A New Perspective on the Ethics of Research with Human Subjects 涉及人的研究的伦理学新观点 Daniel Wikler, Ph.D.

1. A New Perspective on the Ethics of Research with Human Subjects 涉及人的研究的伦理学新观点 Daniel Wikler, Ph.D. Shanghai Children’s Hospital October 17 2013

2. OUTLINE提纲 • History 历史 • The Conventional Ethical Perspective 传统的伦理观点 • An Alternative Perspective 可供选择的观点 • [if time permits…] Application: The “Standard of Care” 应用：“标准治疗”（如时间允许…)

3. I. History 历史

4. Judgment at Nuremberg纽伦堡审判 • http://nuremberg.law.harvard.edu

5. Japanese atrocities in China日本人在中国的暴行

6. World War II era abuses: Germany二战时期的虐行：德国 • Nazi Germany 纳粹德国 • “Racial Hygiene” and biological politics “种族优生”和生物政治学 • Degeneration thesis 退化论点 • Racism 种族主义 • Eugenics 优生学 • Genetic Courts 遗传法院 • T4 • Nazi experimentation 纳粹实验 • Mengele: twin studies 门格尔：双胞胎研究 • Aviation-related research 航空相关研究

7. World War II-Era Abuses: Japan二战时期的虐行：日本 • Unit 731 • Biowarfare research 生化武器研究 • Research on diseases affecting soldiers 感染士兵的疾病的研究 • Example: syphilis research 梅毒研究 • The post-war deal and cover-up 战争结束后的交易和掩盖

8. Cold War era abuses冷战时期的虐行 • USSR: 前苏联 • Maironovsky’s research on poisons 有毒物体的研究 • USA: Cold War research 美国：冷战研究 • Atomic Research 原子能研究 • MK-Ultra “Mind Control” “理智控制” • USA: Other Research Ethics Scandals 美国：其他研究伦理丑闻事件 • Tuskegee Syphilis study 梅毒研究 • Henry Beecher’s landmark NEJM article Henry Beecher 发表在新英格兰杂志上具里程碑意义的文章

9. 60 years of progress60年的进展 • From World War II-era atrocities… 从二战时期的暴行 • Nazi death camps 纳粹死亡集中营 • Japanese biowarfare experimentation 日本生化武器研究 • …To an international consensus on ethics…国际上伦理共识 • Declaration of Helsinki (World Medical Association) 赫尔辛基宣言 （世界医学会） • Research Ethics Committees 研究伦理委员会 • Harmonized national regulations 一致的各国法规

10. II. The Conventional Ethical Perspective传统的伦理观点

11. Ethical ReviewCommittees 伦理审查委员会 Regulations and Oversight Agencies 法规和监管部门 Guidelines onResearchethics 研究伦理指导原则 General MoralPrinciples 普遍的道德原则 The Structure of Research Ethics研究伦理构架

12. A “Social Contract” in research研究中的“社会合同” • The public agrees to support research with public money and to consider volunteering as research subjects, but only if they know that… 公众同意用公共的资金支持研究，并考虑自愿参加研究，前提是他们知道… • Scientists have formulated strict ethical standards, and are being monitored to ensure that they are compliant with these standards. 科学家们明确表达了严格的伦理标准，并受到监督以确保他们遵循了这些标准。

13. International Research Ethics国际研究伦理 • Nuremberg Tribunal 纽伦堡裁决 • World Medical Association 世界医学会 • Declaration of Helsinki 赫尔辛基宣言 • CIOMS • ICH

14. III. A Different Perspective不同的观点

15. Re-thinking Postwar Research Ethics重新思考战后研究伦理 • What basic principles, affirmed by the Nuremberg Tribunal and subsequent international ethical guidelines, should determine the ethics of research with human subjects? 哪些基本原则，经纽伦堡裁决和随后的国际伦理指南确认，应该用来决定涉及人的研究的伦理标准？ • My thesis: The wrong answer to this question was given in the late 1940s. For some decades, this made little difference, but the error is now causing problems and the question requires new thinking. 我的观点：19世纪40年代后期对这个问题做出了错误的回答。几十年以来，没有什么改变，而这个错误正引发了新的问题，需要予以重新思考。

16. Outline of my argument我的论据概要 • The “Conventional” ethical perspective is now widely accepted. For many, it appears to be based on fundamental moral principles that we all share. “传统”伦理观点正被广泛接受。对大多数人而言，它似乎是基于我们共享的基本道德原则。 • But this is not correct. We can understand the conventional perspective better if we understand it as responsive to concerns of the time of its origin - the post-World War II era, 1945-1965 – that have since been forgotten. 但这不正确。如果我们将传统观点理解为对那个起始时期 – 二战后期 1945-1965，当时所关注问题的一个回应，我们将能更好地理解传统观点。

17. Outline of my argument • For reasons that we can only speculate about, the fundamental moral principle in research ethics was identified as giving priority to the individual over the group. 因为某些我们仅能猜测的原因，研究伦理中基本的道德原则被确认为个体优先于群体。 • If we understand research participation as an unavoidable burden that must be shared, we can reach a perspective on research ethics that is free of many of the problems in the conventional view. 如果我们将参加研究理解为不可避免的必须共同分担的一种责任，对研究伦理我们就能获得一个新的观点，它将使我们摆脱传统观点中存在的许多问题。

18. What was the Nazis’ moral error?纳粹的道德错误是什么？ • The conventional view: 传统观点 • Priority for the group over the individual 群体优先于个体 • Leo Alexander, New England Journal of Medicine, 1948 • An alternative view: 可供选择的观点 • Racism 种族主义 • Not treating people as equals 没有公平待人

19. The one and the many一个和许多 • Argument: Alexander’s interpretation does not match the historical record. 论据：Alexander的解释与历史记录不符 • If the principle “Sacrifice individuals for the benefit of the group” were the principle behind Nazi research policies, they would have sacrificed individual Nazis for the benefit of Nazis as a group. That did not happen. 如果纳粹研究背后的原则是“为了群体的利益牺牲个体”，他们应该是为了多数纳粹的利益牺牲纳粹个人。但这没有发生。 • The Nazi principle was rather: do anything you like to members of that group if it will benefit our group.纳粹的原则其实是：只要能对我们这个群体有益，可以对其他群体的人为所欲为。 • The correct label is not “utilitarianism,” but racism.正确的标示并不是“实用主义”而是“种族主义”

20. Possible explanations: 1可能的解释：1 • How could this obvious error have been made – and overlooked? 怎么会犯了这么明显的错误 – 而且被忽视？ • We can only speculate: 我们仅能猜测： • The “one-vs-many” principle provided a good fit with prevailing ideologies during the cold war. The US was the land of the individual; the communists favored the group. This principle put research ethics firmly on the side of the US “个体 vs. 群体”原则非常契合冷战时期的主流意识形态。美国是一片充斥个人主义的大陆，而共产主义是崇尚群体的。这一原则将研究伦理牢牢地锁定在了美国这边。

21. Possible explanations: 2可能的解释：2 • The medical profession feared domination by the state in the postwar era. The British Medical Association, struggling to prevent the creation of the National Health Service, claimed that the Nazi abuses were the inevitable result of state involvement in the delivery of health care. 医学专业人士担心战后被国家控制。英国医学学会，努力阻止国家卫生服务的建立，宣称纳粹的虐行是国家介入提供卫生保健服务所不可避免的结果。

22. Possible explanations: 3可能的解释：3 • Anti-semitism 反犹太主义 • Anti-semitism was by no means limited to the Nazis. Even in the United States, anti-semitic feelings were strong.反犹太主义并不局限于纳粹。甚至在美国，反犹太主义也曾盛行。 • A wrong done to Jews might not be seen a matter of general concern. 对犹太人的不公并不被视为普遍关心的问题 • The “one-vs. many” concept removed all specific ethnic or racial content from the Nazi crimes and universalized their significance. “个体 vs 群体”原则去处了纳粹罪行中所有关乎特殊种族的成分，使其意义普遍化。

23. The Conventional View is based on a series of fictions传统观点是基于一系列的杜撰 • Does research ethics require us to give the highest priority to the individual research subject? 研究伦理是否要求我们将研究受试者个体至于首位？ • We owe research subjects our best effort to provide the care they need, consistent with the goal of conducting research. 我们应尽最大的努力向受试者提供他们需要的医护，这与开展研究的目标相一致。 • But research often requires that the interest of patients be balanced against the requirements of scientific method.但研究常要求患者的利益应平衡与科学方法的要求。 • Example: the last patient enrolled in a double-blinded randomized clinical trial 例：随机双盲研究中最后一名纳入的受试者

24. Research as an unavoidable social obligation研究是不可避免的社会责任 • We all want health care that is safe and effective 我们都希望卫生保健是安全有效的 • Safe and effective health care requires research that in some cases may involve discomfort or moderate risk 安全有效的卫生保健需要研究，某种情况下会有不适或中度的风险 • It is unfair to ask others to accept the risk so that you may benefit 要求他人承担风险而你获益是不公平的 • Analogy: the medical student’s first spinal tap 类推：医学生的第一次腰穿

25. Three forms of unequal treatment:三种不公平的对待 • Members of a group are asked to take risks to benefit others, but others are not asked. 一个群体中的某些成员被要求承担风险，以使其他人获益，而其他人没有被要求。 • Members of a group are excluded from the benefits of research done on themselves or others 一个群体的成员被排除，无法从他们/其他人参加的研究中获益。 • Members of a group receive inadequate health care because little or no research is done on diseases affecting the group 一个群体的成员仅获得有限的卫生保健，因为没有在这个群体中开展疾病的研究。

26. Justice, Groups, and Individuals (1)公平，群体，个人（1） • Research ethics should require: 研究伦理应该要求 • Protection from unnecessary risk 保护，以免不必要的风险 • Informed, voluntary consent to any necessary risk 告知必要的风险，自愿同意 • Subjects endorse the goal of obtaining knowledge 受试者对获得知识这个目标表示赞同 • All risk to subjects must be justified by potential gains to future patients 受试者的所有风险相对于将来患者的潜在获益是合理的 • Concern for subjects; humane standards; no brutality 对受试者的关心，人道标准，没有暴行

27. Justice, Groups, and Individuals (2): Some Principles公平，群体，个人（2）：一些原则 • No one is “expendable” or less important 没有人是“可牺牲”或不那么重要的 • Everyone should bear a fair share of the risks of research, and should receive a fair share of the benefits对每个人应该公平分配研究风险和研究获益 • Patients may be asked to endure some discomfort or moderate risk if: 患者应该被征求承受一些不适或适度的风险，如果 • The research is needed to relieve significant suffering 研究是为了减轻严重的苦痛 • The risk or discomfort is at most moderate 风险和不适至多是中度的 • All unnecessary risk has been avoided 所有不必要的风险已被避免 • Patients are fully informed and free to refuse 患者被充分告知并可自由地拒绝

28. Risk-Benefit Ratio 风险-获益比 • Must all risks to participants be smaller than expected benefits to participants? 是否受试者所有的风险都应小于受试者预期的获益? • Estimating Risk and Benefit 估算风险和获益 • Determining the ethically acceptable ratio 确定伦理可接受的比例 • Distinguishing between: 区别在于 • Research that may yield benefits to future patients 研究可能对将来的患者带来获益 • Poorly designed research 设计不充分的研究 • Research performed chiefly for commercial purposes 研究主要是出于商业目的

29. Ethics Committees should:伦理委员会应该 • Protect human subjects from unnecessary, inhumane, or unreasonable risk 保护受试者免受不必要，不人道，或是不合理的风险 • Ensure that any risk is justified by potential benefits to future patients (note: this is an ethical judgment) 确保任何风险相对于将来患者的潜在获益是合理的 • Ensure that any patients asked to endure risk understand fully what is being asked of them and that they are free to say “no” and to withdraw at any time 确保任何一个被要求承受风险的受试者对风险充分理解并能自由地说“不”，能够随时退出。

30. Ethics committees should not…伦理委员会不应该… • Insist that in all cases, all net expected benefits to individual human subjects always outweigh expected risks. 在任何情况下坚持对受试者个体的净获益必须大于预期的风险 • Fail to estimate potential benefits of research for future patients as well as risks to participants, and make an ethical judgment on whether the risk-benefit ratio is justified. 未能评估研究对未来患者可能带来的获益以及对受试者的风险，没有针对该风险-获益比进行伦理判断

31. Ethics committees should not…伦理委员会不应该… • Judge all research the same way regardless of scientific and humanitarian merit 采取同样的方法评判所有的研究，忽视科学和人道价值 • Research performed for commercial purposes with little social value does not justify risks to subjects 出于商业目的的研究，且没有什么社会价值，对受试者的风险是不正当的 • Act primarily to protect their institutions from bad publicity or financial or legal difficulty. 采取行动，首先为了保护所在机构免受负面宣传或财务/法律困境。

32. Then and now:old principles, new issues当时和现在：旧的原则，新的问题 • The framework for today’s research ethics was designed in part as a response to the Nazi atrocities 现今的伦理构架的部分旨在应对纳粹的暴行 • [The equally criminal atrocities of the Japanese biowarfare scientists were not publicized and did not directly affect the postwar consensus on research ethics.] 日本研究生化武器的科学家们犯有同样的罪行而没有被公开，而且没有直接影响战后研究伦理的共识。 • Where applied effectively, the system has prevented further atrocities 实施中的有效性是该体系防止了进一步的暴行 • But today many of the most pressing issues are new, and the system was not designed to address them 但是今天许多紧急问题都是新问题，这个体系并没有以这些问题为目的

33. IV. Application: The “Standard of Care”应用：标准治疗

34. Example: “Standard of Care”举例：“标准治疗” • Term from malpractice law 术语源自治疗不当法 • Used in controversies over what must be offered to participants in research 实际使用时就“哪些必须提供给研究受试者”颇有争议 • Governs use of placebo 管控安慰剂的使用 • Also governs testing of inexpensive, slightly inferior alternatives to best current therapies 管控相对便宜，而稍逊现今最好的治疗的替代治疗的测试

35. Declaration of Helsinki, #29:赫尔辛基宣言：#29 “ The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.” 获益，风险，负担和一个新方法的有效性必须与那些当今最好的预防，诊断，治疗方法进行对照测试。这并不排除一些研究，当没有已被证明的预防，诊断和治疗方法时，使用安慰剂或空白治疗。

36. Avoiding Double Standards避免双重标准 • Moral Consistency claim: 道德一致性宣称 • Any study sponsored or conducted by first-world funds or scientists must meet the same standards of ethics and safety that apply to research conducted at home. 任何一个第一世界资助或开展的研究必须遵循在本国开展研究时必须遵循的同样的伦理和安全标准。 • David Rothman (N.Y. Review): • “Do unto others as we do unto ourselves -- a principle for researchers everywhere” “己所不欲勿施于人 – 各处研究者的原则”

37. Changed Context?改变的环境？ • Declaration of Helsinki designed to condemn deprivation of a minority of the entitlements of other citizens赫尔辛基宣言旨在谴责剥夺少数人群公民权利的行为 • International collaborative research may aim to provide to a vast majority of citizens of poor countries care that is available only to a small elite, or unavailable at all. 国际合作研究的目的也许是为了使那个贫困国家的大多数人获得仅一些精英可能获得，或根本都不可能获得的医疗照护。

38. Principles in Context环境中的原则 • Issues in Nazi Germany and today are reversed: 纳粹德国的问题与今天面临的情况完全相反 • Nazi Germany: A minority deprived of care that most citizens received.纳粹德国：少部分人被剥夺了大多数人的权利 • Low-income country today: majority lacks care that only the elite can afford 现今的低收入国家：大多数没有医疗照护，仅精英们能够支付 • A principle that made sense in the context of Nazi Germany may have no appropriate application in the context of a developing country in the midst of a pandemic 在纳粹德国环境中讲得通的原则在现今疾病流行的贫困国家不一定适用

39. Single Standard: Advantages一个标准：优点 • Provide best possible care for participants 为患者提供了可能的最好治疗 • Avoid racism, exploitation 避免了种族歧视，被利用 • Avoid hypocrisy 避免了伪善 • Maintain ethical integrity of researchers 保持了研究者的伦理正直 • Preserve noble ethical status of health research 维持了卫生研究的高尚的伦理地位

40. Single Standard: Disadvantages一个标准：缺点 • Deters research on affordable therapies thought to be nearly as effective as best current (unaffordable) therapies 阻止开展一些虽比不上最有效，但价格相对低廉的治疗方法的研究 • Forbids placebo controls if an effective therapy exists, regardless of its cost 如果存在有效治疗，禁止安慰剂对照，无论代价多少 • Placebo controls sometimes needed for proof 为了验证，有时需要安慰剂对照 • Effective therapies that are too expensive to be used in a developing country should not prevent the search for affordable interventions, even if they are less effective 有效治疗在发展中国家太昂贵，不应阻止开展疗效稍逊，但支付得起的疗效的研究

41. Three Standards of Care三种标准疗法 • Helsinki: All receive best current care 所有人都获得现今最好的治疗 • Helsinki alternative: 赫尔辛基替代选择 All are offered care that is no worse than what they would have received had the study not been done 提供给所有人的治疗将不差于不参加研究所获得的治疗 • New proposal: 新的建议 All are offered care that is no worse than what they should have received had the study not been done提供给所有人的治疗应不差于不参加研究所获得的治疗

42. “Should Have received…”“本应该获得的… • Rationale: 原理 • Taking unjust advantage of another’s misfortune is exploitative 不公平地利用他人的不幸是剥削 • Offers and threats: what is the baseline? 提供和风险：底线是什么？ • Moral baselines: how the person should be treated 道德底线：那个人应该如何被对待？ • Practical Realization 实际的实现 • WHO’s World Health Report 2000: 世界卫生组织2000卫生报告 “Performance Assessment” of 191 Health systems191卫生体系的性能评估

44. “Should Have received…”本应该获得的… Standard of Care: 标准治疗 • Compare the site of the research to all other countries with similar resources 将研究所在地与其它所有类似资源国家比较 • Ascertain what treatments are provided by these comparable countries 确认这些有可比性的国家提供的治疗 • Assure subjects of all treatments provided by most of the highest-ranking countries 确认受试者获得最高级别国家提供的治疗方法

45. “Should Have received…”本应该获得… “What they should offer” = 他们应该提供的是= “What countries with similar resources that have the most efficient and equitable health systems do offer” 相类似资源的国家，在最有效最公平的卫生体系下所提供的

46. New proposal: Advantages新的建议：优点 • A single standard 一个标准 • Permits research on affordable therapies 允许开展可支付得起的疗法的研究 • ?Avoids exploitation ？避免剥削 • Permits suitable use of placebo 允许适当地使用安慰剂

47. New Proposal: Disadvantages新的建议：缺点 • Ignores injustice of 忽视不公平 • International maldistribution of wealth 国际贫富分配不均 • High international drug prices 国际药品高价 • May be distorted by idiosyncrasies of health allocation in comparable countries 可能被相比较国家卫生资源分配的特性所扭曲 • Is not limited to research intended to benefit the poor in developing countries 不局限于让发展中国家人民受益的研究

48. Principle and application原则和应用 • The new proposal provides a principle that can be used in specifying a standard of care for a particular research protocol. 新的提议提供的原则可用于为一个特别的研究方案指定治疗标准 • It is possible that we will agree on the principle but disagree on how it should be applied. 有可能我们对原则能达成共识，但对其应用各持异议 • We may disagree on applications because we do not agree on other, relevant issues, such as drug pricing and the international distribution of wealth. Evidence may permit us to agree on some of these; for the others, it is useful to identify the actual issue dividing us. 我们可能不同意其应用，因为我们不能就相关问题达成共识，如药品价格，国际贫富不均。证据可能允许我们就这些问题达成共识，至于其他的，能够辨别那些真正区分开我们的问题是有用的。

49. Standard of Care: Floor or Ceiling?标准治疗：底层还是上限？ • International principles that specify a standard of care determine what must be offered in all research. 国际原则详细说明了标准治疗决定了所有研究中必须提供的治疗 • Ethical review boards may insist on higher standards in particular studies.伦理委员会可能在某些研究中坚持更高的标准 • The amount and distribution of potential benefits may be relevant to this decision 潜在获益的量和分配可能与此决定相关

50. What is owed (entitlement) vs. what should be given (policy reasons)所亏欠的（权利）vs. 所应给的（政策原因） • Two different moral reasons to provide care: 提供医护的两种不同的道德理由： • Because the person has a right to it; or 因为这个人有权利获得，或 • Because giving it to this person will have favorable consequences因为提供给这个人（医护）将会产生好的结果 • Reasons for exceeding entitlements: 超出权利的理由： • As a sign of respect 尊重的表示 • Securing the cooperation of participants 保护受试者的合作 • Preserving the good name of health research 维持卫生研究的好名声