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1991 INTERNATIONAL GUIDELINES
FOR ETHICAL REVIEW
OF EPIDEMIOLOGICAL STUDIES
INTRODUCTION
These Guidelines are intended for investigators, health
policy-makers, members of ethical review committees, and
others who have to deal with ethical issues that arise in
epidemiology. They may also assist in the establishment of
standards for ethical review of epidemiological studies.
The Guidelines are an expression of concern to ensure
that epidemiological studies observe ethical standards.
These standards apply to all who undertake any of the types
of activity covered by the Guidelines. Investigators must
always be held responsible for the ethical integrity of
their studies.
Epidemiology is defined as the study of the distribution
and determinants of health-related states or events in
specified populations, and the application of this study to
control of health problems.
Epidemiology has greatly improved the human condition in
the present century. It has clarified our understanding of
many physical, biological and behavioural dangers to health.
Some of the knowledge obtained has been applied to the
control of environmental and biological threats to health,
such as diseases due to drinking polluted water. Other
epidemiological knowledge has become part of popular
culture, leading to changed values and behaviour, and thus
has led to improved health: examples include attitudes
towards personal hygiene, tobacco smoking, diet and exercise
in relation to heart disease, and the use of seat-belts to
reduce the risk of traffic injury and death.
Epidemiological practice and research are based mostly on
observation, and require no intervention more invasive than
asking questions and carrying out routine medical
examinations. Practice and research may overlap, as, for
example, when both routine surveillance of cancer and
original research on cancer are conducted by professional
staff of a population-based cancer registry.
Epidemiological research is of two main types:
observational and experimental:
Three types of observational epidemiological research are
distinguished: cross-sectional studies (also known as
surveys), case-control studies, and cohort
studies. These types of study carry minimal risk to
study subjects. They involve no intervention other than
asking questions, carrying out medical examinations and,
sometimes, laboratory tests or xray examinations. The
informed consent of subjects is normally required, although
there are some exceptions - for example, very large cohort
studies conducted exclusively by examining medical
records.
A cross-sectional study (survey) is commonly done
on a random sample of a population. Study subjects are asked
questions, medically examined, or asked to submit to
laboratory tests. Its aim is to assess aspects of the health
of a population, or to test hypotheses about possible causes
of disease or suspected risk factors.
A case-control study compares the past history of
exposure to risk among patients who have a specified
condition (cases) with the past history of exposure to this
risk among persons who resemble the cases in such respects
as age and sex, but do not have the specified condition
(controls). Differing frequency of past exposure among cases
and controls can be statistically analysed to test
hypotheses about causes or risk factors. Case-control
studies are the method of choice for testing hypotheses
about rare conditions, because they can be done with small
numbers of cases. They generally do not involve invasion of
privacy or violation of confidentiality. If a case-control
study requires direct contact between research workers and
study subjects, informed consent to participation in the
study is required; if it entails only a review of medical
records, informed consent may not be required and indeed may
not be feasible.
In a cohort study, also known as a longitudinal or
prospective study, individuals with differing exposure
levels to suspected risk factors are identified and observed
over a period, commonly years, and the rates of occurrence
of the condition of interest are measured and compared in
relation to exposure levels. This is a more robust research
method than a cross-sectional or case-control study, but it
requires study of large numbers for a long time and is
costly. Usually it requires only asking questions and
routine medical examinations; sometimes it requires
laboratory tests. Informed consent is normally required, but
an exception to this requirement is a retrospective cohort
study that uses linked medical records. In a retrospective
cohort study, the initial or base-line observations may
relate to exposure many years earlier to a potentially
harmful agent, such as x-rays, a prescribed drug or an
occupational hazard, about which details are known; the
final or endpoint observations are often obtained from death
certificates. Numbers of subjects may be very large, perhaps
millions, so it would be impracticable to obtain their
informed consent. It is essential to identify precisely
every individual studied; this is achieved by methods of
matching that are built into record linkage systems. After
identities have been established to compile the statistical
tables, all personal identifying information is obliterated,
and therefore privacy and confidentiality are
safeguarded.
An experiment is a study in which the investigator
intentionally alters one or more factors under controlled
conditions to study the effects of doing so. The usual form
of epidemiological experiment is the randomized
controlled trial, which is done to test a preventive or
therapeutic regimen or diagnostic procedure. Such
experiments involving human subjects should be regarded as
unethical unless there is genuine uncertainty about the
regimen or procedure and this uncertainty can be clarified
by research.
Usually in this form of experiment, subjects are
allocated at random to groups, one group to receive, the
other group not to receive, the experimental regimen or
procedure. The experiment compares the outcomes in the two
groups. Random allocation removes the effects of bias, which
would destroy the validity of comparisons between the
groups. Since it is always possible that harm may be caused
to at least some of the subjects, their informed consent is
essential.
Epidemiology is facing new challenges and opportunities.
The application of information technology to large
data-files has expanded the role and capacity of
epidemiological studies. The acquired immunodeficiency
syndrome (AIDS) epidemic and its management have given
epidemiological studies new urgency; public health
authorities are using population-screening studies to
establish prevalence levels of human immunodeficiency virus
(HIV) infection for purposes of monitoring and restricting
the spread of infection. Ahead lie entirely new challenges,
such as those arising from the conjunction of molecular and
population genetics.
PREAMBLE
The general conduct of biomedical studies is guided by
statements of internationally recognized principles of human
rights, including the Nuremberg Code and the World Medical
Association's Declaration of Helsinki, as revised (Helsinki
IV). These principles also underlie the Proposed
International Guidelines for Biomedical Research Involving
Human Subjects, issued by the Council for International
Organizations of Medical Sciences in 1982. These and similar
national codes are based on the model of clinical medicine,
and often address interests of "patients" or individual
"subjects". Epidemiological research concerns groups of
people, and the above codes do not adequately cover its
special features. Proposals for epidemiological studies
should be reviewed independently on ethical grounds.
Ethical issues often arise as a result of conflict among
competing sets of values, such as, in the field of public
health, the conflict between the rights of individuals and
the needs of communities. Adherence to these guidelines will
not avoid all ethical problems in epidemiological studies.
Many situations require careful discussion and informed
judgement on the part of investigators, ethical review
committees, administrators, health-care practitioners,
policy-makers, and community representatives. Externally
sponsored epidemiological studies in developing countries
merit special attention. A framework for the application of
these guidelines is set by the laws and practices in each
jurisdiction in which it is proposed to undertake
studies.
The purpose of ethical review is to consider the features
of a proposed study in the light of ethical principles, so
as to ensure that investigators have anticipated and
satisfactorily resolved possible ethical objections, and to
assess their responses to ethical issues raised by the
study. Not all ethical principles weigh equally. A study may
be assessed as ethical even if a usual ethical expectation,
such as confidentiality of data, has not been
comprehensively met, provided the potential benefits clearly
outweigh the risks and the investigators give assurances of
minimizing risks. It may even be unethical to reject such a
study, if its rejection would deny a community the benefits
it offers. The challenge of ethical review is to make
assessments that take into account potential risks and
benefits, and to reach decisions on which members of ethical
review committees may reasonably differ.
Different conclusions may result from different ethical
reviews of the same issue or proposal, and each conclusion
may be ethically reached, given varying circumstances of
place and time; a conclusion is ethical not merely because
of what has been decided but also owing to the process of
conscientious reflection and assessment by which it has been
reached.
GENERAL ETHICAL PRINCIPLES
All research involving human subjects should be conducted in
accordance with four basic ethical principles, namely
respect for persons, beneficence, non-maleficence,
and justice. It is usually assumed that these
principles guide the conscientious preparation of proposals
for scientific studies. In varying circumstances, they may
be expressed differently and given different weight, and
their application, in all good faith, may have different
effects and lead to different decisions or courses of
action. These principles have been much discussed and
clarified in recent decades, and it is the aim of these
Guidelines that they be applied to epidemiology.
Respect for persons incorporates at least two other
fundamental ethical principles, namely:
a) autonomy, which requires that those who are
capable of deliberation about their personal goals 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 is the ethical obligation to maximize
possible benefits and to minimize possible harms and wrongs.
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 assure the well-being of the research subjects.
Non-maleficence ("Do no harm") holds a central
position in the tradition of medical ethics, and guards
against avoidable harm to research subjects.
Justice requires that cases considered to be alike be
treated alike, and that cases considered to be different be
treated in ways that acknowledge the difference. When the
principle of justice is applied to dependent or vulnerable
subjects, its main concern is with the rules of
distributive justice. Studies should be designed to
obtain knowledge that benefits the class of persons of which
the subjects are representative: the class of persons
bearing the burden should receive an appropriate benefit,
and the class primarily intended to benefit should bear a
fair proportion of the risks and burdens of the study.
The rules of distributive justice are applicable within and
among communities. Weaker members of communities should not
bear disproportionate burdens of studies from which all
members of the community are intended to benefit, and more
dependent communities and countries should not bear
disproportionate burdens of studies from which all
communities or countries are intended to benefit.
General ethical principles may be applied at individual and
community levels. At the level of the individual
(microethics), ethics governs how one person should
relate to another and the moral claims of each member of a
community. At the level of the community, ethics applies to
how one community relates to another, and to how a community
treats each of its members (including prospective members)
and members of other groups with different cultural values
(macroethics). Procedures that are unethical at one level
cannot be justified merely because they are considered
ethically acceptable at the other.
ETHICAL PRINCIPLES
APPLIED TO EPIDEMIOLOGY
Informed Consent
Individual consent
1. When individuals are to be subjects of
epidemiological studies, their informed consent will usually
be sought. For epidemiological studies that use personally
identifiable private data, the rules for informed consent
vary, as discussed further below. Consent is informed when
it is given by a person who understands the purpose and
nature of the study, what participation in the study
requires the person to do and to risk, and what benefits are
intended to result from the study.
2. An investigator who proposes not to seek informed consent
has the obligation to explain to an ethical review committee
how the study would be ethical in its absence: it may be
impractical to locate subjects whose records are to be
examined, or the purpose of some studies would be frustrated
- for example, prospective subjects on being informed would
change the behaviour that it is proposed to study, or might
feel needlessly anxious about why they were subjects or
study. The investigator will provide assurances that strict
safeguards will be maintained to protect confidentiality and
that the study is aimed at protecting or advancing health.
Another justification for not seeking informed consent may
be that subjects are made aware through public announcements
that it is customary to make personal data available for
epidemiological studies.
3. An ethical issue may arise when occupational records,
medical records, tissue samples, etc. are used for a purpose
for which consent was not given, although the study
threatens no harm. Individuals or their public
representatives should normally be told that their data
might be used in epidemiological studies, and what means of
protecting confidentiality are provided. Consent is not
required for use of publicly available information, although
countries and communities differ with regard to the
definition of what information about citizens is regarded as
public. However, when such information is to be used, it is
understood that investigators will minimize disclosure of
personally sensitive information.
4. Some organizations and government agencies employ
epidemiologists who may be permitted by legislation or
employees' contracts to have access to data without
subjects' consent. These epidemiologists must then consider
whether it is ethical for them, in a given case, to use this
power of access to personal data. Ethically, they may still
be expected either to seek the consent of the individuals
concerned, or to justify their access without such consent.
Access may be ethical on such grounds as minimal risk of
harm to individuals, public benefit, and investigators'
protection of the confidentiality of the individuals whose
data they study.
Community agreement
5. When it is not possible to request informed
consent from every individual to be studied, the agreement
of a representative of a community or group may be sought,
but the representative should be chosen according to the
nature, traditions and political philosophy of the community
or group. Approval given by a community representative
should be consistent with general ethical principles. When
investigators work with communities, they will consider
communal rights and protection as they would individual
rights and protection. For communities in which collective
decision-making is customary, communal leaders can express
the collective will. However, the refusal of individuals to
participate in a study has to be respected: a leader may
express agreement on behalf of a community, but an
individual's refusal of personal participation is
binding.
6. When people are appointed by agencies outside a group,
such as a department of government, to speak for members of
the group, investigators and ethical review committees
should consider how authentically these people speak for the
group, and if necessary seek also the agreement of other
respresentatives. Representatives of a community or group
may sometimes be in a position to participate in designing
the study and in its ethical assessment.
7. The definition of a community or group for purposes of
epidemiological study may be a matter of ethical concern.
When members of a community are naturally conscious of its
activities as a community and feel common interests with
other members, the community exists, irrespective of the
study proposal. Investigators will be sensitive to how a
community is constituted or defines itself, and will respect
the rights of underprivileged groups.
8. For puposes of epidemiological study, investigators may
define groups that are composed of statistically,
geographically or otherwise associated individuals who do
not normally interact socially. When such groups are
artificially created for scientific study, group members may
not readily be identifiable as leaders or representatives,
and individuals may not be expected to risk disadvantage for
the benefit of others. Accordingly, it will be more
difficult to ensure group representation, and all the more
important to obtain subjects' free and informed consent to
participate.
Selective disclosure of information
9. In epidemiology, an acceptable study technique
involves selective disclosure of information, which seems to
conflict with the principle of informed consent. For certain
epidemiological studies non-disclosure is permissible, even
essential, so as to not influence the spontaneous conduct
under investigation, and to avoid obtaining responses that
the respondent might give in order to please the questioner.
Selective disclosure may be benign and ethically
permissible, provided that it does not induce subjects to do
what they would not otherwise consent to do. An ethical
review committee may permit disclosure of only selected
information when this course is justified.
Undue influence
10. Prospective subjects may not feel free to refuse
requests from those who have power or influence over them.
Therefore the identity of the investigator or other person
assigned to invite prospective subjects to participate must
be made known to them. Investigators are expected to explain
to the ethical review committee how they propose to
neutralize such apparent influence. It is ethically
questionable whether subjects should be recruited from among
groups that are unduly influenced by persons in authority
over them or by community leaders, if the study can be done
with subjects who are not in this category.
Inducement to participate
1 1. Individuals or communities should not be
pressured to participate in a study. However, it can be hard
to draw the line between exerting pressure or offering
inappropriate inducements and creating legitimate
motivation. The benefits of a study, such as increased or
new knowledge, are proper inducements. However, when people
or communities lack basic health services or money, the
prospect of being rewarded by goods, services or cash
payments can induce participation. To determine the ethical
propriety of such inducements, they must be assessed in the
light of the traditions of the culture.
12. Risks involved in participation should be acceptable to
subjects even in the absence of inducement. It is acceptable
to repay incurred expenses, such as for travel. Similarly,
promises of compensation and care for damage, injury or loss
of income should not be considered inducements.
Maximizing Benefit
Communication of study results
13. Part of the benefit that communities, groups and
individuals may reasonably expect from participating in
studies is that they will be told of findings that pertain
to their health. Where findings could be applied in public
health measures to improve community health, they should be
communicated to the health authorities. In informing
individuals of the findings and their pertinence to health,
their level of literacy and comprehension must be
considered. Research protocols should include provision for
communicating such information to communities and
individuals.
Research findings and advice to communities should be
publicized by whatever suitable means are available. When
HIV-prevalence studies are conducted by unlinked anonymous
screening, there should be, where feasible, provision for
voluntary HIV-antibody testing under conditions of informed
consent, with pre- and post-test counselling, and assurance
of confidentiality.
Impossibility of communicating study results
14. Subjects of epidemiological studies should be
advised that it may not be possible to inform them about
findings that pertain to their health, but that they should
not take this to mean that they are free of the disease or
condition under study. Often it may not be possible to
extract from pooled findings information pertaining to
individuals and their families, but when findings indicate a
need of health care, those concerned should be advised of
means of obtaining personal diagnosis and advice.
When epidemiological data are unlinked, a disadvantage to
subjects is that individuals at risk cannot be informed of
useful findings pertinent to their health. When subjects
cannot be advised individually to seek medical attention,
the ethical duty to do good can be served by making
pertinent health-care advice available to their
communities.
Release of study results
15. Investigators may be unable to compel release of
data held by governmental or commercial agencies, but as
health professionals they have an ethical obligation to
advocate the release of information that is in the public
interest.
Sponsors of studies may press investigators to present their
findings in ways that advance special interests, such as to
show that a product or procedure is or is not harmful to
health. Sponsors must not present interpretations or
inferences, or theories and hypotheses, as if they were
proven truths.
Health care for the community under study
16. The undertaking of an epidemiological project in
a developing country may create the expectation in the
community concerned that it will be provided with health
care, at least while the research workers are present. Such
an expectation should not be frustrated, and, where people
need health care, arrangements should be made to have them
treated or they should be referred to a local health service
that can provide the needed care.
Training local health personnel
17. While studies are in progress, particularly in
developing countries, the opportunity should be taken to
train local health workers in skills and techniques that can
be used to improve health services. For instance, by
training them in the operation of measuring devices and
calculating machines, when a study team departs it leaves
something of value, such as the ability to monitor disease
or mortality rates.
Minimizing Harm
Causing harm and doing wrong
18. Investigators planning studies will recognize
the risk of causing harm, in the sense of bringing
disadvantage, and of doing wrong, in the sense of
transgressing values. Harm may occur, for instance, when
scarce health personnel are diverted from their routine
duties to serve the needs of a study, or when, unknown to a
community, its health-care priorities are changed. It is
wrong to regard members of communities as only impersonal
material for study, even if they are not harmed.
19. Ethical review must always assess the risk of subjects
or groups suffering stigmatization, prejudice, loss of
prestige or self-esteem, or economic loss as a result of
taking part in a study. Investigators will inform ethical
review committees and prospective subjects of perceived
risks, and of proposals to prevent or mitigate them.
Investigators must be able to demonstrate that the benefits
outweigh the risks for both individuals and groups. There
should be a thorough analysis to determine who would be at
risk and who would benefit from the study. It is unethical
to expose persons to avoidable risks disproportionate to the
expected benefits, or to permit a known risk to remain if it
can be avoided or at least minimized.
20. When a healthy person is a member of a population or
sub-group at raised risk and engages in high-risk
activities, it is unethical not to propose measures for
protecting the population or sub-group.
Preventing harm to groups
21. Epidemiological studies may inadvertently expose
groups as well as individuals to harm, such as economic
loss, stigmatization, blame, or withdrawal of services.
Investigators who find sensitive information that may put a
group at risk of adverse criticism or treatment should be
discreet in communicating and explaining their findings.
When the location or circumstances of a study are important
to understanding the results, the investigators will explain
by what means they propose to protect the group from harm or
disadvantage; such means include provisions for
confidentiality and the use of language that does not imply
moral criticism of subjects' behaviour.
Harmful publicity
22. Conflict may appear between, on the one hand,
doing no harm and, on the other, telling the truth and
openly disclosing scientific findings. Harm may be mitigated
by interpreting data in a way that protects the interests of
those at risk, and is at the same time consistent with
scientific integrity. Investigators should, where possible,
anticipate and avoid misinterpretation that might cause
harm.
Respect for social mores
23. Disruption of social mores is usually regarded
as harmful. Although cultural values and social mores must
be respected, it may be a specific aim of an epidemiological
study to stimulate change in certain customs or conventional
behaviour to lead through change to healthful behaviour -
for instance, with regard to diet or a hazardous
occupation.
24. Although members of communities have a right not to have
others impose an uninvited "good" on them, studies expected
to result in health benefits are usually considered
ethically acceptable and not harmful. Ethical review
committees should consider a study's potential for
beneficial change. However, investigators should not
overstate such benefits, in case a community's agreement to
participate is unduly influenced by its expectation of
better health services.
Sensitivity to different cultures
25. Epidemiologists often investigate cultural
groups other than their own, inside or outside their own
countries, and undertake studies initiated from outside the
culture, community or country in which the study is to be
conducted. Sponsoring and host countries may differ in the
ways in which, in their cultures, ethical values are
understood and applied - for instance, with regard to
autonomy of individuals.
Investigators must respect the ethical standards of their
own countries and the cultural expectations of the societies
in which epidemiological studies are undertaken, unless this
implies a violation of a transcending moral rule.
Investigators risk harming their reputation by pursuing work
that host countries find acceptable but their own countries
consider offensive. Similarly, they may transgress the
cultural values of the host countries by uncritically
conforming to the expectations of their own.
Confidentiality
26. Research may involve collecting and storing data
relating to individuals and groups, and such data, if
disclosed to third parties, may cause harm or distress.
Consequently, investigators should make arrangements for
protecting the confidentiality of such data by, for example,
omitting information that might lead to the identification
of individual subjects, or limiting access to the data, or
by other means. It is customary in epidemiology to aggregate
numbers so that individual identities are obscured. Where
group confidentiality cannot be maintained or is violated,
the investigators should take steps to maintain or restore a
group's good name and status. Information obtained about
subjects is generally divisible into:
Unlinked information, which cannot be linked,
associated or connected with the person to whom it refers;
as this person is not known to the investigator,
confidentiality is not at stake and the question of consent
does not arise.
Linked information, which may be:
- anonymous, when the information cannot be linked to the
person to whom it refers except by a code or other means
known only to that person, and the investigator cannot know
the identity of the person;
- non-nominal, when the information can be linked to the
person by a code (not including personal identification)
known to the person and the investigator; or
- nominal or nominative, when the information is linked to
the person by means of personal identification, usually the
name.
Epidemiologists discard personal identifying information
when consolidating data for purposes of statistical
analysis. Identifiable personal data will not be used when a
study can be done without personal identification - for
instance, in testing unlinked anonymous blood samples for
HIV infection. When personal identifiers remain on records
used for a study, investigators should explain to review
committees why this is necessary and how confidentiality
will be protected. If, with the consent of individual
subjects, investigators link different sets of data
regarding individuals, they normally preserve
confidentiality by aggregating individual data into tables
or diagrams. In government service the obligation to protect
confidentiality is frequently reinforced by the practice of
swearing employees to secrecy.
Conflict of interest
Identification of conflict of interest
27. It is an ethical rule that investigators should
have no undisclosed conflict of interest with their study
collaborators, sponsors or subjects. Investigators should
disclose to the ethical review committee any potential
conflict of interest. Conflict can arise when a commercial
or other sponsor may wish to use study results to promote a
product or service, or when it may not be politically
convenient to disclose findings.
28. Epidemiological studies may be initiated, or financially
or otherwise supported, by governmental or other agencies
that employ investigators. In the occupational and
environmental health fields, several well-defined
special-interest groups may be in conflict: shareholders,
management, labour, government regulatory agencies, public
interest advocacy groups, and others. Epidemiological
investigators may be employed by any of these groups. It can
be difficult to avoid pressures resulting from such conflict
of interest, and consequent distorted interpretations of
study findings. Similar conflict may arise in studies of the
effects of drugs and in testing medical devices.
29. Investigators and ethical review committees will be
sensitive to the risk of conflict, and committees will not
normally approve proposals in which conflict of interest is
inherent. If, exceptionally, such a proposal is approved,
the conflict of interest should be disclosed to prospective
subjects and their communities.
30. There may appear to be conflict when subjects do not
want to change their behaviour and investigators believe
that they ought to do so for the sake of their health.
However, this may not be a true conflict of interest, as the
investigators are motivated by the subjects' health
interests.
Scientific objectivity and advocacy
31. Honesty and impartiality are essential in
designing and conducting studies, and presenting and
interpreting findings. Data will not be withheld,
misrepresented or manipulated. Investigators may discover
health hazards that demand correction, and become advocates
of means to protect and restore health. In this event, their
advocacy must be seen to rely on objective, scientific
data.
ETHICAL REVIEW PROCEDURES
Requirement of ethical review
32. The provisions for ethical review in a society
are influenced by economic and political considerations, the
organization of health care and research, and the degree of
independence of investigators. Whatever the circumstances,
there is a responsibility to ensure that the Declaration of
Helsinki and the CIOMS International Guidelines for
Biomedical Research Involving Human Subjects are taken into
account in epidemiological studies.
33. The requirement that proposals for epidemiological
studies be submitted to independent ethical review applies
irrespective of the source of the proposals - academic,
governmental, health-care, commercial, or other. Sponsors
should recognize the necessity of ethical review and
facilitate the establishment of ethical review committees.
Sponsors and investigators are expected to submit their
proposals to ethical review, and this should not be
overlooked even when sponsors have legal power to permit
investigators access to data. An exception is justified when
epidemiologists must investigate outbreaks of acute
communicable diseases. Then they must proceed without delay
to identify and control health risks. They cannot be
expected to await the formal approval of an ethical review
committee. Nevertheless, in such circumstances the
investigator will, as far as possible, respect the rights of
individuals, namely freedom, privacy, and
confidentiality.
Ethical review committees
34. Ethical review committees may be created under
the aegis of national or local health administrations,
national medical research councils, or other nationally
representative health-care bodies. The authority of
committees operating on a local basis may be confined to one
institution or extend to all biomedical studies undertaken
in a defined political jurisdiction. However committees are
created, and however their jurisdiction is defined, they
should establish working rules - regarding, for instance,
frequency of meetings, a quorum of members, decision-making
procedures, and review of decisions, and they should issue
such rules to prospective investigators.
35. In a highly centralized administration, a national
review committee may be constituted to review study
protocols from both scientific and ethical standpoints. In
countries with a decentralized administration, protocols are
more effectively and conveniently reviewed at a local or
regional level. Local ethical review committees have two
responsibilities: - to verify that all proposed
interventions have been assessed for safety by a competent
expert body, and - to ensure that all other ethical issues
are satisfactorily resolved.
36. Local review committees act as a panel of investigators'
peers, and their composition should be such as can ensure
adequate review of the study proposals referred to them.
Their membership should include epidemiologists, other
health practitioners, and lay persons qualified to represent
a range of community, cultural and moral values. Committees
should have diverse composition and include representatives
of any populations specially targeted for study. The members
should change periodically to prevent individuals from
becoming unduly influential, and to widen the network
involved in ethical review. Independence from the
investigators is maintained by precluding any member with a
direct interest in a proposal from participating in its
assessment.
Ethical conduct of members of review committees
37. Ethical review committee members must carefully
guard against any tendencies to unethical conduct on their
own part. In particular, they should protect the
confidentiality of review-committee documents and
discussions. Also, they should not compel investigators to
submit to unnecessary repetition of review.
Representation of the community
38. The community to be studied should be
represented in the ethical review process. This is
consistent with respect for the culture, the dignity and
self-reliance of the community, and the aim of achieving
community members' full understanding of the study. It
should not be considered that lack of formal education
disqualifies community members from joining in constructive
discussion on issues relating to the study and the
application of its findings.
Balancing personal and social perspectives
39. In performing reviews, committees will consider
both personal and social perspectives. While, at the
personal level, it is essential to ensure individual
informed and free consent, such consent alone may not be
sufficient to render a study ethical if the individual's
community finds the study objectionable. Social values may
raise broad issues that affect future populations and the
physical environment. For example, in proposals for the
widespread application of measures to control intermediate
hosts of disease organisms, investigators will anticipate
the effects of those measures on communities and the
environment, and review committees will ensure that there is
adequate provision for the investigators to monitor the
application of the measures so as to prevent unwanted
effects.
Assuring scientific soundness
40. The primary functions of ethical review are to
protect human subjects against risks of harm or wrong, and
to facilitate beneficial studies. Scientific review and
ethical review cannot be considered separately: a study that
is scientifically unsound is unethical in exposing subjects
to risk or inconvenience and achieving no benefit in
knowledge. Normally, therefore, ethical review committees
consider both scientific and ethical aspects. An ethical
review committee may refer technical aspects of scientific
review to a scientifically qualified person or committee,
but will reach its own decision, based on such qualified
advice, on scientific soundness. If a review committee is
satisfied that a proposal is scientifically sound, it will
then consider whether any risk to the subject is justified
by the expected benefit, and whether the proposal is
satisfactory with regard to informed consent and other
ethical requirements.
Assessment of safety and quality
41. All drugs and devices under investigation must
meet adequate standards of safety. In this respect, many
countries lack resources to undertake independent assessment
of technical data. A governmental multidisciplinary
committee with authority to co-opt experts is the most
suitable body for assessing the safety and quality of
medicines, devices and procedures. Such a committee should
include clinicians, pharmacologists, statisticians and
epidemiologists, among others; for epidemiological studies,
epidemiologists occupy a position of obvious significance.
Ethical review procedures should provide for consultation
with such a committee.
Equity in the selection of subjects
42. Epidemiological studies are intended to benefit
populations, but individual subjects are expected to accept
any risks associated with studies. When research is intended
to benefit mostly the better off or healthier members of a
population, it is particularly important in selecting
subjects to avoid inequity on the basis of age,
socioeconomic status, disability or other variables.
Potential benefits and harm should be distributed equitably
within and among communities that differ on grounds of age,
gender, race, or culture, or other variables.
Vulnerable and dependent groups
43. Ethical review committees should be particularly
vigilant in the case of proposals involving populations
primarily of children, pregnant and nursing women, persons
with mental illness or handicap, members of communities
unfamiliar with medical concepts, and persons with
restricted freedom to make truly independent choices, such
as prisoners and medical students. Similar vigilance is
called for in the case of proposals for invasive research
with no direct benefit to its subjects.
Control groups
44. Epidemiological studies that require control
(comparison) or placebotreated (i.e., non-treated) groups
are governed by the same ethical standards as those that
apply to clinical trials. Important principles are that:
(i) the control group in a study of a condition that can
cause death, disability or serious distress should receive
the most appropriate currently established therapy; and
(ii) if a procedure being tested against controls is
demonstrated to be superior, it should be offered promptly
to members of the control group.
A study will be terminated prematurely if the outcome in one
group is clearly superior to that in the other, and all
subjects will be offered the better treatment. Research
protocols should include "stopping rules", i.e., procedures
to monitor for, and act upon, such an event. Investigators
must continually bear in mind the potential benefits of the
study to the control group, and the prospect of improved
health care from applying the findings to the control
group.
Randomization
45. Trials in which the choice of regimen or
procedure is determined by random allocation should be
conducted only when there is genuine uncertainty about
differences in outcome of two or more regimens or
procedures. Where randomization is to be used, all subjects
will be informed of the uncertainty about optimum regimens
or procedures, and that the reason for the trial is to
determine which of two or more is in the subjects' best
interests. Informing subjects about such uncertainty can in
itself arouse anxiety among patients, who may already be
anxious for other reasons; therefore, tact and delicacy are
required in communicating the information. Ethical review
committees should ascertain whether investigators refer
explicitly to informing subjects about this uncertainty, and
should enquire what will be done to allay subjects' anxiety
about it.
Random allocation also can cause anxiety: persons chosen
for, or excluded from, the experimental regimen or procedure
may become anxious or concerned about the reasons for their
being chosen or excluded. Investigators may have to
communicate to members of the study population some basic
concepts about application of the laws of chance, and
reassure them that the process of random allocation is not
discriminatory.
Provision for multi-centre studies
46. When participation in a multi-centre study is
proposed according to a common protocol, a committee will
respect different opinions of other committees, while not
compromising on the application of the ethical standards
that it expects investigators to observe; and it will
attempt to reconcile differences so as to preserve the
benefits that only a multi-centre study can achieve. One way
of doing so could be to include in the common protocol the
necessary procedures. Another would be for the several
committees to delegate their review functions to a joint
committee of the centres collaborating in the study.
Compensation for accidental injury
47. Some epidemiological studies may inadvertently
cause harm. Monetary losses should be promptly repaid.
Compensation is difficult when it is not appropriate to make
monetary payments. Breach of confidentiality or insensitive
publication of study findings, leading to loss of group
prestige, or to indignity, may be difficult to remedy. When
harm results from a study, the body that has sponsored or
endorsed the study should be prepared to make good the
injury, by public apology or reparation.
Externally sponsored studies
48. Externally sponsored studies are studies
undertaken in a host country but initiated, financed, and
sometimes wholly or partly carried out by an external
international or national agency, with the collaboration or
agreement of the authorities or the host country.
Such a study implies two ethical obligations:
The initiating agency should submit the study protocol to
ethical review, in which the ethical standards should be no
less exacting than they would be for a study carried out in
the initiating country.
The ethical review committee in the host country should
satisfy itself that the proposed study meets its own ethical
requirements.
49. It is in the interest of the host country to require
that proposals initiated and financed externally be
submitted for ethical approval in the initiating country,
and for endorsement by a responsible authority of the same
country, such as a health administration, a research
council, or an academy of medicine or science.
50. A secondary objective of externally sponsored studies
should be the training of health personnel of the host
country to carry out similar study projects
independently.
51. Investigators must comply with the ethical rules of the
funding country and the host country. Therefore, they must
be prepared to submit study proposals to ethical review
committees in each country. Alternatively, there may be
agreement to the decision of a single or joint ethical
review committee. Moreover, if an international agency
sponsors a study, its own ethical review requirements may
have to be satisfied.
Distinguishing between research and programme
evaluation
52. It may at times be difficult to decide whether a
particular proposal is for an epidemiological study or for
evaluation of a programme on the part of a health-care
institution or department. The defining attribute of
research is that it is designed to produce new,
generalizable knowledge, as distinct from knowledge
pertaining only to a particular individual or programme.
For instance, a governmental or hospital department may want
to examine patients' records to determine the safety and
efficacy of a facility, unit or procedure. If the
examination is for research purposes, the proposal should be
submitted to the committee that considers the ethical
features of research proposals. However, if it is for the
purpose of programme evaluation, conducted perhaps by staff
of the institution to evaluate a therapeutic programme for
its effects, the proposal may not need to be submitted to
ethical review; on the contrary, it could be considered poor
practice and unethical not to undertake this type of quality
assurance. The prospect of benefit or avoidance of harm to
patients may constitute an ethical value that outweighs the
risk of breaching the confidentiality of former patients
whose medical records are liable to be inspected without
their consent.
If if is not clear whether a proposal involves
epidemiological study or routine practice, it should be
submitted to the ethical review committee responsible for
epidemiological protocols, for its opinion on whether the
proposal falls within its mandate.
Information to be provided by investigators
53. Whatever the pattern of the procedure of ethical
review, the investigator must submit a detailed protocol
comprising:
- a clear statement of the objectives, having regard to the
present state of knowledge, and a justification for
undertaking the investigation in human subjects;
- a precise description of all proposed procedures and
interventions, including intended dosages of drugs and
planned duration of treatment;
- a statistical plan indicating the number of subjects to be
involved;
- the criteria for terminating the study; and
- the criteria determining admission and withdrawal of
individual subjects, including full details of the procedure
for obtaining informed consent.
Also, the protocol should:
- include information to establish the safety of each
proposed procedure and intervention, and of any drug,
vaccine or device to be tested, including the results of
relevant laboratory and animal research;
- specify the presumed benefits to subjects, and the
possible risks of proposed procedures
- indicate the means and documents proposed to be used for
eliciting informed consent, or, when such consent cannot be
requested, state what approved alternative means of
obtaining agreement will be used, and how it is proposed to
protect the rights and assure the welfare of subjects;
- provide evidence that the investigator is properly
qualified and experienced, or, when necessary, works under a
competent supervisor, and that the investigator has access
to adequate facilities for the safe and efficient conduct of
the research; - describe the proposed means of protecting
confidentiality during the processing and publication of
study results; and
- refer to any other ethical considerations that may be
involved, and indicate that the provisions of the
Declaration of Helsinki will be respected.
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