Transcript Document
Historical and contemporary foundations of research ethics and research regulation
Clement A. Adebamowo
1
Bioethics – what is it?
• • Morality is the general term for an individual’s or a society’s standard of conduct, both actual and ideal, and of the character traits that determine whether people are considered good or bad The scientific study of morality is called
descriptive ethics –
in this case, a scientist describes the moral judgments, beliefs or actions of individuals or societies in empirical terms and the reasons given for actions and beliefs 2
Bioethics – what is it?
• There are two philosophical approaches to studying ethics • Meta-ethics – analysis (meaning) of the methods, concepts and terms of reasoning • Normative Ethics – analysis of what the standards of moral judgment ought to be. A reflection on the kinds of actions and principles that will promote moral behavior 3
Bioethics - what is it
• • Ethics is different from morals. Ethics tries to probe the reasoning behind our moral life, by examining and analyzing the thinking used to justify our moral choices and actions in particular situations Bioethics is a specific discipline that probes the reasoning behind our moral life within the context of the life sciences; how we decide what is morally right or wrong bioscience 4
Bioethics – what is it
• • Bioethics is normative ethics applied to the practice of science and medicine. It falls under the general group of applied and professional ethics It is predicated on an assumption that some solutions to the ethical problems that arise in science and medicine are more moral than others and that these solutions can be arrived at by moral reasoning and reflections 5
Bioethics – what is it
• • It is a branch of knowledge like mathematics, and thinking in this field is not wholly different from thinking in those other fields, however it cannot be reduced to them. Bioethical conclusions cannot be unambiguously proved like mathematical theorems 6
History of research ethics
• • • Perhaps the earliest clinical trial was that of Lind – conducted over a 6 year period in the 18 th century • Sailors were allocated to receive or not receive fruits and vegetables during an investigation of the etiology of scurvy About 25 years after that, Edward Jenner conducted his famous chickenpox vaccination studies for prevention of smallpox, using children in his neighbourhood including his own children In 1897, Sanarelli discovered the cause of yellow fever and to prove his claim inoculated 5 people with his isolate with disastrous consequences for the participants 7
History of research ethics
• • • • 3 years later, the U.S. commissioned yellow fever study under Walter Reed There was public concern in the United States about this research Walter Reed’s “Yellow Fever Board” sketched some guidelines for research ethics including • Self experimentation • Enrollment of only adults • Signed contract with sliding scale compensation Other early records of research ethics include Smidovich’s The Confessions of a Physician (1901) 8
History of research ethics
• • • • First “national guideline” on health research ethics was a ministerial directive issued by the Prussian Ministry of Health in 1900 The guideline was precipitated by the work of Professor Neisser of the
Neisseria sp
fame In 1898, he tried to develop an anti-syphilis agent by injecting cell-free serum from syphilitic patients to other patients – mostly prostitutes – without their consent. Some of the participants developed syphilis as a result In 1900, the Royal Disciplinary Court fined him the equivalent of 2 / 3 of his annual income 9
History of research ethics
• The issue was discussed in the Prussian parliament and the Minister for Religious, Educational and Medical Affairs issued a regulation in 1900 stating
inter alia
: • Directive to all medical directors of university hospitals, polyclinics and other hospitals • I advise the medical directors of university hospitals, polyclinics and all other hospitals that all medical interventions for other than diagnostic, healing and immunization purposes, regardless of other legal or moral authorization are excluded under all circumstances, if : 10
History of research ethics
• • • The human subject is a minor or not competent due to other reasons The human subject has not given his unambiguous consent The consent is not preceded by a proper explanation of the possible negative consequences of the intervention 11
History of research ethics
• • • Despite these regulations, ethical controversies continued In 1930, in the city of Lubeck, 77 out of 256 children died from contaminated vaccination This incident led to the earliest controversies about therapeutic and non therapeutic research 12
History of research ethics
• • • On February 28, 1931 Germany enacted arguably the first national research ethics regulations – “Regulations on New Therapy and Human Experimentation” This was largely in response to the increasing use of human participants in research being driven by the strength of the German health research and chemical industry The very strict “Richtlinien” outlined how to conduct human experimentation and the use of innovative therapies in medicine 13
History of research ethics
• • Two of the 14 provisions of these guidelines concerned consent requirements It contained this formulation of informed consent “Innovative therapy may be carried out only after the subject or his legal representative has unambiguously consented to the procedure in the light of relevant information being provided in advance” 14
History of research ethics
• • • Questions about nature of appropriate information, bona fide consent, careful research design, special protections for vulnerable subjects were all carefully outlined Experimentation on dying patients was completely forbidden No other nation had such legally and morally advanced regulations at this time 15
History of research ethics
• • • • These regulations were in force and binding throughout Germany before and through the duration of the Second World War Yet, the Nazi experiments comprehensively ignored and violated every one of the regulations The Nuremberg trial that followed the second world war experiments focused attention on the need for a code of research ethics Prosecutors argued that the experiments violated fundamental ethical standards of civilized society 16
Nuremberg code 1948
• • • The defendants argued that voluntary participation by human subjects in medical experimentation was not the norm at that time The judges agreed with the prosecution and in addition to sentencing the defendants also enunciated what is now known as the Nuremberg Code The main components of the code are • Requirement for voluntary participation • Informed consent • Favorable risk/benefit analysis • Right to withdraw without penalty 17
Nuremberg Code 1948
• • • • Did not catch the attention of the popular press or the medical establishment at that time because the actions of the Nazi doctors were considered to be an anomalous part of a brutal and totalitarian regime It was criticized for being legalistic The code did not provide an interpretive or enforcement mechanism It did not mention independent review or fair selection of participants 18
Nuremberg Code 1948
• • • It also seem to prohibit many aspects of medical research because of its unqualified demand for voluntary informed consent The Nazi doctors themselves were not judged on the basis of the code as this would have been an instance of
ex post facto
justice There is also controversy about the origins and inspirations for the Nuremberg code 19
1950s Wichita Jury Study
• • • Social science researchers from the University of Chicago conducted a study involving secret audio taping of jury deliberations in order to better understand decision making process of jurors in criminal trials Their hypothesis was that showmanship on the part of trial attorneys was affecting the outcome of trials When the results were presented in respectable academic forums, public reaction was markedly negative 20
1950s Wichita Jury Study
• • • People objected to deception for research purposes in a setting where privacy and confidentiality were critically important This prompted the U.S. Congress to pass a law prohibiting recording of jury deliberations, marking the first time that actions of well meaning researchers will result in action to protect people from exploitation Case highlighted the fact that some research questions cannot be answered without compromising the integrity of significant and cherished social institutions 21
1950 Willowbrook Hepatitis Study
• • • Researchers deliberately exposed children and adolescents with disabilities to hepatitis virus in order to discover a way of preventing the disease Critics claimed the study was coercive because • New admission into the institution was closed • Parents of children on the waiting list were written to inform them that their children could be placed on a research ward after which they could be transferred to the facility The researchers argued that almost all the children admitted into the facility develop hepatitis anyway and this mitigated the deliberate exposure for the benefit of science 22
1950 Willowbrook Hepatitis Study
• • • • • However at the time the study was initiated, the rates of hepatitis had declined considerably Researchers argued that they had obtained consent from the parents That all various university, state and U.S. Armed Forces Epidemiological Board (which funded the study) committees had reviewed and approved the study Critics argued that because the participants were severely mentally retarded children whose parents wanted placed in one of few public institutions available rendered the consent invalid Researchers argued that the mental retardation was besides the point while critics retorted that that was precisely the point 23
1960s Thalidomide Study
• • Thalidomide was introduced for the treatment of hyperemesis gravidarum in Europe and while still undergoing review in the U.S., an influential group of East Coast practitioners started using it before it became clear that it was causing a large number of birth defects Public outrage led to legislation that required investigators to obtain informed consent before administering investigational medications 24
Jewish Chronic Diseases Hospital Studies
• • • • In July 1963, 2 physicians at the Brooklyn Jewish Chronic Disease Hospital injected ill elderly patients with live hepatic cancer cells without their informed consent The aim of the study was to study “rejection of human cancer cells” Background studies suggest that such cells would be rejected by immune reaction leading to their rejection from the body It was then argued that the experiments present no risk to the participants 25
Jewish Chronic Diseases Hospital Studies
• • • • The researchers argued that informing participants about details of the research would have caused them needless psychological distress Failure to inform was thus based on the need to minimize distress The Board of Regents (Governing Council) of the University of the State of New York argued that while “
therapeutic privilege” may
justify non-disclosure in a physician-patient relation, same is not true of researcher participant relationship This case, among other things, highlighted the problem of conflicting loyalties for physician-researchers 26
Tuskegee
• • • • • • Study was initiated in Macon County, Alabama in 1932 Designed to take advantage of an epidemic of syphilis among the black population to take study the natural history of syphilis Over 400 sharecroppers were recruited Neither they nor their partners were informed about the nature of the research or about their condition When penicillin became available, they were not given an opportunity to use it They were in fact prevented from accessing it or obtaining information about it 27
Tuskegee
• • • • • • Papers from the study were regularly published in medical journals and it did not evoke any ethical response In 1972, press reports finally prompted an investigation and stoppage of the study 74 of the original participants remained alive Some saw no reason for the outrage after all, the study was not secret and was well known Others contented that the issues at stake were more about racism In the 70s participants were compensated and in 1997, U.S. government apologized for the study 28
Other seminal events
• • • • • Henry Beecher’s 1959
Experimentation in Man
’s monograph 1960 – 1963 The Law-Medicine Research Institute of Boston University’s survey of researchers attitudes and the anthology “Clinical Investigation in Medicine” Henry Beecher’s article in out 50 collected cases of unethical research in America’s leading universities
NEJM
in 1966 discussing 22 1966 - Henry Beecher’s editorial in the
Journal of the American Medical Association
and argument for virtue ethics Beecher concluded that two things are needed for ethical research – informed consent and a virtuous researcher 29
Other seminal events
• • • 1967 - M.H. Papworth –
Human Guinea Pigs
collected more than 500 papers describing unethical experiments 1972 Jay Katz, Alex Capron and Eleanor Glass “Experimentation with Human Beings” 1973 Congressional hearings on quality of health care and human experimentation • Main catalyst for this was the Tuskegee Study (1932 – 1972), but there were others, like • 1960 Milgram study of obedience • 1970 San Antonio study of contraceptive pills • 1970 Humphrey’s Tearoom Trade Study • 1970 Zimbardo’s Mock Prison Research 30
Response of the research establishment
• Utilitarian arguments • The medical and social costs of illnesses justified the need for medical research despite the inherent limitations of the informed consent ideal • The need to “play God” is unavoidable • Lasagna wrote “How many of medicines great advances might have been delayed or prevented by the rigid application of some currently proposed principles to regulate research at large” 31
1964 World Medical Council Declaration of Helsinki
• • • Some of the limitations of the Nuremberg code including the unqualified requirement for voluntary consent informed the World Medical Association’s decision to develop its own medical ethics guidelines in 1953 In 1954, the association adopted a resolution that required consent by ill participant or next of kin The resolution contained 5 propositions • Qualifications of researchers • Prudence • Responsibility of researchers • Respect for participants • Confinement of daring procedures to desperate cases 32
1964 World Medical Council Declaration of Helsinki
• • • This basically builds on the Nuremberg code and adds additional points • Allows for sufficiency of legal guardian’s consent • Distinction between therapeutic and non-therapeutic research In 1975, the declaration was revised • It now placed greater emphasis on the need for informed consent • Included a requirement for independent review committees Subsequent revisions in 1983, 1989, 1996 and 2000 addressed specific items like • Conformity of ethics committees with the laws of the country in which the research is being performed 33
1964 World Medical Council Declaration of Helsinki
• In 2000, the distinction between therapeutic and non-therapeutic research was removed • That the interests of the subject should always be given a higher priority than those of society • That every subject in clinical research should get the best known treatment • They have been incorporated in many national and international guidelines 34
1974 U. S. National Research Act
• • This act established the modern research ethics system. The act created U.S. federal regulations that required ethical approval before most kinds of research involving human subjects can be conducted, defined policy and procedures that ethics committees (EC) must follow when reviewing research, and established the criteria that an EC must use to approve research conduct It also established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The National Commission which functioned between 1974 and 1978 issued recommendations on research ethics and in 1978, published the Belmont Report 35
Belmont principles
• Respect for persons • Persons should be treated as autonomous agents • Individuals with diminished autonomy deserve special protection • Derived moral principles • Informed consent; incorporating information, comprehension and voluntariness • Truth telling. In Kant’s “The supposed right to tell lies from benevolent motives”, he wrote that “If then, we define a lie merely as an intentionally false declaration towards another man, we need not add that it must injure another … for it always injures another; if not another individual, yet mankind generally • Confidentiality • Privacy 36
Belmont principles
• Beneficence • Most well known principle to physician from the oft quoted dictum “
Primum non nocere
” What Hippocrates actually said is “I will keep (patients) from harm and injustice; I will … remain free from intentional injustice • Frankena arranged the components of this principle in the following hierarchical order • I ought not to do evil or inflict harm (non-maleficence) • I ought to prevent evil or harm (beneficence) • I ought to remove evil or harm (beneficence) • I ought to do or promote good (beneficence) • This ordering is not universally accepted 37
Belmont principles
• Justice – in the sense of what is fair and what is deserved • An injustice occurs when an entitlement is denied without good reason or burden imposed unduly • Another conception is that equals must be treated equally.
• This plays a role in resource allocation, ensuring that no particular group bears excessive burden on behalf of others • The emphasis on rights in bioethics is another derivative of this principle 38
Belmont report
• • • • All but a few of the Belmont proposals became regulations by January 1981, revised in 1983 and codified as the 45 Code of Federal Regulations 46 (i.e. 45 CFR 46) This became the basis for the 1991 Basic Policy for the Protection of Human Subjects (known as the Common Rule) All U.S. Federal agencies that determined that they were bound by these rules became signatories Further subparts were published addressing specific protections for vulnerable populations 39
U.S. FDA
• Is not a signatory to the common rule and it developed its own guidelines which are largely similar to the Common Rule 40
CIOMS Guidelines
• • • • The Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO) developed its International Ethical Guidelines for Biomedical Research Involving Human Subjects with special attention to research in developing countries Particularly in response to growing research in HIV/AIDS It took the Nuremberg Code and Declaration of Helsinki into account Its principles are designed with the socioeconomic and political circumstances of developing countries in mind 41
CIOMS Guidelines
• • • • Development started in 1982 Involved consultation with participants from developed and developing countries including health ministry officials, ethicists, philosophers and lawyers First version was released in 1993 with 15 guidelines Second version was released in 2002 with 21 guidelines 42
CIOMS guidelines
• • • Starts with an argument on the necessity of research Proclaimed the need for researchers and sponsors to make every effort to ensure that any intervention or product developed or knowledge generated will be made reasonably available for the benefit of the population or community The guidelines tackles the issue of placebo trials in guideline 11, articulating conditions when they can be used 43
ICH-GCP guidelines
• • • International Committee on Harmonization Harmonized Tripartite Guideline – Guideline for Good Clinical Practice was promulgated in 1996 by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and has been agreed upon by the regulatory agencies in Europe, Japan and the United States The ICH-GCP guidelines delineates detailed standards for review committees, investigators and sponsors It is particularly targeted at research on drugs or devices seeking regulatory approval 44
ICH-GCP guidelines
• While it is rooted in the Helsinki Declaration and applicable local codes, it is far more specific than the other codes but not wider in scope • It is criticized for being lax on the use of placebos in clinical trials 45
General comments
• • • • • These guidelines are still evolving Many lack a mechanism for interpretation, implementation, application and enforcement In the U.S. the Common Rule is the most widely used and legally binding There are some inconsistencies and controversies – particularly with placebo controlled trials Failure to comply with the common rule can have dire consequences in the United States but other guidelines often are not legally enforceable 46
Other influences on development of bioethics
• • • • The 60s and 70s civil rights movement in the United States with distrust of authority, emphasis on individual rights and autonomy The pace and variety of development of new health care technology The Cold War and fear of any type of socialism The allocation, by the NHGRI, of substantial funds to bioethics in 1989 leading to codification of the currently predominant academic mode of discourse for bioethicists: research concerning ethical issues as they are encountered and resolved in society, culminating in data that is subject to the same rigors of peer review as other social science. 47
Nigeria’s baby steps
• National Health Research Ethics Committee has been set up with the following membership • Chairman appointed by Hon. Minister of Health • Membership representing Law, Pharmacy, Medicine, Nursing, Community Health Workers, Christians, Muslim, Researchers and 3 other persons • Ex-officio members from Ministries of Education, Environment, Women’s affairs, Agriculture etc. NAFDAC, NUC 48
Functions of NHREC
• • • • Determine guidelines for the functioning of health research ethics committees Register and audit health research ethics committees Set norms and standards for conducting research on humans and
animals
, including norms and standards for conducting
clinical trials Adjudicate
in complaints about the functioning of health research ethics committees and hear any complaint by a researcher who believes that he has been discriminated against by a health research ethics committee 49
Functions of NHREC
• • • Refer to the relevant statutory health professional council matters involving the violation or potential violation of an ethical or professional rule by a health care provider Institute such
disciplinary action
under this Act as may be prescribed against any person found to be in violation of any norms and standards, or guidelines, set for the conduct of research Advise the Federal Ministry of Health and State Ministries on any ethical issues concerning research 50
Functions of HREC
• • Review research proposals and protocols in order to ensure that research conducted by the relevant institution, agency or establishment will promote health, contribute to the prevention of communicable or non-communicable diseases or disability or result in cures for communicable or non-communicable diseases; and Grant approval for research by the relevant institution, agency or establishment in instances where research proposals and protocol meet the ethical standards of that health research ethics committee.
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Highlights of the code
• • Definition of research as systematic investigation designed to generate generalizable knowledge Identification of activities exempted from research and allocation of the power of determination to HREC, for example • De-identified publicly available data • Innovative medical practice • Audit and Quality Assurance studies 52
Highlights
• Registration of HRECs to create a National Database and Categorization of HRECs • HRECs being audit programs must have direct lines of communication with heads of proposing institutions • HREC members must complete NHREC approved training programs in research ethics • Institutions must provide HRECs with space, office, staff and infrastructure to enable them do their work • Institutions shall provide coverage of HREC members from liability 53
Highlights
• • • HRECs shall apply for initial registration and re registration every 2 years • Submission of materials required, including copies of financial statement, evidence that previous commitments by the institution are met and evidence of continuing training of HREC members • Limitation of HREC’s authority to the bounds of proposing authority • Institutions that have no HREC can set up collaborative agreements with registered HRECs HREC membership must always include a lawyer Institutions can have more than 1 HREC 54
Highlights
• • • • • • Provision of liability coverage for members of HRECs HRECs shall include at least 1 lay person HREC members are bound by a perpetual code of confidentiality HRECs shall have continuing oversight of research – a review shall be conducted at least once a year or during the life of the study whichever is shorter NHREC shall categorize HRECs and define limits of activities Clear processes for expedited review, exception and amendment 55
Highlights
• • • • • • HRECs can co-opt members Encourages researchers to be invited to HREC meetings Sets time limits for decision on research applications – 90 days All records relating decision must be kept for at least 10 years Clear process for suspension, revision of suspension and termination of research Clear adjudicatory mechanism to NHREC 56
Highlights
• Review of multi-institutional research • Procedure of 3 or fewer and more than 3 collaborating sites • Options for research review • Opportunity for central research review • Requirement for sharing ethics review from different ethics committees • Requirement for Materials Transfer Agreements, Benefits sharing, IPP, patent and other tangible and intangible benefits’ sharing 57
Highlights
• • • Only applicant(s) with qualification(s) and background sufficient to serve as principal investigator(s) and based in an institution in Nigeria that is capable of carrying out the research shall apply for review of research HREC may adopt the result of review by another HREC rather than conduct a fresh review NHREC may review research • Nationwide research or more than 3 sites • Research referred to NHREC from HREC • There is no HREC in an institution and no collaborative agreement with an institution that has one 58
Highlights
• • • NHREC review of research • Mandating review by a HREC anywhere in the country as the HREC of record • Constituting an
ad hoc
HREC • Constituting itself into a HREC • Oversight will still be provided by local HRECs Incorporation of ethics guidelines in code for guidance during research review Ethics guidelines goes beyond the “4” principles to accommodate recent advances in ethics and emphasizing the role of community, trust, truth telling, GCP and GLP 59
Highlights
• • • • • • • HREC may charge fees Informed consent documents must be legible and not more than 8 pages long All consent activity must be documented HREC must organize training for members and the community of the proposing authority HRECs may offer consultation services to researchers HRECs will demand that researchers submit evidence of recent training in research ethics NHREC will exercise oversight functions on HRECs 60
Highlights
• • HRECs have disciplinary and compliance powers • Include suspension of research • Termination of research • Recommendation to NHREC for disciplinary action NHREC disciplinary powers • Debarment of researchers • Imposition of disciplinary measures • Report to police • Report to other ethics regulatory agencies in case of international collaborative research 61
Current activities
• • • • Code has been released and can be found at http://nhrec.net
where you have the opportunity to either read or download it Comments can be sent to [email protected]
Sub-codes for children, pregnant women, prisoners, people living with AIDS, and others are in development Standard Operating Procedures (SOPs), prototype MTA, consent forms etc are available on NHREC website 62
NHREC website
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