communicate results while, at the same time, maintaining the standards of quality and plausibility necessary to ensure scientific integrity? How to best supervise and use preprints to share potentially accurate information in pandemics is one of the important discussion questions related to Case 3.4.

3.4 Conclusion

The trustworthiness of scientific research has been at stake during the COVID-19 pandemic, perhaps as never before. The cases in this chapter highlight issues related to research quality and publication for readers to consider and address going forward. The cases underline the need for transparent research processes, where scientists disclose conflicts of interest, sources of funding and study limitations. Such processes foster the responsible conduct of research (Smith et al. 2020). Now is the time for the scientific community to coordinate its activities and uphold the standards necessary to advance research quality and create an environment where high-quality research and publications make constructive contributions, including during pandemics. This chapter invites readers to reflect on case studies that raise several concerns and questions, without easy answers.

Appendices

Case 3.1: Self-Experimentation in the Development of COVID-19 Vaccines

This case study was written by members of the case study author group.

Keywords

Researcher roles and responsibilities; Community engagement and participatory processes; Regulatory review; Research publication ethics; Vaccines; Citizen science; Researcher safety

Soon after the outbreak of the COVID-19 pandemic, scientists in the Americas, Europe and Asia started conducting experiments on themselves in order to develop a vaccine against COVID-19 (Regalado 2020; Murphy 2020). Self-experimentation is in a grey area – it is not addressed directly in key research ethics regulations, including the Declaration of Helsinki, and its legal status is often unclear (Manríquez Roa and Biller-Andorno 2020; Regalado 2020).

A group of researchers, innovators and citizen science enthusiasts in a country in the Americas embarked on self-experimentation with the aim of developing a COVID-19 vaccine. This initiative involved designing, producing and self-administering progressive generations of nasal inoculations. This group was established as a not-for-profit organization and has been sharing its knowledge through their website. They work under open licences without using patents or asserting their intellectual property rights.

According to the members of the group, the rationale behind their initiative is compassion. On their website, until at least March 2021, they claimed that public health, commercial and regulatory infrastructures had so far failed to provide a vaccine to protect humanity against COVID-19. They also stated that during a pandemic, there is an ethical imperative to deploy emergency vaccines as quickly and widely as possible and not to restrict access to information about them to a privileged circle.

This group of scientists released information about how to produce and self-administer their intranasal inoculation. They made publicly available a “white paper”: an in-depth report about their product, which contains terms of use, advice about informed consent, goals, technical features, materials, methods, preparation and instructions on how to administer the potential vaccine, as well as an assessment of the immune response in recipients.

This research has not been approved by a research ethics committee. Moreover, the intranasal inoculation was developed without the authorization of the national authority responsible for regulating the development of vaccines. After the publication of an earlier version of the “white paper” in 2020, a professor from a different country offered to produce the nasal inoculation against COVID-19 in his laboratory and to distribute it to the public for free. However, the self-experimenters claim in their website that they cannot guarantee that their nasal vaccine is safe, and that although preliminary assays have shown positive indications regarding efficacy, this requires ongoing confirmation that will be available in another “white paper”. The latest version of their “white paper”, released in September 2021, states that no expectation is given concerning efficacy in granting protection against SARS-CoV-2. The group of scientists behind this self-experimentation project claim that hundreds of people have self-administered the product and provide a map with researchers based in more than 20 countries across the world who are interested in collaborating on this vaccine development.

Questions

• 1. Is self-experimentation ethical in the development of vaccines or therapies during a pandemic? Why or why not?

• 2. What role should national systems for ethical and regulatory review play with respect to self-experimentation during a pandemic? Is it ethical to involve citizen scientists in such a project? Why?

• 3. Is it ethical to release a product formula to the public without knowing if it leads to the creation of antibodies against COVID-19 in humans? Why or why not?

• 4. In the context of the development of COVID-19 vaccines or therapies, are there ways in which self-experimentation should contribute to making science a more inclusive activity? Why?

References

• Manríquez Roa, T., and N. Biller-Andorno. 2020. Going first: The ethics of vaccine self-experimentation in Coronavirus times. Swiss Medical Weekly 150: w20415. https://doi.org/10.4414/smw.2020.20415.

• Murphy, H. 2020. These scientists are giving themselves D.I.Y. Coronavirus vaccines. New York Times, September 1, updated 8 Sept 2020. https://www.nytimes.com/2020/09/01/science/covid-19-vaccine-diy.html%20.

• Regalado, A. 2020. Some scientists are taking a DIY coronavirus vaccine, and nobody knows if it’s legal or if it works. MIT Technology Review, July 29. https://www.technologyreview.com/2020/07/29/1005720/george-church-diy-coronavirus-vaccine/.

Case 3.2: Research with Chlorine Dioxide in a Prison During the COVID-19 Pandemic

This case study was written by members of the case study author group.

Keywords

Researcher roles and responsibilities; Research misconduct; Vulnerability and inclusion; Safety and participant protection; Social and scientific value; Risk/benefit analysis; Ethical review

During the early stages of the pandemic, when evidence about effective treatments for COVID-19 patients was urgently needed, many politicians, health workers, journalists and other influential leaders across the Americas proposed the administration of substances whose effectiveness for preventing or treating the disease was not supported by credible scientific evidence (US Food and Drug Administration 2020b; Gigova 2020; Forgey 2020; Casado et al. 2021).

Large COVID-19 outbreaks were common in prisons across Latin America between June and September 2020. As a result of overcrowding, poor ventilation, limited access to water, and other unsanitary conditions, and prison inmates and their guards were at high risk of contracting COVID-19 (Blakinger and Hamilton 2020; Associated Press 2020). Newspapers featured stories of inmates protesting and pleading for protection from the rapidly spreading virus (Vivanco and Muñoz 2020). To address this situation in a South American city, regional health authorities met with prison officials to discuss possible interventions. After the meeting, the health authorities announced a new trial to test the effectiveness of chlorine dioxide as a treatment for inmates and prison guards with COVID-19 symptoms. Chlorine dioxide is a bleaching product commonly used for water disinfection. A research team of university biochemists and regional health authorities would lead the investigation.

The team developed and finalized their research protocol. Several other university researchers were invited to join the team, but declined to do so, and provided feedback that they felt that the research protocol was neither clear nor appropriate. The research protocol was not reviewed by a research ethics committee, and university authorities did not respond to a request to officially sponsor the study. Despite this, the study went ahead. Despite a lack of evidence about the therapeutic value of chlorine dioxide, its use was common across the country at the time of the research, especially among the poor and marginalized populations, whose access to high-quality health care was limited. Charismatic politicians, journalists and other leaders around the country were promoting chlorine dioxide as a cure for COVID-19 on the radio, television and social media.

In the study, doses of chlorine dioxide were the main intervention and were provided over a period of 25 days to 30 inmates and prison guards with COVID-19 symptoms. According to local and international news reports, the inmates and guards gave their “informed consent” to participate. The study was designed as a pharmacotherapy follow-up study using the Dader method, a common methodology in pharmacology to create standards of practice. All the research subjects recovered from their COVID-19 symptoms during the study. There were no hospitalizations or new cases diagnosed in the prison during the study period. Twenty-one subjects (70%) left the research study after their symptoms resolved but before the 25 days were completed. The reasons for their withdrawal are not known and many other details about the study were not recorded or made public.

After the study was completed, the research team decided not to publicly share their research results. During personal communication between the author of this case study and the lead investigator, the latter mentioned that it was “possible that there were oversights in designing and conducting this experimental research study but the team had good intentions and are open to any recommendations to develop another study going forward”.

Before the study, the United States Federal Drug Administration and the Pan American Health Organization had officially warned against the use of chlorine dioxide to prevent or treat COVID-19, citing significant risks of adverse health effects (US Food and Drug Administration 2020a; PAHO 2020a).

Questions

• 1. What ethical issues were raised by this research?

• 2. Which concerns should be addressed by researchers when planning research with vulnerable populations during pandemics?

• 3. What responsibilities do researchers have to assess the trustworthiness and scientific rigour of information about innovative treatments before conducting research with them during pandemics?

• 4. How should research ethics committees facilitate the ethical conduct of research during health emergencies and pandemics?

References

• Associated Press. 2020. Fear – and the coronavirus – spreads through Latin America’s unruly prisons. Los Angeles Times, April 28. https://www.latimes.com/world-nation/story/2020-04-28/virus-spreads-fear-through-latin-americas-unruly-prisons.

• Blakinger, Keri, and Keegan Hamilton. 2020. “I begged them to let me die”: How federal prisons became Coronavirus death traps. The Marshall Project. June 18. https://www.themarshallproject.org/2020/06/18/i-begged-them-to-let-me-die-how-federal-prisons-became-coronavirus-death-traps.

• Casado, Leticia, Ernesto Londoño, and Adam Rasgon. 2021. As Covid deaths soar in Brazil, Bolsonaro hails an untested nasal spray. New York Times, March 31. https://www.nytimes.com/2021/03/06/world/americas/brazil-covid-bolsonaro-nasal-spray.html.

• Forgey, Quint. 2020. Trump gets stung from all sides after floating injections of disinfectants. Politico, April 24. https://www.politico.com/news/2020/04/24/lysol-maker-warns-against-injecting-disinfectants-trump-coronavirus-theory-206268.

• Gigova, Radina. 2020. Lawmakers push toxic disinfectant as Covid-19 treatment in Bolivia, against Health Ministry’s warnings. CNN, July 20. https://edition.cnn.com/2020/07/29/americas/bolivia-disinfectant-covid-19-intl/index.html.

• Nuffield Council on Bioethics. 2020. Research in global health emergencies: Ethical issues. London: Nuffield Council on Bioethics. https://www.nuffieldbioethics.org/publications/research-in-global-health-emergencies.

• PAHO. 2020a. PAHO does not recommend taking products that contain chlorine dioxide, sodium chlorite, sodium hypochlorite, or derivatives. Pan American Health Organization. 16 July. https://www.paho.org/en/node/72109.

• PAHO. 2020b. Ethics and research 10 key points about research during the pandemic. Washington: Pan American Health Organization. https://www.paho.org/en/documents/infographic-ethics-research-10-key-points-about-research-during-pandemic.

• US Food and Drug Administration. 2020a. Coronavirus (COVID-19) update: FDA warns seller marketing dangerous chlorine dioxide products that claim to treat or prevent COVID-FDA News Release. April 8. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-warns-seller-marketing-dangerous-chlorine-dioxide-products-claim.

• US Food and Drug Administration. April 2020b. Coronavirus (COVID-19) update: Federal judge enters temporary injunction against Genesis II Church of Health and Healing, preventing sale of chlorine dioxide products equivalent to industrial bleach to treat COVID-19. FDA News Release. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-federal-judge-enters-temporary-injunction-against-genesis-ii-church.

• Vivanco, José Miguel, and César Muñoz. 2020. How to prevent Covid-19 outbreaks in Latin America’s prisons. News. May 21. Human Rights Watch. https://www.hrw.org/news/2020/05/21/how-prevent-covid-19-outbreaks-latin-americas-prisons#.

Case 3.3: Evaluating the Role of the BCG Vaccine as a Prophylactic in Elderly Populations

This case study was written by members of the case study author group.

Keywords

Vulnerability and inclusion; Ethical review; Consent; Social and scientific value; Vaccine repurposing

Elderly populations with associated comorbidities like diabetes, hypertension and other chronic illnesses are at a higher risk of contracting COVID-19 and have higher rates of mortality if they do contract it (Daoust 2020). The BCG vaccine is known to protect against respiratory tract infections in children and adults and is included in the childhood immunization programme in many countries. A general observation was reported in the early months of the COVID-19 pandemic that in countries where the BCG vaccination is routine, the incidence of COVID-19 infection and mortality was lower than in countries where the BCG vaccination is not being provided (WHO 2020).

Given that BCG vaccination may protect individuals from severe respiratory illnesses, in 2020 an institution in an Asian country decided to start an open-label clinical trial which aimed to collect evidence about the effectiveness of the BCG vaccination in reducing COVID-19-related mortality in elderly populations. The study would recruit 500 volunteers aged between 60 and 95 years residing in a community with a high incidence of COVID-19 cases. (As an infection-control measure, residents within the community were not allowed to travel outside it.) Apart from age, there were no exclusion criteria, although researchers planned to record which participants had also received the BCG vaccination in childhood. To encourage elderly people to enrol in the trial, advertisements about the study would highlight the potential of the BCG vaccine to reduce COVID-19-related mortality in the elderly. An intradermal single dose of the BCG vaccine would be provided and follow-up conducted on a monthly basis for 6 months to assess morbidity and mortality, or until a positive test result for COVID-19 occurred. Researchers would travel to local health centres within the community to conduct the research rather than asking participants to travel to the research facility. All participants would be tested for COVID-19 at recruitment and when follow-up was completed. Self-reported adverse events would be monitored and progress assessed during monthly follow-ups, which would be conducted by telephone during the lockdown period. Symptomatic individuals would also receive additional COVID-19 tests during the follow-up period.

In this setting, local ethics committee secretariats drew on national guidelines to determine whether submitted proposals should receive expedited review by a subset of committee members, or full committee review. In the context of the pandemic, committees then assessed whether full committee reviews should be fast-tracked, with a turnaround time of 24–72 h. The principal investigator requested that this protocol receive expedited review, despite the requirement that research with vulnerable populations should always be reviewed by the full committee, to safeguard participants’ interests.

Questions

• 1. What ethical issues are raised by the design of the proposed study and how should these be addressed?

• 2. What ethical considerations should inform fast-track review processes for research with vulnerable populations during a pandemic?

• 3. During fast-track review processes, what role should the ethics committee have in evaluating whether the study design is appropriate to answer the research question and/or making recommendations to improve proposed research?

• 4. What ethical issues could arise during the consent processes for this project?

References

• Daoust, J.F. 2020. Elderly people and responses to COVID-19 in 27 countries. PLoS ONE 15(7): e0235590. https://doi.org/10.1371/journal.pone.0235590.

• WHO. 2020. Bacille Calmette-Guérin (BCG) vaccination and COVID-19. Scientific Brief. April 12. Geneva: World Health Organization.

Case 3.4: Publication, Pre-publication and Retraction of Research: How a Pandemic Magnifies Concerns About Publication Ethics

This case study was written by members of the case study author group.

Keywords

Research publication ethics; Research misconduct; Researcher roles and responsibilities; Pre-prints; Retractions

The potentially harmful influence of medical research findings that turn out to be erroneous because of flawed methodology or fraud can be long-lasting and widespread (Wakefield et al. RETRACTED 1998). Although an integral part of the research process, peer review alone is no guarantee of adequate scrutiny, as observed during the COVID-19 pandemic. In July 2020, a paper was published that linked 5G millimetre waves with COVID-19 (Fioranelli et al. RETRACTED 2020). The paper was subsequently retracted as it “showed evidence of substantial manipulation of the peer review” (Biolife SAS 2020). Though the paper was discredited by the scientific community, it likely contributed to the misinformation spreading rapidly online, which made it necessary for the the World Health Organization to issue a statement after 5G phone masts were vandalized (Kaushik 2020). Another example of peer-reviewed research which has now been retracted was the National Institutes of Health-funded paper published on 8 October 2020 claiming that Nephrite-Jade amulets may prevent COVID-19 (Turkle Bility 2020). It was claimed that the paper had undergone a standard review process, with multiple rounds of revisions agreed between the authors and two expert reviewers before finally being accepted (Jarry 2020, Retraction Watch 2020). The paper was heavily criticized on social media upon publication, resulting in its temporary removal on 5 November 2020 and eventual retraction at a later date (Williams 2020).

Even though peer review is imperfect, it has been viewed as providing an additional level of formal scrutiny, which preprints have not undergone. The practice of uploading preprints existed well before COVID-19 but was not standard in the life sciences despite lengthy publication timeframes (Fraser et al. 2020). However, in response to the urgent global need to share scientific findings, the COVID-19 pandemic has prompted an unprecedented increase in preprint publishing, which has enabled access to research months before it would be published in a peer-reviewed journal (Fraser et al. 2020). This, along with the increased retraction rates in 2020, has magnified existing concerns about the impact of preprints on the integrity of biomedical literature and science (Teixeira da Silva et al. 2021). There are also concerns about the spread of misinformation and the resulting threats to public health (Teixeira da Silva et al. 2021). For instance, lay people, eager to find out about treatment for COVID-19, or ways of preventing it, may have easy access to research that has not been thoroughly vetted, and may draw their own inferences from it. In the midst of a global pandemic, the findings of such preprint studies may be widely disseminated by the media, who do not always appreciate the preliminary nature of such findings or convey it to the audiences they engage with.

Nevertheless, the benefits arising from rapid access to some preprints must also be recognized. For example, when a preprint generated by an eminent research group suggested that dexamethasone had the potential to save the lives of critically ill COVID-19 patients (Horby et al. 2020) (see also Case 5.4 in Chap. 5) the World Health Organization and some health-care providers immediately issued guidance based on these findings (WHO 2020; Mahase 2020). On the day the preprint was released, the WHO supported the use of the corticosteroids in appropriate patient groups, presumably because the preprint findings arose from a large, well-designed clinical trial and were consistent with previously known benefits of corticosteroids in reducing inflammation and immune responses. While the research completed peer review a few weeks later and its conclusions remain undisputed, there remains a concern that many preprint studies do not achieve such levels of scientific acceptance if and when independently reviewed by experts (Añazco et al. 2021).

The publication of preprints of scientific research, and the peer-review process itself are two end components of the immense research enterprise. Questions arise about whether they can be expected to carry all the weight for discerning whether research put forth for publication has merit; or whether funding bodies, ethics committees, and other oversight bodies also bear some responsibility, particularly during pandemics.

Questions

• 1. How should the benefits of publishing preprints during a pandemic be weighed against the potential harm they may bring about?

• 2. Where there is a need for rapid dissemination of research findings via preprints, what conditions should be in place during a pandemic to ensure they achieve the scientific standards expected for the research to be of public benefit? How should we balance these competing interests?

• 3. Which stakeholders in research have roles and responsibilities during the conduct of research and dissemination of findings during a pandemic, and what responsibilities do they have?

• 4. Should journals actively encourage the publication of preprints? Why or why not? How should biomedical researchers view the practice of submitting preprints?

References

• Añazco, D., B. Nicolalde, I. Espinosa, J. Camacho, M. Mushtaq, J. Gimenez, and E. Teran. 2021. Publication rate and citation counts for preprints released during the COVID-19 pandemic: The good, the bad and the ugly. PeerJ 9:e10927. https://doi.org/10.7717/peerj.10927.

• Fioranelli, M., et al. RETRACTED. 2020. 5G technology and induction of coronavirus in skin cells. Journal of Biological Regulators and Homeostatic Agents 34(4). https://doi.org/10.23812/20-269-E-4R.

• Fraser, N., L. Brierley, G. Dey, J.K. Polka, M. Pálfy, F. Nanni, and J.A. Coates. 2020. Preprinting the COVID-19 pandemic. bioRxiv. https://doi.org/10.1101/2020.05.22.111294. Published in PLOS Biology. https://doi.org/10.1371/journal.pbio.3000959.

• Horby, P., W.S. Lim, J. Emberson, M. Mafham, J. Bell, L. Linsell, N. Staplin, C. Brightling, A. Ustianowski, E. Elmahi, B. Prudon, C. Green, T. Felton, D. Chadwick, K. Rege, C. Fegan, S.N. Chappell, T. Faust, K. Jaki, A. Jeffery, K. Montgomery, E. Rowan, J.K. Juszczak, R. Baillie, L.C. Haynes, and M.J. Landray. 2020. Effect of dexamethasone in hospitalized patients with COVID-19 – Preliminary report. medRxiv. https://doi.org/10.1101/2020.06.22.20137273. http://medrxiv.org/content/early/2020/06/22/2020.06.22.20137273.abstract. Now published in New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2021436.

• Jarry, J. 2020. This paper argues an amulet may protect from COVID. Should it have been published? November 5. McGill Office for Science and Society. https://www.mcgill.ca/oss/article/covid-19-critical-thinking-pseudoscience/paper-argues-amulet-may-protect-covid-should-it-have-been-published.

• Kaushik, M. 2020. Conspiracy theories blame 5G for COVID-19 as studies on health effects remain scant. Business Today, July 2. https://www.businesstoday.in/sectors/telecom/conspiracy-theories-blame-5g-for-covid19-as-health-effects-remain-unclear/story/408639.html.

• Mahase, E. 2020. Covid-19: Low dose steroid cuts death in ventilated patients by one third, trial finds. British Medical Journal 369: m2422. https://doi.org/10.1136/bmj.m2422.

• Retraction Watch. 2020. Amulets may prevent COVID-19, says a paper in Elsevier journal. (They don’t.) October 29. https://retractionwatch.com/2020/10/29/amulets-may-prevent-covid-19-says-a-paper-in-elsevier-journal-they-dont/.

• Teixeira da Silva, J.A., H. Bornemann-Cimenti, and P. Tsigaris. 2021. Optimizing peer review to minimize the risk of retracting COVID-19-related literature. Medicine, Health Care and Philosophy 24(1): 21–26. https://doi.org/10.1007/s11019-020-09990-z.

• Turkle Bility, M., et al. WITHDRAWN (2020) Can Traditional Chinese Medicine provide insights into controlling the COVID-19 pandemic: Serpentinization-induced lithospheric long-wavelength magnetic anomalies in Proterozoic bedrocks in a weakened geomagnetic field mediate the aberrant transformation of biogenic molecules in COVID-19 via magnetic catalysis. Science of The Total Environment, https://doi.org/10.1016/j.scitotenv.2020.142830.

• Wakefield, A.J., et al. RETRACTED. 1998. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet 351(9103): 637–641. https://doi.org/10.1016/s0140-6736(97)11096-0.

• Williams, S. 2020. Paper proposing COVID-19, magnetism link to be retracted. The Scientist, November 4 and 5. https://www.the-scientist.com/news-opinion/paper-proposing-covid-19-magnetism-link-to-be-retracted-68126.

• WHO. 2020. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 22 June 2020. https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---22-june-2020.

Case 3.5: Retracted Research: Impacts and Outcomes

This case study was written by members of the case study author group.

Keywords

Research publication ethics; Research misconduct; Researcher roles and responsibilities; Ethical review; Regulatory review; Risk/benefit analysis; Data protection, access and sharing; Treatment repurposing; Multi-centre research; Retractions

Ethical standards for publication exist for several reasons: to maintain a high quality of academic output, to enable the public to trust research findings, and to ensure that people receive credit for their work. These standards are being challenged in the time of COVID-19 because of the need and pressure to publish the results of related research quickly to provide evidence to inform responses to the pandemic.

In February 2020 a protocol for a multinational study (Study X) was developed to evaluate whether chloroquine (CQ) and hydroxychloroquine (HCQ) were effective in preventing COVID-19. Owing to the use of CQ and HCQ for rheumatological conditions and for malaria, both as prophylaxis and in mass drug administration, there is a large amount of data supporting the safety of long-term administration of these drugs (White et al. 2020). However, no conclusive evidence of benefit from pre-exposure prophylaxis had so far been produced in relation to COVID-19. Similarly, no other chemoprophylactic agents had been proven to be effective. The rationale behind usage was based on in vitro antiviral activity of chloroquine on SARS-CoV and it was unclear if an in vivo effect with clinical benefit would be observed (Wang et al. 2020). The study aimed to enrol tens of thousands of healthy volunteers from among frontline health-care workers and staff who had close contact with COVID-19 patients. Following ethical and regulatory approval, recruitment commenced for Study X in an Asian country in April, and a European country in May.

On 22 May The Lancet published an article by Mehra et al. entitled “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis” (Mehra et al. 2020a). Based on a database known as the Surgical Outcomes Collaborative (developed by Surgisphere Corporation), the article claimed that the use of HCQ or CQ was associated with “decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19”. The impacts of the article’s claim about cardio-toxicity were rapid, significant and widespread: they included suspensions of recruitment into HCQ studies, and changes in national recommendations for the clinical use of HCQ (Blamont et al. 2020).

Shortly after the publication of this controversial paper, researchers in Study X played a key role in developing an open letter to Mehra et al. and The Lancet setting out some concerns about the published research. Published on 28 May, the letter raised multiple concerns about the statistical analysis, ethics and data integrity in the published article (Watson et al. 2020). On 4 June the Mehra et al. paper was retracted at the request of three of its four authors, following the refusal of Surgisphere to share the dataset to enable independent peer review (Mehra et al. 2020b). The Lancet subsequently announced changes to its peer-review process, which sought to reduce the risk of research and publication misconduct (The Editors of The Lancet Group 2020). For future publications, authors must now declare that more than one author has directly accessed and verified the data reported in the manuscript.

In early June, the national regulator at the initial European site for Study X issued a general requirement that trials using HCQ suspend recruitment pending a review. In late June, following substantial discussion and correspondence between the national regulator and researchers leading HCQ studies, approval was given to recommence recruitment into Study X.

Sites in Africa, Asia and Europe expressed interest in joining Study X. Regulators and local research ethics committees reviewing the study protocol at these sites continued to raise questions about associations between HCQ and cardio-toxicity in healthy volunteers, despite the retraction of Mehra et al. Even in settings where CQ and HCQ are routinely used in clinical care, regulatory agencies which initially had relatively few queries about the study became increasingly precautionary over time. Protracted review processes resulted in some sites missing the opportunity to join the study following reduced COVID-19 incidence levels. Concerns about cardio-toxicity also impacted recruitment – of the 200+ health-care workers in the initial European site who expressed an interest in joining the study, just 25 joined once recruitment recommenced.

More broadly, the responses to Mehra et al. have impacted a range of studies seeking to evaluate the prophylactic effect of CQ and HCQ. Some proposed studies have not received approval, others have dropped proposed CQ/HCQ arms, and others have been unable to reach recruitment targets.

Questions

• 1. How should research publishers balance their responsibilities to ensure that COVID-19 research findings are both rigorous and rapidly disseminated?

• 2. In the context of unprecedented scientific pre-publication, publication and retraction rates during the COVID-19 pandemic, what ethical obligations do regulators, ethics committees and researchers have to monitor, evaluate and respond to research findings of potential relevance to ongoing studies?

• 3. What responsibilities do ethics committees and regulators have to consider the potential consequences of declining to approve research? Should a retracted article influence such decisions? Why?

• 4. What ethical issues should be considered when communicating with study participants about the reasons for, and implications of, pausing and restarting research in response to emerging research findings?

References

• Blamont, M., A. Smout, and E. Parodi. 2020. EU governments ban malaria drug for COVID-19, trial paused as safety fears grow. Reuters, May 28. https://www.reuters.com/article/health-coronavirus-hydroxychloroquine-fr/eu-governments-ban-malaria-drug-for-covid-19-trial-paused-as-safety-fears-grow-idUSKBN2340A6.

• Mehra, M.R., S.S. Desai, F. Ruschitzka, and A.N. Patel RETRACTED. 2020a. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis. The Lancet. May 22. https://doi.org/10.1016/S0140-6736(20)31180-6.

• Mehra, M.R., F. Ruschitzka, and A.N. Patel. 2020b. Retraction – Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis. The Lancet 395(10240): 1820. June 5. https://doi.org/10.1016/S0140-6736(20)31324-6.

• The Editors of The Lancet Group. 2020. Learning from a retraction. The Lancet 396(10257): 1056. https://doi.org/10.1016/S0140-6736(20)31958-9.

• Wang, M., et al. 2020. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 30(3): 269–271.

• Watson, James, et al. 2020. An open letter to Mehra et al. and The Lancet. Version 4. Zenodo, May 28. https://doi.org/10.5281/zenodo.3862789.

• White, N.J., et al. 2020. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med 17(9): e1003252.