Research EthicsResearch Ethicsand Human Subjectsand Human Subjects

Research Ethics - M261Research Ethics - M261

Neil WengerNeil Wenger

Nuremberg Code, 1947Nuremberg Code, 1947““The great weight of evidence before us is to the effect that The great weight of evidence before us is to the effect that

certain types of medical experiments on human beings, certain types of medical experiments on human beings, when kept within reasonably well defined bounds, when kept within reasonably well defined bounds, conform to the ethics of the medical profession conform to the ethics of the medical profession generally. The protagonists of the practice of human generally. The protagonists of the practice of human experimentation justify their views on the basis that such experimentation justify their views on the basis that such experiments yield results for the good of society that are experiments yield results for the good of society that are unprocurable by other methods or means of study. All unprocurable by other methods or means of study. All agree, however, that certain basic principles must be agree, however, that certain basic principles must be observed in order to satisfy moral, ethical and legal observed in order to satisfy moral, ethical and legal concepts:”concepts:”

Nuremberg Code, 1947Nuremberg Code, 19471. The voluntary consent of the human subject is absolutely 1. The voluntary consent of the human subject is absolutely

essential.essential.

2. The experiment should be such as to yield fruitful results 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other means…for the good of society, unprocurable by other means…

3. The experiment should be so designed and based on the 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of results of animal experimentation and a knowledge of the natural history of disease or other problem under the natural history of disease or other problem under study that the anticipated results will justify the study that the anticipated results will justify the performance of the experiment.performance of the experiment.

cont.cont.

Nuremberg Code, 1947Nuremberg Code, 19474. The experiment should be conducted so as to avoid all 4. The experiment should be conducted so as to avoid all

unnecessary physical and mental suffering and injury.unnecessary physical and mental suffering and injury.

5. No experiment should be conducted where there is an a 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury priori reason to believe that death or disabling injury will occur...will occur...

6. The degree of risk to be taken should never exceed that 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the determined by the humanitarian importance of the problem to be solved by the experiment.problem to be solved by the experiment.

cont.cont.

Nuremberg Code, 1947Nuremberg Code, 19477. 7. Proper preparations should be made…to protect the Proper preparations should be made…to protect the

experimental subject….experimental subject….

8. 8. The experiment should be conducted only by The experiment should be conducted only by scientifically qualified persons.scientifically qualified persons.

9. 9. During the experiment the human subject should be at During the experiment the human subject should be at liberty to bring the experiment to an end…liberty to bring the experiment to an end…

10. During the experiment the scientist must be prepared 10. During the experiment the scientist must be prepared to terminate at any stage if….the experiment is likely to terminate at any stage if….the experiment is likely to result in injury, disability or death. to result in injury, disability or death.

The compelling argument for The compelling argument for human researchhuman research

In 1939, a surgical procedure was developed for angina pectoris. The internal mammary artery was ligated to increase myocardial blood flow.

Clinical results were favorable: ¾ of patients reporting improvement or elimination of symptoms.

1959 controlled trial of internal mammary artery ligation included 17 patients: 8 received the actual operation, 9 had sham surgery. No difference in outcomes between groups.

Gastric freezing forduodenal ulcer

Patient swallowed a balloon attached to tubes through which a cold liquid was pumped for one hour to cool the stomach and reduce acid production, thus relieving ulcer pain.

Case series impressive “Since 1961, no patients with duodenal ulcer referred

for elective operation have been operated on in the senior author’s service. This circumstance itself bespeaks the confidence in the method by patients as well as surgeons.”– President of Am Coll Surg

Gastric freezing for DU

2500 gastric freezing machines placed in clinical service

Estimated 15,000 patients chilled

Double blind RCT in late 1960’s with outcome of surgery, bleed or intractable pain: Sham group 44%, Freeze group 51%.

Observational findingsObservational findingslater disprovedlater disproved

Cardioprotective effects of estrogen β-carotene and α-tocopherol and cancer Fiber and colon cancer

Federal DefinitionsFederal Definitions

Research: “A systematic investigation , including Research: “A systematic investigation , including research development, testing and evaluation, research development, testing and evaluation, designed to develop or contribute to generalizable designed to develop or contribute to generalizable knowledge”knowledge”

Human subjects: “Living individuals about whom Human subjects: “Living individuals about whom the investigator conducting research obtains: (1) the investigator conducting research obtains: (1) data through intervention or interaction with the data through intervention or interaction with the individual, or (2) identifiable private information.”individual, or (2) identifiable private information.”

Historical PerspectiveHistorical Perspective

1946-9: Nuremberg Trial of 23 Doctors 1946-9: Nuremberg Trial of 23 Doctors 1963: Jewish Chronic Disease Hospital1963: Jewish Chronic Disease Hospital 1963-6: Willowbrook State School1963-6: Willowbrook State School 1966: Henry Beecher, Experimentation in Man. 1966: Henry Beecher, Experimentation in Man. NEJMNEJM 1966: NIH Office for Protection of Research Subjects created. Policies 1966: NIH Office for Protection of Research Subjects created. Policies

call for IRBscall for IRBs 1931-71: PHS Natural History of Syphilis 1931-71: PHS Natural History of Syphilis 1969-71: San Antonio Southwest Found. Contraceptive Study 1969-71: San Antonio Southwest Found. Contraceptive Study 1979: The National Commission for the Protection of Human Subjects 1979: The National Commission for the Protection of Human Subjects

in Biomedical and Behavioral Researchin Biomedical and Behavioral Research Suspensions at Duke, U Colorado, U Alabama, U Illinois, WLAVA, Suspensions at Duke, U Colorado, U Alabama, U Illinois, WLAVA,

Johns HopkinsJohns Hopkins

The Belmont Report:The Belmont Report:Ethical Principles and Guidelines for the Ethical Principles and Guidelines for the

Protection of Human Subjects of ResearchProtection of Human Subjects of Research

National Commission for the Protection of National Commission for the Protection of Human Subjects of Biomedical and Human Subjects of Biomedical and Behavioral ResearchBehavioral Research

19791979 Sets forth theoretical basis of protecting Sets forth theoretical basis of protecting

human subjects and practical basis of human subjects and practical basis of informed consent for researchinformed consent for research

The Belmont Report:The Belmont Report:Practice versus ResearchPractice versus Research

Practice: Interventions that are designed Practice: Interventions that are designed solely to enhance the well being of an solely to enhance the well being of an individual patient…and that have a individual patient…and that have a reasonable expectation of success.reasonable expectation of success.

Research: An activity designed to test a Research: An activity designed to test a hypothesis, permit conclusions to be drawn, hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to and thereby to develop or contribute to generalizable knowledge.generalizable knowledge.

Practice versus ResearchPractice versus Research

A significant departure from standard A significant departure from standard practice -- innovation -- does not practice -- innovation -- does not necessarily constitute research.necessarily constitute research.

Radically new procedures should be Radically new procedures should be subjected to research to determine safety subjected to research to determine safety and effectiveness.and effectiveness.

Is it Practice or Research?Is it Practice or Research?

An oncologist modifies dosing in a chemotherapy An oncologist modifies dosing in a chemotherapy regimen in a way never tried before in order to regimen in a way never tried before in order to decrease side effects.decrease side effects.

A surgeon develops a radically new method of A surgeon develops a radically new method of performing a surgery.performing a surgery.

A reproductive endocrinologist develops a way to A reproductive endocrinologist develops a way to merge ovum and sperm in a test tube. merge ovum and sperm in a test tube.

A clinician performs a procedure shown to be A clinician performs a procedure shown to be effective, but only in patients different than the effective, but only in patients different than the target patient.target patient.

Is it Practice or Research Is it Practice or Research (cont)(cont)??

A clinician develops an implantable device A clinician develops an implantable device to fulfill a clinical function previously only to fulfill a clinical function previously only carried out by the human body.carried out by the human body.

A clinician scientist uses an approved A clinician scientist uses an approved medication for an unapproved indication.medication for an unapproved indication.

A clinician uses an unapproved medication A clinician uses an unapproved medication in clinical care. in clinical care.

Is there a Standard of Care?Is there a Standard of Care?

Published literature?Published literature? Community practice and professional Community practice and professional

judgmentjudgment Professional Society Guidelines ???Professional Society Guidelines ???

Standard of Care: LocalStandard of Care: Local

-Dartmouth Atlas

The Belmont Report:The Belmont Report:Basic Principles ofBasic Principles of

Research on Human SubjectsResearch on Human Subjects

Respect for personsRespect for persons

BeneficenceBeneficence

Justice (resources)Justice (resources)

Basic Principles of Research on Basic Principles of Research on Human SubjectsHuman Subjects

Respect for personsRespect for persons– Choices of autonomous individuals should be Choices of autonomous individuals should be

respectedrespected– People incapable of making their own choices People incapable of making their own choices

should be protectedshould be protected– Voluntary subjects with adequate informationVoluntary subjects with adequate information

Testing respect for persons:Testing respect for persons:Prisoners as research subjectsPrisoners as research subjects

Prisoners may feel that they need to Prisoners may feel that they need to participate in research or may desire to do participate in research or may desire to do so in order to achieve other goals.so in order to achieve other goals.– ““Voluntary consent” an oxymoron? Limited Voluntary consent” an oxymoron? Limited

other opportunities for care.other opportunities for care.– Group deserves the opportunity to participate in Group deserves the opportunity to participate in

research.research.

Basic Principles of Research on Basic Principles of Research on Human SubjectsHuman Subjects

BeneficenceBeneficence– Participation in research is associated with a Participation in research is associated with a

favorable balance of potential benefits and favorable balance of potential benefits and harmsharms

– ““Maximize possible benefits, minimize Maximize possible benefits, minimize potential harms”potential harms”

Basic Principles of Research on Basic Principles of Research on Human SubjectsHuman Subjects

JusticeJustice– Equitable distribution of the burdens and Equitable distribution of the burdens and

benefits of researchbenefits of research– May not exploit vulnerable individuals or May not exploit vulnerable individuals or

exclude without good reason eligible candidates exclude without good reason eligible candidates who may benefit who may benefit

Justice: “Best v practical sample”Justice: “Best v practical sample”

Studies of AIDS medications are more Studies of AIDS medications are more difficult and expensive if subjects do not difficult and expensive if subjects do not adhere to the many medications many times adhere to the many medications many times per day and who “drop out” of studies. Thus, per day and who “drop out” of studies. Thus, researchers launching a promising drug study researchers launching a promising drug study who want to quickly complete a trial (to who want to quickly complete a trial (to publish it first) enroll highly educated gay publish it first) enroll highly educated gay men and exclude IVDU subjects.men and exclude IVDU subjects.

Application of Ethical Principles Application of Ethical Principles in Human Researchin Human Research

PrinciplePrinciple Aspect of Research Aspect of Research

Respect, ResourcesRespect, Resources Social or scientific valueSocial or scientific value

Respect, ResourcesRespect, Resources Scientific validityScientific validity

JusticeJustice Fair subject selectionFair subject selection

RespectRespect Respect for subjectsRespect for subjects

Beneficence, RespectBeneficence, Respect Favorable risk/benefit ratioFavorable risk/benefit ratio

C of I; ProfessionalismC of I; Professionalism Disclosure/External reviewDisclosure/External review

RespectRespect Informed consentInformed consent

–Emanuel, Wendler, Grady. JAMA. 2000;283:2701-11.Emanuel, Wendler, Grady. JAMA. 2000;283:2701-11.

Research must have ValueResearch must have Value

An evaluation that could lead to An evaluation that could lead to improvements in health or well being to the improvements in health or well being to the population relevant to the potential subject.population relevant to the potential subject.

Asking the Right QuestionAsking the Right Question

Research without ValueResearch without Value

Question already fully answeredQuestion already fully answered Results have no chance to be valuable to Results have no chance to be valuable to

relevant populationrelevant population Results will not be disseminated and thus Results will not be disseminated and thus

cannot have an effectcannot have an effect

Scientific ValidityScientific Validity

Methodologically soundMethodologically sound Feasible Feasible Adequately poweredAdequately powered Analytic plan pre-specifiedAnalytic plan pre-specified

Percentage of trials with reported favorable outcomes,by trial phase within funding source

-Bourgeois F T et al. Ann Intern Med. 2010;153:158-66.

©2010 by American College of Physicians

Fair Subject SelectionFair Subject Selection

Based on the principle of justiceBased on the principle of justice Scientific goals of the study – not vulnerability, Scientific goals of the study – not vulnerability,

privilege or other factors unrelated to the purpose privilege or other factors unrelated to the purpose of the study – is the primary basis to select of the study – is the primary basis to select individuals to be recruited.individuals to be recruited.– Vulnerable patients may not be targeted for risky Vulnerable patients may not be targeted for risky

researchresearch

– Privileged groups may not be targeted for potentially Privileged groups may not be targeted for potentially beneficial research.beneficial research.

Favorable Risk-Benefit RatioFavorable Risk-Benefit Ratio

Potential risks to subjects must be Potential risks to subjects must be minimizedminimized

Potential benefits to subjects are Potential benefits to subjects are maximizedmaximized

Potential benefits to individual subjects Potential benefits to individual subjects and to society are proportionate to the and to society are proportionate to the risksrisks

Assessment of Risks and Assessment of Risks and BenefitsBenefits

Nature and scope of risks and benefitsNature and scope of risks and benefits– physical harmphysical harm– psychological harmpsychological harm– legal harmlegal harm– social harmsocial harm– economic harmeconomic harm– breach of confidentialitybreach of confidentiality

Systematic assessment of risks and benefitsSystematic assessment of risks and benefits– ““risks and benefits must be balanced and shown to be risks and benefits must be balanced and shown to be

in a favorable ratio”in a favorable ratio”

Standards of a “Favorable” Risk-Standards of a “Favorable” Risk-Benefit Ratio in ResearchBenefit Ratio in Research

Some approved medications:Some approved medications:– IL-2 for renal cell caIL-2 for renal cell ca

» 14% response rate (5% complete)14% response rate (5% complete)

» median response duration 20 monthsmedian response duration 20 months

» substantial toxicitysubstantial toxicity

– Camptosar for colon caCamptosar for colon ca» 2 month survival prolongation2 month survival prolongation

– Gemcitabine for pancreatic caGemcitabine for pancreatic ca» 5% response, some improvement in QOL5% response, some improvement in QOL

From Agrawal & Emanuel. JAMA 2003; 290:1075-82.From Agrawal & Emanuel. JAMA 2003; 290:1075-82.

What Standard Determines a What Standard Determines a Favorable Risk-Benefit Ratio?Favorable Risk-Benefit Ratio?

Sick patients willing to accept more burden than Sick patients willing to accept more burden than healthy peoplehealthy people– Willing to undergo chemo with substantial adverse Willing to undergo chemo with substantial adverse

effects for what chance of cure?effects for what chance of cure? 1% - metastatic tumor patients1% - metastatic tumor patients

10% - physicians10% - physicians

50% - nurses50% - nurses

50% - general public50% - general public

From Agrawal & Emanuel. JAMA 2003; 290:1075-82.From Agrawal & Emanuel. JAMA 2003; 290:1075-82.

Additional Privacy Protection: HIPAAAdditional Privacy Protection: HIPAA

Obtaining human subjects information for Obtaining human subjects information for researchresearch– De-identified health information is not Personal Health

Information (PHI)– PHI may be used and disclosed for research with an

individual’s written permission (Authorization).– PHI may be used and disclosed for research without an

Authorization in limited circumstances:» Under a waiver of the Authorization requirement» As a limited data set with a data use agreement» For research on decedents’ information

HIPAA: Waiver of authorizationHIPAA: Waiver of authorization

IRB or Privacy Board approval and satisfies the following criteria:– The use or disclosure of the PHI involves no

more than minimal risk to the privacy of individuals

– The research could not practicably be conducted without the waiver or alteration

– The research could not practicably be conducted without access to and use of the PHI

Informed ConsentInformed Consent

InformationInformation» Research procedure and PurposesResearch procedure and Purposes

» Risks and benefitsRisks and benefits

» Alternative proceduresAlternative procedures

» Ask questions, withdraw, identified researcherAsk questions, withdraw, identified researcher

ComprehensionComprehension VoluntarinessVoluntariness

How Much Information in How Much Information in Informed Consent?Informed Consent?

Reasonable Volunteer: “Extent and nature Reasonable Volunteer: “Extent and nature of information should be such that persons, of information should be such that persons, knowing that the procedure is neither knowing that the procedure is neither necessary for their care nor perhaps fully necessary for their care nor perhaps fully understood, can decide whether they wish understood, can decide whether they wish to participate in the furthering of to participate in the furthering of knowledge.”knowledge.”

Autonomous PersonAutonomous Person

““Appeals to the principle of respect for persons are often Appeals to the principle of respect for persons are often viewed with suspicion not only because they appear to viewed with suspicion not only because they appear to remove people from time but also because they appear to remove people from time but also because they appear to remove people from their communities.”remove people from their communities.”

J Childress. J Childress. Practical Reasoning in Bioethics,Practical Reasoning in Bioethics, 1997 1997

Relational ethics Relational ethics “conceives personhood and autonomy “conceives personhood and autonomy as social constructions which best can be respected as social constructions which best can be respected through mutual understanding and dialogue between through mutual understanding and dialogue between scientist and subject.”scientist and subject.”

Celia Fischer. Celia Fischer. Relational Ethics and Research with Vulnerable Populations, Research Involving Relational Ethics and Research with Vulnerable Populations, Research Involving Persons with Mental Disorders that may Affect Decisionmaking CapacityPersons with Mental Disorders that may Affect Decisionmaking Capacity , ,

National Bioethics Advisory CommissionNational Bioethics Advisory Commission 1999 1999

CoercionCoercion: when an overt threat of harm is : when an overt threat of harm is intentionally presented by one person to intentionally presented by one person to another in order to obtain complianceanother in order to obtain compliance

  Undue InfluenceUndue Influence: an offer of an excessive, : an offer of an excessive,

unwarranted, inappropriate, or improper unwarranted, inappropriate, or improper reward or other overture in order to obtain reward or other overture in order to obtain compliancecompliance

Informed Consent & RecruitmentInformed Consent & Recruitment

How will you identify the subjects?How will you identify the subjects? How will you contact the subjects?How will you contact the subjects? How will you recruit the subjects?How will you recruit the subjects?

– FlyersFlyers– LettersLetters– Announcements (script)Announcements (script)

Outline by subject populationOutline by subject population

When Withholding Information When Withholding Information is Essential to the Research is Essential to the Research

Only permitted under rare circumstances in Only permitted under rare circumstances in which all 3 of the following are true:which all 3 of the following are true:– Incomplete disclosure is necessary to Incomplete disclosure is necessary to

accomplish the goals of the researchaccomplish the goals of the research– No undisclosed risks that are more than minimalNo undisclosed risks that are more than minimal– Adequate plan for debriefing subjectsAdequate plan for debriefing subjects

May not withhold disclose to make research May not withhold disclose to make research more convenient.more convenient.

ComprehensionComprehensionin Informed Consentin Informed Consent

Information must be tailored to the research Information must be tailored to the research subject.subject.

Investigators must ascertain that the subject Investigators must ascertain that the subject understood the informationunderstood the information– Might quiz subjects about purpose, risks, etc.Might quiz subjects about purpose, risks, etc.

Surrogate consent if judgment is limited Surrogate consent if judgment is limited

“ “Therapeutic Misconception”Therapeutic Misconception”

Patients often misconstrue that research is Patients often misconstrue that research is designed to optimize their individual care.designed to optimize their individual care.

Voluntariness may be Voluntariness may be compromised when:compromised when:

Coercion or threat to obtain participationCoercion or threat to obtain participation Excessive inducementsExcessive inducements Pressure from authority figuresPressure from authority figures Requiring participation to receive health Requiring participation to receive health

servicesservices

Informed Consent CaseInformed Consent Case

A researcher believes that subjects want to A researcher believes that subjects want to participate in the research project and that participate in the research project and that participation will benefit the subjects who will participation will benefit the subjects who will receive variable dosing of a new, otherwise receive variable dosing of a new, otherwise unavailable, medication. But potential subjects unavailable, medication. But potential subjects are frightened by the long informed consent are frightened by the long informed consent form. She obtains full verbal consent and form. She obtains full verbal consent and disguises the written document in a series of disguises the written document in a series of forms to be signed. forms to be signed.

Informed Consent: Informed Consent: Conflict of InterestConflict of Interest

A physician receives authorship position on A physician receives authorship position on what will likely be an important paper what will likely be an important paper commensurate with the number of patients commensurate with the number of patients that he refers to a particular research study. that he refers to a particular research study. Because the type of patients in this study Because the type of patients in this study are his specialty and his patients have are his specialty and his patients have strong trust in him, he is able to refer strong trust in him, he is able to refer many.many.

The IRB’s ResponsibilitiesThe IRB’s Responsibilities Risk/benefit analysisRisk/benefit analysis Informed consentInformed consent Selection of subjectsSelection of subjects Privacy and confidentialityPrivacy and confidentiality Monitoring and observationMonitoring and observation Add'l safeguards for vulnerable subjectsAdd'l safeguards for vulnerable subjects Incentives for participationIncentives for participation Continuing reviewContinuing review

Research and QIResearch and QI

ResearchResearch ⇔⇔ Quality Quality Improvement Improvement

Best available treatment? Best available treatment?

Approved therapeutics?Approved therapeutics?

Able to opt out of treatment?Able to opt out of treatment?

Treatment selection method?Treatment selection method?

““The ethical responsibility to cooperate The ethical responsibility to cooperate with QI activities contrasts with the with QI activities contrasts with the fundamental ethical claim that research fundamental ethical claim that research is voluntary.”is voluntary.”

– Ann Intern Med. 2007; 146:666-73. Ann Intern Med. 2007; 146:666-73.

Distinctions between Research Distinctions between Research and QI?and QI?

“Research projects that rapidly give feedback to the care system that generated the data, aiming to change practices within that system, are ‘‘quality improvement’’ no matter whether the findings are published, whether the project is grant funded, and whether contemporaneous controls do not have the intervention.”

– Lynn J. Qual Saf Health Care 2004;13:67–70.

The Clinical TrialThe Clinical Trial

““Equipoise” (Fried, 1974): The state of Equipoise” (Fried, 1974): The state of uncertainty that must exist in order for a uncertainty that must exist in order for a controlled trial to be justified.controlled trial to be justified.

““Clinical Equipoise” (Freedman, 1987): A Clinical Equipoise” (Freedman, 1987): A remaining disagreement in the expert remaining disagreement in the expert community, despite the available evidence, community, despite the available evidence, about the merits of the intervention to be about the merits of the intervention to be tested.tested.

The Clinical TrialThe Clinical Trial Meier (1979): Consider the prospective subject as Meier (1979): Consider the prospective subject as

an individual with a legitimate sense of self-interest an individual with a legitimate sense of self-interest but also with a certain sense of community altruism, but also with a certain sense of community altruism, leading to a desire to help settle important clinical leading to a desire to help settle important clinical questions. questions.

In considering the legitimacy of initiating a clinical In considering the legitimacy of initiating a clinical trial, the investigator should imagine himself as trial, the investigator should imagine himself as such a person and ask whether or not he would be such a person and ask whether or not he would be willing to volunteer to be in the trial.willing to volunteer to be in the trial.

» Brody BA. Brody BA. The Ethics of Biomedical ResearchThe Ethics of Biomedical Research. . Oxford Univ Press, 1998.Oxford Univ Press, 1998.