Appendix V: Ethics References

# A. The Belmont Report

**Ethical Principles and Guidelines for the Protection of**

**Human Subjects of Research**

<http://www.fda.gov/oc/oha/IRB/toc11.html#The_Belmont_Report>

*The National Commission*

*for the Protection of Human Subjects of*

*Biomedical and Behavioral Research*

*April 18, 1979*

**Ethical Principles and Guidelines for Research Involving Human
Subjects**

Scientific research has produced substantial social benefits. It has
also posed some troubling ethical questions. Public attention was drawn
to these questions by reported abuses of human subjects in biomedical
experiments, especially during the Second World War. During the
Nuremberg War Crime Trials, the Nuremberg code was drafted as a set of
standards for judging physicians and scientists who had conducted
biomedical experiments on concentration camp prisoners. This code became
the prototype of many later codes intended to assure that research
involving human subjects would be carried out in an ethical manner.

The codes consist of rules, some general, others specific, that guide
the investigators or the reviewers of research in their work. Such rules
often are inadequate to cover complex situations; at times they come
into conflict, and they are frequently difficult to interpret or apply.
Broader ethical principles will provide a basis on which specific rules
may be formulated, criticized and interpreted.

Three principles, or general prescriptive judgments, that are relevant
to research involving human subjects are identified in this statement.
Other principles may also be relevant. These three are comprehensive,
however, and are stated at a level of generalization that should assist
scientists, subjects, reviewers and interested citizens to understand
the ethical issues inherent in research involving human subjects. These
principles cannot always be applied so as to resolve beyond dispute
particular ethical problems. The objective is to provide an analytical
framework that will guide the resolution of ethical problems arising
from research involving human subjects.

This statement consists of a distinction between research and practice,
a discussion of the three basic ethical principles, and remarks about
the application of these principles.

**A. Boundaries Between Practice and Research.** It is important to
distinguish between biomedical and behavioral research, on the one hand,
and the practice of accepted therapy on the other, in order to know what
activities ought to undergo review for the protection of human subjects
of research. The distinction between research and practice is blurred
partly because both often occur together (as in research designed to
evaluate a therapy) and partly because notable departures from standard
practice are often called \"experimental\" when the terms
\"experimental\" and \"research\" are not carefully defined.

For the most part, the term \"practice\" refers to interventions that
are designed solely to enhance the well being of an individual patient
or client and that have a reasonable expectation of success. The purpose
of medical or behavioral practice is to provide diagnosis, preventive
treatment or therapy to particular individuals. By contrast, the term
\"research\" designates an activity designed to test an hypothesis,
permit conclusions to be drawn, and thereby to develop or contribute to
generalizable knowledge (expressed, for example, in theories,
principles, and statements of relationships). Research is usually
described in a formal protocol that sets forth an objective and a set of
procedures designed to reach that objective.

> When a clinician departs in a significant way from standard or
> accepted practice, the innovation does not, in and of itself,
> constitute research. The fact that a procedure is \"experimental,\" in
> the sense of new, untested or different, does not automatically place
> it in the category of research. Radically new procedures of this
> description should, however, be made the object of formal research at
> an early stage in order to determine whether they are safe and
> effective. Thus, it is the responsibility of medical practice
> committees, for example, to insist that a major innovation be
> incorporated into a formal research project.
>
> Research and practice may be carried on together when research is
> designed to evaluate the safety and efficacy of a therapy. This need
> not cause any confusion regarding whether or not the activity requires
> review; the general rule is that if there is any element of research
> in an activity, that activity should undergo review for the protection
> of human subjects.

#### B. Basic Ethical Principles. The expression \"basic ethical principles\" refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethic of research involving human subjects: the principles of respect for persons, beneficence and justice. 

> 1\. **Respect for Persons.** Respect for persons incorporates at least
> two ethical convictions; first, that individuals should be treated as
> autonomous agents, and second, that persons with diminished autonomy
> are entitled to protection. The principle of respect for persons thus
> divides into two separate moral requirements: the requirement to
> acknowledge autonomy and the requirement to protect those with
> diminished autonomy.
>
> An autonomous person is an individual capable of deliberation about
> personal goals and of acting under the direction of such deliberation.
> To respect autonomy is to give weight to autonomous persons\'
> considered opinions and choices while refraining from obstructing
> their actions unless they are clearly detrimental to others. To show
> lack of respect for an autonomous agent is to repudiate that person\'s
> considered judgments, to deny an individual the freedom to act on
> those considered judgments, or to withhold information necessary to
> make a considered judgment, when there are no compelling reasons to do
> so.
>
> However, not every human being is capable of self-determination. The
> capacity for self-determination matures during an individual\'s life,
> and some individuals lose this capacity wholly or in part because of
> illness, mental disability, or circumstances that severely restrict
> liberty. Respect for the immature and the incapacitated may require
> protecting them as they mature or while they are incapacitated.
>
> Some persons are in need of extensive protection, even to the point of
> excluding them from activities which may harm them; other persons
> require little protection beyond making sure they undertake activities
> freely and with awareness of possible adverse consequences. The extent
> of protection afforded should depend upon the risk of harm and the
> likelihood of benefit. The judgment that any individual lacks autonomy
> should be periodically reevaluated and will vary in different
> situations.
>
> In most cases of research involving human subjects, respect for
> persons demands that subjects enter into the research voluntarily and
> with adequate information. In some situations, however, application of
> the principle is not obvious. The involvement of prisoners as subjects
> of research provides an instructive example. On the one hand, it would
> seem that the principle of respect for persons requires that prisoners
> not be deprived of the opportunity to volunteer for research. On the
> other hand, under prison conditions they may be subtly coerced or
> unduly influenced to engage in research activities for which they
> would not otherwise volunteer. Respect for persons would then dictate
> that prisoners be protected. Whether to allow prisoners to
> \"volunteer\" or to \"protect\" them presents a dilemma. Respecting
> persons, in most hard cases, is often a matter of balancing competing
> claims urged by the principle of respect itself.
>
> 2\. **Beneficence.** Persons are treated in an ethical manner not only
> by respecting their decisions and protecting them from harm, but also
> by making efforts to secure their well-being. Such treatment falls
> under the principle of beneficence. The term \"beneficence\" is often
> understood to cover acts of kindness or charity that go beyond strict
> obligation. In this document, beneficence is understood in a stronger
> sense as an obligation. Two general rules have been formulated as
> complementary expressions of beneficent actions in this sense: (1) do
> not harm and (2) maximize possible benefits and minimize possible
> harms.
>
> The Hippocratic maxim \"do no harm\" has long been a fundamental
> principle of medical ethics. Claude Bernard extended it to the realm
> of research, saying that one should not injure one person regardless
> of the benefits that might come to others. However, even avoiding harm
> requires learning what is harmful; and, in the process of obtaining
> this information, persons may be exposed to risk of harm. Further, the
> Hippocratic Oath requires physicians to benefit their patients
> \"according to their best judgment.\" Learning what will in fact
> benefit may require exposing persons to risk. The problem posed by
> these imperatives is to decide when it is justifiable to seek certain
> benefits despite the risks involved, and when the benefits should be
> foregone because of the risks.
>
> The obligations of beneficence affect both individual investigators
> and society at large, because they extend both to particular research
> projects and to the entire enterprise of research. In the case of
> particular projects, investigators and members of their institutions
> are obliged to give forethought to the maximization of benefits and
> the reduction of risk that might occur from the research
> investigation. In the case of scientific research in general, members
> of the larger society are obliged to give forethought the longer term
> benefits and risks that may result from the improvement of knowledge
> and from the development of novel medical, psychotherapeutic, and
> social procedures.
>
> The principle of beneficence often occupies a well-defined justifying
> role in many areas of research involving human subjects. An example is
> found in research involving children. Effective ways of treating
> childhood diseases and fostering healthy development are benefits that
> serve to justify research involving children - even when individual
> research subjects are not direct beneficiaries. Research also makes is
> possible to avoid the harm that may result from the application of
> previously accepted routine practices that on closer investigation
> turn out to be dangerous. But the role of the principle of beneficence
> is not always so unambiguous. A dive-cult ethical problem remains, for
> example, about research that presents more than minimal risk without
> immediate prospect of direct benefit to the children involved. Some
> have argued that such research is inadmissible, while others have
> pointed out that this limit would rule out much research promising
> great benefit to children in the future. Here again, as with all hard
> cases, the different claims covered by the principle of beneficence
> may come into conflict and force difficult choices.
>
> 3\. **Justice.** Who ought to receive the benefits of research and
> bear its burdens? This is a question of justice, in the sense of
> \"fairness in distribution\" or \"what is deserved.\" An injustice
> occurs when some benefit to which a person is entitled is denied
> without good reason or when some burden is imposed unduly. Another way
> of conceiving the principle of justice is that equals ought to be
> treated equally. However, this statement requires explication. Who is
> equal and who is unequal? What considerations justify departure from
> equal distribution? Almost all commentators allow that distinctions
> based on experience, age, deprivation, competence, merit and position
> do sometimes constitute criteria justifying differential treatment for
> certain purposes. It is necessary, then, to explain in what respects
> people should be treated equally. There are several widely accepted
> formulations of just ways to distribute burdens and benefits. Each
> formulation mentions some relevant property on the basis of which
> burdens and benefits should be distributed. These formulations are (1)
> to each person an equal share, (2) to each person according to
> individual need, (3) to each person according to individual effort,
> (4) to each person according to societal contribution, and (5) to each
> person according to merit.
>
> Questions of justice have long been associated with social practices
> such as punishment, taxation and political representation. Until
> recently these questions have not generally been associated with
> scientific research. However, they are foreshadowed even in the
> earliest reflections on the ethics of research involving human
> subjects. For example, during the 19th and early 20th centuries the
> burdens of serving as research subjects fell largely upon poor ward
> patients, while the benefits of improved medical care flowed primarily
> to private patients. Subsequently, the exploitation of unwilling
> prisoners as research subjects in Nazi concentration camps was
> condemned as a particularly flagrant injustice. In this country, in
> the 1940\'s, the Tuskegee syphilis study used disadvantaged, rural
> black men to study the untreated course of a disease that is by no
> means confined to that population. These subjects were deprived of
> demonstrably effective treatment in order not to interrupt the
> project, long after such treatment became generally available.
>
> Against this historical background, it can be seen how conceptions of
> justice are relevant to research involving human subjects. For
> example, the selection of research subjects needs to be scrutinized in
> order to determine whether some classes (e.g., welfare patients,
> particular racial and ethnic minorities, or persons confined to
> institutions) are being systematically selected simply because of
> their easy availability, their compromised position, or their
> manipulability, rather than for reasons directly related to the
> problem being studied. Finally, whenever research supported by public
> funds leads to the development of therapeutic devices and procedures,
> justice demands both that these not provide advantages only to those
> who can afford them and that such research should not unduly involve
> persons from groups unlikely to be among the beneficiaries of
> subsequent applications of the research.

#### C. Applications. Applications of the general principles to the conflict of research leads to consideration of the following requirements: informed consent, risk/benefit assessment, and the selection of subjects of research. 

> 1\. **Informed Consent.** Respect for persons requires that subjects,
> to the degree that they are capable, be given the opportunity to
> choose what shall or shall not happen to them. This opportunity is
> provided when adequate standards for informed consent are satisfied.
> While the importance of informed consent is unquestioned, controversy
> prevails over the nature and possibility of an informed consent.
> Nonetheless, there is widespread agreement that the consent process
> can be analyzed as containing three elements: information,
> comprehension and voluntariness.
>
> Information. Most codes of research establish specific items for
> disclosure intended to assure that subjects are given sufficient
> information. These items generally include: the research procedure,
> their purposes, risks and anticipated benefits, alternative procedures
> (where therapy is involved), and a statement offering the subject the
> opportunity to ask questions and to withdraw at any time from the
> research. Additional items have been proposed, including how subjects
> are selected, the person responsible for the research, etc.
>
> However, a simple listing of items does not answer the question of
> what the standard should be for judging how much and what sort of
> information should be provided. One standard frequently invoked in
> medical practice, namely the information commonly provided by
> practitioners in the field or in the locale, is inadequate since
> research takes place precisely when a common understanding does not
> exist. Another standard, currently popular in malpractice law,
> requires the practitioner to reveal the information that reasonable
> persons would wish to know in order to make a decision regarding their
> care. This, too, seems insufficient since the research subject, being
> in essence a volunteer, may wish to know considerably more about risks
> gratuitously undertaken than do patients who deliver themselves into
> the hand of a clinician for needed care. It may be that a standard of
> \"the reasonable volunteer\" should be proposed: the extent and nature
> of information should be such that persons, knowing that the procedure
> is neither necessary for their care nor perhaps fully understood, can
> decide whether they wish to participate in the furthering of
> knowledge. Even when some direct benefit to them is anticipated, the
> subjects should understand clearly the range of risk and the voluntary
> nature of participation.
>
> A special problem of consent arises where informing subjects of some
> pertinent aspect of the research is likely to impair the validity of
> the research. In many cases, it is sufficient to indicate to subjects
> that they are being invited to participate in research of which some
> features will not be revealed until the research is concluded. In all
> cases of research involving incomplete disclosure, such research is
> justified only if it is clear that (1) incomplete disclosure is truly
> necessary to accomplish the goals of the research, (2) there are no
> undisclosed risks to subjects that are more than minimal, and (3)
> there is an adequate plan for debriefing subjects, when appropriate,
> and for dissemination of research results to them. Information about
> risks should never be withheld for the purpose of eliciting the
> cooperation of subjects, and truthful answers should always be given
> to direct questions about the research. Care should be taken to
> distinguish cases in which disclosure would destroy or invalidate the
> research from cases in which disclosure would simply inconvenience the
> investigator.
>
> Comprehension. The manner and context in which information is conveyed
> is as important as the information itself. For example, presenting
> information in a disorganized and rapid fashion, allowing too little
> time for consideration or curtailing opportunities for questioning,
> all may adversely affect a subject\'s ability to make an informed
> choice.
>
> Because the subject\'s ability to understand is a function of
> intelligence, rationality, maturity and language, it is necessary to
> adapt the preservation of the information to the subject\'s
> capabilities. Investigators are responsible for ascertaining that the
> subject has comprehended the information. While there is always an
> obligation to ascertain that the information about risk to subjects is
> complete and adequately comprehended, when the risks are more serious,
> that obligation increases. On occasion, it may be suitable to give
> some oral or written tests of comprehension.
>
> Special provision may need to be made when comprehension is severely
> limited \-\-- for example, by conditions of immaturity or mental
> disability. each class of subjects that one might consider as
> incompetent (e.g., infants and young children, mentally disabled
> patients, the terminally ill and the comatose) should be considered on
> its own terms. Even for these persons, however, respect requires
> giving them the opportunity to choose to the extent they are able,
> whether or not to participate in research. The objections of these
> subjects to involvement should be honored, unless the research entails
> pro-providing them a therapy unavailable elsewhere. Respect for
> persons also requires seeking the permission of other parties in order
> to protect the subjects from harm. Such persons are thus respected
> both by acknowledging their own wishes and by the use of third parties
> to protect them from harm.
>
> The third parties chosen should be those who are most likely to
> understand the incompetent subject\'s situation and to act in that
> person\'s best interest. The person authorized to act on behalf of the
> subject should be given an opportunity to observe the research as it
> proceeds in order to be able to withdraw the subject from the
> research, if such action appears in the subject\'s best interest.
>
> Voluntariness. An agreement to participate in research constitutes a
> valid consent only if voluntarily given. This element of informed
> consent requires conditions free of coercion and undue influence.
> Coercion occurs when an overt threat of harm is intentionally
> presented by one person to another in order to obtain compliance.
> Undue influence, by contrast, occurs through an offer of an excessive,
> unwarranted, inappropriate or improper reward or other overture in
> order to obtain compliance. Also, inducements that would ordinarily be
> acceptable may become undue influences if the subject is especially
> vulnerable.
>
> Unjustifiable pressures usually occur when persons in positions of
> authority or commanding influence \-\-- especially where possible
> sanctions are involved - urge a course of action for a subject. A
> continuum of such influencing factors exists, however, and it is
> impossible to state precisely where justifiable persuasion ends and
> undue influence begins. But undue influence would include actions such
> as manipulating a person\'s choice through the controlling influence
> of a close relative and threatening to withdraw health services to
> which an individual would otherwise be entitled.
>
> 2\. **Assessment of Risks and Benefits.** The assessment of risks and
> benefits requires a careful arrayal of relevant data, including, in
> some cases, alternative ways of obtaining the benefits sought in the
> research. Thus, the assessment presents both an opportunity and a
> responsibility to gather systematic and comprehensive information
> about proposed research. For the investigator, it is a means to
> examine whether the proposed research is properly designed. For a
> review committee, it is a method for determining whether the risks
> that will be presented to subjects are justified. For prospective
> subjects, the assessment will assist the determination whether or not
> to participate.
>
> The Nature and Scope of Risks and Benefits. The requirement that
> research be justified on the basis of a favorable risk / benefit
> assessment bears a close relation to the principle of beneficence,
> just as the moral requirement that informed consent be obtained is
> derived primarily from the principle of respect for persons.
>
> The term \"risk\" refers to a possibility that harm may occur.
> However, when expressions such as \"small risk\" or \"high risk\" are
> used, they usually refer (often ambiguously) both to the chance
> (probability) of experiencing a harm and the severity (magnitude) of
> the envisioned harm.
>
> The term \"benefit\" is used in the research context to refer to
> something of positive value related to health or welfare. Unlike
> \"risk,\" \"benefit\" is not a term that expresses probabilities. Risk
> is properly contrasted to probability of benefits, and benefits are
> properly contrasted with harms rather than risks of harm. Accordingly,
> so-called risk/ benefit assessments are concerned with the
> probabilities and magnitudes of possible harms and anticipated
> benefits. Many kinds of possible harms and benefits need to be taken
> into account. There are, for example, risks of psychological harm,
> physical harm, legal harm, social harm and economic harm and the
> corresponding benefits. While the most likely types of harms to
> research subjects are those of psychological or physical pain or
> injury, other possible kinds should not be overlooked.
>
> Risks and benefits of research may affect the individual subjects, the
> families of the individual subjects, and society at large (or special
> groups of subjects in society). Previous codes and Federal regulations
> have required that risks to subjects be outweighed by the sum of both
> the anticipated benefit to the subject, if any, and the anticipated
> benefit to society in the form of knowledge to be gained from the
> research. In balancing these different elements, the risks and
> benefits affecting the immediate research subject will normally carry
> special weight. On the other hand, interests other than those of the
> subject may on some occasions be sufficient by themselves to justify
> the risks involved in the research, so long as the subjects\' rights
> have been protected. Beneficence thus requires that we protect against
> risk of harm to subjects and also that we be concerned about the loss
> of the substantial benefits that might be gained from research.
>
> The Systematic Assessment of Risks and Benefits. It is commonly said
> that benefits and risks must be \"balanced\" and shown to be \"in a
> favorable ratio.\" The metaphorical character of these terms draws
> attention to the difficulty of making precise judgments. Only on rare
> occasions will quantitative techniques be available for the scrutiny
> of research protocols. However, the idea of systematic, non-arbitrary
> analysis of risks and benefits should be emulated insofar as possible.
> This ideal requires those making decisions about the justifiability of
> research to be thorough in the accumulation and assessment of
> information about all aspects of the research, and to consider
> alternatives systematically. This procedure renders the assessment of
> research more rigorous and precise, while making communication between
> review board members and investigators less subject to
> misinterpretation, misinformation and conflicting judgments. Thus,
> there should first be a determination of the validity of the
> presuppositions of the research; then the nature, probability and
> magnitude of risk should be distinguished with as much clarity as
> possible. The method of ascertaining risks should be explicit,
> especially where there is no alternative to the use of such vague
> categories as small or slight risk. It should also be determined
> whether an investigator\'s estimates of the probability of harm or
> benefits are reasonable, as judged by known facts or other available
> studies.
>
> Finally, assessment of the justifiability of research should reflect
> at least the following considerations: (1) Brutal or inhumane
> treatment of human subjects is never morally justified. (2) Risks
> should be reduced to those necessary to achieve the research
> objective. It should be determined whether it is in fact necessary to
> use human subjects at all. Risk can perhaps never be entirely
> eliminated, but it can often be reduced by careful attention to
> alternative procedures. (3) When research involves significant risk of
> serious impairment, review committees should be extraordinarily
> insistent on the justification of the risk (looking usually to the
> likelihood of benefit to the subject - or, in some rare cases, to the
> manifest voluntariness of the participation), (4) When vulnerable
> populations are involved in research, the appropriateness of involving
> them should itself be demonstrated. A number of variables go into such
> judgments, including the nature and degree of risk, the condition of
> the particular population involved, and the nature and level of the
> anticipated benefits. (5) Relevant risks and benefits must be
> thoroughly arrayed in documents and procedures used in the informed
> consent process.
>
> 3\. **Selection of Subjects.** Just as the principle of respect for
> persons finds expression in the requirements for consent, and the
> principle of beneficence in risk/ benefit assessment, the principle of
> justice gives rise to moral requirements that there be fair procedures
> and outcomes in the selection of research subjects.
>
> Justice is relevant to the selection of subjects of research at two
> levels: the social and the individual. Individual justice in the
> selection of subjects would require that researchers exhibit fairness:
> thus, they should not offer potentially beneficial research only to
> some patients who are in their favor or select only \"undesirable\"
> persons for risky research. Social justice requires that distinction
> be drawn between classes of subjects that ought, and ought not, to
> participate in any particular kind of research, based on the ability
> of members of that class to bear burdens and on the appropriateness of
> placing further burdens on already burdened persons. Thus, it can be
> considered a matter of social justice that there is an order of
> preference in the selection of classes of subjects (e.g., adults
> before children) and that some classes of potential subjects (e.g.,
> the institutionalized mentally infirm or prisoners) may be involved as
> research subjects, if at all, only on certain conditions.
>
> Injustice may appear in the selection of subjects, even if individual
> subjects are selected fairly by investigators and treated fairly in
> the course of research. Thus injustice arises from social, racial,
> sexual and cultural biases institutionalized in society. Thus, even if
> individual researchers are treating their research subjects fairly,
> and even if IRBs are taking care to assure that subjects are selected
> fairly within a particular institution, unjust social patterns may
> nevertheless appear in the overall distribution of the burdens and
> benefits of research. Although individual institutions or
> investigators may not be able to resolve a problem that is pervasive
> in their social setting. They can consider distributive justice in
> selecting research subjects.
>
> Some populations, especially institutionalized ones, are already
> burdened in many ways by their infirmities and environments. When
> research is proposed that involves risks and does not include a
> therapeutic component, other less burdened classes of persons should
> be called upon first to accept these risks of research, except where
> the research is directly related to the specific conditions of the
> class involved. Also, even though public funds for research may often
> flow in the same directions as public funds for health care, it seems
> unfair that populations dependent on public health care constitute a
> pool of preferred research subjects if more advantaged populations are
> likely to be the recipients of the benefits.
>
> One special instance of injustice results from the involvement of
> vulnerable subjects. Certain groups, such as racial minorities, the
> economically disadvantaged, the very sick, and the institutionalized
> may continually be sought as research subjects, owing to their ready
> availability in settings where research is conducted. Given their
> dependent status and their frequently compromised capacity for free
> consent, they should be protected against the danger of being involved
> in research solely for administrative convenience, or because they are
> easy to manipulate as a result of their illness or socioeconomic
> condition.
>
> \[FR 3751, Jan. 18, 1980, as amended at FR 58843, Sept. 5, 1980; FR
> 15622, Apr. 12, 1983\]

# B. Declaration of Helsinki (1996)

# 

**World Medical Association Declaration of Helsinki:**

**Recommendations Guiding Medical Doctors in**

**Biomedical Research Involving Human Subjects**

*Adopted by the 18th World Medical Assembly, Helsinki, Finland, June
1964*

*and amended by the*

*29th World Medical Assembly, Tokyo, Japan, October 1975,*

*35th World Medical Assembly, Venice, Italy, October 1983,*

*41st World Medical Assembly, Hong Kong, September 1989,*

*and the 48th General Assembly, Somerset West, Republic of South Africa,
October 1996*

**Introduction**

It is the mission of the physician to safeguard the health of the
people. His or her knowledge and conscience are dedicated the
fulfillment of this mission.

The Declaration of Geneva of the World Medical Assembly binds the
physician with the words, \"The health of my patient will be my first
consideration,\" and the International Code of Medical Ethics declares
that, \"A physician shall act only in the patient\'s interest when
providing medical care which might have the effect of weakening the
physical and mental condition of the patient.\"

The purpose of biomedical research involving human subjects must be to
improve diagnostic, therapeutic and prophylactic procedures and the
understanding of the aetiology and pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic
procedures involve hazards. This applies especially to biomedical
research.

Medical progress is based on research, which ultimately must rest in
part on experimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be
recognized between medical research in which the aim is essentially
diagnostic or therapeutic for a patient, and medical research, the
essential object of which is purely scientific and without implying
direct diagnostic or therapeutic value to the person subjected to the
research.

Special caution must be exercised in the conduct of research, which may
affect the environment, and the welfare of animals used for research
must be respected.

Because it is essential that the results of laboratory experiments be
applied to human beings to further scientific knowledge and to help
suffering humanity, the World Medical Association has prepared the
following recommendations as a guide to every physician in biomedical
research involving human subjects. They should be kept under review in
the future. It must be stressed that the standards as drafted are only a
guide to physicians all over the world. Physicians are not relieved from
criminal, civic and ethical responsibilities under the laws of their own
countries.

## I. Basic Principles

1\. Biomedical research involving human subjects must conform to
generally accepted scientific principles and should be based on
adequately performed laboratory and animal experimentation and on a
thorough knowledge of the scientific literature.

2\. The design and performance of each experimental procedure involving
human subjects should be clearly formulated in an experimental protocol
which should be transmitted for consideration, comment and guidance to a
specially appointed committee independent of the investigator and the
sponsor provided that this independent committee is in conformity with
the laws and regulations of the country in which the research experiment
is performed.

3\. Biomedical research involving human subjects should be conducted
only by scientifically qualified persons and under the supervision of a
clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never
rest on the subject of the research, even though the subject has given
his or her consent.

4\. Biomedical research involving human subjects cannot legitimately be
carried out unless the importance of the objective is in proportion to
the inherent risk to the subject.

5\. Every biomedical research involving human subjects should be
preceded by careful assessment of predictable risks in comparison with
foreseeable benefits to the subject or to others. Concern for the
interest of the subject must always prevail over the interests of
science and society.

6\. The right of the research subject to safeguard his or her integrity
must always be respected. Every precaution should be taken to respect
the privacy of the subject and to minimize the impact of the study on
the subject\'s physical and mental integrity and on the personality of
the subject.

7\. Physicians should abstain from engaging in research projects
involving human subjects unless they are satisfied that the hazards
involved are believed to be predictable. Physicians should cease any
investigation if the hazards are found to outweigh the potential
benefits.

8\. In publication of the results of his or her research, the physician
is obliged to preserve the accuracy of the results. Reports of
experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.

9\. In any research on human beings, each potential subject must be
adequately informed of the aims, methods, anticipated benefits and
potential hazards of the study and the discomfort it may entail. He or
she should be informed that he or she is a liberty to abstain from
participation in the study and that he or she is free to withdraw his or
her consent to participation at any time. The physician should then
obtain the subject\'s freely-given informed consent, preferably in
writing.

10\. When obtaining informed consent for the research project the
physician should be particularly cautious if the subject is in a
dependent relationship to him or her or may consent under duress. In
that case the informed consent should be obtained by a physician who is
not engaged in the investigation and who is completely independent of
this official relationship.

11\. In case of legal incompetence, informed consent should be obtained
from the legal guardian in accordance with national legislation. Where
physical or mental incapacity makes it impossible to obtain informed
consent, or when the subject is a minor, permission from the responsible
relative replaces that of the subject in accordance with national
legislation.

> Whenever the minor child is in fact able to give consent, the minor\'s
> consent must be obtained in addition to the consent of the minor\'s
> legal guardian.

12\. The research protocol should always contain a statement of the
ethical considerations involved and should indicate that the principles
enunciated in the present Declaration are complied with.

**II. Medical research combined with clinical care**

**(Clinical research)**

1\. In the treatment of the sick person, the physician must be free to
use a new diagnostic and therapeutic measure, if in his or her judgment
it offers hope of saving life, reestablishing health or alleviating
suffering.

2\. The potential benefits, hazards and discomfort of a new method
should be weighed against the advantages of the best current diagnostic
and therapeutic methods.

3\. In any medical study, every patient---including those of a control
group, if any--- should be assured of the best proven diagnostic and
therapeutic method. This does not exclude the use of inert placebo in
studies where no proven diagnostic or therapeutic method exists.

4\. The refusal of the patient to participate in a study must never
interfere with the physician---patient relationship.

5\. If the physician considers it essential not to obtain informed
consent, the specific reasons for this proposal should be stated in the
experimental protocol for transmission to the independent committee (I,
2).

6\. The physician can combine medical research with professional care,
the objective being the acquisition of new medical knowledge, only to
the extent that medical research is justified by its potential
diagnostic or therapeutic value for the patient.

III\. Non-therapeutic biomedical research involving human subjects

(Non-clinical biomedical research)

1\. In the purely scientific application of medical research carried out
on a human being, it is the duty of the physician to remain the
protector of the life and health of that person on whom biomedical
research is being carried out.

2\. The subject should be volunteers---either healthy persons or
patients for whom the experimental design is not related to the
patient\'s illness.

3\. The investigator or the investigating team should discontinue the
research if in his/her or their judgment it may, if continued, be
harmful to the individual.

4\. In research on man, the interest of science and society should never
take precedence over considerations related to the well being of the
subject.

# C. Declaration of Helsinki (2000)

# 

***WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI***

***Ethical Principles for Medical Research Involving Human Subjects***

*Adopted by the 18th WMA General Assembly*

*Helsinki, Finland, June 1964*

*and amended by the*

*29th WMA General Assembly, Tokyo, Japan, October 1975*

*35th WMA General Assembly, Venice, Italy, October 1983*

*41st WMA General Assembly, Hong Kong, September 1989*

*48th WMA General Assembly, Somerset West, Republic of South Africa,
October 1996*

*and the*

*52nd WMA General Assembly, Edinburgh, Scotland, October 2000*

##### INTRODUCTION

> 1\. The World Medical Association has developed the Declaration of
> Helsinki as a statement of ethical principles to provide guidance to
> physicians and other participants in medical research involving human
> subjects. Medical research involving human subjects includes research
> on identifiable human material or identifiable data.

2\. It is the duty of the physician to promote and safeguard the health
of the people. The physician\'s knowledge and conscience are dedicated
to the fulfillment of this duty.

3\. The Declaration of Geneva of the World Medical Association binds the
physician with the words, \"The health of my patient will be my first
consideration,\" and the International Code of Medical Ethics declares
that, \"A physician shall act only in the patient\'s interest when
providing medical care which might have the effect of weakening the
physical and mental condition of the patient.\"

4\. Medical progress is based on research, which ultimately must rest in
part on experimentation involving human subjects.

5\. In medical research on human subjects, considerations related to the
well-being of the human subject should take precedence over the
interests of science and society.

6\. The primary purpose of medical research involving human subjects is
to improve prophylactic, diagnostic and therapeutic procedures and the
understanding of the aetiology and pathogenesis of disease. Even the
best proven prophylactic, diagnostic, and therapeutic methods must
continuously be challenged through research for their effectiveness,
efficiency, accessibility and quality.

7\. In current medical practice and in medical research, most
prophylactic, diagnostic and therapeutic procedures involve risks and
burdens.

8\. Medical research is subject to ethical standards that promote
respect for all human beings and protect their health and rights. Some
research populations are vulnerable and need special protection. The
particular needs of the economically and medically disadvantaged must be
recognized. Special attention is also required for those who cannot give
or refuse consent for themselves, for those who may be subject to giving
consent under duress, for those who will not benefit personally from the
research and for those for whom the research is combined with care.

9\. Research Investigators should be aware of the ethical, legal and
regulatory requirements for research on human subjects in their own
countries as well as applicable international requirements. No national
ethical, legal or regulatory requirement should be allowed to reduce or
eliminate any of the protections for human subjects set forth in this
Declaration.

A.  **BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH**

10\. It is the duty of the physician in medical research to protect the
life, health, privacy, and dignity of the human subject.

11\. Medical research involving human subjects must conform to generally
accepted scientific principles, be based on a thorough knowledge of the
scientific literature, other relevant sources of information, and on
adequate laboratory and, where appropriate, animal experimentation.

12\. Appropriate caution must be exercised in the conduct of research
which may affect the environment, and the welfare of animals used for
research must be respected.

13\. The design and performance of each experimental procedure involving
human subjects should be clearly formulated in an experimental protocol.
This protocol should be submitted for consideration, comment, guidance,
and where appropriate, approval to a specially appointed ethical review
committee, which must be independent of the investigator, the sponsor or
any other kind of undue influence. This independent committee should be
in conformity with the laws and regulations of the country in which the
research experiment is performed. The committee has the right to monitor
ongoing trials. The researcher has the obligation to provide monitoring
information to the committee, especially any serious adverse events. The
researcher should also submit to the committee, for review, information
regarding funding, sponsors, institutional affiliations, other potential
conflicts of interest and incentives for subjects.

14\. The research protocol should always contain a statement of the
ethical considerations involved and should indicate that there is
compliance with the principles enunciated in this Declaration.

15\. Medical research involving human subjects should be conducted only
by scientifically qualified persons and under the supervision of a
clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never
rest on the subject of the research, even though the subject has given
consent.

16\. Every medical research project involving human subjects should be
preceded by careful assessment of predictable risks and burdens in
comparison with foreseeable benefits to the subject or to others. This
does not preclude the participation of healthy volunteers in medical
research. The design of all studies should be publicly available.

17\. Physicians should abstain from engaging in research projects
involving human subjects unless they are confident that the risks
involved have been adequately assessed and can be satisfactorily
managed. Physicians should cease any investigation if the risks are
found to outweigh the potential benefits or if there is conclusive proof
of positive and beneficial results.

18\. Medical research involving human subjects should only be conducted
if the importance of the objective outweighs the inherent risks and
burdens to the subject. This is especially important when the human
subjects are healthy volunteers.

19\. Medical research is only justified if there is a reasonable
likelihood that the populations in which the research is carried out
stand to benefit from the results of the research.

20\. The subjects must be volunteers and informed participants in the
research project.

21\. The right of research subjects to safeguard their integrity must
always be respected. Every precaution should be taken to respect the
privacy of the subject, the confidentiality of the patient\'s
information and to minimize the impact of the study on the subject\'s
physical and mental integrity and on the personality of the subject.

22\. In any research on human beings, each potential subject must be
adequately informed of the aims, methods, sources of funding, any
possible conflicts of interest, institutional affiliations of the
researcher, the anticipated benefits and potential risks of the study
and the discomfort it may entail. The subject should be informed of the
right to abstain from participation in the study or to withdraw consent
to participate at any time without reprisal. After ensuring that the
subject has understood the information, the physician should then obtain
the subject\'s freely-given informed consent, preferably in writing. If
the consent cannot be obtained in writing, the non-written consent must
be formally documented and witnessed.

23\. When obtaining informed consent for the research project the
physician should be particularly cautious if the subject is in a
dependent relationship with the physician or may consent under duress.
In that case the informed consent should be obtained by a well-informed
physician who is not engaged in the investigation and who is completely
independent of this relationship.

24\. For a research subject who is legally incompetent, physically or
mentally incapable of giving consent or is a legally incompetent minor,
the investigator must obtain informed consent from the legally
authorized representative in accordance with applicable law. These
groups should not be included in research unless the research is
necessary to promote the health of the population represented and this
research cannot instead be performed on legally competent persons.

25\. When a subject deemed legally incompetent, such as a minor child,
is able to give assent to decisions about participation in research, the
investigator must obtain that assent in addition to the consent of the
legally authorized representative.

26\. Research on individuals from whom it is not possible to obtain
consent, including proxy or advance consent, should be done only if the
physical/mental condition that prevents obtaining informed consent is a
necessary characteristic of the research population. The specific
reasons for involving research subjects with a condition that renders
them unable to give informed consent should be stated in the
experimental protocol for consideration and approval of the review
committee. The protocol should state that consent to remain in the
research should be obtained as soon as possible from the individual or a
legally authorized surrogate.

27\. Both authors and publishers have ethical obligations. In
publication of the results of research, the investigators are obliged to
preserve the accuracy of the results. Negative as well as positive
results should be published or otherwise publicly available. Sources of
funding, institutional affiliations and any possible conflicts of
interest should be declared in the publication. Reports of
experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.

C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE

28\. The physician may combine medical research with medical care, only
to the extent that the research is justified by its potential
prophylactic, diagnostic or therapeutic value. When medical research is
combined with medical care, additional standards apply to protect the
patients who are research subjects.

29\. The benefits, risks, burdens and effectiveness of a new method
should be tested against those of the best current prophylactic,
diagnostic, and therapeutic methods. This does not exclude the use of
placebo, or no treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists.

30\. At the conclusion of the study, every patient entered into the
study should be assured of access to the best proven prophylactic,
diagnostic and therapeutic methods identified by the study.

31\. The physician should fully inform the patient which aspects of the
care are related to the research. The refusal of a patient to
participate in a study must never interfere with the patient-physician
relationship.

32\. 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 judgment 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.

# D. The Nuremberg Code 

**NUREMBERG CODE**

**Directives for Human Experimentation**

<http://ohrp.osophs.dhhs.gov/references/nurcode.htm>

The voluntary consent of the human subject is absolutely essential. This
means that the person involved should have legal capacity to give
consent; should be so situated as to be able to exercise free power of
choice, without the intervention of any element of force, fraud, deceit,
duress, over-reaching, or other ulterior form of constraint or coercion;
and should have sufficient knowledge and comprehension of the elements
of the subject matter involved as to enable him to make an understanding
and enlightened decision. This latter element requires that before the
acceptance of an affirmative decision by the experimental subject there
should be made known to him the nature, duration, and purpose of the
experiment; the method and means by which it is to be conducted; all
inconveniences and hazards reasonable to be expected; and the effects
upon his health or person which may possibly come from his participation
in the experiment.

The duty and responsibility for ascertaining the quality of the consent
rests upon each individual who initiates, directs or engages in the
experiment. It is a personal duty and responsibility, which may not be
delegated to another with impunity.

The experiment should be such as to yield fruitful results for the good
of society, unprocurable by other methods or means of study, and not
random and unnecessary in nature.

The experiment should be so designed and based on the results of animal
experimentation and acknowledge of the natural history of the disease or
other problem under study that the anticipated results will justify the
performance of the experiment.

The experiment should be so conducted as to avoid all unnecessary
physical and mental suffering and injury.

No experiment should be conducted where there is an a priori reason to
believe that death or disabling injury will occur; except, perhaps, in
those experiments where the experimental physicians also serve as
subjects.

The degree of risk to be taken should never exceed that determined by
the humanitarian importance of the problem to be solved by the
experiment.

Proper preparations should be made and adequate facilities provided to
protect the experimental subject against even remote possibilities of
injury, disability, or death.

The experiment should be conducted only by scientifically qualified
persons. The highest degree of skill and care should be required through
all stages of the experiment of those who conduct or engage in the
experiment.

During the course of the experiment the human subject should be at
liberty to bring the experiment to an end if he has reached the physical
or mental state where continuation of the experiment seems to him to be
impossible.

During the course of the experiment the scientist in charge must be
prepared to terminate the experiment at any stage, if he has probable
cause to believe, in the exercise of the good faith, superior skill and
careful judgment required of him that a continuation of the experiment
is likely to result in injury, disability, or death to the experimental
subject.

Reprinted from Trials of War Criminals before the Nuremberg Military
Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182.
Washington, D.C.: U.S. Government Printing Office, 1949.

#