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Presentation
at the Workshop on Research Ethics held at Jazan University 14-15th May 2012 by Professor Omar Hasan Kasule Sr.
MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Chairman Institutional Review Board
and Department of Bioethics King Fahad
Medical City Riyadh EM: omarkasule@yahoo.com,
WEB: www.omarkasule-tib.blogspot.com
1.0 EARLY HUMAN EXPERIMENTS
Experiments on humans are as old as history.
Early humans experimented with several plants and by trial and error found some
to be useful as medicines and others to be poisonous. Such trials have
continued throughout human history giving rise to a corpus of traditional
medicine. Many medical systems including tibb nabawi represent empirical
knowledge accumulated over time by many informal and often un recognized
medical experiments. These early experiments were not planned in a systematic
way neither were they documented. Planned medical experiments are quite recent.
Galen is credited with being the founder of experimental medicine before 200
CE. In 1747 CE James Lind found out by experimentation that lemon juice
prevented scurvy. Dr Edward Jenner found in 1798 that material from cowpox
lesions prevented small pox. In 1914 Goldberger discovered the prevention of
pellagra. Experiments were sometimes carried out on whole communities such as
the study of vitamin C in the prevention of the common cold, the Salk and HBV
vaccine trials, the multiple risk factor intervention trial (MRFIT) against
cardiac disease, and fluoridation of community water supplies to prevent dental
caries. Some trials are therapeutic such as the randomized study of aspirin
myocardial infarction study. One of the earliest clinical trials was the use of
streptomycin in the treatment of tuberculosis in 1948. Preventive studies such
as the women’s health study in which vitamin C and low dose aspirin were given
to prevent cancer and cardiovascular disease or the use of alpha-tocopherol and
beta-carotene to prevent lung cancer among smokers. Modern sophisticated
research on humans in search of new drugs is an outgrowth of these early
efforts. Modern medicine would not have progressed as it has without some form of experimentation on humans. If a
new drug is to be used on humans, it has to be tried on humans because animal
experiments are not adequate and may not be relevant to humans.
2.0 HUMAN TRANSGRESSION
Humans are wont to transgress against
other humans. The angels questioned the creation of Adam on the basis of human
aggression and spilling of blood[i].
The son of Adam committed the first homicide in human history[ii].
Daughters were buried alive in pre-Islamic Arabia[iii].
Dhu Nuwaas a Jewish King in Yaman persecuted believers by burning them alive[iv].
The Pharaohs carried out a systematic genocide of the Israelites[v].
King Nimrod carried out an experiment to prove he could give and take life by
ordering killing of one prisoner while sparing another one[vi].
King Muteesa I tested the efficacy of a new gun presented to him by ordering
its use on any person outside the palace. There is great suspicion that nations
that manufacture weapons encourage some low level conflicts for the purposes of
testing their new weapons. Human transgression has also manifested in several
forms of human experimentation. The search for new cures using human
experimentation showed extreme forms of human transgression and disrespect for
human life in the Nazi and Japanese inhumane medical experiments on prisoners
in the second world war. These were extreme but not isolated incidents. Despite
the horror of the details revealed at the Nuremberg trials of Nazi medical
experiments, unethical medical experiments without informing the subjects or
getting their consent continued after the second world war. In the 1950s LSD
and other drugs were used in experiments to discover drugs that could control
human behavior. In 1953 a CIA employee used in an experiment on LSD without
consent developed psychiatric symptoms and committed suicide. In 1953 Harold
Blauer, a hospitalized psychiatric patient in a research project funded by the
US Army, died after injection of mescaline. In the period 1940s to 1960s the US
Atomic Energy Commission conducted experiments on unsuspecting subjects
including children to study the effect atomic weapon irradiation. In 1954-56
elderly patients at the Brooklyn Jewish Chronic Diseases Hospital had cancer
cells injected directly into their veins. In the period 1932-1972 under the
Tuskegee Syphilis Study, 400 Black American men with syphilis were deprived of
any treatment in a study of the natural history of syphilis without their
informed consent. In 1946-1956 retarded teenage boys in Massachusetts had
radioactive iron and calcium put in their breakfast cereals. In the early 1950s
in Massachusetts pregnant women had radioactive iron injections to study fetal
circulation. Some of the pregnant women involved in the thalidomide disaster
were not informed of the experimental nature of the drug. Violations continued
into the post 911 era[vii].
Violation of basic ethics in
research prompted issuing of ethical codes starting with the Nuremberg code and
followed by several others[viii].
The major ethical documents on research were: Nuremberg Code, the Declaration
of Helsinki, Henry Beecher's landmark paper, the Belmont Report, the U.S.
Common Rule, the Guideline for Good Clinical Practice, and the National
Bioethics Advisory Commission's report on research protections for the mentally
ill.[ix].
Australia has the National Statement on Ethical Conduct in Human Research and
the Australian Code for the Responsible Conduct of Research[x]. The concept of minimal risk[xi].
Special codes were promulgated to
protect research subjects vulnerable to coercion.. The horrors of Nuremberg
haunt researchers on prisoners who are vulnerable to exploitation yet there are
conditions that can only be researched among prisoners so a balance needs to be
established between protection and advance of science and knowledge[xii].
Aboriginal people may have to be considered differently in research ethics as
in Canada[xiii].
The poor people in developing countries Informed consent not taken in
developing countries[xiv].
Perspectives of research different in developing countries[xv].
3.0 NUREMBER CODE 1946
Twenty-five physicians were charged at
Nuremberg after World War II for Nazi inhuman experimentation on humans. Seven
were acquitted, 9 were imprisoned, and 9 were sentenced to death. The Nuremberg
code was laid down in 1946 in response to the criminal Nazi experiments on
humans during the war. Two military physicians developed the tenitems of the
code[xvi].
The main provisions of the code were: (a) Voluntary informed consent (b) No
random or unnecessary experiments (c) Animal experiments and survey of disease
natural history before subjecting humans to similar experiments (d) Avoiding
unnecessary physical and mental suffering (e) The researchers must be
scientifically qualified (f) subjects can withdraw at any time (g) the
investigation is stopped if the patient is in danger. There was however no
mention of experiments involving children. Children have been used in
experients starting with first trial of cowpox vaccine, the first human trial
of rabies vaccine, and the first treatment of Listerian wound antisepsis [xvii] The Nuremberg code is considered the mother
of all research ethical codes over the past 60 years[xviii].
Its provisions about informed consent were not observed in Bangladesh[xix].
4.0 HELSINKI DECLARATION
The World Medical Association drew up the
Helsinki Declaration, incorporating the Nuremberg code, in 1964. The latest
version (1996) was approved by The 48th Assembly of the World
Medical Association held in South Africa in 1996 approved the latest version.
The code is divided into three sections: Introduction, Basic principles,
clinical research, and non-clinical research.
The introduction asserted that the primary duty
of the physician was to act in the best interests of the patient. It pointed
out the role of research in advancing knowledge of diagnosis, therapy, or
prophylaxis with the caution that such research always carries a risk to the
subject. A distinction was made between clinical research involving search for
new treatment and diagnostic modalities and purely scientific research that had
no direct benefit to the patient. This distinction is however questionable
because clinical research in based on prior basic scientific research. The code
also alluded to environmental concerns and the welfare of animals used in
research.
The following basic principles were included in
the code. Research on human subjects must conform to generally accepted scientific
principles and must be preceded by laboratory and animal experiments. A
competent and independent committee must approve the research protocol, setting
out all details of the research and a statement of adherence to the Helsinki
declaration. The research is carried out by qualified researchers and
under the supervision of a medically qualified person who must assume full
responsibility for the welfare of the research subjects. The research must be
preceded by careful risk-benefit assessment. The research can be carried
out only if its risks are predictable, the objectives are important when
considered with the potential risks, and the benefits outweigh the risks.
Research subject integrity in the form of privacy, physical, and mental
welfare must be respected. Research subjects are entitled to full disclosure
that covers the aims, methods, and potential hazards of the research before they
give their voluntary informed consent. They should be informed that they
are free to abstain from the study or to withdraw at any stage. Proxy consent
is obtained for the legally incompetent, children or the mentally retarded.
Results of the research will be accepted for publication only if they are
accurate and conform to the principles of the Helsinki Declaration.
The declaration defined and approved clinical
research as medical research combined with medical care. The physician is free
to use a new therapeutic or diagnostic measure that in their judgment has hope
of improving life and alleviating suffering. The potential benefits, hazards,
and discomfort of the new method must be weighed against the best current and
available diagnostic and therapeutic methods. Use of a placebo in a control
group is allowed if no better method is available.
The declaration defined non-clinical biomedical
research as non-therapeutic research involving humans carried out only on
volunteers either healthy volunteers or patient volunteers. In case of patient
volunteers the experimental design should not be related to their illness. The
lead physician in the research team retains responsibility for subject welfare.
The research is terminated as soon as is judged harmful to the research
subjects. In any case the interests of science and society should never take
precedence over the welfare of the research subjects.
The wording of the DOH is not congruent with
principles[xx].
The vaguw wording of the DOH allowed pharmacueritical companies to carry out
placebo controlled trials in Developing countries[xxi].
The DOH is not law and its wording seems not obligatory[xxii].
Differences arose as DOH was translated[xxiii].
5.0 BELMONT REPORT
The US Congress enacted the
National Research Act of 1974 that led to the creation of the National
Commission for Protection of Human Subjects of Biomedical and Behavioral
Research. After many consultations and deliberations the commission issues the
Belmont Report that enunciated 3 fundamental principles for conducting
human-subjects research: respect for persons, beneficence, and justice. The
Office of Human Research Protections oversees Title 45, Part 46 of the Code for
Federal Regulations, which pertains to human-subjects research.[xxiv].
The Belmot report has three principles: beneficence, justice, and respect for
persons [xxv].
Belmont report and children's autonomy in research[xxvi].
Ethical dilemma of enrolling children in phase 1 and phase 2 trials[xxvii].
The Belmont report and the boundary between clinical research and clinical
practice[xxviii].
6.0 US COMMON RULE
Federal Policy for the Protection
of Human Subjects ('Common Rule') published in 1991 was derived from the Belmont Report of 1979 by the National Commission for
the Protection of Human Subjects of Biomedical and Behavioral Research. The
Common rule is codified in separate regulations by various federal agencies.
Besides general protection for all research subjects there are special
provisions for the vulnerable: pregnant women, human fetuses, and neonates;
prisoners; and children. The Common Rule has provisions on the functioning of
IRBs, informed consent, and assurance of compliance.
7.0 FWA
The Federalwide Assurance For The
Protection Of Human Subjects (FWA) of the U. S. Department of Health and Human Services
(HHS) under the Office for Human Research Protections (OHRP) requires that the
following ethical principles should guide all human research: Belmont Report,
Helsinki Declaration, and other relevant international codes. IRBs designated
under the FWA at a minimum will comply with one or more of the following: (a) The
Common Rule; (b) The U.S. Food and Drug Administration regulations at 21 CFR
parts 50 and 56; (c) The May 1, 1996, International Conference on Harmonization
E-6 Guidelines for Good
Clinical Practice, Sections 1 through 4 (d) The 2002 Council for International
Organizations of Medical Sciences International Ethical Guidelines for
Biomedical Research Involving Human Subjects; (e) The 1998 (with 2000, 2002,
and 2005 amendments) Medical Research Council of Canada Tri-Council Policy
Statement on Ethical Conduct for Research Involving Humans; (f) The 2006 Indian
Council of Medical Research Ethical Guidelines for Biomedical Research on Human
Subjects; or (g) Other standard(s) for the protection of human subjects
recognized by U.S. federal departments and agencies which have adopted the U.S.
Federal Policy for the Protection of Human Subjects. The Institution submitting
the FWA has established written procedures for ensuring prompt reporting to the
IRB, appropriate institutional officials, the head of any U.S. federal department
or agency conducting or supporting the research (or designee), and OHRP of any:
1) unanticipated problems involving risks to subjects or others; 2) serious or continuing noncompliance with
the applicable U.S. federal regulations or the requirements or determinations
of the IRB(s); and 3) suspension or termination of IRB approval. The
Institution will ensure that the IRB(s) that reviews research to which the FWA
applies has established written procedures for: 1) conducting IRB initial and
continuing review (not less than once per year), of research, and reporting IRB
findings to the investigator and the Institution; 2) determining which projects
require review more often than annually and which projects need verification
from sources other than the investigator that no material changes have occurred
since the previous IRB review; and 3) ensuring prompt reporting to the IRB of
proposed changes in a research activity, and for ensuring that such changes in approved
research, during the period for which IRB approval has already been given, may
not be initiated without IRB review and
approval, except when necessary to
eliminate apparent immediate hazards to the subjects. Upon request, the Institution will provide a
copy of these written procedures to OHRP or any U.S. federal department or
agency conducting or supporting research to which the FWA applies. The Institution will ensure that each IRB that
it relies upon for review of research to which the FWA applies has meeting
space and sufficient staff to The Institution must renew its FWA every 5 years,
even if no changes have occurred, in order to maintain an active FWA. The
Institution must update its FWA within 90 days after changes occur regarding
the legal name of the Institution, the designation of IRBs, the Human
Protections Administrator, or the Signatory Official. Any renewal or update that is submitted to,
and accepted by, OHRP begins a new 5-year effective period. Failure to renew or update an FWA
appropriately may result in restriction, suspension, or termination of OHRP’s
approval of the Institution’s FWA.
8.0 THE UNESCO
UNIVERSAL DECLARATION ON BIOETHICS
AND HUMAN RIGHTS 2005.
Unesco declaration has been criticized[xxix]
[xxx]
[xxxi]
It is considered unnecessary after the other documents[xxxii].
Will universal human rights subsume ethics?[xxxiii]
9.0 EUROPEAN CONVENTION ON HUMAN RIGHTS AND
BIOMEDICINE 1997
10.0 GCP
11.0 OTHERS
The current International Conference on
Harmonization E-6 Guidelines for Good Clinical Practice (ICH-GCP-E6)
The current Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines for
Biomedical Research Involving Human Subjects
[i] (2:30)
[ii] (KS41
Bukhari K60 B1, Bukhari K87 B2, Bukhari K96 B15, Muslim K28 H27, Ibn Majah K21
B1, Ahmad 1:383, Ahmad 1:430, Ahmad 1:433)
[iii] (81:8)
[iv]
(85:4-8)
[v] (2:40)
[vi] (2:258)
[vii] Account Res. 2010 Mar;17(2):96-113. Unethical
research and the C.I.A. Inspector General Report of 2004: observations implicit
in terms of the common rule. Llanusa-Cestero R. Source La Cesta Consultants, L.L.C., Miami, FL
33157, USA. rllanusa@bellsouth.net Abstract Declassification of documents has given rise
to the allegation that the Central Intelligence Agency may have conducted
unethical research targeting detainee subjects. That allegation is examined
using document analysis and the development of research goals and roles as
defined in the Common Rule. This article sets aside issues as to whether
enhanced interrogation techniques described in the declassified documents rise
to legal definitions of torture. Instead, it presents a post hoc ethics review
raising questions addressed by Institutional Review Boards recommending the
filing of a for-cause noncompliance complaint with the Office for Human
Research Protection against the Central Intelligence Agency.
[viii]
Insight. 2009 Jul-Sep;34(3):14-6. Protecting human subjects in research. Orticio
LP. Source Bascom Palmer Eye Institute, Anne
Bates Leach
Eye Hospital,
Miami, Florida
33136, USA.
Abstract The quest for advancing scientific knowledge through human
experimentations using vulnerable groups is traced back to ancient history,
when Herophilus performed vivisections on prisoners. The
violation of the rights of human subjects through the 20th century led to the
formulation of the Nuremberg Code in 1947 and the Declaration of Helsinki in
1964. In the United States,
the most infamous was the Tuskegee
public health study that resulted in the enactment of the National Research Act
that authorized the creation of the National Commission for the Protection of
Human Subjects in Biomedical and Behavioral Research in 1974. In spite
of existing federal regulations, the system of protecting human subjects is
still flawed. Transparency of conflict of interest, clarity, and strict
adherence to institutional guidelines are critical in safeguarding the rights
and safety of human subjects and the integrity of research. Education on ethics
and emerging complex ethical issues, global awareness, and governmental
cooperation and sanctions are important steps in addressing the inadequacies in
protecting the most vulnerable populations in experimentations worldwide.
Investigators must always remember that the primary safeguards of protecting human
life rest in their hands.
[ix] Schizophr
Bull. 2006 Jan;32(1):69-80. Epub 2005 Sep 28. A summary of important documents in the field of
research ethics. Fischer BA 4th. Source Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland
School of Medicine, P.O. Box 21247, Baltimore,
MD, 21228,
USA. bfisc001@umaryland.edu Abstract Today's
researchers are obligated to conduct their studies ethically. However, it often
seems a daunting task to become familiar with the important ethical codes
required to do so. The purpose of this article is to examine the content of
those ethical documents most relevant to the biomedical researcher. Documents
examined include the Nuremberg Code, the Declaration of
Helsinki, Henry Beecher's landmark paper, the Belmont Report, the U.S. Common
Rule, the Guideline for Good Clinical Practice, and the National Bioethics
Advisory Commission's report on research protections for the mentally ill.
[x] Monash
Bioeth Rev. 2011 Sep;29(4):16.1-7. Research governance and change in research ethics
practices at a major Australian university. Krastev Y, Grimm M, Metcalfe A. Source
University of New
South Wales. Abstract Recent revisions of the National Statement on Ethical Conduct in Human Research and
the Australian Code for the Responsible Conduct of Research put a great
emphasis on research governance. Institutional responsibility for the
governance of the research is not limited only to the ethical review by the Human
Research Ethics Committee (HREC), but also to the accountability for quality,
safety, privacy, risk management and financial management of the research.
Despite the development of proposed research governance frameworks, many
Australian institutions do not have such structures in place and rely
excessively on HRECs to perform administrative functions that are not their
responsibility. In this paper we report on implementation of a research
governance framework at University
of New South Wales which
led to reduced HREC workload and allowed more attention to its core functions.
We present the approach undertaken by the university to separate the ethical
review process by HREC from the research governance. We recommend that with
proper research governance frameworks in place, the role of HRECs and the
institutional responsibility of governance of the research can be defined
clearly.
[xi] J Med
Philos. 2004 Jun;29(3):351-78. Minimal risk as an international ethical standard in
research. Kopelman
LM. Source
Brody School
of Medicine, Greenville, NC 27858-4354,
USA. kopelmanlo@mail.ecu.edu Abstract Classifying
research proposals by risk of harm is fundamental to the approval process and
the most pivotal risk category in most regulations is that of "minimal
risk." If studies have no more than a minimal risk, for example, a nearly
worldwide consensus exists that review boards may sometimes: (1) expedite
review, (2) waive or modify some or all elements of informed consent, or (3)
enroll vulnerable subjects including healthy children, incapacitated persons
and prisoners even if studies do not hold out direct benefits to them. The moral
and social purposes behind this threshold are discussed along with relevant
views from the National Commission, NBAC, NHRPAC, Grimes v. Kennedy Krieger
Institute, The Nuremberg Code, and The WMA's Declaration of Helsinki.
Representative policies from Australia,
Canada, South Africa, the U.S., and CIOMS are reviewed
revealing different understandings of this sorting threshold. Six of nine
frequently cited interpretations of "minimal risk" are untenable. The
"absolute" interpretation of the "routine examination"
standard is defended as best.
[xii] Int J
Prison Health. 2008 Dec;4(4):184-97. Ethics in
research involving prisoners. Pont
J Source Medizinische Universität Wien and Médecins Sans Frontières, Austria.
joerg.pont@meduniwien.ac.at Abstract
Research involving prisoners repeatedly went astray during the last century,
culminating in the cruel medical experiments inside the Nazi concentration
camps that gave rise to the Nuremberg Code. However, prisoners continued to
become victims of scientific exploitation by the rapidly evolving biomedical
research industry. The common roots of these abuses were the flawed philosophy
that the needs of the society outweigh the needs of the individual and the
researchers' view that prisoners are cheap, easy to motivate and stable
research subjects. Prisoners are vulnerable to exploitation and abuse by
research because their freedom for consent can easily be undermined, and
because of learning disabilities, illiteracy and language barriers prevailing
within prisoner populations. Therefore, penal laws of some countries supported
by a number of internationally agreed documents prohibit research involving
prisoners completely. However, prisoners must also be regarded as vulnerable to
the specific health problems in prisons, e.g. transmissible diseases, mental
disorders and suicide - problems that need to be addressed by research
involving prisoners. Additionally, the participation of prisoner patients in
research they directly can benefit from should be provided. Hence, it must be a
common objective to find the right balance between protection from exploitation
and access to research beneficial to prisoners.
[xiii] Can J
Public Health. 2012 Jan-Feb;103(1):19-22. Public health research involving aboriginal peoples:
research ethics board stakeholders' reflections on ethics principles and
research processes. Flicker
S, Worthington
CA. Source Faculty of Environmental Studies, York
University, Toronto, ON.
Abstract OBJECTIVES: The second edition (2010) of the Tri-Council Policy
Statement on Ethical Conduct for Research Involving Humans (TCPS2) prescribes a
set of principles and provisions for engagement with Aboriginal communities.
The objective of this study was to explore research ethics board (REB)
stakeholder perspectives on the principles and processes of reviewing and
conducting public health research with Aboriginal populations and communities. METHOD:
Twenty-four semi-structured qualitative interviews were conducted with REB
staff, chairs, members (academic, community and student), and ethics policy key
informants with knowledge of the ethics review process, including four
Aboriginal participants. Interviews were professionally transcribed verbatim
and thematically analyzed using NVivo 8 qualitative data management software. RESULTS:
Three dominant themes emerged specific to ethical research practices with
Aboriginal communities: 1) the importance of understanding Aboriginal research
as a distinct form of research; 2) the unique nature and complexity of
negotiating community consent; and 3) the importance of trust and
relationship-building in the research process. CONCLUSION: Thematic results
highlight the most prominent issues that REB participants encountered in
reviewing research involving Aboriginal peoples. Continued attention needs to
be paid to acknowledging and respecting issues of diversity in research
involving diverse First Nations, Inuit and Métis peoples. While specific to
Aboriginal peoples, the TCPS2 guidelines also illustrate processes and
practices that may assist in the development of respectful, collaborative
public health research relationships with other historically marginalized
populations.
[xiv] Dev
World Bioeth. 2006 Mar;6(1):33-40. Informed consent and collaborative research:
perspectives from the developing world. Hyder AA, Wali SA. Abstract INTRODUCTION: Informed consent has been recognized as an important
component of research protocols and procedures of disclosure and consent in
collaborative research have been criticized, as they may not be in keeping with
cultural norms of developing countries. This study, which is part of a larger
project funded by the United States National Bioethics Advisory Commission,
explores the opinions of developing country researchers regarding informed
consent in collaborative research. METHODS: A survey of developing country
researchers, involved in human subject research, was conducted by distributing
a questionnaire with 169 questions, which included questions relating to
informed consent. In addition, six focus group discussions, eight in-depth
interviews and 78 responses to open-ended questions in the questionnaire
provided qualitative data. RESULTS: 203 surveys were considered complete and
were included in the analysis. Written consent was not used by nearly 40% of
the researchers in their most recent studies. A large proportion of respondents
recommended that human subject regulations should allow more flexibility in
ways of documenting informed consent. 84% of researchers agreed that a
mechanism to measure understanding should be incorporated in research studies
as part of the process of informed consent. DISCUSSION: This paper is an
empirical step in highlighting the ethical issues concerning disclosure. Health
researchers in developing countries are well aware of the importance of consent
in health research, and equally value the significance of educating human
subjects regarding study protocols and associated risks and benefits. However,
respondents emphasize the need for modifying ethical regulations in
collaborative research.
[xv] J Med
Ethics. 2004 Feb;30(1):68-72. Ethical review of health research: a perspective from
developing country researchers. Hyder AA, Wali SA, Khan AN, Teoh NB, Kass NE, Dawson L. Source
Bloomberg School of
Public Health, Johns Hopkins University,
Baltimore, MD, USA.
ahyder@jhsph.edu Abstract BACKGROUND:
Increasing collaboration between industrialised and developing countries in
human research studies has led to concerns regarding the potential exploitation
of resource deprived countries. This study, commissioned by the former National
Bioethics Advisory Commission of the United States, surveyed developing country
researchers about their concerns and opinions regarding ethical review
processes and the performance of developing country and US international review
boards (IRBs). METHODS: Contact lists from four international organisations
were used to identify and survey 670 health researchers in developing
countries. A questionnaire with 169 questions explored issues of IRB review,
informed consent, and recommendations. RESULTS: The majority of the developing country
researchers were middle aged males who were physicians and were employed by
educational institutions, carrying out research on part time basis. Forty four
percent of the respondents reported that their studies were not reviewed by a
developing country IRB or Ministry of Health and one third of these studies
were funded by the US.
During the review process issues such as the need for local language consent
forms and letters for approval, and confidentiality protection of participants
were raised by US IRBs in significantly higher proportions than by host country
IRBs. CONCLUSION: This survey indicates the need for the ethical review of
collaborative research in both US and host countries. It also reflects a desire
for focused capacity development in supporting ethical review of research.
[xvi] Aviat Space
Environ Med. 2003 Dec;74(12):1297-300. Ethics in human experimentation: the two military
physicians who helped develop the Nuremberg Code. Temme
LA. Source Naval Aerospace Medical Research Laboratory, Pensacola, FL 32508-1046, USA.
temme@namrl.navy.mil Abstract The
Nuremberg Code is generally considered the beginning of modern ethics in human
experimentation. The Code is a list of 10 principles that Judge Walter Beals
included in the judgment he delivered at the close of the Nuremberg Medical
Trial on 19 August 1947. Recently, scholars have studied the origin of the
Code, who wrote it, and why. This is important to military medicine and the
Aerospace Medical Association in particular because many of the defendants
claimed their crimes were experiments in aviation and environmental physiology
conducted under wartime conditions. The chief prosecutor of the Nuremberg
Medical Trial, General Telford Taylor, relied on the guidance of an advisor
provided by the American Medical Association, Andrew C. Ivy, one of the
foremost physiologists of his time. The neurologist, Leo Alexander, then a
colonel in the U.S. Army Reserves, was another medical advisor. Both men were
crucial to the development of Taylor's
courtroom strategy. The material Alexander and Ivy provided was incorporated
verbatim in the section of the judgment that became the Code. Although both men
contributed to the Code, Ivy provided what seems to be the first formulation of
many of these principles during a meeting of Allied medical investigators at
the Pasteur Institute in July 1946. Naval researchers should note that Ivy had
been the Director of the Research Division of the Naval Medical Research
Institute when it was commissioned on October 27, 1942.
[xvii]
Account Res. 2003 Jan-Mar;10(1):1-16. Children as guinea pigs: historical perspective.
Lederer
SE. Source Yale
University, School
of Medicine, 333
Cedar Street, New Haven, CT
06510, USA.
susan.lederer@yale.edu Abstract Experimentation
involving children is not a new phenomenon. Children have been used as research
subjects in a diverse set of experiments, including the trials of new vaccines
and sera, in efforts to understand normal pediatric anatomy and physiology and
in the development of new drugs and procedures. Concern about child participants
in research is also not a new development. For more than a century, critics of
medical research have called attention to the fact that children and other
vulnerable populations--pregnant women, prisoners, the mentally ill--have too
often served as the unwitting and unwilling subjects of medical experiments.
This paper looks at several early cases in which children participated,
including the first trial of cowpox vaccine, the first human trial of rabies
vaccine, and the first treatment of Listerian wound antisepsis. The history of
concern for children, especially institutionalized children, in medical
research is considered along with the development of regulations or guidelines,
including the Declaration of Helsinki (1964).
[xviii] Lancet
Oncol. 2007 Dec;8(12):1139-46. Running an
ethical trial 60 years after the Nuremberg Code. Markman
JR, Markman
M. Source Department of History and Interdisciplinary Centre for Bioethics,
Yale University,
New Haven, CT, USA.
Abstract The Nuremberg Code has served as a foundation
for ethical clinical research since its publication 60 years ago. This
landmark document, developed in response to the horrors of human
experimentation done by Nazi physicians and investigators, focused crucial
attention on the fundamental rights of research participants and on the
responsibilities of investigators. Although the Nuremberg Code has provided an
important framework for discussions on the requirements of ethical clinical
research, and has resulted in the development of other initiatives-eg, the
Declaration of Helsinki and the Belmont Report-designed to ensure the rights
and safety of human beings taking part in medical research, knowledge of both
past events and the current complexity of research suggests further
improvements are necessary in the existing approaches to human clinical
research.
[xix] Bangladesh
Med Res Counc Bull. 2006 Dec;32(3):92-7. Critical evaluation of research articles in relation
to informed consent. Biswas
B, Ahmad
R. Source Deptt. of Transfussion Medicine, Sher-e-Bangla
Medical College
(SBMC), Barisal.
Abstract The concept of research bioethics arose and developed over the last
three decades mainly in response to moral crisis created by rapidly advancing
medical science and technology. Accordingly, reinterpretation of some
fundamental principles of ethics is needed. At the heart of the ethical
principle of respect for person, lies the informed consent process. Nuremberg
Code, Helsinki Declaration of World Medical Association (WMA), Council for
International Organizations of Medical Sciences (CIOMS) Guidelines etc.
demonstrated the importance of informed consent in biomedical research
involving human subjects. This article was planned to evaluate the reflection
of informed consent in the published research articles. Fifty-two articles
published in national and international journals were studied among which
informed consent was found to be taken only in 21(40.4%) occasions and the same
was not taken in 31(59.6%) occasions. Study showed that out of 38 articles
published in national journals, informed consent was taken from only in
12(31.6%) situations, while out of 14 articles published in international
journals, informed consent was taken in 9(64.3%) situations. Out of 36
observational studies, informed consent (both written and verbal) was taken
from only 27.8% cases, whereas out of 16 interventional experiments, informed
consent was taken in 68.8% situations.
[xx] Med
Law. 2006 Jun;25(2):341-54. The declaration of Helsinki 2000: ethical principles
and the dignity of difference. Salako SE. Source
School of Law, Liverpool
John Moores
University, Liverpool, United Kingdom.
Abstract The first detailed regulations about nontherapeutic research were
promulgated by the Prussian Government in 1900.
In 1947, the Nuremberg Code was decreed. Since then, the Declaration of
Helsinki (DOH) was adopted in 1964 and has been revised five times. The object
of this article is to evaluate the 2000 Revision of the DOH and discuss three
problems of concern. These problems are: (1) If, unlike its predecessors, the
DOH (2000) has recast itself as a minimum set of international standards
'binding' on physicians worldwide, from where does it derive its authority? (2)
The wording of the DOH is incongruent with the underlying ethical principles.
(3) The projection of the DOH into the realms of social justice raises the
issue of human dignity. Finally, the feasibility or desirability of a theory of
justice privileging human dignity as one of its guiding principles and the
future of the DOH are examined.
[xxi] Indian
J Med Ethics. 2012 Jan-Mar;9(1):13-8. International collaborative trials, placebo controls
and The Declaration of Helsinki: need for clarification in paragraph 32.
Malik
AY, Ghafoor
F. Source Ethox Centre, Department
of Public Health, University of Oxford, Oxford,
OX3 7LF United
Kingdom. aisha.malik@ethox.ox.ac.uk Abstract
Inequities in socio-economic and healthcare systems between developed and
developing countries have been thrown into sharp relief by globalisation. At
the same time, pharmaceutical companies have started conducting clinical trials
in developing countries in order to reduce their costs substantially. Together,
these two developments create ethical challenges for sponsors and researchers
of these trials. One such challenge is that of placebo-controlled trials
(PCTs). In this paper we analyse Paragraph 32 of the Declaration of Helsinki
referring to PCTs, identifying ambiguities in the wording, and then examine
three arguments presented by sponsors of PCTs in developing countries, in
defence of such trials. These arguments are: (i) a placebo control provides a
definitive answer, and is therefore methodologically superior; (ii)
placebo-controlled trials are ethical because they serve the principle of
utility, and (iii) interpreting the "best current proven
intervention" as the local standard of care allows PCTs to be conducted,
if the local standard of care is "no treatment". We argue that PCTs
are not methodologically superior; nor are they ethically defensible. Other
trial designs conforming to the ethics of research are feasible; the reason for
conducting PCTs is expediency. We further propose that, given the global
applicability of the Declaration of Helsinki, it is imperative to remove the
ambiguities in Paragraph 32. In the context of collaborative trials, when a
treatment exists, conducting PCTs is ethically unacceptable, irrespective of
the geographic location of the trial. Universal standards ought to be applied
universally.
[xxii] Med
Law. 2010 Dec;29(4):565-91. Interpreting the declaration of Helsinki (2008):
"must", "should" and different kinds of obligation.
Schmidt H, Mehring S, McMillan J. Source LSE
Health, Nuffield Council on Bioethics, London,
UK. h.t.schmidt@lse.ac.uk Abstract The
Declaration of Helsinki is widely regarded as the preeminent code of research
ethics. Revised six times since 1964, the versions differ in their substantive
requirements, and also in the way that obligations are expressed, especially
regarding the use of the prescriptors "should" and "must".
The 2000 version contained roughly two-thirds "should" versus
one-third " must". But this ratio was inversed in the final 2008
version--although in its penultimate draft practically all occurrences of
"must" had been replaced with "should". We consider and
analyze the significance of these variations for policy and practice. We argue
that the Declaration can plausibly be viewed as 'soft law'. In interpreting it
in legislative and jurisdictional contexts the terms "should" and
"must" cannot be seen as synonymous. Even if the soft-law claim is
rejected, and the Declaration is viewed as providing ethical guidance only, the
question of how to interpret "should" and "must" remains.
We explore three possible interpretations: categorical versus hypothetical
requirements; perfect versus imperfect obligations; and aspiration versus
obligation. We conclude that the most plausible way of understanding the
distinction is in relation to the strength of the categorical obligations which
the Declaration seeks to set out.
[xxiii] J
Med Ethics. 2007 Sep;33(9):545-8. The three official language versions of the
Declaration of Helsinki: what's lost in translation? Carlson RV, van Ginneken NH, Pettigrew LM, Davies A, Boyd KM, Webb DJ. Source Archie Duncan Fellow in Medical Ethics, Medical Teaching Organisation, University of Edinburgh,
Chancellor's Building, Edinburgh
EH16 4SB, UK. rcarlson@ed.ac.uk Abstract BACKGROUND: The
Declaration of Helsinki, the World Medical Association's (WMA's) statement of
ethical guidelines regarding medical research, is published in the three
official languages of the WMA: English, French and Spanish. METHODS: A detailed
comparison of the three official language versions was carried out to determine
ways in which they differed and ways in which the wording of the three versions
might illuminate the interpretation of the document. RESULTS: There were many
minor linguistic differences between the three versions. However, in paragraphs
1, 6, 29, 30 and in the note of clarification to paragraph 29, there were
differences that could be considered potentially significant in their ethical
relevance. INTERPRETATION: Given the global status of the Declaration of
Helsinki and the fact that it is translated from its official versions into
many other languages for application to the ethical conduct of research, the
differences identified are of concern. It would be best if such differences
could be eliminated but, at the very least, a commentary to explain any
differences that are unavoidable on the basis of language or culture should
accompany the Declaration of Helsinki. This evidence further strengthens the
case for international surveillance of medical research ethics as has been
proposed by the WMA.
[xxiv] Respir
Care. 2008 Oct;53(10):1325-9. The historical,
ethical, and legal background of human-subjects research. Rice
TW. Source Division of Allergy, Pulmonary, and Critical Care Medicine,
T-1218 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2650,
USA. todd.rice@vanderbilt.edu Abstract
The current system of human-subject-research oversight and protections has
developed over the last 5 decades. The principles of conducting human research
were first developed as the Nuremberg
code to try Nazi war criminals. The 3 basic elements of the Nuremberg Code
(voluntary informed consent, favorable risk/benefit analysis, and right to
withdraw without repercussions) became the foundation for subsequent ethical
codes and research regulations. In 1964 the World Medical Association released
the Declaration of Helsinki, which built on the principles of the Nuremberg
Code. Numerous research improprieties between 1950 and 1974 in the United States
prompted Congressional deliberations about human-subject-research oversight.
Congress's first legislation to protect the rights and welfare of human
subjects was the National Research Act of 1974, which
created the National Commission for Protection of Human Subjects of Biomedical
and Behavioral Research, which issued the Belmont Report. The Belmont Report
stated 3 fundamental principles for conducting human-subjects research: respect
for persons, beneficence, and justice. The Office of Human Research Protections
oversees Title 45, Part 46 of the Code for Federal Regulations, which pertains
to human-subjects research. That office indirectly oversees
human-subjects research through local institutional review boards (IRB). Since
their inception, the principles of conducting human research, IRBs, and the
Code for Federal Regulations have all advanced substantially. This paper
describes the history and current status of human-subjects-research regulations
[xxv] Dimens
Crit Care Nurs. 2010 Jul-Aug;29(4):173-4. A brief review of the Belmont report. Sims
JM. Source JennyARNP@yahoo.com Abstract
he Belmont Report is one of the leading works concerning ethics and health care
research. Its primary purpose is to protect subjects and participants in
clinical trials or research studies. This report consists of 3 principles: beneficence, justice, and respect for persons. This
article reviews the Belmont Report and these 3 principles as well as its
importance to nurse researchers.
[xxvi]
J Hist Med Allied Sci. 2011 Jan;66(1):82-115. Epub 2010 Apr 23. The limits of autonomy: the Belmont Report and the
history of childhood. Carroll TW, Gutmann MP. Source Department of History, Cornell
University, 450 McGraw Hall, Ithaca, New York
14853, USA.
twc57@cornell.edu Abstract This article
examines the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research recommendations on children as research
subjects in the context of the history of American childhood. The Commission's
deliberations took place during the post-World War II period of rapid changes
in understandings of childhood and adolescence, brought on in part by school
children's highly visible roles as risk-taking protagonists in the polio
vaccine trials and the civil rights movement; by the children's rights movement
and court decisions granting children and adolescents greater autonomy in
divorce cases and in delinquency and mental health hearings, among other
rights; and finally by a renewed movement for child protection led by parents
of disabled children and by polio survivors themselves. The National
Commission's final recommendations emphasized the need for parents to approve,
for children above age seven to assent to research, and for children in special
care (either medical, psychiatric, or because they were orphans or had
committed juvenile crimes) generally to be subjects of research only if there
was some direct connection between the reasons for their special care and the
objectives of the research. Ultimately, in these recommendations, the National
Commission charted a middle ground between the children's rights movement,
which advocated enhanced self-determination for children, and the disability
rights movement, which urged greater protection for children. Ethical dilemma
of emrolling children in phase 1 and phase 2 trials.
[xxvii] J Pediatr Oncol Nurs. 2009
Mar-Apr;26(2):107-12. Epub 2009 Feb 3. Ethical considerations in pediatric oncology phase I
clinical trials according to The Belmont Report. Haylett
WJ. Source Drexel
University's Clinical Trials Research
program, USA.
wjh34@drexel.edu Abstract Whether to
suggest enrollment of pediatric oncology patients with advanced or refractory
disease into a Phase I clinical trial may present a significant ethical dilemma
for health care professionals. Phase I trials are experimental and
unpredictable by nature, yet health care professionals must ensure the trial's
therapeutic intent as well as address the many vulnerabilities of the child
with terminal cancer. After reviewing the role and phases of clinical research
in pediatric oncology, this article discusses ethical considerations in Phase I
clinical trials according to The Belmont Report: Ethical Principles and
Guidelines for the Protection of Human Subjects in Research and discusses
specific applications of these key ethical principles.
[xxviii] Theor
Med Bioeth. 2012 Feb;33(1):45-56. The historical foundations of the research-practice
distinction in bioethics. Beauchamp
TL, Saghai
Y. Source Kennedy Institute of Ethics, Georgetown
University, Washington, DC 20057,
USA. beauchat@georgetown.edu Abstract The
distinction between clinical research and clinical practice directs how we
partition medicine and biomedical science. Reasons for a sharp distinction date
historically to the work of the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research, especially to its analysis of
the "boundaries" between research and practice in the Belmont Report
(1978). Belmont
presents a segregation model of the research-practice distinction, according to
which research and practice form conceptually exclusive sets of activities and
interventions. This model is still the standard in federal regulations today.
However, the Commission's deliberations and conclusions about the boundaries
are more complicated, nuanced, and instructive than has generally been
appreciated. The National Commission did not conclude that practice needs no
oversight comparable to the regulation of research. It debated the matter and
inclined to the view that the oversight of practice needed to be upgraded,
though the Commission stopped short of proposing new regulations for its
oversight, largely for prudential political reasons.
[xxix] J
Med Philos. 2009 Jun;34(3):195-203. Epub 2009 Apr 22. The UNESCO Declaration
on Bioethics and Human Rights: a canon for the
ages?
Trotter G. Source Department of Health Care
Ethics, Center for Health Care Ethics, Saint Louis
University, 221
North Grand Boulevard, St. Louis, MO 63103-2006,
USA. trotterc@slu.edu Abstract The UNESCO Universal Declaration on Bioethics
and Human Rights of 2005 purports to articulate universal norms for bioethics. However, this document has met with mixed
reviews. Some deny that the elaboration of universal bioethics
norms is needed; some deny that UNESCO has the
expertise or authority to articulate such norms; some regard the content of the
UNESCO document as too vague or general to be
useful; and some regard the document as a cog in the effort of like-minded
cosmopolitans to codify their particular moral intuitions in international law.
This issue examines the potential merits and pitfalls of the Universal Declaration on Bioethics
and Human Rights.
[xxx] Med Law.
2008 Dec;27(4):805-23. The
UNESCO Universal Declaration
on Bioethics and Human Rights: protecting future
generations and the quest for a global consensus. Salako
SE. Source School of Law, Liverpool. John Moores University, Liverpool,
United Kingdom.
Abstract Since the coining of the term 'ectogenesis' by Haldane in 1924, we
have witnessed sensational biotechnological triumphs such as in vitro
fertilisation, the cloning of "Dolly" the sheep, and the publication
of the human genetic code. These triumphs mix benefits with portents in one
seamless package. The object of this article is to assess critically the
Universal Declaration on Bioethics
and Human Rights. It is argued that the Declaration
is not a suitable international instrument for regulating
[xxxi] J Med Ethics. 2007 Mar;33(3):150-4. Global bioethics at UNESCO:
in defence of the Universal Declaration on Bioethics and Human Rights.
Andorno R. Source Ethics Centre, University of Zurich,
Zollikerstrasse 115, 8008 Zurich,
Switzerland. andorno@ethik.unizh.ch
Abstract he Universal Declaration
on Bioethics and Human Rights adopted by the
United Nations Educational, Scientific, and Cultural Organisation (UNESCO) on 19 October 2005 is an important step in the
search for global minimum standards in biomedical research and clinical
practice. As a member of UNESCO International Bioethics Committee, I participated in the drafting of
this document. Drawing on this experience, the principal features of the Declaration are outlined, before responding to two
general charges that have been levelled at UNESCO's
bioethical activities and at this particular document, are outlined. One
criticism is to the effect that UNESCO is
exceeding its mandate by drafting such bioethical instruments--in particular,
the charge is that it is trespassing on a topic that lies in the responsibility
of the World Health Organization. The second criticism is that UNESCO's reliance on international human rights norms is
inappropriate.
[xxxii] Health Care Anal. 2008 Mar;16(1):39-51.
Epub 2007 Jun 28. The UNESCO Universal Declaration on Bioethics
and Human Rights: perspectives from Kenya and South Africa. Langlois
A. Source Department of Development Policy and Practice, Faculty of
Technology, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK. a.langlois@open.ac.uk Abstract In
October 2005, UNESCO (the United Nations
Educational, Scientific and Cultural Organization) adopted the Universal Declaration on Bioethics
and Human Rights. This was the culmination of nearly 2 years of deliberations
and negotiations. As a non-binding instrument, the declaration
must be incorporated by UNESCO's member states
into their national laws, regulations or policies in order to take effect.
Based on documentary evidence and data from interviews, this paper compares the
declaration's universal principles with national bioethics guidelines and practice in Kenya and South Africa. It concentrates on
areas of particular relevance to developing countries, such as protection of
vulnerable persons and social responsibility. The comparison demonstrates the
need for universal principles to be contextualised before they can be applied
in a meaningful sense at national level. The paper also assesses the 'added
value' of the declaration in terms of biomedical
research ethics, given that there are already well-established international
instruments on bioethics, namely the World Medical
Association Declaration of Helsinki and the CIOMS
(Council for International Organizations of Medical Sciences) guidelines on
biomedical research. It may be that the added value lies as much in the
follow-up capacity building activities being initiated by UNESCO as in the document itself.
[xxxiii] J Med Ethics. 2005 Mar;31(3):173-8. Will international human rights subsume medical ethics? Intersections
in the UNESCO Universal Bioethics
Declaration. Faunce
TA. Source Law Faculty, Australian
National University,
Canberra ACT 0200, Australia. Thomas.Faunce@anu.edu.au Abstract The
International Bioethics Committee (IBC) of the
United Nations Educational, Scientific and Cultural Organisation (UNESCO) is currently drafting a Universal Bioethics Declaration
("the declaration"). The content and
even the name of the declaration has yet to be
finalized, but it is expected to range widely over human and non-human bioethics. It appears likely to include many articles
directly related to medical ethics. The declaration
may well evolve, like the Universal Declaration of
Human Rights, into a component of international customary law, or be the
precursor to an International Convention on Bioethics.
This article discusses whether this process will facilitate bioethics and, in particular, medical ethics, being
subsumed by the normative system of international human rights.