David Resnik

This chapter summarizes the arguments and conclusions developed in the book and discusses proposed reforms to the system of overseeing research with human subjects including mandating that sponsors of institutions provide fair compensation to subjects for research-related injuries; creating a national registry for healthy volunteers to protect them from harm and promote data integrity; harmonizing regulations from different federal agencies, including DHHS, FDA, and EPA; closing loopholes in the federal regulations; simplifying and streamlining the process for adopting reliance agreements between institutions that are collaborating on a research project; developing federal regulations or policies for participation of adults with impaired decision-making in research; providing additional logistical, financial, and educational support for IRBs; enhancing support for local participation on IRBs; enhancing public and community engagement with human subjects research; promoting evidence-based IRB decisions-making in research with subjects; and controlling IRB mission-creep. The chapter also discusses some areas for future research, such as the ethics of testing emerging technologies on human beings, such as human gene editing (germline and somatic); nanomedicine; stem cell therapy and regenerative medicine, robotics, bionics, neural implants, wearable devices, and machine-human interfaces; microbiome interventions; and artificial intelligence.

This chapter explores a variety of issues related to the participation of vulnerable subjects in research including the definition of vulnerability; categories of vulnerable subjects; criticisms of classifying subjects or populations as vulnerable; arguments for providing additional protections for vulnerable subjects; arguments for including vulnerable subjects in research; evolving approaches to the protection vs. exclusion dilemma; the types of additional protections for vulnerable subjects; federal regulations and international guidance pertaining to vulnerable subjects; and ethical issues related to enrolling children, prisoners, pregnant women, students, employees, and adults with impaired decision-making abilities in research. The chapter also applies ethical principles, including the principles of trust, justice, beneficence, nonmaleficence, and respect for persons, to research with vulnerable subjects. The chapter concludes by arguing that there are no simple solutions to the protection vs. inclusion dilemma and that the best way forward is to carefully consider the different factors in favor of inclusion or exclusion of vulnerable participants for each study, such as the risks of the research, the ability of the subject to provide informed consent, and the importance of the research for promoting the health of the population of which the group is a member.

This chapter explores various issues related to informed consent in research including the elements of consent; the moral and legal foundations of consent; research without consent; medical records research; emergency research; consent by parties other than the subject; documentation of consent; general (or broad) consent; tiered consent; readability of consent forms; opt-in vs. opt-out consent; deception in research; payment for research participation; information disclosure standards; (mis) understanding of information disclosed during consent; the therapeutic misconception; the difference between decision-making capacity and legal competence; assent; coercion and undue influence; the relationship between consent and trust; the right to withdraw from research; and empirical studies of informed consent. Although the federal regulations provide considerable guidance pertaining to informed consent, ethical issues still arise due to controversies concerning the interpretation of the regulations, conflicts between ethical principles (e.g., respect for human dignity vs. beneficence) and the need to acknowledge local customs and traditions concerning consent. The chapter argues that trust plays a key role throughout the consent process and that reflecting on the importance of promoting trust can help us address ethical issues pertaining to consent.

This chapter describes key historical events that have shaped ethical rules and policies concerning research with human subjects, including the Tuskegee Syphilis Study, the Nazi experiments on concentration camp prisoners, the Willowbrook hepatitis experiments, the US government’s secret human radiation experiments, Stanley Milgram’s obedience to authority experiments, the Stanford prison experiment, and Jesse Gelsinger’s tragic death in a gene therapy study. The chapter also discusses the Belmont Report and its impact; provides an overview of the US federal regulations, including the Common Rule, the FDA regulations, and the IRB system; and reviews international guidelines, such as the Nuremberg Code and the Helsinki Declaration. The chapter argues that the social and political response to historical events has been to develop an oversight system to restore and maintain public trust in research. An important question that emerges at the end of this chapter is whether the current system provides too much or too little protection for human research subjects. To answer this question satisfactorily, one needs a philosophical framework that can address ethical and regulatory dilemmas in research with human subjects.

This chapter explores a variety of issues related to managing risks and benefits in research with human subjects, including defining risks and benefits; minimizing risks; the relationship between scientific study design issues and risks and benefits; assessing risks and benefits; balancing risks and benefits; the role of empirical evidence and intuition in risk/benefit decision-making; social benefits and risks; harms to communities, family members, and other third parties; the ethics of randomly assigning patients to different treatment groups; the use of placebos in research; the relevance of equipoise to clinical trial design and problems with the equipoise concept; challenge studies involving healthy human subjects; phase I clinical studies on healthy volunteers and cancer patients; limits for risks in studies involving healthy volunteers; controversies concerning the definition of minimal risk; alternative study designs, such as uncontrolled trials; sharing individualized results with research participants; providing ancillary medical care to research participants; post-trial access to medications; and fair sharing of the benefits of research.

This chapter provides an overview of moral concepts, theories, and principles that can be serve as a philosophical framework for making decisions involving dilemmas and issues in research with human subjects. The theories and ideas discussed in this chapter include the difference between science and ethics; moral justification and knowledge; reflective equilibrium; moral relativism and subjectivism; divine command theory; virtue ethics; natural law theory; natural rights theory; social contract theory; utilitarianism; Kantianism; Rawls’ principles of justice; feminist ethics; and principlism. The chapter observes that each of the moral theories examined have strengths and weaknesses and emphasize different aspects of morality. The chapter argues that principlism is the most reasonable approach to moral theory because it is better able to accommodate conflicting intuitions concerning moral values than the other approaches and has a workable decision procedure. The principles defended in this chapter include respect for human dignity, nonmaleficence, beneficence, and justice. Principlism, like other moral theories, must still deal with the problem of priority-setting when conflicts arise among principles. In the following chapter, I argue that an additional principle, the principle of trust, can help resolve conflict among the other moral principles.

This chapters explores a variety of topics related to integrity in research with human subjects including the importance of integrity in protecting human subjects; the definition of misconduct; questionable research practices; the prevalence of misconduct; misconduct vs. fraud; misconduct vs. error or negligence; procedures for reporting, investigating and adjudicating misconduct; famous cases of research misconduct; non-compliance in research; procedures for reporting, investigating, and correcting non-compliance; unanticipated problems in research involving increased risks of harm; serious or continuing non-compliance; serious adverse events; conflicts of interests; the definition of conflict of interests; empirical evidence concerning conflict of interest; why conflicts of interests are an ethical concern in science; the relationship between conflicts of interest, bias, and misconduct; famous cases of conflict of interest; policies for disclosing and managing conflicts of interest; and strategies for promoting integrity in research, such as support for education in responsible conduct of research; ethical leadership; development of policies for research ethics; auditing of data and research records; and mechanisms for providing consultation on ethics issues and protecting whistleblowers.

This chapters explores a variety of issues related to protecting privacy and confidentiality in research including the moral and legal basis for privacy and confidentiality; the relationship between trust and privacy and confidentiality; the difference between privacy and confidentiality; the Privacy Rule of the Health Information Portability and Accountability Act (HIPPA); the European General Data Protection Regulation; methods and strategies for protecting privacy and confidentiality; the conflict between sharing data and biospecimens and protecting privacy and confidentiality; data security, data use agreements; the difference between identified and de-identified data and biospecimens; the Tarasoff case; privacy in genetic and genomic research involving family members; reporting of suspected abuse and neglect of children or vulnerable adults; and reasons for breaching privacy and confidentiality in some situations. The chapter also argues that recognizing the importance of trust in research can provide investigators with useful guidance and help solve some ethical dilemmas involving privacy and confidentiality.

Research with human subjects exemplifies the perennial conflict between the good of the individual and the good of society. Policies and procedures that protect the rights and welfare of human subjects may hinder scientific research that benefits society. Due to this conflict, research with human subjects continues to be one of the most controversial topics in bioethics, despite ample government regulation, institutional oversight, and professional guidance. This chapter introduces the reader to a philosophical framework for thinking about these conflicts and issues. The framework, which will be described and defended in greater depth in subsequent chapters in the book, is grounded on widely accepted moral principles and the ethos of trust. The chapter also discusses seven controversial cases that serve to illustrate the importance of developing a philosophical framework for thinking about the ethics of research with human subjects. Cases discussed in the chapter include perinatal HIV prevention trials, the SUPPORT study, the Facebook deception study, xenotransplantation experiments, COVID-19 challenge studies, and the Henrietta Lacks case.

The chapter describes and defends a trust-based approach to the ethics of research with human subjects. The key premise of the framework is that research is founded on trust: trust between participants and investigators and institutions; between communities and investigators and institutions; among investigators, staff, and trainees; and between the public and the research enterprise. The chapter argues that the goal of promoting trust augments other moral principles, and that reflecting on the nature and importance of trust can often help one decide how resolve ethical and policy dilemmas in research with human subjects. Although promoting trust does not solve all ethical dilemmas in research, it can be an essential tool in helping us to develop workable solutions. The chapter also explains what trust is, distinguishes between trust and verification, discusses alternative views about trust in research, and discusses methods for promoting trust in research with human subjects, such as community and public engagement.

As I write this chapter, the entire world is reeling from the COVID-19COVID-19pandemicPandemic, one of the worst disease outbreaks in modern history. COVID-19 is a respiratory infection caused by the novel coronavirus SARS-CoV-2SARS-CoV-2 (see Fig. 9.1). The pandemic is thought to have started in December 2019 in the wet marketsWet marketsof WuhanWuhan, China, ChinaChina, when a virus that normally resides in horseshoe bats acquired the mutationsMutation that allowed it to infect people. The mutationsMutation were for genesGenes that code for the protein spike on the receptor binding domain of the virus. The protein spike enables the virus to bind to human lung epithelial cells (Andersen et al. 2020; Zhou et al. 2020). There has been speculation that SARS-CoV-2 is a genetically engineered virus that escaped from the WuhanWuhan, China Institute of Virology, a BSL-IV laboratory in WuhanWuhan, China, China, where researchers had been working with coronaviruses. However, researchers from the lab have denied this claim and there is no direct evidence to support it (Bryner 2020). Most scientists believe the virus mutated naturally but some dispute this claim and argue that a laboratory accident is a plausible scenario that cannot be ruled out (Andersen et al. 2020; Latham and Wilson 2020). The virus, which is transmissible by respiratory water droplets, quickly spread from China to EuropeEurope, the USUnited States, and other parts of the world. As of January 14, 2021, there were 92.6 million confirmed COVID-19 cases and nearly 2 million deaths, for a case fatality rate of 2.1%.

Decision theoryDecision theory is the study of how people make rational choices, where rationality is defined as taking effective means to one’s goals and conforming to the rules of logicLogic and axiomsProbabilityaxioms of probability theory (Resnik in Choices: An Introduction to Decision Theory. University of Minnesota Press, Minneapolis, MN, 1987; PetersonPeterson, MartinIntroduction to Decision Theory, 2nd ed. Cambridge University Press, Cambridge, UK, 2017). As noted in Chap. 1, this type of rationality, known as instrumentalRationalityinstrumentalrationalityReasonablenessvs. rationality, is different from reasonableness because reasonableness is founded on moral and social valuesValue(s)social. A decision could be rational in the decision theorist’sDecision theory sense but not reasonable. For example, it might be rational to jump off a tall building to commit suicide (if that is one’s goal) but not reasonable to do this.

Scientific researchScientific research benefits societySociety in many ways. The knowledgeKnowledge generated by science has practical applications in medicine, publicHealthpublichealthPublic health, engineering, industryIndustry, transportation, navigation, communication, educationEducation, public policyPublic policy, and numerous other aspects of human lifeHuman life. However, knowledgeKnowledge can also be used to cause harm to individuals, societySociety, and the environment. The knowledgeKnowledge used to build a nuclear reactor may also be used to build nuclear weapons; the knowledgeKnowledge used to launch a rocket to the moon may also be used to guide a missile to kill innocent civilians; and the knowledgeKnowledge used to develop a vaccine might also be used to make a bioweapon.

I began this book with some general reflections on how we think about risks, benefits, and precautionsPrecaution. I observed that as individuals we make decisions involving precautionsPrecaution in a variety of situations that we face each day, ranging from deciding whether to drive to work when snow is in the forecast, to taking a new job, to seeking medical treatment for chest pain. As groups we make decisions involving precautionsPrecaution in businessBusiness, industryIndustry, governmentGovernment, research, engineering, and educationEducation. Precautionary reasoningPrecautionary reasoning, I argued, involves deciding what is a reasonable precautionPrecaution to take, given the available optionsOptions (e.g. risk avoidanceRiskavoidance, risk minimizationRiskminimization, or risk managementRiskmanagement), our values (e.g. publicHealthpublichealthPublic health and safetySafety, human rightsRightshumanHuman rights, economic developmentEconomic development, environmental protection), our toleranceRisktolerance for risk and uncertainty, and our knowledgeKnowledge and information. Risks may arise from our choices and actions or they may arise on their own with little or no human involvement (e.g. natural disastersNatural disasters).

Every day we make decisions involving risks, benefits, and precautionsPrecaution. We engage in what I call precautionary reasoningPrecautionary reasoning in a variety of decision-making contextsDecision-makingcontext, including lifestyle choices (e.g. smokingSmokingtobaccoTobacco, riding motorcycles, eating excessively), financial decisions (e.g. investing money, loaning money, purchasing goods), health care choices (e.g. seeking medical treatment, taking preventative measures), and public policyPublic policy decisions (e.g. approving drugs, developing new technologiesTechnology, enacting environmentalHealthenvironmental or publicHealthpublichealthPublic health protections). Precautionary decisions range from the mundane (e.g. whether to take an umbrella to work) to the profound (e.g. whether to permit human genomeGenomehuman editing), and they may impact anywhere from a few people to the entire world.

In the previous chapter, we explored decision-theoretic approaches to precautionary reasoningPrecautionary reasoning and found them wanting. While decision theoryDecision theory offers important insights into making individual and group choices involving risks and benefits, it does not provide use with adequate guidance for precautionary reasoningPrecautionary reasoning, because it lacks moral content. Decision theoryDecision theory can tell us how to make decisions, given our values, but it cannot tell us what those values should be or how to rank them. For insight into values, we need to look beyond decision theoryDecision theory toward moral theoryMoral theory(ies).

Recent advancements in brain research have drastically increased the need for serious ethical consideration. Postmortem brain research has taken a significant step in the development of BrainEx. The technology can metabolically resuscitate pig brains from pigs that were “clinically dead” for hours. Ethical discourse around organoids ranges from being overly cautious and sensational to highly permissive and skeptical of even minimal consciousness emerging in such a model. Some of these criticisms are allayed in postmortem brains. As such, postmortem brain research presents philosophers and policymakers with a higher risk model of being conscious. The outcome of researchers unknowingly subjecting postmortem brains to negative mental states through research will be termed brain-in-a-vat-world. We will provide some motivation to believe this is a reasonable outcome of proceeding with postmortem brain research. As such, we propose applying the PP to all postmortem brain research. These precautions go beyond previous precautions of brain activity monitoring and the willingness to administer anesthetics to the brains should they appear awake. These precautions aim to avoid potential negative mental states. Such precautions reasonably mitigate the risk of postmortem brain research causing suffering. We recommend several practical precautions. First, anesthetics may prevent any conscious experience at all, cingulotomies prevent painful experiences, and the administration of opioids may prevent boredom or isolation. IRBs should work to determine how these precautions interact with experimental outcomes and how to balance the risk of side effects in light of the experimentation period. The upshot of the article is such PP applications avoid overapplication of the PP, which has occurred in the brain organoid literature. Further, the PP, we argue, provides better guidance to precautionary policy than decision theory, given the difficulties with applying decision theory in medical ethics.

_Ethics of Science_ is a comprehensive and student-friendly introduction to the study of ethics in science and scientific research. The book covers: * Science and Ethics * Ethical Theory and Applications * Science as a Profession * Standards of Ethical Conduct in Science * Objectivity in Research * Ethical Issues in the Laboratory * The Scientist in Society * Toward a More Ethical Science * Actual case studies include: Baltimore Affair * cold fusion * Milikan's oil drop experiments * human and animal cloning * Cold War experiments * Strategic Defence Initiative * the Challenger accident * Tobacco Research.

In this article I defend a rule utilitarian approach to paternalistic policies in research with human participants. Some rules that restrict individual autonomy can be justified on the grounds that they help to maximize the overall balance of benefits over risks in research. The consequences that should be considered when formulating policy include not only likely impacts on research participants, but also impacts on investigators, institutions, sponsors, and the scientific community. The public reaction to adverse events in research (such as significant injury to participants or death) is a crucial concern that must be taken into account when assessing the consequences of different policy options, because public backlash can lead to outcomes that have a negative impact on science, such as cuts in funding, overly restrictive regulation and oversight, and reduced willingness of individuals to participate in research. I argue that concern about the public reaction to adverse events justifies some restrictions on the risks that competent, adult volunteers can face in research that offers them no significant benefits. The paternalism defended here is not pure, because it involves restrictions on the rights of investigators in order to protect participants. It also has a mixed rationale, because individual autonomy may be restricted not only to protect participants from harm but also to protect other stakeholders. Utility is not the sole justification for paternalistic research policies, since other considerations, such as justice and respect for individual rights/autonomy, must also be taken into account.

Financial relationships in academic research can create institutional conflicts of interest (COIs) because the financial interests of the institution or institutional officials may inappropriately influence decision-making. Strategies for dealing with institutional COIs include establishing institutional COI committees that involve the board of trustees in conflict review and management, developing policies that shield institutional decisions from inappropriate influences, and establishing private foundations that are independent of the institution to own stock and intellectual property and to provide capital to start-up companies.

In the first four chapters of this book, I examined the historical and philosophical foundations of the ethics of research with human subjects and developed a theoretical framework for decision-making. The key insight of this framework is that promoting trust is an important principle for making ethical decisions concerning research with human subjects. In the book’s remaining eight chapters I will apply my framework to various topics in human research ethics and discuss its implications for practice and policy. The first topic I will address is informed consent, since trust and consent are closely connected.

The previous two chapters have provided some historical and philosophical background to set the stage for the discussions that will take place in this chapter. In Chap. 2, I examined the history of the ethics of research with human subjects and argued that existing regulations and guidelines were adopted to restore and maintain public trust and prevent ethical abuses from occurring again. However, since ethical issues involving conflicts between the rights/welfare of human subjects and the advancement of knowledge will continue to arise when interpreting and applying existing regulations or deciding whether to revise them, we need an ethical decision-making framework to guide policy formation and help us establish priorities. In Chap. 3, I examined some influential moral theories to determine whether they could supply such a framework. I argued that the theories have strengths and weaknesses but that no single theory satisfactorily answers all objections and satisfies all critics, and that the most reasonable position is to adopt some form of moral pluralism. I proposed that four moral principles, similar to those defended by Beauchamp and Childress (2012), can guide ethical decision-making and policy formation. I noted, however, that the pluralistic approach still faces the issue of priority-setting when moral conflicts arise. I suggested that a fifth principle, the principle of trust, can help investigators, oversight committees, institutions, and funding agencies set priorities in research with human subjects when conflicts arise. In this chapter I will elaborate on and defend an approach to research with human subject based on the notion of trust.

In the previous chapter I argued that a review of the history of the ethics of research with human subjects indicates that the regulations and ethical guidelines have evolved in response to egregious abuses of human subjects and ethically questionable research. Society has adopted rules to prevent these problems from occurring again and to restore and maintain public trust in research. The regulations and guidelines form a system of rules designed to protect the rights and welfare of human research subjects. Ethical dilemmas involving research with human subjects continue to emerge, however, because the rules do not completely resolve fundamental questions related to the conflict between the rights and welfare of human subjects and the goal of advancing human knowledge to benefit society. To be sure, regulations and guidelines can help investigators, IRBs, institutional leaders, policymakers, and concerned citizens address these issues, but questions remain because dilemmas occur when interpreting, applying, prioritizing, and revising regulations and guidelines. What is needed, I argued, is an ethical decision-making framework which justifies rules and policies and can establish priorities when ethical conflicts arise. This chapter will consider whether moral theories can provide such a framework.

In this book I have covered a broad array of issues pertaining to the ethics and regulation of research involving human subjects, ranging from theoretical and historical matters to practical and policy dilemmas. In the first chapter, I observed that moral predicaments involving research with human subjects often boil down to a conflict between protecting individual rights and welfare and promoting scientific research that benefits the public. I argued that while most people agree that both values are important, ethical disagreements can arise with respect priority-setting. I suggested that a philosophical framework that emphasizes promoting trust can help us set priorities when values conflict. I set the stage for my trust-based approach by reviewing the history of research with human subjects in Chap. 2 and examining influential moral theories in Chap. 3. In Chap. 4, I reflected on the nature and importance of trust and discussed some strategies for promoting trust among the various stakeholders in involved in research, i.e. subjects, investigators, institutions, communities, sponsors, IRBs, and the general public. I argued that we can apply four widely recognized moral principles, respect for dignity and autonomy, non-maleficence, beneficence, and justice to practical and policy questions involving research with human subjects and that we can appeal to the goal of promoting trust to adjudicate conflicts among the four principles. The trust principle compliments the other four principles but it is not a meta-rule that can resolve all conflicts. Difficult questions may still arise when trust conflicts with other principles, such as respect for dignity and autonomy or justice. Even so, the principle can play augment and fortify ethical decision-making in research with human subjects. In Chaps. 5, 6, 7, 8, 9, 10 and 11, I applied my decision-making framework to various topics in research with human subjects, including informed consent, privacy and confidentiality, risks, benefits, vulnerable subjects, research integrity, and regulatory reform.

In the previous chapter, I applied the trust-based approach to ethical issues related risks to research with human subjects. In this chapter, I will shift the focus from risks to benefits. As noted in the last chapter, the federal regulations require that risks be reasonable in relation to the benefits to the subjects or the importance of the knowledge expected to be gained (45 CFR 46.111). Other guidance documents, such as the Nuremberg Code (1949), Belmont Report (National Commission 1979), Helsinki Declaration (World Medical Association 2013), and Council for the International Organizations of Medical Sciences guidelines (2002, 2016) include similar statements concerning research benefits. Although few people would dispute the notion that research with human subjects should yield benefits for subjects or society, ethical issues can arise concerning the interpretation and application of the principle of beneficence in research. Before examining these examining issues, it will be useful to define the term ‘benefit.’