1 Historical and contemporary foundations of research ethics and research regulation Clement A....

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Historical and contemporary Historical and contemporary foundations of research ethics and foundations of research ethics and

research regulationresearch regulation

Clement A. AdebamowoClement A. Adebamowo

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Bioethics – what is it?Bioethics – what is it?

• Morality is the general term for an individual’s or Morality is the general term for an individual’s or a society’s standard of conduct, both actual and a society’s standard of conduct, both actual and ideal, and of the character traits that determine ideal, and of the character traits that determine whether people are considered good or badwhether people are considered good or bad

• The scientific study of morality is calledThe scientific study of morality is called descriptive ethics – descriptive ethics – in this case, a scientist in this case, a scientist describes the moral judgments, beliefs or actions describes the moral judgments, beliefs or actions of individuals or societies in empirical terms and of individuals or societies in empirical terms and the reasons given for actions and beliefsthe reasons given for actions and beliefs

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Bioethics – what is it?Bioethics – what is it?

• There are two philosophical approaches to There are two philosophical approaches to studying ethicsstudying ethics• Meta-ethics – analysis (meaning) of the Meta-ethics – analysis (meaning) of the

methods, concepts and terms of reasoningmethods, concepts and terms of reasoning• Normative Ethics – analysis of what the Normative Ethics – analysis of what the

standards of moral judgment ought to be. A standards of moral judgment ought to be. A reflection on the kinds of actions and principles reflection on the kinds of actions and principles that will promote moral behaviorthat will promote moral behavior

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Bioethics - what is itBioethics - what is it

• Ethics is different from morals. Ethics tries to Ethics is different from morals. Ethics tries to probe the reasoning behind our moral life, by probe the reasoning behind our moral life, by examining and analyzing the thinking used to examining and analyzing the thinking used to justify our moral choices and actions in particular justify our moral choices and actions in particular situationssituations

• Bioethics is a specific discipline that probes the Bioethics is a specific discipline that probes the reasoning behind our moral life within the context reasoning behind our moral life within the context of the life sciences; how we decide what is of the life sciences; how we decide what is morally right or wrong biosciencemorally right or wrong bioscience

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Bioethics – what is itBioethics – what is it

• Bioethics is normative ethics applied to the Bioethics is normative ethics applied to the practice of science and medicine. It falls under the practice of science and medicine. It falls under the general group of applied and professional ethicsgeneral group of applied and professional ethics

• It is predicated on an assumption that some It is predicated on an assumption that some solutions to the ethical problems that arise in solutions to the ethical problems that arise in science and medicine are more moral than others science and medicine are more moral than others and that these solutions can be arrived at by moral and that these solutions can be arrived at by moral reasoning and reflectionsreasoning and reflections

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Bioethics – what is itBioethics – what is it

• It is a branch of knowledge like It is a branch of knowledge like mathematics, and thinking in this field is mathematics, and thinking in this field is not wholly different from thinking in those not wholly different from thinking in those other fields, however it cannot be reduced other fields, however it cannot be reduced to them. to them.

• Bioethical conclusions cannot be Bioethical conclusions cannot be unambiguously proved like mathematical unambiguously proved like mathematical theoremstheorems

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History of research ethicsHistory of research ethics

• Perhaps the earliest clinical trial was that of Lind – Perhaps the earliest clinical trial was that of Lind – conducted over a 6 year period in the 18conducted over a 6 year period in the 18thth century century• Sailors were allocated to receive or not receive fruits and Sailors were allocated to receive or not receive fruits and

vegetables during an investigation of the etiology of scurvyvegetables during an investigation of the etiology of scurvy

• About 25 years after that, Edward Jenner conducted his About 25 years after that, Edward Jenner conducted his famous chickenpox vaccination studies for prevention of famous chickenpox vaccination studies for prevention of smallpox, using children in his neighbourhood including smallpox, using children in his neighbourhood including his own childrenhis own children

• In 1897, Sanarelli discovered the cause of yellow fever and In 1897, Sanarelli discovered the cause of yellow fever and to prove his claim inoculated 5 people with his isolate with to prove his claim inoculated 5 people with his isolate with disastrous consequences for the participantsdisastrous consequences for the participants

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• 3 years later, the U.S. commissioned yellow fever study 3 years later, the U.S. commissioned yellow fever study under Walter Reedunder Walter Reed

• There was public concern in the United States about this There was public concern in the United States about this researchresearch

• Walter Reed’s “Yellow Fever Board” sketched some Walter Reed’s “Yellow Fever Board” sketched some guidelines for research ethics includingguidelines for research ethics including• Self experimentationSelf experimentation• Enrollment of only adultsEnrollment of only adults• Signed contract with sliding scale compensationSigned contract with sliding scale compensation

• Other early records of research ethics include Smidovich’s Other early records of research ethics include Smidovich’s The Confessions of a Physician (1901)The Confessions of a Physician (1901)

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• First “national guideline” on health research ethics was a First “national guideline” on health research ethics was a ministerial directive issued by the Prussian Ministry of ministerial directive issued by the Prussian Ministry of Health in 1900Health in 1900

• The guideline was precipitated by the work of Professor The guideline was precipitated by the work of Professor Neisser of the Neisser of the Neisseria spNeisseria sp fame fame

• In 1898, he tried to develop an anti-syphilis agent by In 1898, he tried to develop an anti-syphilis agent by injecting cell-free serum from syphilitic patients to other injecting cell-free serum from syphilitic patients to other patients – mostly prostitutes – without their consent. Some patients – mostly prostitutes – without their consent. Some of the participants developed syphilis as a resultof the participants developed syphilis as a result

• In 1900, the Royal Disciplinary Court fined him the In 1900, the Royal Disciplinary Court fined him the equivalent of equivalent of 22//33 of his annual income of his annual income

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• The issue was discussed in the Prussian parliament and the The issue was discussed in the Prussian parliament and the Minister for Religious, Educational and Medical Affairs Minister for Religious, Educational and Medical Affairs issued a regulation in 1900 stating issued a regulation in 1900 stating inter aliainter alia::• Directive to all medical directors of university hospitals, Directive to all medical directors of university hospitals,

polyclinics and other hospitalspolyclinics and other hospitals• I advise the medical directors of university hospitals, I advise the medical directors of university hospitals,

polyclinics and all other hospitals that all medical polyclinics and all other hospitals that all medical interventions for other than diagnostic, healing and interventions for other than diagnostic, healing and immunization purposes, regardless of other legal or immunization purposes, regardless of other legal or moral authorization are excluded under all moral authorization are excluded under all circumstances, if :circumstances, if :


• The human subject is a minor or not competent The human subject is a minor or not competent due to other reasonsdue to other reasons

• The human subject has not given his unambiguous The human subject has not given his unambiguous consentconsent

• The consent is not preceded by a proper The consent is not preceded by a proper explanation of the possible negative consequences explanation of the possible negative consequences of the intervention of the intervention

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• Despite these regulations, ethical Despite these regulations, ethical controversies continued controversies continued

• In 1930, in the city of Lubeck, 77 out of In 1930, in the city of Lubeck, 77 out of 256 children died from contaminated 256 children died from contaminated vaccinationvaccination

• This incident led to the earliest This incident led to the earliest controversies about therapeutic and non-controversies about therapeutic and non-therapeutic researchtherapeutic research

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• On February 28, 1931 Germany enacted arguably On February 28, 1931 Germany enacted arguably the first national research ethics regulations – the first national research ethics regulations – “Regulations on New Therapy and Human “Regulations on New Therapy and Human Experimentation”Experimentation”

• This was largely in response to the increasing use This was largely in response to the increasing use of human participants in research being driven by of human participants in research being driven by the strength of the German health research and the strength of the German health research and chemical industrychemical industry

• The very strict “Richtlinien” outlined how to The very strict “Richtlinien” outlined how to conduct human experimentation and the use of conduct human experimentation and the use of innovative therapies in medicineinnovative therapies in medicine


• Two of the 14 provisions of these guidelines Two of the 14 provisions of these guidelines concerned consent requirementsconcerned consent requirements

• It contained this formulation of informed consent It contained this formulation of informed consent “Innovative therapy may be carried out only after “Innovative therapy may be carried out only after the subject or his legal representative has the subject or his legal representative has unambiguously consented to the procedure in the unambiguously consented to the procedure in the light of relevant information being provided in light of relevant information being provided in advance”advance”

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• Questions about nature of appropriate Questions about nature of appropriate information, bona fide consent, careful information, bona fide consent, careful research design, special protections for research design, special protections for vulnerable subjects were all carefully vulnerable subjects were all carefully outlinedoutlined

• Experimentation on dying patients was Experimentation on dying patients was completely forbiddencompletely forbidden

• No other nation had such legally and No other nation had such legally and morally advanced regulations at this timemorally advanced regulations at this time

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• These regulations were in force and binding These regulations were in force and binding throughout Germany before and through the throughout Germany before and through the duration of the Second World War duration of the Second World War

• Yet, the Nazi experiments comprehensively Yet, the Nazi experiments comprehensively ignored and violated every one of the regulationsignored and violated every one of the regulations

• The Nuremberg trial that followed the second The Nuremberg trial that followed the second world war experiments focused attention on the world war experiments focused attention on the need for a code of research ethicsneed for a code of research ethics

• Prosecutors argued that the experiments violated Prosecutors argued that the experiments violated fundamental ethical standards of civilized society fundamental ethical standards of civilized society

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Nuremberg code 1948Nuremberg code 1948

• The defendants argued that voluntary participation by The defendants argued that voluntary participation by human subjects in medical experimentation was not the human subjects in medical experimentation was not the norm at that timenorm at that time

• The judges agreed with the prosecution and in addition to The judges agreed with the prosecution and in addition to sentencing the defendants also enunciated what is now sentencing the defendants also enunciated what is now known as the Nuremberg Codeknown as the Nuremberg Code

• The main components of the code areThe main components of the code are• Requirement for voluntary participationRequirement for voluntary participation• Informed consentInformed consent• Favorable risk/benefit analysisFavorable risk/benefit analysis• Right to withdraw without penaltyRight to withdraw without penalty

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Nuremberg Code 1948Nuremberg Code 1948

• Did not catch the attention of the popular press or Did not catch the attention of the popular press or the medical establishment at that time because the the medical establishment at that time because the actions of the Nazi doctors were considered to be actions of the Nazi doctors were considered to be an anomalous part of a brutal and totalitarian an anomalous part of a brutal and totalitarian regimeregime

• It was criticized for being legalistic It was criticized for being legalistic • The code did not provide an interpretive or The code did not provide an interpretive or

enforcement mechanismenforcement mechanism• It did not mention independent review or fair It did not mention independent review or fair

selection of participantsselection of participants

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Nuremberg Code 1948Nuremberg Code 1948

• It also seem to prohibit many aspects of medical It also seem to prohibit many aspects of medical research because of its unqualified demand for research because of its unqualified demand for voluntary informed consentvoluntary informed consent

• The Nazi doctors themselves were not judged on The Nazi doctors themselves were not judged on the basis of the code as this would have been an the basis of the code as this would have been an instance of instance of ex post factoex post facto justice justice

• There is also controversy about the origins and There is also controversy about the origins and inspirations for the Nuremberg codeinspirations for the Nuremberg code

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1950s Wichita Jury Study 1950s Wichita Jury Study

• Social science researchers from the University of Social science researchers from the University of Chicago conducted a study involving secret audio Chicago conducted a study involving secret audio taping of jury deliberations in order to better taping of jury deliberations in order to better understand decision making process of jurors in understand decision making process of jurors in criminal trialscriminal trials

• Their hypothesis was that showmanship on the part of Their hypothesis was that showmanship on the part of trial attorneys was affecting the outcome of trialstrial attorneys was affecting the outcome of trials

• When the results were presented in respectable When the results were presented in respectable academic forums, public reaction was markedly academic forums, public reaction was markedly negativenegative

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1950s Wichita Jury Study1950s Wichita Jury Study

• People objected to deception for research purposes in a People objected to deception for research purposes in a setting where privacy and confidentiality were critically setting where privacy and confidentiality were critically importantimportant

• This prompted the U.S. Congress to pass a law prohibiting This prompted the U.S. Congress to pass a law prohibiting recording of jury deliberations, marking the first time that recording of jury deliberations, marking the first time that actions of well meaning researchers will result in action to actions of well meaning researchers will result in action to protect people from exploitationprotect people from exploitation

• Case highlighted the fact that some research questions Case highlighted the fact that some research questions cannot be answered without compromising the integrity of cannot be answered without compromising the integrity of significant and cherished social institutionssignificant and cherished social institutions

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1950 Willowbrook Hepatitis Study1950 Willowbrook Hepatitis Study

• Researchers deliberately exposed children and adolescents Researchers deliberately exposed children and adolescents with disabilities to hepatitis virus in order to discover a with disabilities to hepatitis virus in order to discover a way of preventing the diseaseway of preventing the disease

• Critics claimed the study was coercive becauseCritics claimed the study was coercive because• New admission into the institution was closedNew admission into the institution was closed• Parents of children on the waiting list were written to inform them Parents of children on the waiting list were written to inform them

that their children could be placed on a research ward after which that their children could be placed on a research ward after which they could be transferred to the facility they could be transferred to the facility

• The researchers argued that almost all the children The researchers argued that almost all the children admitted into the facility develop hepatitis anyway and this admitted into the facility develop hepatitis anyway and this mitigated the deliberate exposure for the benefit of sciencemitigated the deliberate exposure for the benefit of science

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1950 Willowbrook Hepatitis Study1950 Willowbrook Hepatitis Study

• However at the time the study was initiated, the rates of However at the time the study was initiated, the rates of hepatitis had declined considerablyhepatitis had declined considerably

• Researchers argued that they had obtained consent from Researchers argued that they had obtained consent from the parentsthe parents

• That all various university, state and U.S. Armed Forces That all various university, state and U.S. Armed Forces Epidemiological Board (which funded the study) Epidemiological Board (which funded the study) committees had reviewed and approved the studycommittees had reviewed and approved the study

• Critics argued that because the participants were severely Critics argued that because the participants were severely mentally retarded children whose parents wanted placed in mentally retarded children whose parents wanted placed in one of few public institutions available rendered the one of few public institutions available rendered the consent invalidconsent invalid

• Researchers argued that the mental retardation was besides Researchers argued that the mental retardation was besides the point while critics retorted that that was precisely the the point while critics retorted that that was precisely the point point

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1960s Thalidomide Study1960s Thalidomide Study

• Thalidomide was introduced for the treatment of Thalidomide was introduced for the treatment of hyperemesis gravidarum in Europe and while still hyperemesis gravidarum in Europe and while still undergoing review in the U.S., an influential undergoing review in the U.S., an influential group of East Coast practitioners started using it group of East Coast practitioners started using it before it became clear that it was causing a large before it became clear that it was causing a large number of birth defectsnumber of birth defects

• Public outrage led to legislation that required Public outrage led to legislation that required investigators to obtain informed consent before investigators to obtain informed consent before administering investigational medicationsadministering investigational medications

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Jewish Chronic Diseases Hospital Jewish Chronic Diseases Hospital StudiesStudies

• In July 1963, 2 physicians at the Brooklyn Jewish Chronic In July 1963, 2 physicians at the Brooklyn Jewish Chronic Disease Hospital injected ill elderly patients with live Disease Hospital injected ill elderly patients with live hepatic cancer cells without their informed consenthepatic cancer cells without their informed consent

• The aim of the study was to study “rejection of human The aim of the study was to study “rejection of human cancer cells”cancer cells”

• Background studies suggest that such cells would be Background studies suggest that such cells would be rejected by immune reaction leading to their rejection from rejected by immune reaction leading to their rejection from the bodythe body

• It was then argued that the experiments present no risk to It was then argued that the experiments present no risk to the participantsthe participants

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Jewish Chronic Diseases Hospital Jewish Chronic Diseases Hospital StudiesStudies

• The researchers argued that informing participants about The researchers argued that informing participants about details of the research would have caused them needless details of the research would have caused them needless psychological distresspsychological distress

• Failure to inform was thus based on the need to minimize Failure to inform was thus based on the need to minimize distressdistress

• The Board of Regents (Governing Council) of the The Board of Regents (Governing Council) of the University of the State of New York argued that while University of the State of New York argued that while ““therapeutic privilege”therapeutic privilege” maymay justify non-disclosure in a justify non-disclosure in a physician-patient relation, same is not true of researcher-physician-patient relation, same is not true of researcher-participant relationshipparticipant relationship

• This case, among other things, highlighted the problem of This case, among other things, highlighted the problem of conflicting loyalties for physician-researchersconflicting loyalties for physician-researchers

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TuskegeeTuskegee

• Study was initiated in Macon County, Alabama in 1932Study was initiated in Macon County, Alabama in 1932• Designed to take advantage of an epidemic of syphilis Designed to take advantage of an epidemic of syphilis

among the black population to take study the natural among the black population to take study the natural history of syphilishistory of syphilis

• Over 400 sharecroppers were recruitedOver 400 sharecroppers were recruited• Neither they nor their partners were informed about the Neither they nor their partners were informed about the

nature of the research or about their conditionnature of the research or about their condition• When penicillin became available, they were not given an When penicillin became available, they were not given an

opportunity to use itopportunity to use it• They were in fact prevented from accessing it or obtaining They were in fact prevented from accessing it or obtaining

information about itinformation about it

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TuskegeeTuskegee

• Papers from the study were regularly published in medical Papers from the study were regularly published in medical journals and it did not evoke any ethical responsejournals and it did not evoke any ethical response

• In 1972, press reports finally prompted an investigation In 1972, press reports finally prompted an investigation and stoppage of the studyand stoppage of the study

• 74 of the original participants remained alive74 of the original participants remained alive• Some saw no reason for the outrage after all, the study was Some saw no reason for the outrage after all, the study was

not secret and was well knownnot secret and was well known• Others contented that the issues at stake were more about Others contented that the issues at stake were more about

racism racism • In the 70s participants were compensated and in 1997, In the 70s participants were compensated and in 1997,

U.S. government apologized for the studyU.S. government apologized for the study

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Other seminal eventsOther seminal events

• Henry Beecher’s 1959 Henry Beecher’s 1959 Experimentation in ManExperimentation in Man’s ’s monographmonograph

• 1960 – 1963 The Law-Medicine Research Institute of 1960 – 1963 The Law-Medicine Research Institute of Boston University’s survey of researchers attitudes and the Boston University’s survey of researchers attitudes and the anthology “Clinical Investigation in Medicine”anthology “Clinical Investigation in Medicine”

• Henry Beecher’s article in Henry Beecher’s article in NEJMNEJM in 1966 discussing 22 in 1966 discussing 22 out 50 collected cases of unethical research in America’s out 50 collected cases of unethical research in America’s leading universitiesleading universities

• 1966 - Henry Beecher’s editorial in the 1966 - Henry Beecher’s editorial in the Journal of the Journal of the American Medical AssociationAmerican Medical Association and argument for virtue and argument for virtue ethicsethics

• Beecher concluded that two things are needed for ethical Beecher concluded that two things are needed for ethical research – informed consent and a virtuous researcherresearch – informed consent and a virtuous researcher

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Other seminal eventsOther seminal events

• 1967 - M.H. Papworth – 1967 - M.H. Papworth – Human Guinea PigsHuman Guinea Pigs collected collected more than 500 papers describing unethical experiments more than 500 papers describing unethical experiments

• 1972 Jay Katz, Alex Capron and Eleanor Glass 1972 Jay Katz, Alex Capron and Eleanor Glass “Experimentation with Human Beings” “Experimentation with Human Beings”

• 1973 Congressional hearings on quality of health care and 1973 Congressional hearings on quality of health care and human experimentationhuman experimentation• Main catalyst for this was the Tuskegee Study (1932 – 1972), but Main catalyst for this was the Tuskegee Study (1932 – 1972), but

there were others, likethere were others, like• 1960 Milgram study of obedience1960 Milgram study of obedience• 1970 San Antonio study of contraceptive pills1970 San Antonio study of contraceptive pills• 1970 Humphrey’s Tearoom Trade Study 1970 Humphrey’s Tearoom Trade Study • 1970 Zimbardo’s Mock Prison Research 1970 Zimbardo’s Mock Prison Research

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Response of the research Response of the research establishmentestablishment

• Utilitarian argumentsUtilitarian arguments• The medical and social costs of illnesses justified the The medical and social costs of illnesses justified the

need for medical research despite the inherent need for medical research despite the inherent limitations of the informed consent ideallimitations of the informed consent ideal

• The need to “play God” is unavoidable The need to “play God” is unavoidable

• Lasagna wrote “How many of medicines great Lasagna wrote “How many of medicines great advances might have been delayed or prevented by the advances might have been delayed or prevented by the rigid application of some currently proposed principles rigid application of some currently proposed principles to regulate research at large”to regulate research at large”

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1964 World Medical Council 1964 World Medical Council Declaration of HelsinkiDeclaration of Helsinki

• Some of the limitations of the Nuremberg code including Some of the limitations of the Nuremberg code including the unqualified requirement for voluntary consent the unqualified requirement for voluntary consent informed the World Medical Association’s decision to informed the World Medical Association’s decision to develop its own medical ethics guidelines in 1953develop its own medical ethics guidelines in 1953

• In 1954, the association adopted a resolution that required In 1954, the association adopted a resolution that required consent by ill participant or next of kinconsent by ill participant or next of kin

• The resolution contained 5 propositions The resolution contained 5 propositions • Qualifications of researchersQualifications of researchers• PrudencePrudence• Responsibility of researchersResponsibility of researchers• Respect for participantsRespect for participants• Confinement of daring procedures to desperate casesConfinement of daring procedures to desperate cases

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• This basically builds on the Nuremberg code and adds This basically builds on the Nuremberg code and adds additional pointsadditional points• Allows for sufficiency of legal guardian’s consentAllows for sufficiency of legal guardian’s consent• Distinction between therapeutic and non-therapeutic researchDistinction between therapeutic and non-therapeutic research

• In 1975, the declaration was revisedIn 1975, the declaration was revised• It now placed greater emphasis on the need for informed consentIt now placed greater emphasis on the need for informed consent• Included a requirement for independent review committeesIncluded a requirement for independent review committees

• Subsequent revisions in 1983, 1989, 1996 and 2000 Subsequent revisions in 1983, 1989, 1996 and 2000 addressed specific items likeaddressed specific items like• Conformity of ethics committees with the laws of the country in Conformity of ethics committees with the laws of the country in

which the research is being performedwhich the research is being performed

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• In 2000, the distinction between therapeutic and In 2000, the distinction between therapeutic and non-therapeutic research was removednon-therapeutic research was removed

• That the interests of the subject should always That the interests of the subject should always be given a higher priority than those of societybe given a higher priority than those of society

• That every subject in clinical research should That every subject in clinical research should get the best known treatmentget the best known treatment

• They have been incorporated in many They have been incorporated in many national and international guidelinesnational and international guidelines

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1974 U. S. National Research Act1974 U. S. National Research Act

• This act established the modern research ethics system. The act This act established the modern research ethics system. The act created U.S. federal regulations that required ethical approval created U.S. federal regulations that required ethical approval before most kinds of research involving human subjects can be before most kinds of research involving human subjects can be conducted, defined policy and procedures that ethics conducted, defined policy and procedures that ethics committees (EC) must follow when reviewing research, and committees (EC) must follow when reviewing research, and established the criteria that an EC must use to approve research established the criteria that an EC must use to approve research conductconduct

• It also established the National Commission for the Protection It also established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. of Human Subjects of Biomedical and Behavioral Research. The National Commission which functioned between 1974 and The National Commission which functioned between 1974 and 1978 issued recommendations on research ethics and in 1978, 1978 issued recommendations on research ethics and in 1978, published the Belmont Reportpublished the Belmont Report

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Belmont principlesBelmont principles

• Respect for persons Respect for persons • Persons should be treated as autonomous agentsPersons should be treated as autonomous agents• Individuals with diminished autonomy deserve special Individuals with diminished autonomy deserve special

protectionprotection• Derived moral principlesDerived moral principles

• Informed consent; incorporating information, comprehension Informed consent; incorporating information, comprehension and voluntarinessand voluntariness

• Truth telling. In Kant’s “The supposed right to tell lies from Truth telling. In Kant’s “The supposed right to tell lies from benevolent motives”, he wrote that “If then, we define a lie benevolent motives”, he wrote that “If then, we define a lie merely as an intentionally false declaration towards another merely as an intentionally false declaration towards another man, we need not add that it must injure another … for it man, we need not add that it must injure another … for it always injures another; if not another individual, yet mankind always injures another; if not another individual, yet mankind generallygenerally

• ConfidentialityConfidentiality• PrivacyPrivacy

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• BeneficenceBeneficence• Most well known principle to physician from the oft Most well known principle to physician from the oft

quoted dictum “quoted dictum “Primum non nocerePrimum non nocere” What Hippocrates ” What Hippocrates actually said is “I will keep (patients) from harm and actually said is “I will keep (patients) from harm and injustice; I will … remain free from intentional injustice; I will … remain free from intentional injusticeinjustice

• Frankena arranged the components of this principle in Frankena arranged the components of this principle in the following hierarchical orderthe following hierarchical order

• I ought not to do evil or inflict harm (non-maleficence)I ought not to do evil or inflict harm (non-maleficence)• I ought to prevent evil or harm (beneficence)I ought to prevent evil or harm (beneficence)• I ought to remove evil or harm (beneficence)I ought to remove evil or harm (beneficence)• I ought to do or promote good (beneficence)I ought to do or promote good (beneficence)

• This ordering is not universally acceptedThis ordering is not universally accepted

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• Justice – in the sense of what is fair and what is Justice – in the sense of what is fair and what is deserveddeserved• An injustice occurs when an entitlement is denied An injustice occurs when an entitlement is denied

without good reason or burden imposed undulywithout good reason or burden imposed unduly• Another conception is that equals must be treated Another conception is that equals must be treated

equally.equally.• This plays a role in resource allocation, ensuring that This plays a role in resource allocation, ensuring that

no particular group bears excessive burden on behalf of no particular group bears excessive burden on behalf of others others

• The emphasis on rights in bioethics is another The emphasis on rights in bioethics is another derivative of this principlederivative of this principle

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Belmont reportBelmont report

• All but a few of the Belmont proposals became All but a few of the Belmont proposals became regulations by January 1981, revised in 1983 and regulations by January 1981, revised in 1983 and codified as the 45 Code of Federal Regulations 46 codified as the 45 Code of Federal Regulations 46 (i.e. 45 CFR 46)(i.e. 45 CFR 46)

• This became the basis for the 1991 Basic Policy This became the basis for the 1991 Basic Policy for the Protection of Human Subjects (known as for the Protection of Human Subjects (known as the Common Rule)the Common Rule)

• All U.S. Federal agencies that determined that All U.S. Federal agencies that determined that they were bound by these rules became signatoriesthey were bound by these rules became signatories

• Further subparts were published addressing Further subparts were published addressing specific protections for vulnerable populationsspecific protections for vulnerable populations

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U.S. FDAU.S. FDA

• Is not a signatory to the common rule and it Is not a signatory to the common rule and it developed its own guidelines which are developed its own guidelines which are largely similar to the Common Rulelargely similar to the Common Rule

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CIOMS GuidelinesCIOMS Guidelines

• The Council for International Organizations of Medical The Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Sciences (CIOMS) in collaboration with the World Health Organization (WHO) developed its International Ethical Organization (WHO) developed its International Ethical Guidelines for Biomedical Research Involving Human Guidelines for Biomedical Research Involving Human Subjects with special attention to research in developing Subjects with special attention to research in developing countriescountries

• Particularly in response to growing research in HIV/AIDSParticularly in response to growing research in HIV/AIDS• It took the Nuremberg Code and Declaration of Helsinki It took the Nuremberg Code and Declaration of Helsinki

into accountinto account• Its principles are designed with the socioeconomic and Its principles are designed with the socioeconomic and

political circumstances of developing countries in mindpolitical circumstances of developing countries in mind

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CIOMS GuidelinesCIOMS Guidelines

• Development started in 1982Development started in 1982• Involved consultation with participants from Involved consultation with participants from

developed and developing countries including developed and developing countries including health ministry officials, ethicists, philosophers health ministry officials, ethicists, philosophers and lawyersand lawyers

• First version was released in 1993 with 15 First version was released in 1993 with 15 guidelinesguidelines

• Second version was released in 2002 with 21 Second version was released in 2002 with 21 guidelinesguidelines

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CIOMS guidelinesCIOMS guidelines

• Starts with an argument on the necessity of Starts with an argument on the necessity of researchresearch

• Proclaimed the need for researchers and sponsors Proclaimed the need for researchers and sponsors to make every effort to ensure that any to make every effort to ensure that any intervention or product developed or knowledge intervention or product developed or knowledge generated will be made reasonably available for generated will be made reasonably available for the benefit of the population or communitythe benefit of the population or community

• The guidelines tackles the issue of placebo trials in The guidelines tackles the issue of placebo trials in guideline 11, articulating conditions when they guideline 11, articulating conditions when they can be usedcan be used

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ICH-GCP guidelinesICH-GCP guidelines

• International Committee on Harmonization Harmonized International Committee on Harmonization Harmonized Tripartite Guideline – Guideline for Good Clinical Practice Tripartite Guideline – Guideline for Good Clinical Practice was promulgated in 1996 by the International Conference was promulgated in 1996 by the International Conference on Harmonization of Technical Requirements for on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and has Registration of Pharmaceuticals for Human Use and has been agreed upon by the regulatory agencies in Europe, been agreed upon by the regulatory agencies in Europe, Japan and the United StatesJapan and the United States

• The ICH-GCP guidelines delineates detailed standards for The ICH-GCP guidelines delineates detailed standards for review committees, investigators and sponsorsreview committees, investigators and sponsors

• It is particularly targeted at research on drugs or devices It is particularly targeted at research on drugs or devices seeking regulatory approvalseeking regulatory approval

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ICH-GCP guidelinesICH-GCP guidelines

• While it is rooted in the Helsinki While it is rooted in the Helsinki Declaration and applicable local codes, it is Declaration and applicable local codes, it is far more specific than the other codes but far more specific than the other codes but not wider in scopenot wider in scope

• It is criticized for being lax on the use of It is criticized for being lax on the use of placebos in clinical trialsplacebos in clinical trials

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General commentsGeneral comments

• These guidelines are still evolvingThese guidelines are still evolving• Many lack a mechanism for interpretation, Many lack a mechanism for interpretation,

implementation, application and enforcementimplementation, application and enforcement• In the U.S. the Common Rule is the most widely In the U.S. the Common Rule is the most widely

used and legally bindingused and legally binding• There are some inconsistencies and controversies There are some inconsistencies and controversies

– particularly with placebo controlled trials– particularly with placebo controlled trials• Failure to comply with the common rule can have Failure to comply with the common rule can have

dire consequences in the United States but other dire consequences in the United States but other guidelines often are not legally enforceableguidelines often are not legally enforceable

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Other influences on development of Other influences on development of bioethicsbioethics

• The 60s and 70s civil rights movement in the United States The 60s and 70s civil rights movement in the United States with distrust of authority, emphasis on individual rights with distrust of authority, emphasis on individual rights and autonomyand autonomy

• The pace and variety of development of new health care The pace and variety of development of new health care technologytechnology

• The Cold War and fear of any type of socialismThe Cold War and fear of any type of socialism• The allocation, by the NHGRI, of substantial funds to The allocation, by the NHGRI, of substantial funds to

bioethics in 1989 leading to codification of the currently bioethics in 1989 leading to codification of the currently predominant academic mode of discourse for bioethicists: predominant academic mode of discourse for bioethicists: research concerning ethical issues as they are encountered research concerning ethical issues as they are encountered and resolved in society, culminating in data that is subject and resolved in society, culminating in data that is subject to the same rigors of peer review as other social science. to the same rigors of peer review as other social science.

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Nigeria’s baby stepsNigeria’s baby steps

• National Health Research Ethics Committee has National Health Research Ethics Committee has been set up with the following membershipbeen set up with the following membership• Chairman appointed by Hon. Minister of HealthChairman appointed by Hon. Minister of Health

• Membership representing Law, Pharmacy, Medicine, Membership representing Law, Pharmacy, Medicine, Nursing, Community Health Workers, Christians, Nursing, Community Health Workers, Christians, Muslim, Researchers and 3 other personsMuslim, Researchers and 3 other persons

• Ex-officio members from Ministries of Education, Ex-officio members from Ministries of Education, Environment, Women’s affairs, Agriculture etc. Environment, Women’s affairs, Agriculture etc. NAFDAC, NUC NAFDAC, NUC

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Functions of NHRECFunctions of NHREC

• Determine guidelines for the functioning of health research Determine guidelines for the functioning of health research ethics committeesethics committees

• Register and audit health research ethics committeesRegister and audit health research ethics committees• Set norms and standards for conducting research on Set norms and standards for conducting research on

humans and humans and animalsanimals, including norms and standards for , including norms and standards for conducting conducting clinical trialsclinical trials

• AdjudicateAdjudicate in complaints about the functioning of health in complaints about the functioning of health research ethics committees and hear any complaint by a research ethics committees and hear any complaint by a researcher who believes that he has been discriminated researcher who believes that he has been discriminated against by a health research ethics committeeagainst by a health research ethics committee

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Functions of NHRECFunctions of NHREC

• Refer to the relevant statutory health professional council Refer to the relevant statutory health professional council matters involving the violation or potential violation of an matters involving the violation or potential violation of an ethical or professional rule by a health care providerethical or professional rule by a health care provider

• Institute such Institute such disciplinary actiondisciplinary action as may be prescribed as may be prescribed against any person found to be in violation of any norms against any person found to be in violation of any norms and standards, or guidelines, set for the conduct of and standards, or guidelines, set for the conduct of research under this Actresearch under this Act

• Advise the Federal Ministry of Health and State Ministries Advise the Federal Ministry of Health and State Ministries on any ethical issues concerning researchon any ethical issues concerning research

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Functions of HRECFunctions of HREC

• Review research proposals and protocols in order to ensure Review research proposals and protocols in order to ensure that research conducted by the relevant institution, agency that research conducted by the relevant institution, agency or establishment will promote health, contribute to the or establishment will promote health, contribute to the prevention of communicable or non-communicable prevention of communicable or non-communicable diseases or disability or result in cures for communicable diseases or disability or result in cures for communicable or non-communicable diseases; andor non-communicable diseases; and

• Grant approval for research by the relevant institution, Grant approval for research by the relevant institution, agency or establishment in instances where research agency or establishment in instances where research proposals and protocol meet the ethical standards of that proposals and protocol meet the ethical standards of that health research ethics committee.health research ethics committee.

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Highlights of the codeHighlights of the code

• Definition of research as systematic investigation Definition of research as systematic investigation designed to generate generalizable knowledgedesigned to generate generalizable knowledge

• Identification of activities exempted from research Identification of activities exempted from research and allocation of the power of determination to and allocation of the power of determination to HREC, for exampleHREC, for example• De-identified publicly available dataDe-identified publicly available data

• Innovative medical practiceInnovative medical practice

• Audit and Quality Assurance studiesAudit and Quality Assurance studies

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HighlightsHighlights

• Registration of HRECs to create a National Registration of HRECs to create a National Database and Categorization of HRECsDatabase and Categorization of HRECs• HRECs being audit programs must have direct lines of HRECs being audit programs must have direct lines of

communication with heads of proposing institutionscommunication with heads of proposing institutions• HREC members must complete NHREC approved HREC members must complete NHREC approved

training programs in research ethicstraining programs in research ethics• Institutions must provide HRECs with space, office, Institutions must provide HRECs with space, office,

staff and infrastructure to enable them do their workstaff and infrastructure to enable them do their work• Institutions shall provide coverage of HREC members Institutions shall provide coverage of HREC members

from liabilityfrom liability

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• HRECs shall apply for initial registration and re-HRECs shall apply for initial registration and re-registration every 2 yearsregistration every 2 years• Submission of materials required, including copies of financial Submission of materials required, including copies of financial

statement, evidence that previous commitments by the institution statement, evidence that previous commitments by the institution are met and evidence of continuing training of HREC membersare met and evidence of continuing training of HREC members

• Limitation of HREC’s authority to the bounds of proposing Limitation of HREC’s authority to the bounds of proposing authorityauthority

• Institutions that have no HREC can set up collaborative Institutions that have no HREC can set up collaborative agreements with registered HRECsagreements with registered HRECs

• HREC membership must always include a lawyerHREC membership must always include a lawyer• Institutions can have more than 1 HRECInstitutions can have more than 1 HREC

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• Provision of liability coverage for members of HRECsProvision of liability coverage for members of HRECs• HRECs shall include at least 1 lay personHRECs shall include at least 1 lay person• HREC members are bound by a perpetual code of HREC members are bound by a perpetual code of

confidentialityconfidentiality• HRECs shall have continuing oversight of research – a review HRECs shall have continuing oversight of research – a review

shall be conducted at least once a year or during the life of the shall be conducted at least once a year or during the life of the study whichever is shorterstudy whichever is shorter

• NHREC shall categorize HRECs and define limits of activitiesNHREC shall categorize HRECs and define limits of activities• Clear processes for expedited review, exception and Clear processes for expedited review, exception and

amendmentamendment

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• HRECs can co-opt membersHRECs can co-opt members• Encourages researchers to be invited to HREC Encourages researchers to be invited to HREC

meetingsmeetings• Sets time limits for decision on research Sets time limits for decision on research

applications – 90 daysapplications – 90 days• All records relating decision must be kept for at All records relating decision must be kept for at

least 10 yearsleast 10 years• Clear process for suspension, revision of Clear process for suspension, revision of

suspension and termination of researchsuspension and termination of research• Clear adjudicatory mechanism to NHRECClear adjudicatory mechanism to NHREC

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• Review of multi-institutional researchReview of multi-institutional research• Procedure of 3 or fewer and more than 3 collaborating Procedure of 3 or fewer and more than 3 collaborating

sitessites• Options for research reviewOptions for research review• Opportunity for central research reviewOpportunity for central research review• Requirement for sharing ethics review from different Requirement for sharing ethics review from different

ethics committeesethics committees• Requirement for Materials Transfer Agreements, Requirement for Materials Transfer Agreements,

Benefits sharing, IPP, patent and other tangible and Benefits sharing, IPP, patent and other tangible and intangible benefits’ sharing intangible benefits’ sharing

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• Only applicant(s) with qualification(s) and background Only applicant(s) with qualification(s) and background sufficient to serve as principal investigator(s) and based in sufficient to serve as principal investigator(s) and based in an institution in Nigeria that is capable of carrying out the an institution in Nigeria that is capable of carrying out the research shall apply for review of researchresearch shall apply for review of research

• HREC may adopt the result of review by another HREC HREC may adopt the result of review by another HREC rather than conduct a fresh reviewrather than conduct a fresh review

• NHREC may review research NHREC may review research • Nationwide research or more than 3 sitesNationwide research or more than 3 sites• Research referred to NHREC from HRECResearch referred to NHREC from HREC• There is no HREC in an institution and no collaborative agreement There is no HREC in an institution and no collaborative agreement

with an institution that has onewith an institution that has one

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• NHREC review of researchNHREC review of research• Mandating review by a HREC anywhere in the country as the Mandating review by a HREC anywhere in the country as the

HREC of recordHREC of record• Constituting an Constituting an ad hocad hoc HREC HREC• Constituting itself into a HRECConstituting itself into a HREC

• Oversight will still be provided by local HRECsOversight will still be provided by local HRECs

• Incorporation of ethics guidelines in code for guidance Incorporation of ethics guidelines in code for guidance during research reviewduring research review

• Ethics guidelines goes beyond the “4” principles to Ethics guidelines goes beyond the “4” principles to accommodate recent advances in ethics and emphasizing accommodate recent advances in ethics and emphasizing the role of community, trust, truth telling, GCP and GLPthe role of community, trust, truth telling, GCP and GLP

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• HREC may charge feesHREC may charge fees• Informed consent documents must be legible and not more Informed consent documents must be legible and not more

than 8 pages longthan 8 pages long• All consent activity must be documentedAll consent activity must be documented• HREC must organize training for members and the HREC must organize training for members and the

community of the proposing authoritycommunity of the proposing authority• HRECs may offer consultation services to researchersHRECs may offer consultation services to researchers• HRECs will demand that researchers submit evidence of HRECs will demand that researchers submit evidence of

recent training in research ethicsrecent training in research ethics• NHREC will exercise oversight functions on HRECsNHREC will exercise oversight functions on HRECs

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• HRECs have disciplinary and compliance powersHRECs have disciplinary and compliance powers• Include suspension of researchInclude suspension of research• Termination of researchTermination of research• Recommendation to NHREC for disciplinary actionRecommendation to NHREC for disciplinary action

• NHREC disciplinary powersNHREC disciplinary powers• Debarment of researchersDebarment of researchers• Imposition of disciplinary measures Imposition of disciplinary measures • Report to policeReport to police• Report to other ethics regulatory agencies in case of Report to other ethics regulatory agencies in case of

international collaborative researchinternational collaborative research

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Current activitiesCurrent activities

• Code has been released and can be found at Code has been released and can be found at http://nhrec.net where you have the opportunity to either where you have the opportunity to either read or download itread or download it

• Comments can be sent to Comments can be sent to [email protected], , [email protected] or or [email protected]

• Sub-codes for children, pregnant women, Sub-codes for children, pregnant women, prisoners, people living with AIDS, and others are prisoners, people living with AIDS, and others are in developmentin development

• Standard Operating Procedures (SOPs), prototype Standard Operating Procedures (SOPs), prototype MTA, consent forms etc are available on NHREC MTA, consent forms etc are available on NHREC websitewebsite

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NHREC websiteNHREC website

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