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International
Ethical Guidelines for Biomedical Research Involving Human
Subjects
Prepared by the Council for
International Organizations of Medical Sciences (CIOMS) in
collaboration with the World Health Organization (WHO)
CIOMS
Geneva
2002
CONTENTS
ACKNOWLEDGEMENTS
BACKGROUND
INTRODUCTION
INTERNATIONAL INSTRUMENTS AND GUIDELINES
GENERAL ETHICAL PRINCIPLES
PREAMBLE
THE GUIDELINES
Ethical justification and scientific validity of
biomedical research involving human subjects
Ethical review
Ethical review committees
Ethical review of externally sponsored research
Informed consent
Individual informed consent
Obtaining informed consent: Essential
information for prospective research subjects
Obtaining informed consent: Obligations of sponsors and
investigators
Inducement to participate
Benefits and risks of study participation
Special limitations on risk when research involves
individuals who are not capable of giving informed consent
* *
* * *
Research in populations and communities with limited resources
* *
* * *
Choice of control in clinical trials
Vulnerable groups
Equitable distribution of burdens and benefits in the selection of
groups of subjects in research
Research involving vulnerable persons
Research involving children
Research involving individuals who by reason of mental or
behavioural disorders are not capable of giving adequately
informed consent
Women as research participants
Women as research participants
Pregnant women as research participants
* * * * *
Safeguarding
confidentiality
Right of injured subjects to treatment and compensation
Strengthening capacity for ethical and scientific review
and biomedical research
Ethical obligation of external sponsors to provide health-care
services
Appendix 1: Items to be included in a protocol (or associated
documents) for biomedical
research involving human subjects.
Appendix 2: The Declaration of Helsinki
Appendix 3: The phases of clinical trials of vaccines and drugs
ACKNOWLEDGEMENTS
The Council for International Organizations of Medical Sciences (CIOMS)
acknowledges the substantial financial contribution of the Joint
United Nations Programme on HIV/AIDS (UNAIDS) to the preparation
of the 2002 International Ethical Guidelines for
Biomedical Research Involving Human Subjects. The World Health
Organization in Geneva contributed generously also through the
departments of Reproductive Health and Research, Essential Drugs
and Medicines Policy, Vaccines and Biologicals, and
HIV/AIDS/Sexually Transmitted Infections, as well as the Special
Programme for Research and Training in Tropical Diseases. CIOMS
was at all times free to avail of the services and facilities of
WHO.
CIOMS acknowledges also with much appreciation the financial
support to the project from the Government of Finland, the
Government of Switzerland, the Swiss Academy of Medical Sciences,
the Fogarty International Center at the National Institutes
of Health, USA, and the Medical Research Council of the United
Kingdom.
A number of institutions and organizations made valuable
contributions by making their experts available at no cost to
CIOMS for the three meetings held in relation to the revision
project. This has been highly appreciated.
The task of finalizing the various drafts was in the hands of
Professor Robert J. Levine, who served as consultant to the
project and chair of the steering committee, and whose profound
knowledge and understanding of the field is remarkable. He was
ably assisted by Dr James Gallagher of the CIOMS secretariat, who
managed the electronic discussion and endeavoured to accommodate
or reflect in the text the numerous comments received. He also
edited the final text. Special mention must be made of the
informal drafting group set up to bring the influence of various
cultures to bear on the process. The group, with two members of
the CIOMS secretariat, met for five days in New York in January
2001 and continued for several months to interact electronically
with one another and with the secretariat to prepare the third
draft, posted on the CIOMS website in June 2001: Fernando Lolas
Stepke (chair), John Bryant, Leonardo de Castro, Robert Levine,
Ruth Macklin, and Godfrey Tangwa; the group continued from October
2001, together with Florencia Luna and Rodolfo Saracci, to
cooperate in preparing the fourth draft. The contribution of this
group was invaluable.
The interest and comments of the many organizations and
individuals who responded to the several drafts of the guidelines
posted on the CIOMS website or otherwise made available are
gratefully acknowledged (Appendix 6)
At CIOMS, Sev Fluss was at all times ready and resourceful when
consulted, with advice and constructive comment, and Mrs Kathryn
Chalaby-Amsler responded most competently to the sometimes
considerable demands made on her administrative and secretarial
skills.
BACKGROUND
The Council for International Organizations of Medical Sciences (CIOMS)
is an international nongovernmental organization in official
relations with the World Health Organization (WHO). It was founded
under the auspices of WHO and the United Nations Educational,
Scientific and Cultural and Organization (UNESCO) in 1949 with
among its mandates that of maintaining collaborative relations
with the United Nations and its specialized agencies, particularly
with UNESCO and WHO.
CIOMS, in association with WHO, undertook its work on ethics in
relation to biomedical research in the late 1970s. At that time,
newly independent WHO Member States were setting up health-care
systems. WHO was not then in a position to promote ethics as an
aspect of health care or research. It was thus that CIOMS set out,
in cooperation with WHO, to prepare guidelines " to indicate how
the ethical principles that should guide the conduct of biomedical
research involving human subjects, as set forth in the Declaration
of Helsinki, could be effectively applied, particularly in
developing countries, given their socioeconomic circumstances,
laws and regulations, and executive and administrative
arrangements". The World Medical Association had issued the
original Declaration of Helsinki in 1964 and an amended version in
1975. The outcome of the CIOMS/WHO undertaking was, in 1982,
Proposed International Ethical Guidelines for Biomedical
Research Involving Human Subjects.
The period that followed saw the outbreak of the HIV/AIDS pandemic
and proposals to undertake large-scale trials of vaccine and
treatment drugs for the condition. These raised new ethical issues
that had not been considered in the preparation of Proposed
Guidelines. There were other factors also – rapid advances in
medicine and biotechnology, changing research practices such as
multinational field trials, experimentation involving vulnerable
population groups, and also a changing view, in rich and poor
countries, that research involving human subjects was largely
beneficial and not threatening. The Declaration of Helsinki
was revised twice in the 1980s – in 1983 and 1989. It was timely
to revise and update the 1982 guidelines, and CIOMS, with the
cooperation of WHO and its Global Programme on AIDS, undertook the
task. The outcome was the issuing of two sets of
guidelines: in 1991, International Guidelines for Ethical
Review of Epidemiological Studies; and, in 1993,
International Ethical Guidelines for Biomedical Research
Involving Human Subjects.
After 1993, ethical issues arose for which the CIOMS Guidelines
had no specific provision. They related mainly to controlled
clinical trials, with external sponsors and investigators, carried
out in low-resource countries and to the use of comparators other
than an established effective intervention. The issue in question
was the perceived need in those countries for low-cost,
technologically appropriate, public-health solutions, and in
particular for HIV/AIDS treatment drugs or vaccines that poorer
countries could afford. Commentators took opposing sides on this
issue. One advocated, for low-resource countries, trials of
interventions that, while they might be less effective than the
treatment available in the better-off countries, would be less
expensive. All research efforts for public solutions appropriate
to developing countries should not be rejected as unethical, they
claimed. The research context should be considered. Local
decision-making should be the norm. Paternalism on the part of the
richer countries towards poorer countries should be avoided. The
challenge was to encourage research for local solutions to the
burden of disease in much of the world, while providing clear
guidance on protecting against exploitation of vulnerable
communities and individuals.
The other side argued that such trials constituted, or risked
constituting, exploitation of poor countries by rich countries and
were inherently unethical. Economic factors should not influence
ethical considerations. It was within the capacity of rich
countries or the pharmaceutical industry to make established
effective treatment available for comparator purposes. Certain
low-resource countries had already made available from their own
resources established effective treatment for their HIV/AIDS
patients.
This conflict complicated the revision and updating of the 1993
Guidelines. Ultimately, it became clear that the conflicting views
could not be reconciled, though the proponents of the former view
claimed that the new guidelines had built in effective safeguards
against exploitation. The commentary to the Guideline concerned
(11) recognizes the unresolved, or unresolvable, conflict.
The revision/updating of the 1993 Guidelines began in December
1998, and a first draft prepared by the CIOMS consultant for the
project was reviewed by the project steering committee, which met
in May 1999. The committee proposed amendments and listed topics
on which new or revised guidelines were indicated; it recommended
papers to be commissioned on the topics, as well as authors and
commentators, for presentation and discussion at a CIOMS interim
consultation. It was considered that an interim consultation
meeting, of members of the steering committee together with the
authors of commissioned papers and designated commentators,
followed by further redrafting and electronic distribution and
feedback, would better serve the purpose of the project than the
process originally envisaged, which had been to complete the
revision in one further step. The consultation was accordingly
organized for March 2000, in Geneva.
At the consultation, progress on the revision was reported and
contentious matters reviewed. Eight commissioned papers previously
distributed were presented, commented upon, and discussed.
The work of the consultation continued with ad hoc electronic
working groups over the following several weeks, and the outcome
was made available for the preparation of the third draft. The
material commissioned for the consultation was made the subject of
a CIOMS publication: Biomedical Research Ethics: Updating
International Guidelines. A Consultation (December 2000).
An informal redrafting group of eight, from Africa, Asia, Latin
America, the United States and the CIOMS secretariat met in New
York City in January 2001, and subsequently interacted
electronically with one another and with the CIOMS secretariat. A
revised draft was posted on the CIOMS website in June 2001 and
otherwise widely distributed. Many organizations and individuals
commented, some extensively, some critically. Views on certain
positions, notably on placebo-controlled trials, were
contradictory. For the subsequent revision two members were added
to the redrafting group, from Europe and Latin America. The
consequent draft was posted on the website in January 2002 in
preparation for the CIOMS Conference in February/ March 2002
The CIOMS Conference was convened to discuss and, as far as
possible, endorse a final draft to be submitted for final approval
to the CIOMS Executive Committee. Besides representation of member
organizations of CIOMS, participants included experts in ethics
and research from all continents. They reviewed the draft
guidelines seriatim and suggested modifications. Guideline 11,
Choice of control in clinical trials, was redrafted at
the conference in an effort to reduce disagreement. The
redrafted text of that guideline was intensively discussed and
generally well received. Some participants, however, continued to
question the ethical acceptability of the exception to the general
rule limiting the use of placebo to the conditions set out in the
guideline; they argued that research subjects should not be
exposed to risk of serious or irreversible harm when an
established effective intervention could prevent such harm, and
that such exposure could constitute exploitation. Ultimately, the
commentary of Guideline 11 reflects the opposing positions on use
of a comparator other than an established effective intervention
for control purposes.
The new text, the 2002 text, which supersedes that of 1993,
consists of a statement of general ethical principles, a preamble
and 21 guidelines, with an introduction and a brief account of
earlier declarations and guidelines. Like the 1982 and 1993
Guidelines, the present publication is designed to be of use,
particularly to low-resource countries, in defining national
policies on the ethics of biomedical research, applying ethical
standards in local circumstances, and establishing or redefining
adequate mechanisms for ethical review of research involving human
subjects
Comments on the Guidelines are welcome and should be addressed to
the Secretary-General, Council for International Organizations of
Medical Sciences, c/o World Health Organization, CH-1211 Geneva
27, Switzerland; or by e-mail to cioms@who.int
INTRODUCTION
This is the third in the series of international ethical
guidelines for biomedical research involving human subjects issued
by the Council for International Organizations of Medical Sciences
since 1982. Its scope and preparation reflect well the
transformation that has occurred in the field of research ethics
in the almost quarter century since CIOMS first undertook to make
this contribution to medical sciences and the ethics of research.
The CIOMS Guidelines, with their stated concern for the
application of the Declaration of Helsinki in developing
countries, necessarily reflect the conditions and the needs of
biomedical research in those countries, and the implications for
multinational or transnational research in which they may be
partners.
An issue, mainly for those countries and perhaps less pertinent
now than in the past, has been the extent to which ethical
principles are considered universal or as culturally relative –
the universalist versus the pluralist view. The challenge to
international research ethics is to apply universal ethical
principles to biomedical research in a multicultural world with a
multiplicity of health-care systems and considerable variation in
standards of health care. The Guidelines take the position
that research involving human subjects must not violate any
universally applicable ethical standards, but acknowledge that, in
superficial aspects, the application of the ethical principles,
e.g., in relation to individual autonomy and informed consent,
needs to take account of cultural values, while respecting
absolutely the ethical standards.
Related to this issue is that of the human rights of research
subjects, as well as of health professionals as researchers in a
variety of sociocultural contexts, and the contribution that
international human rights instruments can make in the application
of the general principles of ethics to research involving human
subjects. The issue concerns largely, though not exclusively, two
principles: respect for autonomy and protection of dependent or
vulnerable persons and populations. In the preparation of the
Guidelines the potential contribution in these respects of human
rights instruments and norms was discussed, and the Guideline
drafters have represented the views of commentators
on safeguarding the corresponding rights of subjects.
Certain areas of research are not
represented by specific guidelines. One such is human genetics. It
is, however, considered in Guideline 18 Commentary under Issues
of confidentiality in genetics research. The ethics of
genetics research was the subject of a commissioned paper and
commentary.
Another unrepresented area is research with products of conception
(embryo and fetal research, and fetal tissue research). An attempt
to craft a guideline on the topic proved unfeasible. At issue was
the moral status of embryos and fetuses and the degree to which
risks to the life or well-being of these entities are ethically
permissible.
In relation to the use of comparators in controls, commentators
have raised the the question of standard of care to be provided to
a control group. They emphasize that standard of care refers to
more than the comparator drug or other intervention, and that
research subjects in the poorer countries do not usually enjoy the
same standard of all-round care enjoyed by subjects in richer
countries. This issue is not addressed specifically in the
Guidelines.
In one respect the Guidelines depart from the terminology of the
Declaration of Helsinki.
‘Best current intervention’ is the term most commonly used to
describe the active comparator that is ethically preferred in
controlled clinical trials. For many indications, however, there
is more than one established ‘current’ intervention and expert
clinicians do not agree on which is superior. In other
circumstances in which there are several established ‘current’
interventions, some expert clinicians recognize one as superior to
the rest; some commonly prescribe another because the superior
intervention may be locally unavailable, for example, or
prohibitively expensive or unsuited to the capability of
particular patients to adhere to a complex and rigorous regimen.
‘Established effective intervention’ is the term used in Guideline
11 to refer to all such interventions, including the best and the
various alternatives to the best. In some cases an ethical review
committee may determine that it is ethically acceptable to use an
established effective intervention as a comparator, even in cases
where such an intervention is not considered the best current
intervention.
The mere formulation of ethical guidelines for biomedical research
involving human subjects will hardly resolve all the moral doubts
that can arise in association with much research, but the
Guidelines can at least draw the attention of sponsors,
investigators and ethical review committees to the need to
consider carefully the ethical implications of research protocols
and the conduct of research, and thus conduce to high scientific
and ethical standards of biomedical research.
INTERNATIONAL INSTRUMENTS AND
GUIDELINES
The first international instrument on the ethics of medical
research, the Nuremberg Code, was promulgated in 1947 as a
consequence of the trial of physicians (the Doctors’ Trial) who
had conducted atrocious experiments on unconsenting prisoners and
detainees during the second world war. The Code, designed to
protect the integrity of the research subject, set out conditions
for the ethical conduct of research involving human subjects,
emphasizing their voluntary consent to research.
The Universal Declaration of Human Rights was adopted by the
General Assembly of the United Nations in 1948. To give the
Declaration legal as well as moral force, the General Assembly
adopted in 1966 the International Covenant on Civil and Political
Rights. Article 7 of the Covenant states "No one shall
be subjected to torture or to cruel, inhuman or degrading
treatment or punishment. In particular, no one shall be subjected
without his free consent to medical or scientific
experimentation". It is through this statement that society
expresses the fundamental human value that is held to govern all
research involving human subjects – the protection of the rights
and welfare of all human subjects of scientific experimentation.
The Declaration of Helsinki, issued by the World Medical
Association in 1964, is the fundamental document in the field of
ethics in biomedical research and has influenced the formulation
of international, regional and national legislation and codes of
conduct. The Declaration, amended several times, most recently in
2000 (Appendix 2), is a comprehensive international statement of
the ethics of research involving human subjects. It sets out
ethical guidelines for physicians engaged in both clinical and
nonclinical biomedical research.
Since the publication of the CIOMS 1993 Guidelines, several
international organizations have issued
ethical guidance on
clinical trials. This has included, from the World Health
Organization, in 1995, Guidelines
for Good Clinical Practice for Trials on Pharmaceutical
Products; and from the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), in 1996, Guideline
on Good Clinical Practice, designed to ensure that data
generated from clinical trials are mutually acceptable to
regulatory authorities in the European Union, Japan and the United
States of America. The Joint United Nations Programme on HIV/AIDS
published in 2000 the UNAIDS Guidance Document Ethical
Considerations in HIV Preventive Vaccine Research.
In 2001 the Council of Ministers of the European Union adopted a
Directive on clinical trials, which will be binding in law in the
countries of the Union from 2004. The Council of Europe, with more
than 40 member States, is developing a Protocol on Biomedical
Research, which will be an additional protocol to the Council’s
1997 Convention on Human Rights and Biomedicine.
Not specifically concerned with biomedical research involving
human subjects but clearly pertinent, as noted above, are
international human rights instruments. These are mainly the
Universal Declaration of Human Rights, which, particularly in its
science provisions, was highly influenced by the Nuremberg Code;
the International Covenant on Civil and Political Rights; and the
International Covenant on Economic, Social and Cultural Rights.
Since the Nuremberg experience, human rights law has expanded to
include the protection of women
(Convention on the Elimination of All Forms of Discrimination
Against Women) and children (Convention on the Rights of the
Child). These and other such international instruments endorse in
terms of human rights the general ethical principles that underlie
the CIOMS International Ethical Guidelines.
GENERAL ETHICAL PRINCIPLES
All research involving human subjects should be conducted in
accordance with three basic ethical principles, namely respect for
persons, beneficence and justice. It is generally agreed that
these principles, which in the abstract have equal moral force,
guide the conscientious preparation of proposals for scientific
studies. In varying circumstances they may be expressed
differently and given different moral weight, and their
application may lead to different decisions or courses of action.
The present guidelines are directed at the application of these
principles to research involving human subjects.
Respect for persons incorporates at least two
fundamental ethical considerations, namely:
a) respect for autonomy, which requires that those who are capable
of deliberation about their personal choices should be treated
with respect for their capacity for self-determination; and
b) protection of
persons with impaired or diminished autonomy, which requires that
those who are dependent or vulnerable be afforded security against
harm or abuse.
Beneficence refers to the ethical obligation to
maximize benefits and to minimize harms. This principle gives rise
to norms requiring that the risks of research be reasonable in the
light of the expected benefits, that the research design be sound,
and that the investigators be competent both to conduct the
research and to safeguard the welfare of the research subjects.
Beneficence further proscribes the deliberate infliction of harm
on persons; this aspect of beneficence is sometimes expressed as a
separate principle, nonmaleficence (do no harm).
Justice refers to the ethical obligation to
treat each person in accordance with what is morally right and
proper, to give each person what is due to him or her. In the
ethics of research involving human subjects the principle refers
primarily to distributive justice, which requires
the equitable distribution of both the burdens and the benefits of
participation in research. Differences in distribution of burdens
and benefits are justifiable only if they are based on morally
relevant distinctions between persons; one such distinction is
vulnerability. "Vulnerability" refers to a substantial incapacity
to protect one's own interests owing to such impediments as lack
of capability to give informed consent, lack of alternative means
of obtaining medical care
or other expensive necessities, or being a junior or subordinate
member of a hierarchical group. Accordingly, special provision
must be made for the protection of
the rights and welfare of
vulnerable persons.
Sponsors of research or investigators cannot, in general, be held
accountable for unjust conditions where the research is conducted,
but they must refrain from practices that are likely to worsen
unjust conditions or contribute to new inequities. Neither should
they take advantage of the relative inability of low-resource
countries or vulnerable populations to protect their own
interests, by conducting research inexpensively and avoiding
complex regulatory systems of industrialized countries in order to
develop products for the lucrative markets of those countries.
In general, the research project should leave low-resource
countries or communities better off than previously or, at least,
no worse off. It should be responsive to their health needs and
priorities in that any product developed is made reasonably
available to them, and as far as possible leave the population in
a better position to obtain effective health care and protect its
own health.
Justice requires also that the research be responsive to the
health conditions or needs of vulnerable subjects. The subjects
selected should be the least vulnerable necessary to accomplish
the purposes of the research. Risk to vulnerable subjects is most
easily justified when it arises from interventions or procedures
that hold out for them the prospect of direct health-related
benefit. Risk that does not hold out such prospect must be
justified by the anticipated benefit to the population of which
the individual research subject is representative.
PREAMBLE
The term "research" refers to a class of activity designed to
develop or contribute to generalizable knowledge. Generalizable
knowledge consists of theories, principles or relationships, or
the accumulation of information on which they are based, that can
be corroborated by accepted scientific methods of observation and
inference. In the present context "research" includes both medical
and behavioural studies pertaining to human health. Usually
"research" is modified by the adjective "biomedical" to indicate
its relation to health.
Progress in medical care and disease prevention depends upon an
understanding of physiological and pathological processes or
epidemiological findings, and requires at some time research
involving human subjects. The collection, analysis and
interpretation of information obtained from research involving
human beings contribute significantly to the improvement of human
health.
Research involving human subjects includes:
- studies of a physiological, biochemical or pathological process,
or of the response to a specific intervention – whether physical,
chemical or psychological – in healthy subjects or patients;
- controlled
trials of diagnostic, preventive or therapeutic measures in larger
groups of persons, designed to demonstrate a specific
generalizable response to these measures against a background of
individual biological variation;
- studies
designed to determine the consequences for individuals and
communities of specific preventive or therapeutic measures; and
- studies
concerning human health-related behaviour in a variety of
circumstances and environments.
Research involving human subjects may employ either observation or
physical, chemical or psychological intervention; it may also
either generate records or make use of existing records containing
biomedical or other information about individuals who may or may
not be identifiable from the records or information. The use of
such records and the protection of the confidentiality of data
obtained from those records are discussed in International
Guidelines for Ethical Review of Epidemiological Studies (CIOMS,
1991).
The research may be concerned with the social environment,
manipulating environmental factors in a way that could affect
incidentally-exposed individuals. It is defined in broad terms in
order to embrace field studies of pathogenic organisms and toxic
chemicals under investigation for health-related purposes.
Biomedical research with human subjects is to be distinguished
from the practice of medicine, public health and other forms of
health care, which is designed to contribute directly to the
health of individuals or communities. Prospective subjects may
find it confusing when research and practice are to be conducted
simultaneously, as when research is designed to obtain new
information about the efficacy of a drug or other therapeutic,
diagnostic or preventive modality.
As stated in Paragraph 32 of the Declaration of Helsinki, "In the
treatment of a patient, where proven prophylactic, diagnostic and
therapeutic methods do not exist or have been ineffective, the
physician, with informed consent from the patient, must be free to
use unproven or new prophylactic, diagnostic and therapeutic
measures, if in the physician's judgement it offers hope of saving
life, re-establishing health or alleviating suffering. Where
possible, these measures should be made the object of research,
designed to evaluate their safety and efficacy. In all cases, new
information should be recorded and, where appropriate, published.
The other relevant
guidelines of this Declaration should be followed."
Professionals whose roles combine investigation and treatment have
a special obligation to protect the rights and welfare of the
patient-subjects. An investigator who agrees to act as
physician-investigator undertakes some or all of the legal and
ethical responsibilities of the subject's primary-care physician.
In such a case, if the subject withdraws from the research owing
to complications related to the research or in the exercise of the
right to withdraw without loss of benefit, the physician has an
obligation to continue to provide medical care, or to see that the
subject receives the necessary care in the health-care system, or
to offer assistance in finding another physician.
Research with human subjects should be carried out only by, or
strictly supervised by, suitably qualified and experienced
investigators and in accordance with a protocol that clearly
states: the aim of the research; the reasons for proposing that it
involve human subjects; the nature and degree of any known risks
to the subjects; the sources from which it is proposed to recruit
subjects; and the means proposed for ensuring that subjects'
consent will be adequately informed and voluntary. The protocol
should be scientifically and ethically appraised by one or more
suitably constituted review bodies, independent of the
investigators.
New vaccines and medicinal drugs, before being approved for
general use, must be tested on human subjects in clinical trials;
such trials constitute a substantial part of all research
involving human subjects.
THE GUIDELINES
Guideline 1: Ethical justification and scientific validity
of biomedical research involving human beings
The ethical justification of biomedical research involving
human subjects is the prospect of discovering new ways of
benefiting people's health. Such research can be ethically
justifiable only if it is carried out in ways that respect and
protect, and are fair to, the subjects of that research and are
morally acceptable within the communities in which the research is
carried out. Moreover, because scientifically invalid research is
unethical in that it exposes research subjects to risks without
possible benefit, investigators and sponsors must ensure that
proposed studies involving human subjects conform to generally
accepted scientific principles and are based on adequate knowledge
of the pertinent scientific literature.
Commentary on Guideline 1
Among the essential features of ethically justified research
involving human subjects, including research with
identifiable human tissue or data,
are that the research offers a means of developing
information not otherwise obtainable, that the design of the
research is scientifically sound,
and that the investigators and other research personnel
are competent. The methods to be used should be appropriate to the
objectives of the research and the field of study. Investigators
and sponsors must also ensure that all who participate in the
conduct of the research are qualified by virtue of their education
and experience to perform competently in their roles. These
considerations should be adequately reflected in the research
protocol submitted for review and clearance to scientific and
ethical review committees (Appendix I).
Scientific review is discussed further in the Commentaries to
Guidelines 2 and 3: Ethical review committees and
Ethical review of externally sponsored research. Other ethical
aspects of research are discussed in the remaining guidelines and
their commentaries. The protocol designed for submission
for review and clearance to scientific and ethical review
committees should include, when relevant, the items specified in
Appendix I, and should be
carefully followed in conducting the research.
Guideline 2: Ethical review committees
All proposals to conduct research involving human subjects must
be submitted for review of their scientific merit and ethical
acceptability to one or more scientific review and ethical review
committees. The review committees must be independent of
the research team, and any direct financial or other material
benefit they may derive from the research should not be contingent
on the outcome of their review. The investigator must obtain their
approval or clearance before undertaking the research. The ethical
review committee should conduct further reviews as necessary in
the course of the research, including monitoring of the progress
of the study.
Commentary on Guideline 2
Ethical review committees may function at the institutional,
local, regional, or national level, and in some cases at the
international level. The
regulatory or other governmental authorities concerned should
promote uniform standards across committees within a country, and,
under all systems, sponsors of research and institutions in which
the investigators are employed
should allocate sufficient resources to the review process.
Ethical review committees may receive money for the
activity of reviewing protocols, but under no circumstances may
payment be offered or accepted for a review committee`s approval
or clearance of a protocol.
Scientific review. According to the Declaration of Helsinki
(Paragraph 11), medical research involving humans
must conform to generally accepted scientific principles, and be
based on a thorough knowledge of the scientific literature, other
relevant sources of information, and adequate laboratory
and, where indicated, animal experimentation. Scientific review
must consider, inter alia, the study design, including the
provisions for avoiding or minimizing risk and for monitoring
safety. Committees competent to review and approve scientific
aspects of research proposals must be multidisciplinary.
Ethical review. The ethical review committee is responsible
for safeguarding the rights, safety, and well-being of the
research subjects. Scientific review and ethical review cannot be
separated: scientifically unsound research involving humans as
subjects is ipso facto unethical in that it may expose them to
risk or inconvenience to no purpose; even if there is no risk of
injury, wasting of subjects` and
researchers` time in unproductive
activities represents loss of a valuable resource. Normally,
therefore, an ethical review committee considers both the
scientific and the ethical aspects of proposed research. It must
either carry out a proper scientific review or verify that a
competent expert body has determined that the research is
scientifically sound. Also, it considers provisions for monitoring
of data and safety.
If the ethical review committee
finds a research proposal scientifically sound, or verifies that a
competent expert body has found it so, it should then consider
whether any known or possible risks to the subjects are justified
by the expected benefits, direct or indirect, and whether the
proposed research methods will minimize harm and maximize benefit.
(See Guideline 8: Benefits and risks of study participation.)
If the proposal is sound and the balance of risks to
anticipated benefits is reasonable, the committee should then
determine whether the procedures proposed for
obtaining informed consent are satisfactory and those proposed for
the selection of subjects are equitable.
Ethical review of emergency compassionate use of an
investigational therapy. In some countries, drug regulatory
authorities require that the so-called compassionate or
humanitarian use of an investigational treatment be reviewed by an
ethical review committee as though it were research.
Exceptionally, a physician may undertake the compassionate use of
an investigational therapy before obtaining the approval or
clearance of an ethical review committee, provided three criteria
are met: a patient needs emergency treatment, there is some
evidence of possible effectiveness of the
investigational treatment, and there is no other treatment
available that is known to be equally effective or superior.
Informed consent should be obtained according to the legal
requirements and cultural standards of the community in which the
intervention is carried out. Within one week the physician must
report to the ethical review committee the details of the case and
the action taken, and an independent health-care professional must
confirm in writing to the ethical review committee the treating
physician's judgment that the use of the investigational
intervention was justified according to the three specified
criteria. (See also Guideline 13 Commentary section: Other
vulnerable groups.)
National (centralized) or local review. Ethical review
committees may be created under the aegis of national or local
health administrations, national (or centralized) medical
research councils or other nationally representative bodies. In a
highly centralized administration a national, or centralized,
review committee may be constituted for both the scientific
and the ethical review of research protocols. In countries where
medical research is not centrally administered, ethical review is
more effectively and conveniently undertaken at a local or
regional level. The authority of a local ethical review committee
may be confined to a single institution or may extend to
all institutions in which biomedical research is carried out
within a defined geographical area. The basic responsibilities of
ethical review committees are:
- to determine
that all proposed interventions, particularly the administration
of drugs and vaccines or the use of medical devices or
procedures under development, are acceptably safe to be
undertaken in humans or to verify that another competent expert
body has done so;
- to determine
that the proposed research is scientifically sound or to verify
that another competent expert body has done so;
- to ensure
that all other ethical concerns arising from a protocol are
satisfactorily resolved both in principle and in practice;
- to consider
the qualifications of the investigators, including education in
the principles of research practice, and the
conditions of the research site with a view to ensuring the safe
conduct of the trial; and
- to keep records of decisions and to take
measures to follow up on the conduct of ongoing research
projects.
Committee membership.
National or local ethical review committees should be so
composed as to be able to provide complete and adequate review of
the research proposals submitted to them. It is generally
presumed that their membership should include physicians,
scientists and other professionals such as nurses, lawyers,
ethicists and clergy, as well as lay persons qualified to
represent the cultural and moral values of the community and to
ensure that the rights of the research subjects will be respected.
They should include both men and women. When uneducated or
illiterate persons form the focus of a study they should also be
considered for membership or invited to be represented and
have their views expressed.
A number of members should
be replaced periodically with the aim of blending the
advantages of experience with those of fresh perspectives.
A national or local ethical review committee responsible for
reviewing and approving proposals for externally sponsored
research should have among its members or consultants persons who
are thoroughly familiar with the customs and traditions of the
population or community concerned and sensitive to issues of human
dignity.
Committees that often review research proposals directed at
specific diseases or impairments, such as HIV/AIDS or paraplegia,
should invite or hear the views of individuals or bodies
representing patients with such diseases or impairments.
Similarly, for research involving such subjects as children,
students, elderly persons or employees, committees should invite
or hear the views of their representatives or advocates.
To maintain the review committee’s independence from the
investigators and sponsors and to avoid conflict of
interest, any member with a special or particular, direct or
indirect, interest in a proposal should not take part in its
assessment if that interest could subvert the member`s objective
judgment. Members of ethical review committees should be held to
the same standard of disclosure as scientific and medical research
staff with regard to financial or other interests that could be
construed as conflicts of interest. A practical way of avoiding
such conflict of interest is for the committee to insist on a
declaration of possible conflict of interest by any of its
members. A member who makes such a declaration should then
withdraw, if to do so is clearly the appropriate action to take,
either at the member`s own discretion or at the request of
the other members. Before withdrawing, the member should be
permitted to offer comments on the protocol or to respond to
questions of other members.
Multi-centre research. Some research projects are designed
to be conducted in a number of centres in different
communities or countries. Generally, to ensure that the results
will be valid, the study must be conducted in an identical way at
each centre. Such studies include clinical trials, research
designed for the evaluation of health service programmes, and
various kinds of epidemiological research. For such studies, local
ethical or scientific review committees are not normally
authorized to change doses of drugs, to change inclusion or
exclusion criteria, or to make other similar modifications.
They should be fully empowered to prevent a study that they
believe to be unethical. Moreover, changes that local review
committees believe are necessary to protect the research subjects
should be documented and reported to the research institution or
sponsor responsible for the whole research programme for
consideration and due action, to ensure that all other subjects
can be protected and that the research will be valid across sites.
To ensure the validity of multi-centre research, any change in the
protocol should be made at every collaborating centre or
institution, or, failing this, explicit inter-centre comparability
procedures must be introduced; changes made at some but not all
will defeat the purpose of multi-centre research. For some multi-centre
studies, scientific and ethical review may be facilitated by
agreement among centres to accept the conclusions of a single
review committee; its members could include a representative of
the ethical review committee at each of the centres at which the
research is to be conducted, as well as individuals competent to
conduct scientific review. In other circumstances, a centralized
review may be complemented by local review relating to the local
participating investigators and institutions. The central
committee could review the study from a scientific and ethical
standpoint, and the local committees could verify the
practicability of the study in their communities, including the
infrastructures, the state of training, and ethical considerations
of local significance.
In a large multi-centre trial, individual investigators will not
have authority to act independently, with regard to data analysis
or to preparation and publication of manuscripts, for instance.
Such a trial usually has a set of committees which operate
under the direction of a steering committee and are responsible
for such functions and decisions. The function of the
ethical review committee in such cases is to review the relevant
plans with the aim of avoiding abuses.
Sanctions. Ethical review committees generally have no
authority to impose sanctions on researchers who violate ethical
standards in the conduct of research involving humans. They may,
however, withdraw ethical approval of a research project if judged
necessary. They should be required to monitor the
implementation of an approved protocol and its progression, and
to report to institutional or governmental authorities any
serious or continuing non-compliance with ethical standards as
they are reflected in protocols that they have approved or in the
conduct of the studies. Failure to submit a protocol to the
committee should be considered a clear and serious violation of
ethical standards.
Sanctions imposed by governmental, institutional, professional or
other authorities possessing disciplinary power should be
employed as a last resort. Preferred methods of control include
cultivation of an atmosphere of mutual trust, and education and
support to promote in researchers and in sponsors the capacity for
ethical conduct of research.
Should sanctions become necessary, they should be directed at the
non-compliant researchers or sponsors. They may include fines or
suspension of eligibility to receive research funding, to use
investigational interventions, or to practise medicine. Unless
there are persuasive reasons to do otherwise, editors should
refuse to publish the
results of research conducted unethically, and retract any
articles that are subsequently found to contain falsified or
fabricated data or to have been based on unethical research. Drug
regulatory authorities should consider refusal to accept
unethically obtained data submitted in support of an application
for authorization to market a
product. Such sanctions, however, may deprive of
benefit not only the errant researcher or sponsor but also that
segment of society intended to benefit from the research;
such possible consequences merit careful consideration.
Potential conflicts of interest related to project support.
Increasingly, biomedical studies receive funding from commercial
firms. Such sponsors have good reasons to support research methods
that are ethically and scientifically acceptable, but cases have
arisen in which the conditions of funding could have introduced
bias. It may happen that investigators have little or no input
into trial design, limited access to the raw data, or limited
participation in data interpretation, or that the results of a
clinical trial may not be published if they are
unfavourable to the sponsor's product. This risk of bias may also
be associated with other sources of support, such as government or
foundations. As the persons directly responsible for their work,
investigators should not enter into agreements that interfere
unduly with their access to the data or their ability to analyse
the data independently, to prepare manuscripts, or to publish
them. Investigators must also disclose potential or apparent
conflicts of interest on their part to the ethical review
committee or to other institutional committees designed to
evaluate and manage such conflicts. Ethical review committees
should therefore ensure that these conditions are met. See also
Multi-centre research, above.
Guideline 3: Ethical review of externally sponsored research
An external sponsoring organization and individual
investigators should submit the research protocol for
ethical and scientific review in the country of the sponsoring
organization, and the ethical standards applied should be no less
stringent than they would be for research carried out in that
country. The health authorities of the host country, as well as a
national or local ethical review committee, should ensure that the
proposed research is responsive to the health needs and priorities
of the host country and meets the requisite ethical standards.
Commentary on Guideline 3
Definition. The term externally sponsored research
refers to research undertaken in a host country but
sponsored, financed, and sometimes wholly or partly carried out by
an external international or national organization or
pharmaceutical company with the collaboration or agreement of the
appropriate authorities, institutions and personnel of the host
country.
Ethical and scientific review. Committees in both the
country of the sponsor and the host country have responsibility
for conducting both scientific and ethical review, as well as the
authority to withhold approval of research proposals that fail to
meet their scientific or ethical standards. As far as possible,
there must be assurance that the review is independent and that
there is no conflict of interest that might affect the judgement
of members of the review committees in relation to any
aspect of the research. When the external sponsor is an
international organization, its review of the research protocol
must be in accordance with its own independent ethical-review
procedures and standards.
Committees in the external sponsoring country or international
organization have a special responsibility to determine
whether the scientific methods are sound and suitable to the aims
of the research; whether the drugs, vaccines, devices or
procedures to be studied meet adequate standards of safety;
whether there is sound justification for conducting the research
in the host country rather than in the country of the external
sponsor or in another country;
and whether the proposed research is in compliance with the
ethical standards of the external sponsoring country or
international organization.
Committees in the host country have a special responsibility to
determine whether the objectives of the research are responsive to
the health needs and priorities of that country. The
ability to judge the ethical acceptability of various aspects of a
research proposal requires a thorough understanding of a
community's customs and traditions. The ethical review committee
in the host country, therefore, must have as either members or
consultants persons with such understanding; it will then be in a
favourable position to determine the acceptability of
the proposed means of obtaining informed consent and otherwise
respecting the rights of prospective subjects as well as of the
means proposed to protect the welfare of the research subjects.
Such persons should be able, for example, to indicate
suitable members of the community to serve as intermediaries
between investigators and subjects, and to advise on whether
material benefits or inducements may be regarded as appropriate in
the light of a community's gift-exchange and other customs and
traditions.
When a sponsor or investigator in one country proposes to carry
out research in another, the ethical review committees in the two
countries may, by agreement, undertake to review different aspects
of the research protocol. In short, in respect of host
countries either with developed capacity for independent ethical
review or in which external sponsors and investigators are
contributing substantially to such capacity, ethical review in the
external, sponsoring country may be limited to ensuring compliance
with broadly stated ethical standards. The ethical review
committee in the host country can be expected to have greater
competence for reviewing the detailed plans for compliance, in
view of its better understanding of the cultural and moral values
of the population in which it is proposed to conduct the research;
it is also likely to be in a better position to monitor compliance
in the course of a study. However, in respect of research in host
countries with inadequate capacity for independent ethical review,
full review by the ethical review committee in the external
sponsoring country or international agency is necessary.
Guideline 4: Individual informed consent
For all biomedical research involving humans the investigator
must obtain the voluntary informed consent of the
prospective subject or, in the case of an individual who is not
capable of giving informed consent, the permission of a legally
authorized representative in accordance with applicable law.
Waiver of informed consent is to be regarded as uncommon and
exceptional, and must in all cases be approved by an ethical
review committee.
Commentary on Guideline 4
General considerations. Informed consent is a decision to
participate in research, taken by a competent individual
who has received the necessary information; who has adequately
understood the information; and who, after considering the
information, has arrived at a decision without having been
subjected to coercion, undue influence or inducement, or
intimidation.
Informed consent is based on the principle that competent
individuals are entitled to choose freely whether to participate
in research. Informed consent protects the individual's freedom of
choice and respects the individual's autonomy. As an additional
safeguard, it must always be complemented by independent ethical
review of research proposals. This safeguard of independent review
is particularly important as many individuals are limited
in their capacity to give adequate informed consent; they include
young children, adults with severe mental or behavioural
disorders, and persons who are unfamiliar with medical concepts
and technology (See Guidelines 13, 14, 15).
Process. Obtaining informed consent is a process that is
begun when initial contact is made with a prospective subject and
continues throughout the course of the study. By informing the
prospective subjects, by repetition and explanation, by
answering their questions as they arise, and by ensuring that each
individual understands each procedure, investigators elicit
their informed consent and in so doing manifest respect for their
dignity and autonomy. Each individual
must be given as much time as is needed to reach a
decision, including time for consultation with family members or
others. Adequate time and resources should be set aside for
informed-consent procedures.
Language. Informing the individual subject must not be
simply a ritual recitation of the contents of a written document.
Rather, the investigator must convey the information, whether
orally or in writing, in language that suits the individual's
level of understanding. The investigator must bear in mind
that the prospective subject`s ability to understand the
information necessary to give informed consent depends on that
individual's maturity, intelligence, education and belief system.
It depends also on the investigator's ability and
willingness to communicate with patience and sensitivity.
Comprehension. The investigator must then ensure
that the prospective subject has adequately understood the
information. The investigator should give each one full
opportunity to ask questions and should answer them honestly,
promptly and completely. In some instances the investigator
may administer an oral or a written test or otherwise determine
whether the information has been adequately understood.
Documentation of consent. Consent may be indicated in a
number of ways. The subject may imply consent by voluntary
actions, express consent orally, or sign a consent form. As a
general rule, the subject should sign a consent form, or, in the
case of incompetence, a legal guardian or other duly authorized
representative should do so. The ethical review committee may
approve waiver of the requirement of a signed consent form if the
research carries no more than minimal risk – that is, risk that is
no more likely and not greater than that attached to routine
medical or psychological examination – and if the procedures to be
used are only those for which signed consent forms are not
customarily required outside the research context. Such waivers
may also be approved when existence of a signed consent form would
be an unjustified threat to the subject's confidentiality. In some
cases, particularly when the information is complicated, it is
advisable to give subjects information sheets to retain; these may
resemble consent forms in all respects except that subjects are
not required to sign them. Their wording should be cleared by the
ethical review committee. When consent has been obtained orally,
investigators are responsible for providing documentation or proof
of consent.
Waiver of the consent requirement. Investigators should
never initiate research involving human subjects without obtaining
each subject's informed consent, unless they have received
explicit approval to do so from an ethical review committee.
However, when the research design involves no more than minimal
risk and a requirement of individual informed consent would make
the conduct of the research impracticable
(for example, where the research involves only excerpting
data from subjects' records), the ethical review committee may
waive some or all of the elements of informed consent.
Renewing consent. When material changes occur in the
conditions or the procedures of a study, and also periodically in
long-term studies, the investigator should once again seek
informed consent from the subjects. For example, new information
may have come to light, either from the study or from other
sources, about the risks or benefits of products being tested or
about alternatives to them. Subjects should be given such
information promptly. In many clinical trials, results are not
disclosed to subjects and investigators until the study is
concluded. This is ethically acceptable if an ethical review
committee has approved their non-disclosure.
Cultural considerations. In some cultures an investigator
may enter a community to conduct research or approach prospective
subjects for their individual consent only after obtaining
permission from a community leader, a council of elders, or
another designated authority. Such customs must be respected.
In no case, however, may the permission of a community leader
or other authority substitute for individual informed consent. In
some populations the use of a number of local languages may
complicate the communication of information to potential subjects
and the ability of an investigator to ensure that they truly
understand it. Many people in all cultures are unfamiliar with, or
do not readily understand, scientific concepts such as those of
placebo or randomization. Sponsors and
investigators should develop culturally appropriate
ways to communicate information that is necessary for adherence to
the standard required in the informed consent process. Also, they
should describe and justify in the research protocol the procedure
they plan to use in communicating information to
subjects. For collaborative research in developing countries the
research project should, if necessary, include the provision of
resources to ensure that informed consent can indeed be obtained
legitimately within different linguistic and cultural settings.
Consent to use for research purposes biological materials
(including genetic material) from subjects in clinical trials.
Consent forms for the research protocol should include a separate
section for clinical-trial subjects who are requested to provide
their consent for the use of their biological specimens for
research. Separate consent may be appropriate in some cases (e.g.,
if investigators are requesting permission to conduct basic
research which is not a necessary part of the clinical trial), but
not in others (e.g., the clinical trial requires the use of
subjects’ biological materials).
Use of medical records and biological specimens. Medical
records and biological specimens taken in the course of clinical
care may be used for research without the consent of the
patients/subjects only if an ethical review committee has
determined that the research poses minimal risk, that the rights
or interests of the patients will not be violated, that their
privacy and confidentiality or anonymity are assured,
and that the research is designed to answer an
important question and would be impracticable
if the requirement for informed consent were to be imposed.
Patients have a right to know that their records or specimens may
be used for research.
Refusal or reluctance of individuals to agree to participate would
not be evidence of impracticability sufficient to warrant waiving
informed consent. Records and specimens of individuals who have
specifically rejected such uses in the past may be used only in
the case of public health emergencies. (See Guideline 18
Commentary, Confidentiality between physician and patient)
Secondary use of research records or biological specimens.
Investigators may want to use records or biological specimens that
another investigator has used or collected for use, in another
institution in the same or another country.
This raises the issue of whether the records or specimens
contain personal identifiers, or can be linked to such
identifiers, and by whom. (See also Guideline 18:
Safeguarding confidentiality) If informed consent or
permission was required to authorize the original collection or
use of such records or specimens for research purposes,
secondary uses are generally constrained by the conditions
specified in the original consent. Consequently, it is essential
that the original consent
process anticipate, to the extent that this is feasible, any
foreseeable plans for future use of the records or
specimens for research. Thus, in the original process of seeking
informed consent a member of the research team should discuss
with, and, when indicated, request the permission of,
prospective subjects as to: i) whether there will or could be
any secondary use and, if so, whether such secondary use will be
limited with regard to the type of study that may be performed on
such materials; ii) the conditions under which
investigators will be required to contact the research
subjects for additional authorization for secondary use; iii) the
investigators' plans, if any, to destroy or to strip of
personal identifiers the records or specimens; and iv) the rights
of subjects to request destruction or anonymization of biological
specimens or of records or parts of records that they might
consider particularly sensitive, such as photographs, videotapes
or audiotapes.
(See also Guidelines 5: Obtaining informed consent: Essential
information for prospective research subjects; 6: Obtaining
informed consent: Obligations of sponsors and investigators;
and 7: Inducement to participate.)
Guideline 5: Obtaining informed consent: Essential
information for prospective research subjects
Before requesting an individual's consent to participate in
research, the investigator must provide the following information,
in language or another form of communication that the individual
can understand:
- that the
individual is invited to participate in research, the reasons
for considering the individual suitable for the research, and
that participation is voluntary;
- that the
individual is free to refuse to participate and will be free to
withdraw from the research at any time without penalty or loss
of benefits to which he or she would otherwise be entitled;
- the
purpose of the research, the procedures to be carried out by the
investigator and the subject, and an explanation of how the
research differs from routine medical care;
- for
controlled trials, an explanation of features of the
research design (e.g., randomization, double-blinding), and that
the subject will not be told of the assigned treatment until the
study has been completed and the blind has been broken;
- the
expected duration of the individual's participation (including
number and duration of visits to the research centre and the
total time involved) and the possibility of early termination of
the trial or of the individual’s participation in it;
- whether
money or other forms of material goods will be provided in
return for the individual's participation and, if so, the kind
and amount;
- that,
after the completion of the study, subjects will be informed of
the findings of the research in general, and individual subjects
will be informed of any finding that relates to their particular
health status;
- that
subjects have the right of access to their data on demand, even
if these data lack immediate clinical utility (unless the
ethical review committee has approved temporary or permanent
non-disclosure of data, in which case the subject should be
informed of, and given, the reasons for such non-disclosure);
- any
foreseeable risks, pain or discomfort, or inconvenience to the
individual (or others) associated with participation in the
research, including risks to the health or well-being of a
subject’s spouse or partner;
- the
direct benefits, if any, expected to result to subjects from
participating in the research
- the
expected benefits of the research to the community or to society
at large, or contributions to scientific knowledge;
- whether,
when and how any products or interventions proven by the
research to be safe and effective will be made available to
subjects after they have completed their participation in the
research, and whether they will be expected to pay for them;
- any
currently available alternative interventions or courses of
treatment;
- the
provisions that will be made to ensure respect for the privacy
of subjects and for the confidentiality of records in which
subjects are identified;
- the
limits, legal or other, to the investigators' ability to
safeguard confidentiality, and the possible consequences of
breaches of confidentiality;
- policy
with regard to the use of results of genetic tests and familial
genetic information, and the precautions in place to prevent
disclosure of the results of a subject's genetic tests to
immediate family relatives or to others (e.g., insurance
companies or employers) without the consent of the subject;
- the
sponsors of the research, the institutional affiliation of the
investigators, and the nature and sources of funding for the
research;
- the
possible research uses, direct or secondary, of the subject`s
medical records and of biological specimens taken in the course
of clinical care (See also Guidelines 4 and 18 Commentaries);
- whether
it is planned that biological specimens collected in the
research will be destroyed at its conclusion, and, if not,
details about their storage (where, how, for how long, and final
disposition) and possible future use, and that subjects have the
right to decide about such future use, to refuse storage, and to
have the material destroyed (See Guideline 4 Commentary);
- whether
commercial products may be developed from biological specimens,
and whether the participant will receive monetary or other
benefits from the development of such products;
- whether
the investigator is serving only as an investigator or as both
investigator and the subject`s physician;
- the
extent of the investigator's responsibility to provide medical
services to the participant;
- that
treatment will be provided free of charge for specified types of
research-related injury or for complications associated with the
research, the nature and duration of such care, the name of the
organization or individual that will provide the treatment, and
whether there is any uncertainty regarding funding of such
treatment.
- in what
way, and by what organization, the subject or the subject`s
family or dependants will be compensated for disability or death
resulting from such injury (or, when indicated, that there are
no plans to provide such compensation);
- whether
or not, in the country in which the prospective subject is
invited to participate in research, the right to compensation is
legally guaranteed;
- that an ethical review committee has
approved or cleared the research protocol.
Guideline 6: Obtaining informed consent: Obligations of
sponsors and investigators
Sponsors and investigators have a duty to:
- refrain
from unjustified deception,
undue influence, or
intimidation;
- seek
consent only after ascertaining that the prospective subject
has adequate understanding of the relevant facts and of the
consequences of participation and has had sufficient opportunity
to consider whether to participate;
- as a
general rule, obtain from each prospective subject a signed form
as evidence of informed consent – investigators should justify
any exceptions to this general rule and obtain the approval
of the ethical review committee
(See Guideline 4 Commentary, Documentation of consent);
- renew the informed consent of each
subject if there are significant changes in the conditions or
procedures of the research or if new information becomes
available that could affect the willingness of subjects to
continue to participate; and,
- renew the informed consent of each
subject in long-term studies at pre-determined intervals, even
if there are no changes
in the design or objectives of the research.
Commentary on Guideline 6
The investigator is responsible for ensuring the adequacy of
informed consent from each subject. The person obtaining informed
consent should be knowledgeable about the research and capable of
answering questions from prospective subjects. Investigators in
charge of the study must make themselves available to answer
questions at the request of subjects. Any restrictions on the
subject`s opportunity to ask questions and receive answers before
or during the research undermines the validity of the informed
consent.
In some types of research, potential subjects should receive
counselling about risks of acquiring a disease unless they take
precautions. This is especially true of HIV/AIDS vaccine research
(UNAIDS Guidance Document Ethical Considerations in HIV
Preventive Vaccine Research, Guidance Point 14).
Withholding information and deception. Sometimes, to ensure
the validity of research, investigators withhold certain
information in the consent process. In biomedical research, this
typically takes the form of withholding information about the
purpose of specific procedures. For example, subjects in clinical
trials are often not told the purpose of tests performed to
monitor their compliance with the protocol, since if they knew
their compliance was being monitored they might modify their
behaviour and hence invalidate results. In most such cases, the
prospective subjects are asked to consent to remain uninformed of
the purpose of some procedures until the research is completed;
after the conclusion of the study they are given the omitted
information. In other cases, because a request for permission to
withhold some information would jeopardize the validity of the
research, subjects are not told that some information has
been withheld until the research has been completed. Any
such procedure must receive the explicit approval of the ethical
review committee.
Active deception of subjects is considerably more controversial
than simply withholding certain information. Lying to subjects
is a tactic not commonly employed in biomedical research.
Social and behavioural scientists, however, sometimes deliberately
misinform subjects to study their attitudes and behaviour. For
example, scientists have pretended to be patients to study the
behaviour of health-care professionals and patients in their
natural settings.
Some people maintain that active deception is never permissible.
Others would permit it in certain circumstances.
Deception is not permissible, however, in cases in
which the deception itself would disguise the possibility of the
subject being exposed to more than minimal risk. When deception is
deemed indispensable to the methods of a study the investigators
must demonstrate to an ethical review committee that no other
research method would suffice; that significant advances could
result from the research; and that nothing has been withheld that,
if divulged, would cause a reasonable person to refuse to
participate. The ethical review com |
