Short form

Question 1

I. History of Research (1):

Answer 1

1. James DuBois (2008). ‘Solving ethical problems,’
   SFNO. Justification of our decisions involves: view of human nature, one’s profession, and of the hierarchy of values. Disagreements can occur over stakeholders, facts, norms/values.
2. Susan Lederer (1995). Subjected to Science,
   Details the rise and fall of the anti-vivisection movement:
   1: In the 19th century, the physician shifted from caregiver to scientist. This shift raised questions about the appropriateness of research practices on patients.
   2: Advocates for animal protection regulation opposed vivisection practices in medicine. They were concerned about the wellbeing of animals as well as the slippery slope leading from animal vivisection to human vivisection.
   3: The AMA defended the practices of human experimentation against the proposal to regulate human experimentation. They made their defense not by defending the principle of research, but by pointing towards the benefits of research and the misrepresentations and factual errors of charges leveled against their practices.
   4: In the early 20th century, the medical community struggled internally over the ethics of experimentation. It remained divided over nontherapeutic practices and the necessity of consent. Although propositions were made to add content about experimentation to their code of ethics, the AMA did not issue regulation on clinical research practices, consent, or nontherapeutic experimentation.
   5: For the first three decades of the 20th century, the antivivisectionists continue to object to experimentation on vulnerable populations. As an indirect response, the research community emphasized the importance of consent and avoidance of risk but did not issue any policy or regulatory statements on the matter.
   6: In the 1930s, public opinion of medicine skyrocketed and research and its participants were idealized. This shift in public sentiment undermined the antivivisectionists’ argument such that it was no longer a significant threat to medical progress through experimentation.

Question 2

II. History of Research (2)

Answer 2

1. Henry K. Beecher (1966). ‘Ethics and Clinical Research,’
   Beecher argues that mainstream medical research frequently involves unethical designs that jeopardize the life of research subjects. Beecher stresses three ideas to address this problem: Unethical research should not be published. Researchers should strive to achieve consent from patients who understand risks of research. Researchers must be responsible, informed, and conscientious.
2. David J. Rothman (1987). ‘Ethics and Human Experimentations: Henry Beecher Revisited,’
   The attitude toward human experimentation created during World War II laid the foundation for the utilitarian mentality that led to exploitative and unethical research on patients and vulnerable populations. Beecher’s article and a growing orientation towards rights incited a movement to emphasize protection of research subjects in the late 1960s.
3. Mastroianni A, Kahn J (2001). ‘Swinging on the pendulum: Shifting views of justice in human research subjects,’
   In the 1970s, policies emphasized the risks of harm in research and therefore emphasized protection of subjects. Since the 90s, the pendulum has swung toward ensuring access to the benefits of research. The pendulum has swung too far toward the emphasis on access to research benefits. Benefits/access and harms/protection need to be balanced more evenly because research is inherently risky.

Question 3

III. Ethical Foundations of Research

Answer 3

1. Hans Jonas (1969). ‘Philosophical reflections on experimenting with human subjects,’
   1) Because research uses the subject as a passive thing, it is inherently problematic. The justification of research by the aim medical progress is generally overstated in our society. 2) Progress is optional, not imperative; therefore, medical research should proceed cautiously, according to the rule of descending order. If caution slows the pace of progress, the social good is not harmed.
2. Alan Wertheimer (2011). Rethinking the Ethics of Clinical Research.
   Commonly accepted principles are hard to defend and other principles should be proposed. Jonas did not end the conversation on research ethics.
3. Leon Eisenberg (1977). ‘The Social Imperatives of Medical Research,’
   Medical research is a social imperative because it stands alone in its ability to reduce suffering and death. It ought not to be regulated too strictly as to impede its progress, because failure to progress through research is a risk to society that will surely outweigh the aggregate risk posed to all research subjects. Any regulation that occurs must realize that not doing research is also harmful.
4. Belmont Report:
   Details what counts as research, the three principles of research, and the 3 applications of research.
5. Emanuel EJ, Wendler D, Grady C. (2000). ‘What makes clinical research ethical?’
   Informed consent is not sufficient (or necessary!) for ethical research. The authors propose seven principles that ensure that research is likely to be ethical. These are based on famous documents (Nuremberg, Helsinki, Belmont, CIOMS)

Question 4

IV. Informed Consent/Therapeutic Misconception

Answer 4

1. Robert Levine (1988). Ethics and Regulation of Clinical Research,
   Informed consent is a robust principle that creates duties and obligations that must be negotiated in clinical research.
2. TL Beauchamp (2010) ‘Autonomy and Consent’ In The Ethics of Consent
   Because attention has centered on the “informed” of “informed consent”, the provision of information, rather than the voluntariness of consent, has been emphasized. Beauchamp proposes a theory of autonomous action that emphasizes choice and voluntariness as central notions of consent. Judgments about the sufficiency of a participant’s informed consent are a matter of degree, not black and white.
3. FG Miller (2010). ‘Consent to Clinical Research’ In The Ethics of Consent
   Because clinical research usually does not lead to poorer outcomes than medical care, therapeutic misconception is of incremental (not categorical) concern. Informed consent without therapeutic misconception is the ideal; however, therapeutic misconception does not necessarily invalidate consent and investigators are not obligated to exclude patients with the misconception.
4. PJ Candilis and CW Lidz (2010). ‘Advances in Informed Consent Research,’
   How informed patients are in making “informed consents” is often not considered. Empirical evidence suggests that informed consent continues to be a challenge. Empirical research must continue to pursue ways to improve informed consent. Education must help people understand the larger goals of research. Policy must be made to ensure proper management of under-informed consents.

Question 5

V. Informed consent/Therapeutic misconception

Answer 5

1. Miller, Wertheimer (2010). ‘Preface to a theory of consent transactions: beyond valid consent,’
   The central question about consent is not if consent is “valid,” but whether a bilateral consent transaction between two people is morally transformative. Moral transformation comes from fair transaction, not from autonomous authorization.
2. Jansen et al. (2011). ‘Unrealistic Optimism in early-phase oncology trials,’
   This empirical study found that an optimistic bias (excessive optimism about a specific event or outcome) is present in early phase cancer trial subjects and is not related to misunderstanding the trials. This means that optimism is an independent cause of expecting therapeutic benefit from trials, an effect that cannot be easily remedied with more info. Instead, it must be addressed by understanding more about the ways that subjects apply and appreciate information and the way social/psych effects this appreciation.
3. Paul S. Appelbaum, Loren H. Roth, Charles W. Lidz, Paul Benson and William Winslade (1987). ‘False Hopes and Best Data: Consent to research and the Therapeutic Misconception,
   Misunderstandings about research are common. With greater effort to convey the realities of the scientific method to future research participants, the therapeutic misconception can be dispelled.
4. Nancy Kass, Jeremy Sugarman, Ruth Faden, Monica Schoch-Spana (1996). ‘Trust: The Fragile Foundation of Contemporary Biomedical Research,
   We usually assume that informing patients of risks and benefits is the necessary condition for sound research choices. In fact, interviews with patient/subjects illustrated that they tend to trust their physician to guide their decisions more than their understanding of risks and benefits.

Question 6

VI. IRBs

Answer 6

Alan Wertheimer (2011). Rethinking the Ethics of Clinical Research.  
(1) Regulatory system for human research is justifiably paternalistic. (2) This form of paternalism is, nevertheless, compatible with the primacy of informed consent. An appeal to group soft paternalism for research subjects does not necessarily conflict with the liberal values of respect for individual autonomy

Robert Levine (1988). Ethics and Regulation of Clinical Research, 
Discusses the evolution of IRBs, their composition, and how they review.

Edgar H and Rothman D. (1995). The Institutional Review Board and Beyond: Future Challenges to the Ethics of Human Experimentation.
Goals: Defines the structure of IRBs, their goals, how committees are composed, the history of IRBs, the pros and cons of localism and authors give recommendations for the future.

 Ivor Pritchard (2011). ‘How do IRB members make decisions?
There is no uniformity in IRB determinations, mostly due to psychological factors of members of the IRB. Psychological literature can further elucidate this variation in (1) Risk/benefit evaluation (2) types of decision making (3) nonrational group process

S Kim (2009). ‘Pruning the Regulatory Tree,’ 
Thesis: The requirement of expensive protocols reviews for minimal risk research yield no ethical benefit. IRBs are underfunded, patients are affected by lack of quality-improvement in research. It is unethical to support a system that creates a significant financial, scientific, clinical and ethical burden with virtually no counterbalancing good.

Question 7

VII. Risk/Benefit Issues

Answer 7

1. Robert Levine (1988). Ethics and Regulation of Clinical Research,
   Harms and benefits of research must be balanced. Risks should be minimized and benefits maximized.
2. P Slovic.(1987) ‘Perception of Risk,’
   As is evidenced by psychometric research, people tend to perceive and assess risk in terms of characteristics that far exceed and sometimes do not account for mortality rates. Although the risk of mortality emphasized by experts is important, risk communication and management must include the complexity of characteristics with which people actually assess risk.
3. Rid, Emanuel, Wendler. (2010) ‘Evaluating the Risks of Clinical Research,’
   Assessing risk without a specific criterion for risk is problematic. The SERR method provides a way to gain consistency over risk assessment in research.
4. Peter C. Williams (1984). ‘Success in Spite of Failure: Why IRBs Falter in Reviewing Risks and Benefits,’
   Because of their biases, composition, and psychological dimensions, IRBs are bad at assessing risks and benefits in comparison to their ability to protect rights (autonomy, informed consent, etc)
5. LF Ross et al (2010). ‘Human subjects protections in community-engaged research: a research ethics framework,’
   A 3 by 3 framework including categories of risk and agents involved is necessary to assess community based research. All community based research should involve partnerships.
6. Douglas K. Martin et al. (1995). ‘Incommensurability of Research Risks and Benefits; Practical Help for Research Ethics Committees,’
   IRBs cannot sufficiently assess risks and benefits of research. Thus, they should engage the community of potential research subjects and ask for feedback to determine the moral permissibility of the study.

Question 8

VIII. Privacy/Confidentiality Issues

Answer 8

Robert Levine (1988). Ethics and Regulation of Clinical Research, New Haven: Yale University Press, Chapter 7: 163-181
We must protect the confidentiality of subjects. The most direct social injuries to research subjects result from breaches in confidentiality. 

Nosowsky and Giordano. (2006) The Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule: Implications for Clinical Research
HIPPA has had a significant adverse impact on the conduct of clinical research in the US, without substantial corresponding increase in privacy protection for research participants Additional revisions to HIPAA based on the principles and trade-offs reflected in the Common Rule, which balance individual privacy with public interest, can help.

MA Rothstein. Is Deidentification Sufficient?
The use of deidentified health information and biological specimens in research creates a range of privacy and other risks to individuals and groups. The current regulatory system needs to be revised

Beskow: Certificates of Confidentiality and Compelled Disclosure of Data
Certificates of confidentiality are not rigorously held to in the courts

Case: Havasupai
Shows how important it is for IRBs to consider group harms. Members of the tribe gave DNA samples to ASU researchers, so that ASU could help them in handling their diabetes problem. But then the tribe learned that the samples were used to study other things, including mental illness and theories of the geographical origins of the tribes which were not consistent with the tribe’s traditional stories.

Question 9

IX. Vulnerability (1):

Answer 9

1. Robert Levine (1988). Ethics and Regulation of Clinical Research,
   The principle of justice demands that we be careful about the subjects we use in clinical research
2. Coleman, C. (2009). ‘Vulnerability as a regulatory category in human subject research,’
   There is little consensus on what it means in human subject protection, or more importantly, how a finding of vulnerability should affect the process of research review. We need to ask what are vulnerable persons vulnerable to? The answer falls under 3 categories: consent, risk, justice.
3. K Kipnis (2001) ‘Vulnerability in research subjects: A bioethical taxonomy’
   We should not think of vulnerability in terms of subpopluations, we need an analytical approach to consider circumstances of vulnerability. 6 types of vulnerability are identified.

Case: Tuskegee

Question 10

X. Vulnerability (2): Special populations

Answer 10

1. Robert Levine (1988). Ethics and Regulation of Clinical Research
   Children are considered vulnerable subjects because of their mental capacity and so the principle of justice and respect for persons require additional protections
   There are two special and intractable ethical problems: (1) can prisoners exercise free choice? (2) do prisoners bear a fair share of burdens and receive benefits of research?
2. Michael A. Grodin and Joel J. Alpert (1988) ‘Children as participants in medical research,’
   Children should not be orphaned from the benefits of research and yet, as a vulnerable population are clearly in need of added protections. Pediatricians should participate in this debate.
3. Nancy E. Kass, Holly A. Taylor, Patricia A. King (1996). ‘Harms of excluding pregnant women from clinical research: The case of HIV-infected pregnant women”,
   Policies that exclude pregnant women result in inadequate information being available to guide clinical practice for HIV-infected pregnant women
4. IOM Report of Prisoner research (2006)
   There is a need to expand protections to prisoners
5. Chwang. (2009) Against Risk-benefit review of prisoner research.
   Additional risk-benefit constraints on prisoner research are unnecessary: the current Common Rule regulations, plus 4 IOM recommendations, ensure that prisoner research is as ethical as non-prisoner research

Case: Prisoners’ rights
Case: Kennedy-Krieger: Courts said parents in the state of Maryland could not consent to their minor children’s participation in research that posed even a minimal risk of harm if it offered no prospect of direct medical benefit to the subjects. Johns Hopkins University, conducted a 2-year study (1993–1995) to measure the effectiveness of differing levels of lead abatement procedures in housing.

Question 11

XI. Exploitation and Undue Inducement

Answer 11

1. Denny, Colleen C and Christine Grady (2007). ‘Clinical research with economically disadvantaged populations,’
   Economically disadvantaged groups should be considered vulnerable subjects because decision impairing inducements render subjects “relatively or absolutely incapable of protecting their own interests”, the very definition of vulnerability and they are liable to exploitation.
2. Wilkinson, Martin and Andrew Moore (1997). ‘Inducement in Research,’
   Money is not an undue inducement, because it is not coercing/forcing anyone to participate in research. ‘Freedom requires the presence of more than one acceptable option’
3. McNeill, Paul (1997). ‘Paying People to Participate in Research: Why Not?’
   Research volunteers must clearly understand the extent and nature of risk, and financial reward can induce participants to disregard and/or downplay risk.
4. Dickert N and Grady C. (1999). What’s the Price of a Research Subject? Approaches to Payment for Research Participation.
   We can address the ‘undue inducement’ problem 3 ways: market model, wage payment model, reimbursement model.
5. EJ Emanuel (2005). ‘Undue Inducement: nonsense on stilts?,’
   Undue inducement claims are bogus and they mask legitimate concerns about independent review, informed consent and unfair subject selection.
6. D Festinger (2005). ‘Do research payments precipitate drug use or coerce participants?’
   Our findings revealed that neither the mode nor the magnitude of payment had a significant effect on rates of new drug use or on participants perception of coercion.
7. Lemmens T and Elliott C. (2001). Justice for the Professional Guinea Pig.
   Healthy human subjects should be treated like laborers to receive a fair wage and legal resources available to high-risk workers.
8. Alan Wertheimer (2011). Rethinking the Ethics of Clinical Research.
   It is hard to justify interference with trials that exploit the poor for the benefit of the poor.

Case: Guinea Pig Zero

Question 12

XII. Genetic Research Issues

Answer 12

1. Neil Manson and Onora O’Neill (2007). Rethinking Informed Consent.
   There may sometimes be prudential reasons for taking account of the feelings that people have about genetic information, but they offer no basis for a general argument for the intrinsic ethical significance of genetic information, or to establish rights to genetic privacy. Informed consent is about an interaction between two or more agents, not a transfer of a thing (data) from one person to another.
2. McGuire, Caulfield, Cho (2008). ‘Research ethics and the challenge of whole genome sequencing,’
   Identifies three major ethical considerations to be addressed in whole-genome sequencing (circumstances of disclosure, obligations to relatives, how to put information into a health record)
3. Karen J. Maschke (2010). ‘Wanted: Human Biospecimens,’
   Researchers, IRBs, federal regulators, and the public will continue to grapple with complex ethical and policy dilemmas that inevitably arise when conducting research with human biospecimens.
4. Haga and Beskow (2008). Ethical, Legal, and Social Implications of Biobanks for Genetics Research.
   There are several factors that suggest a prudent approach for biobanks may be to proceed with caution but consider ‘never saying never’ with regard to offering individual results. Offering research participants a summary of aggregate results has been encouraged as an alternative to offering individual results
5. Tomlinson, T (2009). ‘Protection of non-welfare interests in the research use of archived biological samples’
   Risk to one’s welfare of privacy is NOT the only sort of interest that individuals have in the use of their tissues. There are two different ethical bases for their accommodation in biobanking: the pragmatic and the principled.

Case: Henrietta Lacks

Question 13

XIII. International Research

Answer 13

1. Alan Wertheimer (2011). Rethinking the Ethics of Clinical Research.
   He rejects the interaction principle, but claims research ethics presumes it. The interaction principle maintains that an investigator is ethically bound to provide super-contractual obligations to a subject by entering into a relationship with the subject, even if the subject agrees to less than this, and even if the investigator would have no obligation to the subject if she did not enter into a contract with her. As a matter of ethical theory, it is difficult, although not impossible, to defend the view that mutually advantageous and consensual transactions are wrong or otherwise problematic if they are better for all than non-interactions that we would not regard as wrong.
2. Macklin R. (1999). International Research and Ethical Imperialism.
   It is not the cultural relativity of values that poses the problems within research, but rather the different facts and circumstances in which the ethical judgments rest. We must adhere to core ethical principles in research, but adapt procedural requirements appropriately to different circumstances.

Case: Vertical Transmission AZT
Clinical equipoise- That there is no good reason to think one treatment is better than another. Need to find a more cost-effective regimen. (Short course, low dose AZT)

Question 14

XIV. Alternative forms of research

Answer 14

1. Bernard M. Dickens, (1975). ‘What Is a Medical Experiment?’
   The distinction between innovative therapy and medical experimentation has notable implications for the legal requirements of informed consent, therapeutic privilege, and implied consent.
2. James DuBois (2006). ‘Ethics in behavioral and social science research’ in Iltis
   Although behavioral and social science research rarely poses life threatening risks, significant ethical issues exist in this type of research and these issues must be addressed.
3. C. Larry Gostin (1991). ‘Ethical Principles for the Conduct of Human Subject Research: Population-Based Research and Ethics,’
   Whereas ethics usually focuses on rights and duties of individuals, it needs to focus on moral boundaries in regards to populations. This paper attempts to outline ethical guidelines for research on populations.
4. LD Richardson (1995). ‘The Ethics of Research without Consent in Emergency Situations,’
   This is a review of the waiver of consent for research in emergency settings.
5. Morisson, Horwitz, Carrick (2009). ‘Ethical and Legal Issues in Emergency Research: Barriers to Conducting Prospective Randomized Trials in an Emergency Setting,’
   More research in emergency settings needs to occur because emergency medicine lacks empirical justification and sound scientific standards.

Case: Polyheme study:
Industry sponsored clinical trials for PolyHeme – artificial blood. The lab was accused of hiding events of adverse effects.

Question 15

XV. The business of research

Answer 15

1. Ezekiel Emanuel ad Daniel Steiner, “Institutional Conflict of Interest”,
   Institutional conflicts of interest could compromise scientific research and validity, alter internal practices of research institutions, and lead to a loss of public trust. There should be a prima facie norm that significant institutional conflicts of interest make that research impermissible. This norm could be overturned in rare instances. Such instances require added safeguards and monitoring.
2. Stuart E. Lind (1990). ‘Finder’s Fees for Research Subjects,’
   Finder’s fees, like fee-splitting, are morally unacceptable because they undermine patient trust and sound professional decisions. Instead, research and clinical care should aim towards closer collaboration.
3. Christensen and Orlowski (2005). ‘Bounty-Hunting and Finder’s Fees,’
   Financial incentives for research enrollments raise ethical issues of conflict of interest, informed consent, and justice. Finder’s fees should not be allowed, and bounty-hunting fees should be carefully monitored.
4. Cherry. The market and medical innovation: human passions and medical advancement,’
   Cherry seems to have a positive attitude towards the market and innovation, pointing towards some of the potential ethics issues that could arise.
5. S. Loewenberg (2009). ‘The Bayh-Dole Act: A model for promoting research translation?,’
   There is disagreement over the benefit of the Bayh-Dole Act. Many are concerned that it has not achieved the hoped for results and others worry that it could even lead to the pursuit of a research agenda that lacks foundational scientific knowledge. Some researchers and research institutions have independently taken measures to directly address concerns over the patenting and profitability of medical innovation.

Case: Canada industry-academy
The case exposes tension between academic freedom and control of research by pharma. Oliveri was part of a drug trial (deferiprone) at the Hospital for Sick Children. She noticed that the drug appeared toxic and inefficacious. She reported this to the research board and the drug maker (Apotex). The IRB suggested she inform patients, but Apotex said that she signed a confidentiality agreement and telling subjects would violate the agreement. Apotex threatened Oliveri. Oliveri ended up disclosing the study to subjects. Deferiprone is not licensed for use in 50 countries, but not the US or Canada.