|
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)
http://www.cioms.ch/frame_guidelines_nov_2002.htm
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
| 
