Appelbaum and his colleagues observed informed consent transactions on several psychiatry protocols. They found that research subjects systematically misinterpreted the risk/benefi t ratio

Before starting your paper, please read the following documents which have been posted to the course site (and I recommend that you read/view them in this order):

“History of Human Subjects Protections” (article appears cut off at the end, but no needed information is omitted)

“The Belmont Report”

“The Nuremberg Code”

And view the following videos at the listed links:

Nuremberg Code (approx. 10 minutes)

https://www.youtube.com/watch?v=ula7dzU2umw

Tuskegee Syphilis Study (approx. 4 minutes)

Milgram’s Obedience Study (approx. 9 minutes)

After finishing the readings and watching the videos, specifically think about the Tuskegee Syphilis study AND/OR Milgram’s Obedience Study, and knowing what you know now about current human subjects protections, how would you have approached this/these studies differently if you had been the lead researcher? Utilize the knowledge you gain from the readings to help you incorporate more ethical ways to obtain informed consent, protect your subjects from harm, and abide by ethical guidelines in at least one of these studies. Please incorporate specific aspects of the readings into your paper. (No other references are needed, but if you do reference other sources, you must cite these in APA format.)

Complete a 4-6 page reaction paper (at least 4 FULL pages; title page or reference page do NOT count toward length requirement if included).  The paper should be typed in Times New Roman 12 point font, double-spaced, with one inch margins and saved as a Microsoft Word document.  Submit electronically via the Turnitin feature on our course site.  Points will be deducted for poor grammar and punctuation. Late papers will not be accepted in the system.  The paper is worth 30 points.

THE NUREMBERG CODE

1. 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 reasonably 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.

2. 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.

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

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

5. 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.

6. 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.

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

8. 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.

9. 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 seemed to him to be impossible.

10. 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 judgement required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

[“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.]

SoCRA SOURCE – May, 2004 – 37SOURCE – May, 2004 – 37SOURCE

ETHICS IN CLINCAL RESEARCH A HISTORY OF

HUMAN SUBJECT PROTECTIONS AND PRACTICAL IMPLEMENTATION

OF ETHICAL STANDARDS

David Perlman, Ph.D. Senior Education Advisor

Glaxo Smith Kline Adjunct Assistant Professor

Temple University School of Pharmacy

Abstract: The current regulations for clinical research are based on a combination of ethical thought and history, some of it being very tragic. This article presents the ethical and historical underpinnings of these regulations, including the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, Title 21 Code of Federal Regulations (CFR) Parts 50 and 56, 45 CFR Part 46, and the International Conference on Harmonization Good Clinical Practices. In addition, the article highlights the role of the therapeutic misconception, which occurs when patients enrolling as research subjects misinterpret and perhaps even distort information about the research because they believe that aspects of the research will directly benefi t them.

The current regulations for clinical research are based on a combination of ethical thought and history, some of it being very tragic. The word ‘ethics’ derives from the Greek, ethos, which means custom or character. Ethics is contrasted with morality, which frequently relates to how you were raised and what values you learned from parents, religion, culture, and other infl uences. Ethics is more systematic, as the following conception suggests: ethics is the systematic study of values by which a determination of what is the right and wrong thing to do is made.

Ethics is also different from law and regulation, both of which mandate a certain way of acting. The United States regulations for the protection of human subjects provide baseline minimums with which everyone must comply in operating an institutional review board (IRB), obtaining informed consent from research subjects, and conducting research in an ethical manner.

Ethical thought has helped shape the regulations. But ethics goes beyond what the regulations require to include for what we ought to do. Ethics asks, “What ought I to do?” and “What is the right thing to do?”

Throughout the 4,000 year history of ethics ther have been many interesting theories about what ethics ought to be and what principles should be at the forefront of our thinking. In examining and using these ethical theories, we are trying to justify particular rules, procedures, or outlooks on ethics and what we ought to do. The challenge, especially in a practical environment such as clinical research, is to translate the theoretical concepts from ethics into action. The regulations help us accomplish this task.

ETHICAL PRINCIPLES FOR CLINICAL RESEARCH A variety of codes and reports

SoCRA SOURCE – May, 2004 – 38SOURCE – May, 2004 – 38SOURCE

form the bedrock or foundation for the ethical conduct of clinical research (Table 1). These codes and reports have been translated into particular practices, guidelines, and requirements in our current regulations. However, ethical principles must be discussed within their historical context. There have been many tragedies throughout the history of research involving human subjects, and many people were harmed as a result of their unwitting participation in research. From an ethical perspective, it does an injustice to them to abstract thinking regarding the regulations away from its historical and ethical context.

The Nuremberg Code The modern history of human subject protections begins with the discovery of the atrocities committed by Nazi physicians. For example, such atrocities included twin experiments, where one twin was exposed to a pathogen and then autopsied to determine the natural progression of the disease. The other uninfected “control” twin was then “sacrifi ced” to see what the differences were. It may constitute a very interesting comparison from a scientifi c perspective, but such an experiment was wholly unethical and inhumane.

The judges at the trial had no basis in law by which to judge the Nazi physicians. They developed 10 principles for this purpose, and these principles formed the basis of what came to be known as the Nuremberg Code for research involving human subjects. Highlights of the Nuremberg Code include: • Voluntary consent is essential.

This requirement is at the heart of what the Nazis did wrong. They did not ask any of the people who were subject to their experiments if they wanted to participate.

• Research risks must be minimized and relative to the anticipated benefi ts of the research.

• The research must benefi t society. It is unethical to needlessly endanger the well being of human volunteers if other methods of investigation exist. Poorly designed human subject research is unethical from its inception. If you do not have the statistical power to answer your research question, no IRB should approve the research. If you have a fl aw in the research design, or if you can improve the research design to have a better risk/benefi t profi le, you must do it.

• Research must be based on pre-clinical studies in animals and knowledge of the condition under study. Many of the Nazi experiments were performed just because the physicians found them interesting.

• Subjects have the right to end their participation in research.

Unfortunately, the Nuremberg Code did not have much impact in the United States outside of the scholarly community.

The Declaration of Helsinki The Declaration of Helsinki is a “living” document that attempts to take into account the evolving

nature of scientifi c research. It was fi rst adopted by the World Medical Assembly in 1964, and revised in 1975, 1983, 1996, and 2000. Highlights of the Declaration of Helsinki include: • In research, the well being of

subjects should take precedence over the interests of science and society.

• Several ethical standards are articulated: respect for persons and protection of subjects’ health and rights.

• Some populations are vulnerable (e.g., the physically or mentally handicapped) and require special protections.

• Experimental procedures must be detailed in a protocol, which is submitted to an ethical review committee. This statement represents one of the fi rst articulations of the requirement for a protocol, which includes the scientifi c reasons for and the purpose of the study, and what questions the researchers hope to answer by conducting the study.

• Investigators must submit information regarding the research (especially monitoring information such as serious adverse events) to the ethical review committee.

• Assessment of risks and benefi ts to subjects or others is required before conducting the research.

• Subjects must be informed volunteers. If they cannot consent for themselves, then legally authorized representatives must consent on their behalf.

• Subjects have the right to safeguard their own integrity (another application of the principle of respect for persons).

• Informed consent must be documented.

• The context of obtaining informed consent is as important as the information presented in the informed consent document itself. If the researcher is also the

TABLE 1 The Foundation for the Ethical Conduct of Clinical Research

• The Nuremberg Code • The Declaration of Helsinki • The Belmont Report • 21 CFR Parts 50 and 56 • 45 CFR Part 46

International Conference on Harmonization Good Clinical Practices

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subject’s physician, a physician not connected with the research or the subject’s medical care should obtain informed consent to minimize undue infl uence.

Research Abuses In 1966, Henry Beecher, a Harvard anesthesiologist, authored an exposé of numerous unethical experiments that had been published in prominent medical journals. Beecher did not furnish names or references to the research. His goal was not to encourage prosecution but rather to increase awareness of broader ethical problems in human experimentation. He wanted to heighten awareness that unethical activities in the United States were very similar to what happened in Nazi Germany. His article had a major impact on the development of the regulations. His conclusions included: • Unethical treatment of human

subjects was not confi ned to the barbarism of the Nazis.

• Informed consent is a goal. It is something we may never be able to achieve, but we should strive for it.

• It is not enough to mention that consent was obtained; subjects must be informed and understand the risks.

• There should be a second safeguard: “an intelligent, informed, conscientious, compassionate, responsible investigator.”

• Experiments are ethical or not ethical at their inception, experiments do not become ethical or unethical afterwards. If you design the research properly, you should have an ethically conducted protocol as long as adequate protections are built into the protocol to protect human subjects.

Beecher was correct. The saddest example in our country of a research abuse was the so-called

Tuskegee Syphilis Study (1932- 1972). In 1972, The New York Times published articles exposing ethical atrocities associated with a Public Health Service study on the natural progression of syphilis in poor and largely uneducated African-American men in rural Tuskegee, Alabama. The study was only supposed to last about six months but the researchers were getting “good data” and decided to continue it. In the 1940s, when penicillin became widely available, researchers withheld treatment from the men.

These revelations spurred Congressional hearings. The resulting National Research Act in 1974 authorized the formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission’s charge included examination of the conduct of all federally sponsored human subject research in the United States and development of the philosophical and ethical principles that should govern scientifi c research with human beings as the test subjects. The Commission produced many reports, the most infl uential of which is the Belmont Report.

The Belmont Report The Belmont Report articulates three core ethical principles: • Respect for persons: This

principle concerns the ability of a person to direct his/her own actions. The requirement to obtain informed consent from prospective subjects is the practical translation of this ethical principle. Capacity to consent is also important. You must ensure that the person you are asking to undergo a clinical trial has the capacity to freely authorize his/her participation.

• Benefi cence: This principle

requires a balance between minimizing harms by good study design and maximizing any benefi ts that might accrue to study participants.

• Justice: This principle asks us to take a broader view of the research. There should be an equitable distribution of benefi ts and burdens, with equitable subject selection. Sometimes implementing this principle can be daunting due to entrenched social inequalities and disparities that exist in our country and in the world.

Each of these principles is translated into specifi c requirements in all current regulations of the Food and Drug Administration (FDA), the Department of Health and Human Services (DHHS), and the International Conference on Harmonization (ICH).

Respect for persons is translated into the requirement to obtain informed consent from subjects before they participate in research. There are three components of a valid informed consent process: information, comprehension, and willful volunteering. There are several questions related to these components. How much information should be disclosed? We all know how long and complicated consent forms can be. Most are supposed to be written between a sixth- and eighth-grade level; I have seen few informed consent documents written at that level. How should complex medical information regarding risks be presented to subjects? The manner and context in which information is conveyed infl uences comprehension and can be as important as the information itself. The subject must make a free and uncoerced decision to participate (e.g., not to be pushed by family members, by the prospect of receiving reimbursement for participation, by free access to

SoCRA SOURCE – May, 2004 – 40SOURCE – May, 2004 – 40SOURCE

investigational drugs, or by offers of free medical care).

The principle of benefi cence asks us to balance the risks and benefi ts. Everyone needs to be involved in this—the investigator, the IRB, and subjects. • The investigator must determine

whether the research design is sound, and whether there are other ways to achieve the benefi ts of the research. Such determinations require thinking “outside of the clinical research box.” The IRB can often be a good source of information because it has seen so many protocols.

• The IRB must determine whether the risks are justifi ed.

• The subjects have a responsibility to decide whether to risk any of the possible harms that are mentioned in the information presented to them.

The determination must be a “favorable” risk/benefi t assessment. There is no one formula for conducting a risk/benefi t assessment, and determining the balance is frequently diffi cult. In addition, investigators and subjects may confuse the severity of harm with the possibility of harm. There are fi ve factors to consider in making a risk/ benefi t assessment: 1. Brutal/inhumane treatment is

never justifi ed. 2. Risks must be minimized. Ask

whether human subjects are even needed. Technology might allow the use of in vitro models, computer software modeling, or tissue samples instead of human subjects.

3. A high probability of harm must be justifi ed.

4. Involvement of vulnerable populations must be justifi ed.

5. The relevant risks and benefi ts must be presented in the informed consent document.

Justice requires fair and equitable procedures in the selection of research subjects. Achieving justice in clinical research is sometimes diffi cult. Investigators should not offer benefi cial research only to some individuals and select “undesirable” subjects for more risky research. To society, adults are preferred as subjects before children, and some classes of subjects (e.g., the mentally ill, people who are institutionalized, and prisoners) may not participate unless certain conditions pertain. The Belmont Report notes that we may not be able to eliminate deeply entrenched societal injustices, but efforts should be made to target as wide an audience as possible.

TRANSLATION OF ETHICAL PRINCIPLES INTO REGULATIONS Sections 111 of both the FDA and DHHS regulations for the protection of human subjects outline criteria that the IRB must consider when determining whether research can be approved (Table 2): 1. Risks are minimized through

a sound research design. The IRB can frequently help with research design. Investigators should respond to IRB research design suggestions as part of the IRB’s mission to ensure protection of human volunteers, not as interference in the science. Having someone who is familiar with research design to help craft the protocol is also a good idea; sponsors are generally good at designing their protocols. In addition, IRBs should have at least one member with research design expertise.

2. Risks are reasonable relative to anticipated benefi ts (the principle of benefi cence).

3. Selection of subjects is equitable (the principle of justice).

4. Informed consent will be obtained and documented. Who will obtain informed consent? How will it be documented?

What sort of safeguards will be put into place so that people know the tests for which they are volunteering?

5. Data safety monitoring is adequate.

6. Privacy and confi dentiality provisions are adequate.

7. Appropriate safeguards are included for vulnerable subjects.

In the background of each of these considerations are principles from the Belmont Report, the Declaration of Helsinki, or the Nuremberg Code. Since the IRB’s focus is to protect human subjects, including information about each of these required elements in a bulleted list within a protocol should make the IRB’s job easier.

TABLE 2 Translation of Ethical Principles

into Regulations

• Risks are minimized through a sound research design

• Risks are reasonable relative to the anticipated benefi ts

• Selection of subjects is equitable • Informed consent will be

obtained and documented • Data safety monitoring is

adequate • Privacy and confi dentiality

provisions are adequate • Appropriate safeguards are

included for vulnerable subjects

Informed Consent Requirements • Legally effective informed

consent • No coercion or undue infl uence • Language understandable to the

subject • No exculpatory language where

subjects waive or appear to waive legal rights

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TABLE 3 The Therapeutic Misconception

Defi nition: • The therapeutic

misconception occurs when patients enrolling as research subjects misinterpret and perhaps even distort information about the research, such that they believe that aspects of the research will directly benefi t them

Causes: • Human nature: we hear only

what we want to hear • The trenchant notion of

“personal care” in clinical medicine: confusion of roles of physician as clinician and as researcher

• The confusing methods of science (randomization, use of a study protocol, use of placebos, blinding, and control groups)

The principle of respect for persons is translated into requirements for informed consent (Table 2). “Legally effective informed consent” means ensuring that subjects have the legal right to consent for themselves or that an appropriate legally-authorized representative is used when the subject cannot consent for himself/ herself. In recruitment, investigators and study coordinators must ensure that they introduce no coercion or undue infl uence in their presentation of the informed consent information. Language must be understandable to the subject and must not include exculpatory language where a subject either waivers or appears to waive a legal right to which they would otherwise be entitled.

A written consent document is required. It must be in language understandable to the subject or the subject’s legally-authorized representative and signed by the subject (or the legally-authorized representative). A copy of the informed consent document must be given to the subject, who must have an opportunity to read the document before signing it.

THE THERAPEUTIC MISCONCEPTION The therapeutic misconception can be a vexing ethical issue for obtaining valid informed consent (Table 3). The therapeutic misconception occurs when patients enrolling as research subjects misinterpret and perhaps even distort information about the research, such that they believe that aspects of the research will directly benefi t them, or that there is a benefi t at all. The term fi rst appeared in the literature in 1987, when Paul Appelbaum and colleagues published “False Hopes and Best Data: Consent to Research and the Therapeutic Misconception” in the Hastings Center Report. The information in this article is based on that publication.

The therapeutic misconception is very common in Phase 1 oncology trials. It is rare for people to benefi t from a dose-escalation trial. When you ask research subjects, even in Phase 1 studies, why they are enrolling, the literature on therapeutic misconception indicates that they frequently misconstrue the difference between research and treatment and wrongly believe that they will directly benefi t from their participation in the Phase 1 study.

The therapeutic misconception is caused by a variety of factors. • Human nature (we hear

only what we want to hear): For example, people only hear “access to cutting-edge interventions” and “free medical care,” not “scientifi c research study.”

• The trenchant notion of “personal care” in clinical medicine (confusion of roles of physician as clinician and as researcher): Any clinician who conducts a clinical trial must follow the protocol, in which the notion of personal care must usually be abandoned in order to properly follow the dictates of the scientifi c protocol.

• The methods of science (randomization, use of a study protocol, use of placebos, blinding, and control groups): These concepts can be very confusing to subjects if they are not explained adequately. The notion of personal care is the physician’s fi rst obligation. The physician makes decisions, with the patient’s input, that will benefi t the patient most. The application of this shared decision-making model is not necessarily the case in a clinical trial. Moreover, the methods of human experimentation listed above may inhibit the application of personal care in clinical research in the following ways: o There is always a chance

that the subject’s interests may become secondary to the investigator’s scientifi c interests; and

o Randomizing subjects for the sake of good science negates the concept of “personal care” — the physician cannot determine which treatment a subject receives. Subjects who will be randomized often think they will get the treatment, not the placebo.

Appelbaum and his colleagues observed informed consent transactions on several psychiatry protocols. They found that research subjects systematically misinterpreted the risk/benefi t ratio

THE BELMONT REPORT Office of the Secretary Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979

AGENCY: Department of Health, Education, and Welfare.

ACTION: Notice of Report for Public Comment.

SUMMARY: On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the charges to the Commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: (i) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, (ii) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, (iii) appropriate guidelines for the selection of human subjects for participation in such research and (iv) the nature and definition of informed consent in various research settings.

The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. It is the outgrowth of an intensive four-day period of discussions that were held in February 1976 at the Smithsonian Institution’s Belmont Conference Center supplemented by the monthly deliberations of the Commission that were held over a period of nearly four years. It is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. By publishing the Report in the Federal Register, and providing reprints upon request, the Secretary intends that it may be made readily available to scientists, members of Institutional Review Boards, and Federal employees. The two-volume Appendix, containing the lengthy reports of experts and specialists who assisted the Commission in fulfilling this part of its charge, is available as DHEW Publication No. (OS) 78-0013 and No. (OS) 78-0014, for sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.

Unlike most other reports of the Commission, the Belmont Report does not make specific recommendations for administrative action by the Secretary of Health, Education, and Welfare. Rather, the Commission recommended that the Belmont Report be adopted in its entirety, as a statement of the Department’s policy. The Department requests public comment on this recommendation.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Members of the Commission Kenneth John Ryan, M.D., Chairman, Chief of Staff, Boston Hospital for Women.

Joseph V. Brady, Ph.D., Professor of Behavioral Biology, Johns Hopkins University.

Robert E. Cooke, M.D., President, Medical College of Pennsylvania.

Dorothy I. Height, President, National Council of Negro Women, Inc.

Albert R. Jonsen, Ph.D., Associate Professor of Bioethics, University of California at San Francisco.

Patricia King, J.D., Associate Professor of Law, Georgetown University Law Center.

Karen Lebacqz, Ph.D., Associate Professor of Christian Ethics, Pacific School of Religion.

*** David W. Louisell, J.D., Professor of Law, University of California at Berkeley.

Donald W. Seldin, M.D., Professor and Chairman, Department of Internal Medicine, University of Texas at

Dallas.

*** Eliot Stellar, Ph.D., Provost of the University and Professor of Physiological Psychology, University of

Pennsylvania.

*** Robert H. Turtle, LL.B., Attorney, VomBaur, Coburn, Simmons & Turtle, Washington, D.C. *** Deceased.

Table of Contents Ethical Principles and Guidelines for Research Involving Human Subjects

A. Boundaries Between Practice and Research

B. Basic Ethical Principles

1. Respect for Persons

2. Beneficence

3. Justice

C. Applications

1. Informed Consent

2. Assessment of Risk and Benefits

3. Selection of Subjects

Ethical Principles & 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 [1] 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.

Part A: Boundaries Between Practice & Research 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 [2]. 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 [3].

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.

Part B: Basic Ethical Principles 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 ethics of research involving human subjects: the principles of respect of 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 consequence. 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 recognize 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 it 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 difficult 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.

Part C: Applications C. Applications

Applications of the general principles to the conduct 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 presentation of the information to the subject’s capacities. 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 disable 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 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 harm 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, nonarbitrary 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: (i)Brutal or inhumane treatment of human subjects is never morally justified. (ii) 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. (iii) 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). (iv) 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. (v) 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.

[1] Since 1945, various codes for the proper and responsible conduct of human experimentation in medical research have been adopted by different organizations. The best known of these codes are the Nuremberg Code of 1947, the Helsinki Declaration of 1964 (revised in 1975), and the 1971 Guidelines (codified into Federal Regulations in 1974) issued by the U.S. Department of Health, Education, and Welfare Codes for the conduct of social and behavioral research have also been adopted, the best known being that of the American Psychological Association, published in 1973.

[2] Although practice usually involves interventions designed solely to enhance the well-being of a particular individual, interventions are sometimes applied to one individual for the enhancement of the well-being of another (e.g., blood donation, skin grafts, organ transplants) or an intervention may have the dual purpose of enhancing the well-being of a particular individual, and, at the same time, providing some benefit to others (e.g., vaccination, which protects both the person who is vaccinated and society generally). The fact that some forms of practice have elements other than immediate benefit to the individual receiving an intervention, however, should not confuse the general distinction between research and practice. Even when a procedure applied in practice may benefit some other person, it remains an intervention designed to enhance the well-being of a particular individual or groups of individuals; thus, it is practice and need not be reviewed as research.

[3] Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research, the Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.

  • THE BELMONT REPORT
    • Office of the Secretary
    • Ethical Principles and Guidelines for the Protection of Human Subjects of Research
    • The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
    • April 18, 1979
    • National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
      • Members of the Commission
      • Table of Contents
      • Ethical Principles & Guidelines for Research Involving Human Subjects
      • Part A: Boundaries Between Practice & Research
      • Part B: Basic Ethical Principles
      • Part C: Applications

 

 

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