CITI Collaborative Institutional Training Initiative

 

 

 

Belmont Report and CITI Course Introduction

 

The Belmont Report, released in 1979 by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, provides the ethical framework for the Federal Regulations designed to protect human research subjects.

 

The Belmont Report

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 fulfillingthis 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.

 

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 undergoreview 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.

 

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(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.

 

 

History and Ethical Principles

 

Content Authors:

 

Elizabeth Bankert, MA

Dartmouth College, Hanover, NH

 

Jeffrey A. Cooper, MD

AAHRPP, Inc., Washington, DC

 

Introduction

 

The first century physician Celsus justified experiments on condemned criminals in Egypt using wording that became a classic defense for hazardous experimentation: "It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries." [Brady and Jonsen].

 

Both the ethics regarding human subjects research and regulations for such research have changed considerably since Celsus' time. This module discusses the evolution of ethical review principles, and how they have influenced research involving human subjects.

 

By the end of this module you will be able to:

 

•Discuss why ethics are necessary when conducting research involving human subjects.

•Describe the major historical events that have influenced how research involving human subjects is conducted.

•Identify problems with past studies that have violated ethical standards.

•Describe the Belmont Principles.

•Discuss the ethical standards for research that guide us today.

 

Why Ethics is Important

 

We are concerned with normative ethics, asking questions such as: What should morality require? How should researchers behave? How should researchers not behave? What character traits should researchers cultivate as virtues? And, what character traits should researchers try to avoid?

 

There are many advantages to understanding research ethics. Concepts of research ethics:

 

•Provide us with a structure for analysis and decision-making.

•Support and remind researchers to protect human subjects.

•Provide workable definitions of benefits and risks, along with guidelines for evaluating and balancing the benefits and risks of our studies

 

Definition of "Benefit"

A benefit is the positive value or advantage of being part of the research study. This value or advantage might be concrete for individual subjects, like a greater chance of having a good therapeutic outcome. Alternatively, it might be more intangible and general. For example, the results from a study could be crucial to understanding the underlying socioeconomic causes of drug addiction.

 

Definition of "Risk"

Risks generally are evaluated according to the probability and magnitude of any harm that might occur. Will the risk occur in almost all subjects or in only one of 10,000 subjects? We can also quantify risk according to the magnitude of harm. Will the harm consist of some minor itchiness, or will some subjects die? Risks can also be classified according to their type. In medical research we often focus on physical risk. However, risks may also be social, legal, economic or psychological in nature. In addition, risks may apply to the individual subject or may apply to a broader segment of the society.

 

Balancing Potential Benefits and Risks

Risks to the subject or society must be weighed against potential benefits. The probability of harm relative to the probability of benefit should be determined, as well as the relative magnitude of risks and possible benefits. As an aside, payment for study participation should never be considered a benefit. One of the most difficult things that researchers and IRBs have to do is to determine that the potential benefits of the outcomes of the research outweigh the risks of conducting the research. This is difficult because:

 

•Neither the potential benefits or risks can be known ahead of time

•The risks are assumed by individuals, while the benefits may accrue to society at large rather than to individuals.

 

Historical Events that Have Influenced Human Research

First Documented Human Subject Research

Research ethics has evolved. Among the first human subject research experiments to be documented were vaccination trials in the 1700's. In these early trials physicians used themselves or their family members as test subjects. For example:

 

•Edward Jenner (1749-1823) first tested smallpox vaccines on his son and on neighborhood children.

•Johann Jorg (1779-1856) swallowed 17 drugs in various doses to record their properties.

•Louis Pasteur (1822-1895) "agonized over treating humans," even though he was confident of the results obtained through animal trials. He finally did so only when he was convinced the death of the child, the first test subject, "appeared inevitable." [Rothman]

 

The Era of Modern Science

The era of modern science started in the 1900's and the progress of medicine began to accelerate. Walter Reed's well-known experiments to develop an inoculation for yellow fever were at the forefront of these advances. These experiments, however, unlike earlier experiments with vaccinations, were carefully scrutinized.

 

Consider this dialog from testimony before the Royal Commission of Vivisection (1908) by Dr. William Osler, a noted physician and scholar [Brady & Jonsen]:

 

Commission: I understand that in the case of yellow fever the recent experiments have been on man.

 

Osler: Yes, definitely with the specific consent of these individuals who went into the camp voluntarily

 

Commission: We were told by a witness yesterday that, in his opinion, to experiment upon man with possible ill result was immoral. Would that be your view?

 

Osler: It is always immoral, without a definite, specific statement from the individual himself, with a full knowledge of the circumstances. Under these circumstances, any man, I think is at liberty to submit himself to experiments.

 

Commission: Given voluntary consent, you think that entirely changes the question of morality or otherwise?

 

Osler: Entirely.

 

Nuremberg Code

Society's high regard for the medical profession, however, was not to last. At the end of World War II, 23 Nazi doctors and scientists were put on trial for the murder of concentration camp inmates who were used as research subjects. Of the 23 professionals tried at Nuremberg, 15 were convicted, 7 were condemned to death by hanging, 8 received prison sentences from 10 years to life, and 8 were acquitted. [Mitscherlich & Mielke] Included in the legal judgment and sentences handed down at the culmination of the trial were ten points describing required elements for conducting research with humans. These points became known as the Nuremberg Code.

 

In summary, the Nuremberg Code includes the following guidance for researchers:

 

•Informed consent is essential.

•Research should be based on prior animal work.

•The risks should be justified by the anticipated benefits.

•Only qualified scientists must conduct research.

•Physical and mental suffering must be avoided.

•Research in which death or disabling injury is expected should not be conducted.

 

Effect of the Nuremberg Code

The Code had little impact on researchers in the United States, who thought that the principles in the Code were already implicit in their work and that it was simply a document to condemn the Nazi atrocities and to convict the Nazi doctors. There were a number of problems with the Code itself. For example it did not have the strength of law, it was created post hoc, and it applied to only non-therapeutic human subjects research.

 

Declaration of Helsinki

In 1964 the World Medical Association developed a code of research ethics that came to be known as the Declaration of Helsinki. It was a reinterpretation of the Nuremberg Code, with an eye to medical research with therapeutic intent. Subsequently, journal editors required that research be performed in accordance with the Declaration. In principle, this document set the stage for the implementation of the Institutional Review Board (IRB) process. [Shamoo & Irving]

 

Beecher Article

In 1966 Dr. Henry K. Beecher, an anesthesiologist, wrote an article (Beecher HK. "Ethics and Clinical Research" NEJM June 16, 1966) describing 22 examples of research studies with controversial ethics that had been conducted by reputable researchers and published in major journals. Beecher wrote, "medicine is sound, and most progress is soundly attained;" however, if unethical research is not prohibited it will "do great harm to medicine." Beecher provides estimates of the number of unethical studies and concludes, "unethical or questionably ethical procedures are not uncommon." [Beecher]

 

Beecher's article played an important role in heightening the awareness of researchers, the public, and the press to the problem of unethical human subjects research. "Until this article we assumed that unethical research could only occur in a depraved regime like the Nazis."- Robert J. Levine, MD (personal communication).

 

Ethical Problems with Past Studies

 

Ethical Problems

The Beecher article and increased public awareness brought to light problems with ethics in research such as the following:

 

•Lack of informed consent

•Coercion or undue pressure on volunteers (or on a parent to volunteer their child)

•Use of a vulnerable population

•Exploitation of a vulnerable population

•Withholding information

•Withholding available treatment

•Withholding information about risks

•Putting subjects at risk

•Risks to subjects outweigh benefits

•Deception

•Violation of rights

 

Historic Case Studies

Each of the following exhibited one or more of the ethical problems listed above.

 

Willowbrook Hepatitis Study

In 1956, at an institution for mentally retarded children in Staten Island, New York, a study was initiated to determine the natural history of viral hepatitis and to test the effectiveness of gamma globulin as an agent for inoculating against hepatitis. Children were deliberately infected with a mild form of hepatitis.

 

The investigators defended the study by stating that most new children would become infected with hepatitis within their first 6-12 months at the institution. Although permission was obtained from parents, the parents were not fully informed of the possible hazards involved in the study. There is evidence that the parents were led to believe that the child would not be enrolled at the school unless the parents signed the consent form.

 

Ethical problems: exploitation of a vulnerable group of subjects, withholding information about risks, coercion or undue pressure on parents to volunteer their children. [Munson]

 

Jewish Chronic Disease Hospital Study

In 1963 live cancer cells were injected into senile patients without their knowledge as part of a study of immunity to cancer. Since the investigators believed that the cells would be rejected, the researchers did not inform the patients or seek consent because they did not want to frighten them.

 

Ethical problems: lack of informed consent, use of a vulnerable group of subjects. [Levine]

 

San Antonio Contraception Study

In San Antonio, Texas, a number of Mexican-American women participated in a 1971 study to determine side effects of an oral contraceptive. The women came to a clinic seeking contraceptives. Unbeknownst to them, the study was designed so that half the women would receive oral contraceptives for the first half of the study, then switched to placebo. The women initially receiving placebo were placed on the oral contraceptive for the second half of the study. Ten of the 76 subjects became pregnant while using placebo.

 

Ethical problems: lack of informed consent, use of a vulnerable group of subjects, risks to subjects outweighed benefits. [Levine]

 

Tea Room Trade Study

The study planned first to obtain information about homosexual practices in public restrooms and then to conduct further investigation on the men who took part in the acts. The researcher went undercover and gained the confidence of the men by acting as a "look out." The researcher identified 100 active subjects by tracing their car license numbers. A year after he completed the initial study of direct observation of homosexual acts the researcher distributed a "social health survey" throughout the communities where he knew the subjects lived.

 

Ethical problems: use of a vulnerable population, reinforced image that social scientists use deception casually in research, lack of informed consent. [Warwick]

 

Obedience to Authority Study (Milgram Study)

The purpose of this study was to determine response to authority in normal humans. The researchers told recruited volunteers that the purpose was to study learning and memory. Each subject was told to teach a "student" and to punish the students' errors by administering increasing levels of electric shocks. The "student" was a confederate of the researcher who pretended to be a poor learner and mimicked pain and even unconsciousness as the subject increased the levels of electric shock. 63% of the subjects administered lethal shocks; some even after the "student" claimed to have heart disease. Some of the subjects, after being "debriefed" from the study experienced serious emotional crises.

 

Ethical Problems: deception, unanticipated psychological harms.

 

The Public Health Service Syphilis Study (1932-1971)

Initiated by the Public Health Service, this study was designed to document the natural history of syphilis in African-American men.

 

At the time the study began there was no known treatment for syphilis. Hundreds of men with syphilis and hundreds of men without syphilis (serving as controls) were enrolled into the study. The men were recruited without truly informed consent. They were deliberately misinformed about the need for some of the procedures. For example, spinal taps were described as necessary and special "free treatment."

 

Even after penicillin was found to be a safe and effective treatment for syphilis in the 1940's, the men were denied antibiotics. The study continued to track these men until 1972 when the first public accounts of the study appeared in the national press. The study resulted in 28 deaths, 100 cases of disability, and 19 cases of congenital syphilis. [Levine]

 

Ethical problems: lack of informed consent, deception, withholding information, withholding available treatment, putting men and their families at risk, exploitation of a vulnerable group of subjects who would not benefit from participation.

 

The Belmont Principles

Research Ethics since the 1970s

The Public Health Service (PHS)Syphilis Study is among the most influential in shaping public perceptions of research involving human subjects. After, media sources reported on the PHS Syphilis Study, Congress formed an Ad Hoc Panel. The Panel determined that the PHS Syphilis Study should be stopped immediately and that oversight of human research was inadequate. The Panel recommended that federal regulations be designed and implemented to protect human research subjects in the future. Subsequently, federal regulations were enacted including the National Research Act, 45 Code of Federal Regulations 46, and 21 Code of Federal Regulations 50.

 

The National Commission

In 1974 Congress authorized the formation of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, known to most people in research ethics as The National Commission. Congress charged the National Commission to identify the basic ethical principles that underlie the conduct of human research--to look at the writings and discussion that had taken place up to this time and to ask, "What are the basic ethical principles that people are using to judge the ethics of human subject research?"

 

Congress also asked the National Commission to develop guidelines to assure that human research is conducted in accordance with those principles.

 

The Belmont Report

The National Commission met and in 1979 published the Belmont Report. The Belmont Report is "required reading" for everyone involved in human subject research.

 

The Belmont Report identifies three basic ethical principles that underlie all human subject research. These principles are commonly called the Belmont Principles. The Belmont Principles are respect for persons, beneficence, and justice.

 

The Belmont Principles

Respect for Persons

This principle is found in the writings of philosopher Immanuel Kant. It requires us to treat individuals as autonomous human beings and not use people as a means to an end. We must allow people to choose for themselves, and provide extra protection to those with limited autonomy.

 

Elements of autonomy include:

 

•Mental capacity, the ability to understand and process information.

•Voluntariness, freedom from the control or influence of others.

 

Therefore, subjects have full autonomy when they have the capacity to understand and process information, and the freedom to volunteer for research without coercion or undue influence from others.

 

Rules derived from the principle of respect for persons include:

 

•The requirement to obtain informed consent.

•The requirement to respect the privacy of research subjects.

 

Beneficence

This principle reminds us to minimize harms and maximize benefits. Derived rules include:

 

•The requirement to use the best possible research design to maximize benefits and minimize harms.

•The requirements to make sure the researchers are able to perform the procedures and handle the risks.

•The prohibition of research that is without a favorable risk-benefit ratio.

 

Justice

The principle of justice requires us to treat people fairly and to design research so that its burdens and benefits are shared equitably. Derived rules include:

 

•The requirement to select subjects equitably.

•The requirement to avoid exploitation of vulnerable populations or populations of convenience.

 

Balancing the Three Principles

It was the Commission's intention that each of the three principles should have equal moral force. This means that in some situations, the three principles might be in conflict with one another. For example, we might derive from the principle of respect for persons that we should limit the involvement of children in research because children are unable to choose for themselves. But, we might derive from the principle of justice that we must involve children in studies so that children will have the opportunity to benefit from the research. The Belmont Report says that one principle does not always outweigh another. Rather, we are required to consider each case separately and on its own merits in light of all three principles.

 

Ethical Standards for Research that Guide Us Today

In the last several years reports of unethical studies including gene transfer, cancer, and psychiatric research have heightened the public awareness of these issues even further. Two recent examples follow:

 

Death of a Normal Volunteer

 

On March 31, 1996, a 19-year-old Asian American student at the University of Rochester responded to an advertisement for study subjects to undergo bronchoscopy for the harvest of alveolar macrophages. The bronchoscopy was difficult and required numerous doses of topical lidocaine. The investigators repeatedly asked the subject if she wanted to continue and the subject nodded her head "yes". The study was completed, but the subject returned to the hospital in cardiac arrest from an overdose of lidocaine and died April 2, 1996. An investigation into this death revealed that the protocol did not limit lidocaine doses, that the doses were not documented, that the subject was not observed after the bronchoscopy, and that the concentrations of lidocaine were increased without IRB approval.

 

Death on Gene Therapy Trial

 

In the fall of 1999, 18-year-old Jesse Gelsinger died as a result of his participation in a gene transfer trial. Jesse had a rare metabolic disorder, ornithine transcarbamylase deficiency syndrome (OTC) that was being controlled by medication and diet. Researchers at the University of Pennsylvania, were testing an innovative technique using adenovirus gene transfer. Shortly after treatment Jesse Gelsinger experienced multiple organ failure and subsequently died. This case catapulted research with human subjects into the national media. Serious concerns related to conflict of interest, data safety monitoring, and informed consent have made the Gelsinger case a contemporary illustration of continued doubts about the ethical integrity of research with human subjects. This case has instigated deliberations on all these controversial topics at the national level.

 

Applying the Belmont Principles

The need for protecting human subjects through research ethics and regulations is as prevalent now as ever. Applying the Belmont principles to our studies is an important start:

 

•From the principle of respect for persons we need to conduct initial and continuing informed consent. We need to evaluate whether the research allows subjects to withdraw from the research and maintains the welfare of each subject.

•From the principle of beneficence we need to evaluate the social and scientific value of the research, the scientific validity of the research, and determine whether the research has a favorable risk benefit ratio.

•From the principle of justice we need to evaluate whether there is fair subject selection. We also need to evaluate the inclusion and exclusion criteria and the methods of recruitment.

 

Applying Research Ethics

Additional considerations in research ethics include the following:

 

Principal Investigator's (PI's)Relationship with Staff

A responsible PI will:

 

•Obtain team management skills

•Encourage questions from colleagues and staff

•Listen to the concerns of the research staff, as they may be the first to point out problems with the protocol and with compliance

•Build consensus with the research team

•Eliminate intimidation by those in supervisory positions

 

Authority relationships are not limited to the PI and the staff, but can also include the authority of the sponsor over the PI, the authority of the PI over the subject, and the authority of the protocol over the PI.

 

Investigator-Subject Relationship

The investigator must place the subject's rights, welfare, and safety above all other personal and scientific concerns. The relationship between researcher and subject is similar to a physician-patient relationship, but different in the following ways:

 

Informed consent is required for participation in research.

 

Example: Let us suppose that a patient insists that she does not want to hear about the risks, benefits, and alternatives of a proposed medical procedure. She insists that the physician decide for her. Many would say that it is ethical for the physician to go ahead with the treatment, provided that he/she is convinced that it is in the best interest of the patient.

 

In research the issue is more complex and the relationship more formal. If a potential research subject is given a consent form, and the subject does not want to read the document and simply asks, "Where do I sign?" the investigator must insist that the subject listen to the investigator's description of the study and other important information. The Investigator must insist that the potential subject read and understand the consent document. If the subject refuses to read the consent or hear a full disclosure of the information about the research, then the investigator has the ethical obligation to prohibit enrollment of the subject.

 

Withdrawal from a study is at the discretion of the subject.

 

Example: A healthy research subject enrolls in a pharmacokinetic study of a drug that is known to cause anxiety and feelings of distrust. After receiving two doses, the subject declares he no longer trusts the researchers and says he will leave. The investigator says, "It's the drug talking" and tries to continue the procedure.

 

An ethical researcher will permit subjects to withdraw for whatever reason or for no reason. Of course, a researcher must do what is needed for subject safety; in the example above, the investigator should ensure the subject's emotional equilibrium returns to normal.

 

Investigators should be sensitive to power relationships.

 

Example: It is common in basic science laboratories to obtain blood from healthy volunteers, usually staff in the research lab. Some blood donors have difficult veins and may need to be stuck several times to obtain blood. Despite the increased pain of multiple sticks, staff members in an investigator's lab may feel obliged to say, "Stick me. I don't care. I don't mind needles." Responsible investigators should recognize the problem and excuse such a person from the study. The investigator should say something to the effect that, "You are experiencing more harm than the average subject. I will find someone else to enter the study who will not experience the same anxiety and harm."

 

The investigator has a moral fiduciary relationship with the subject.

 

Example: There are conflicts of interest that are so great that even the moral investigator will have a difficult time making the right decision. If doing what is right for the subject means losing $10 million, many of us could be susceptible to making the wrong decision. It is up to the institution and the IRB to detect and minimize these conflicts of interests. However, it is also up to the investigator to avoid entering into these untenable conflicts.

 

Research Ethics and Regulations

Federal regulations are derived from all of these ethical concerns. Federal regulations provide three basic protections to human subjects involved in research:

 

•Institutional Assurances

•Review by an Institutional Review Board

•Informed Consent

 

Module 3 of this program will review the Informed Consent process in detail.

 

Institutional Assurances

Institutional assurances are a mechanism to apply federal regulations to all human subject research. When institutions sign federal assurances, they may also elect to apply the Health and Human Services regulations and terms of the assurance to all research of the institution, regardless of the source of funding.

 

IRB Registration

Both HHS and FDA require that IRBs register through the OHRP registration systems. The regulations at 45 CFR 46, subpart E, require all IRBs to register with HHS if they will review human subjects research conducted or supported by HHS and are to be designated under an assurance of compliance approved for federalwide use [i.e., a federal wide assurance (FWA)] by OHRP. The FDA states IRBs that "review clinical investigations regulated by FDA or review clinical investigations that are intended to support applications for research or marketing permits for FDA-regulated products" must register.

 

Review by an Institutional Review Board

Review by the Institutional Review Board is the glue that holds the evaluation process together. IRB review (described in detail in Module 2) is guided by the ethical principles described in the Belmont Report and asks the following questions when evaluating a study:

 

Respect for persons

•Does the consent process maximize autonomy?

•Does the protocol maximize autonomy?

•Does this study require additional protections to be put in place for vulnerable populations?

•Does this study maximally protect subject privacy and confidentiality?

 

Beneficence

•Is the research design adequate? Can it be improved?

•What are the risks? Have they been minimized? Will the subject be informed?

•What are the benefits? Have they been maximized? Will the subject be informed?

 

Justice

•Does recruitment for the study target the population that will benefit from the research?

•Does the recruitment unfairly target a population?

•Are the inclusion/exclusion criteria fair?

 

Ethical principles and federal regulation provide a framework for IRBs to evaluate research involving human subjects. However each research study is unique and thus a comprehensive review may be a complicated process.

 

Basic Institutional Review Board (IRB) Regulations and Review Process

 

Content Authors

 

Ada Sue Selwitz MA

The University of Kentucky

 

Norma Epley MS

East Carolina University

 

Janelle Erickson MPH

Group Health Cooperative

 

Introduction

The purpose of this module is to provide a basic understanding of the human subject protection regulations that govern the participation of human volunteers in research in the United States. By end of the module you will be able to:

 

•Describe the role, authority, and composition of the IRB.

•List the IRB requirements for conducting research involving human subjects.

•Describe the types of IRB review.

•Describe the process of working with the IRB.

•Identify other regulations and regulatory groups that require compliance based on the type of research being conducted.

 

IRB Role, Authority, and Composition

The Role of the IRB

An Institutional Review Board (IRB) is a review committee established to help protect the rights and welfare of human research subjects. Regulations require IRB review and approval for research involving human subjects if it is funded or regulated by the federal government. Most research institutions, professional organizations, and scholarly journals apply the same requirements to all human research. Although federal regulations refer to IRBs, an institution may have chosen a different name for this committee.

 

To clarify when IRB review is required, let's define some terms:

 

Research: Federal regulations define research as: "a systematic investigation designed to develop or contribute to generalizable knowledge." [45 CFR 46.102(d)] If an investigator is unclear about whether a planned activity is research, the investigator should contact his/her IRB office.

 

Human Subjects: The Department of Health and Human Services (DHHS) regulations define a human subject as "a living individual about whom an investigator (whether professional or student) conducting research obtains:

 

1.Data through intervention or interaction with the individual.
Or

2.Identifiable private information." [45 CFR 46.102 (f)]

 

Note: Some state laws include deceased individuals and fetal materials as "human subjects." Check with the local IRB about the definition of a human subject that applies in the state where the research will be conducted.

 

Private Information includes:

 

1.Information about behavior that occurs in a setting in which the individual can reasonably expect that no observation or recording is taking place.

2.And information that has been provided for specific purposes, other than research, where the individual can reasonably expect that it will not be made public (e.g., a medical record.) [45 CFR 46.102(f)].

 

Coded Private Information or Biological Specimens.

DHHS Office of Human Research Protection (OHRP) policy considers private information or specimens to be individually identifiable when they can be linked to specific individuals either directly or indirectly through coding systems. DHHS OHRP guidance states that only a knowledgeable person or entity is authorized to determine if coded specimen or data constitute research. An investigator cannot make that determination. [OHRP DHHS Guidance on Research Involving Coded Private Information of Biological Specimens, August 2004.]

 

Clinical Investigation: The Food and Drug Administration (FDA) defines clinical investigation as "any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the Food and Drug Administration, or is not subject to requirements for prior submission to the Food and Drug Administration, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit." [21 CFR 56.102(c)]

 

The Authority of the IRB

Federal regulations stipulate that an IRB can:

 

•Approve research.

•Disapprove research.

•Modify research.

•Conduct continuing reviews.

•Observe / verify changes.

•Suspend or terminate approval.

•Observe the consent process and the research procedures.

 

The Composition of the IRB

Federal regulations dictate that the IRB membership will include:

 

•At least five members.

•Member of both sexes.

•Members that come from varied professions.

•At least one member whose primary concerns are in nonscientific areas.

•At least one member whose primary concerns are in scientific areas.

•At least one member who is not otherwise affiliated with the institution.

 

The regulations also stipulate that the IRB membership will include:

 

•Reviewers with experience and expertise in all of the areas of research being reviewed. At its discretion, an IRB may invite individuals with competence in special areas to assist in the review of issues which require expertise beyond or in addition to that available on the IRB.

•Diversity of backgrounds.

•Sensitivity to community attitudes.

•Knowledge of institutional commitments and regulations, applicable laws, and standards of professional conduct.

•Knowledge and experience with vulnerable populations.

 

Note: If an IRB reviews research that involves vulnerable subjects, the IRB must consider the inclusion of an individual who has knowledge of, and experience with, these vulnerable subjects. The regulations may also require a voting IRB member who has relevant research expertise (for example, research involving prisoners). IRBs may call experts to help with problematic reviews, but those persons may not vote on the disposition of the application. If an IRB member has a conflict of interest, that member cannot be present for the review of that project except to provide the IRB with information as requested and may not vote on that project.

 

IRB Requirements for Human Subjects Research

IRB Requirements

Institutions and IRBs vary in the practices that assure they meet the federal regulations and in the details of the standards they apply. What follows are the minimum federal requirements. Institutions and/or IRBs may add additional protections or procedures to these minimum requirements.

 

IRB applications usually contain, at a minimum, information that allows IRB members to assess:

 

•Risk / anticipated benefit analysis.

oIdentification and assessment of risks and anticipated benefits.

oDetermination that risks are minimized.

oDetermination that risks are reasonable in relation to potential benefits.

•Informed consent.

oInformed consent process and documentation.

•Assent. The affirmative agreement of a minor or decisionally impaired individual to participate in research.

oAssent process and documentation.

•Selection of subjects.

oEquitable selection in terms of gender, race, ethnicity.

oBenefits are distributed fairly among the community's populations.

oAdditional safeguards are provided for vulnerable populations susceptible to pressure to participate.

•Safeguards that ensure that subject recruitment does not invade individuals' privacy and that procedures are in place to assure that the confidentiality of the information, collected during the research, is monitored.

•Research plan for collection, storage, and analysis of data.

oClinical research studies often include data safety monitoring plans and/or data safety monitoring boards (DSMB). IRBs will review the plans to ensure they are adequate to protect human subjects.

•Research design / methods that are appropriate, scientifically valid and therefore, justify exposing subjects to research risks.

•Additional information about identification, recruitment and safeguards if the research involves special populations.

•In addition, the IRB must review:

oThe qualifications of the principal investigator (PI) and scientific collaborators.

oA complete description of the proposed research.

oProvisions for the adequate protection of rights and welfare of subjects.

oCompliance with pertinent federal and state laws/regulations and institutional policy.

 

Responsibilities of the Principal Investigators and Research Staff

Principal investigators and research staff have specific responsibilities. They are required to:

 

•Protect the rights and welfare of human subjects who participate in research.

•Understand the ethical standards and regulatory requirements governing research activities with human subjects.

•Personally conduct or supervise the research.

•Ensure that all staff, collaborators and colleagues assisting in the conduct of the study are informed about the study, the regulations governing research and the institutional policies.

•Ensure that all research activities have IRB approval and other approvals required by the institution before human subjects are involved.

•Implement the research activity as it was approved by the IRB.

•Obtain the informed consent of subjects before the subject is involved in the research and document consent as approved by the IRB.

•Maintain written records of IRB reviews and decisions and obtain and keep documented evidence of informed consent of the subjects or their legally authorized representative.

•Obtain IRB approval for any proposed change to the research protocol prior to its implementation.

•Comply with the IRB requirements for timely reporting of unanticipated problems involving risks to subjects or others including adverse events, safety reports received from the sponsor, or data safety and monitoring summary reports.

•Obtain continuation approval from the IRB on the schedule prescribed by the IRB.

•Make provisions for the secured retention of complete research records and all research materials.

•Ensure the confidentiality and security of all information obtained from and about human subjects.

•Verify that IRB approval has been obtained from all participating institutions in collaborative activities with other institutions.

•Notify the IRB regarding the emergency use of an investigational drug or device within 5 working days of the administration of the test article.

 

When IRB regulations are not followed, consequences could include:

•Suspension of research project.

•Suspension of all of a PI's research projects.

•Inability to use data or publish results.

•Notification of sponsors, regulatory agencies and funding agencies of noncompliance.

•Debarment by FDA from using investigational products.

•Inability to receive funding from federal grants.

•Additional monitoring and oversight by the IRB and/or third party monitoring of research activities.

•Termination of employment.

•Loss of licenses.

•Immediate shut-down of ALL research at an organization.

 

These are not theoretical consequences. Some or all of these consequences have occurred at sites where human subjects research was conducted improperly or without IRB approval.

 

The Types of IRB Review

Contact the IRB office for the guidelines for submitting a study for IRB review. Under federal regulations, there are three possible IRB review procedures:

 

•Full Committee Review.

•Expedited Review.

•Review for Exemption Status.

 

Full Committee Review

Full committee review or review by the convened IRB is the standard type of review described in the Federal regulations. It must be used for the initial review of all studies that are not eligible for expedited review or exemption status. The procedures and conditions for full committee review require that:

 

•The review must be conducted at a convened meeting of the IRB. A majority of IRB members (a quorum) must be present at the meeting.

•At least one member whose primary concerns are in nonscientific areas must be present at the meeting (in addition, FDA policy requires that a physician be present).

•In order to approve research, the IRB must determine that all of the requirements specified in 45 CFR 46.111 (and if applicable, 21 CFR 56.111) are satisfied.
See: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm and www.fda.gov/oc/ohrt/irbs/appendixc.html.

•A majority of the members present at the meeting must approve the research.

•IRB members who have a conflict of interest in a research project may provide information to the IRB, but cannot participate in the review. Members with a conflict do not count toward the quorum for the review of that study.

•The IRB must notify investigators and the institution in writing of its decision to approve, modify or disapprove the research.

•IRBs must keep detailed documentation of meeting activities including attendance, voting on actions, the basis for the actions, and a written summary of the IRB discussion of controverted issues and their resolution.

 

Although not specifically addressed in the regulations, IRBs may employ a "primary reviewer system". In such a system, all IRB members receive basic information about the research application, but a "primary reviewer" with experience and/or expertise in the study area is assigned to conduct a thorough review of the IRB application and any accompanying documentation (e.g., an Investigator's Brochure or grant application). The "primary reviewer" will then report his/her findings for discussion at a convened meeting of the full board. At some institutions reviewers may contact the investigator with questions or suggestions prior to the meeting. At some institutions the IRB may ask that investigators attend the IRB meeting or be available by phone to answer questions that may arise at the meeting.

 

Expedited Review

Federal regulations permit the IRB chairperson or one or more experienced members to review a study if it involves no more than minimal risk for the subjects and if it fits within certain categories. The term "Expedited Review" only describes the process by which an IRB submission can be reviewed. The information the expedited reviewer(s) is required to consider is the same as if the submission were receiving Full Committee Review.

 

The Federal Regulations establish two main criteria for an expedited review. There are:

 

•The research may not involve more than "minimal risk".

"Minimal risk" means that "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests." ([45 CFR 46.102(i)] and [21 CFR Part 56.102(i)])

•The entire research project must be consistent with one or more of the following federally defined categories (quoted from the OHRP, the IRB oversight agency, guidance document on Expedited Reviews.) [http://www.hhs.gov/ohrp/humansubjects/guidance/exprev.htm]

 

Some institutions/IRBs have additional requirements. Check with your IRB office for more information about how expedited review is handled by your IRB.

 

Research Categories that Qualify for Expedited Review

Federal Regulations establish 9 categories that IRBs may use to invoke the expedited review process. Institutions may adopt some or all of the categories when determining if a research activity can be appropriately reviewed by an expedited review process. Categories 1 through 7 pertain to both the initial and to the continuing IRB review. Categories 8 and 9 pertain only to continuing review. The 9 categories are listed below. Follow the hyperlink for more details about each category at https://www.citiprogram.org/members/learnersII/References.asp?intReferenceID=25799.

 

Category 1:

Clinical studies on drugs or medical devices for which an investigational new drug (IND) or an investigational device exemption (IDE) application is NOT required. Similarly, a study with a cleared/approved medical device that is being used in accordance with its cleared/approved labeling.

 

Category 2:

Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture.

 

Category 3:

Prospective collection of biological specimens for research purposes by noninvasive means.

 

Category 4:

Collection of data through noninvasive procedures routinely employed in clinical practice provided that:

•The noninvasive procedure must not involve general anesthesia or sedation routinely employed in clinical practice or procedures involving x-rays or microwaves.

•Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

 

Examples of noninvasive procedures are:

•Physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject's privacy.

•Weighing or testing sensory acuity.

•Magnetic resonance imaging.

•Electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography.

•Moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.

 

Category 5:

Research involving data, documents, records, or specimens that:

 

•Have been collected.
or

•Will be collected solely for non-research purposes (such as for medical treatment or diagnosis).

 

Note: Some research in this category may be exempt from the DHHS regulations for the protection of human subjects. 45 CFR 46.101(b)(4). This listing refers only to research that is not exempt.

 

Category 6:

Collection of data from voice, video, digital, or image recordings made for research purposes.

 

Category 7:

Research on individual or group characteristics or behavior.

 

Category 8:

Continuing review of research previously approved by the convened IRB where:

 

•The research is permanently closed to the enrollment of new subjects; all subjects have completed all research-related interventions; and, the research remains active only for long-term follow-up of subjects,
Or where:

•No subjects have been enrolled and no additional risks have been identified.
Or where:

•The remaining research activities are limited to data analysis.

 

Category 9:

Continuing review of research not conducted under an investigational new drug (IND) application or investigational device exemption (IDE) and where categories two (2) through eight (8) do not apply.

 

Expedited Review Process

 

The IRB chairperson or one or more experienced IRB members, designated by the Chair, can conduct an expedited review. IRB members with a conflict of interest cannot be designated to serve as an expedited reviewer. In conducting the review, a determination must be made that the research meets the conditions for expedited review procedures.

 

The reviewer conducting the expedited review may exercise all of the authorities of the IRB with one important exception, the reviewer may not disapprove research. To approve a research activity, the reviewer must make the determination that all of the requirements specified in Federal regulations (45 CFR 46.111 and 21 CFR 56.111) are satisfied. The reviewer (s) may either approve the research, require modifications (to secure approval) or refer the research to a convened IRB meeting for review in accordance with the "full committee review" procedures described in section 2 above, and set forth in DHHS regulations at 45 CFR 46.108(b) and 21 CFR 56.108(c).

 

Expedited procedures can also be used to review minor modifications of previously approved research. [45 CFR 46.110(b) and 21 CFR 56.110(b)]

 

Review for Exemption Status

Federal regulations specifically define 6 categories of human subjects research that are exempt from the other provisions of the regulations. Federal Guidance indicates that applying exempt status to a project is a decision to be made by the IRB and that investigators can not make this determination for themselves. Therefore, institutions / IRBs have established procedures to certify that a project is exempt. Check with the IRB office to find out who has been granted authority to make the exemption determination. Note: the determination must be made prior to initiation of research or of the activity; it cannot be made retroactively.

 

Research that is Exempt

The regulations found in 45 CFR 46 have determined that the following six categories of research are eligible for exemption status, [45 CFR 46.101(b)]: See the hyperlinked material for the regulatory details and conditions associated with each category at https://www.citiprogram.org/members/learnersII/References.asp?intReferenceID=25800.

 

1.Research conducted in established or commonly accepted educational settings, involving normal educational practices.

2.Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior. Some Observations studies do not qualify for exemption.

3.Research not exempt under "2" above, may still qualify for an exemption if the human subjects are elected or appointed public officials or candidates for public office.

4.Research involving the collection or study of freely available de-identified existing data, documents, records, pathological specimens, or diagnostic specimens.

5.Research and demonstration projects conducted by heads of government departments or agencies which are designed to evaluate public programs.

6.Taste and food quality evaluation and consumer acceptance studies.

 

When Review of Exemption Status is Not Appropriate

According to the DHHS regulations 45 CFR 46, NO research involving prisoners, as subjects, can be exempted. Additionally, including children and survey or interview procedures or observations of public behavior does not apply, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed.

 

Additional HIPAA Requirements That Indirectly Impact The Review Of Exemption Status

The Privacy Rule is a Federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996. [45 CFR 160 and 164]. If an IRB has been given the responsibility to consider HIPAA in research issues and if the research potentially falls under the purview of HIPAA, an IRB will be applying not only the 45 CFR 46 exemption categories but also determining if HIPAA applies. In some cases, HIPAA applicability requirements are more stringent than DHHS exemption requirements and in other cases less stringent. A research project that is exempt from the human research subject IRB requirements may not be exempt from HIPAA provisions. Also, a project that is not exempt from IRB might be exempt from HIPAA. See the DHHS OHRP "Guidance on Research Involving Coded Private Information or Biological Specimens," [http://www.hhs.gov/ohrp/humansubjects/guidance/cdebiol.pdf] and the NIH and guidance entitled "Institutional Review Boards and HIPAA Privacy Rule" [http://privacyruleandresearch.nih.gov/irb_default.asp].

 

Process of Working with the IRB

Criteria for IRB Approval

Federal policy lists Basic Criteria that the IRB must apply [45 CFR Part 46.111 and 21 CFR Part 56.111] when reviewing research involving human subjects. To approve a research project, the IRB must determine that:

 

•The risks to subjects are minimized.

•The risks are reasonable in relation to any anticipated benefits to the subject, and to the advancement of knowledge.

•The selection of subjects is equitable.

•Informed consent will be sought.

•Informed consent will be documented.

•Where appropriate, the research plan makes adequate provisions for monitoring the data collected to ensure safety of subjects.

•There are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

•Where any of the subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect subjects.

 

In addition, there are specific requirements regarding the informed consent process. These will be detailed in Module 3, "Informed Consent".

 

The IRB must determine that these conditions exist at the time of initial review and at each subsequent review conducted by the IRB.

 

Types of IRB Submissions

1.Application for initial review: The first request for approval of a specific project is the application for initial review.

2.Application for Continuing review: The IRB must re-review studies at a minimum of once every 365 days. An IRB may require review more frequently depending on the IRB's assessment of the study's risk/benefit ratio. The review may be a full or expedited review.

3.Amendments or modifications: Changes can not be made to approved studies, including the informed consent document, without prior IRB review and approval. The review may be full or expedited, depending on the magnitude of the change and the effect of the change on the risks / benefit ratio.

4.Reports: The IRB may require a report for:

a.Adverse events or unanticipated problems involving risks to subjects or others.

b.incidents of noncompliance.

c.Deviations from an approved study protocol and violations of the terms of approval.

d.Data Safety and Monitoring Report summaries.

 

Application for Initial Review

The initial review may be either a "Full Committee" or "Expedited" review depending on the type of study, the subjects and the level of risk.

 

Application for Continuing Review

The IRB must do substantive continuing review and must consider the same issues as during initial review. Specifically:

 

•When conducting a continuation review, the IRB uses "Full Committee Review" procedures unless the research meets the expedited review criteria.

•To approve research, the IRB must determine that all the requirements for initial approval (specified in 45 CFR 46.111 and 21 CFR 56.111) continue to be satisfied.

•IRB should review, at a minimum, the protocol and any amendments as well as a status report including:

oThe number of subjects accrued.

oA description of adverse events, unanticipated problems, withdrawal of subjects, complaints, summary of relevant new information.

oA copy of current informed consent document.

 

Follow the link to view the latest GUIDANCE FROM OHRP ON IRB CONTINUING REVIEW [http://www.hhs.gov/ohrp/humansubjects/guidance/contrev0107.htm].

 

It is an investigator's responsibility to know when IRB approval will expire. However, most institutions/IRBs, as a courtesy to their investigators, send out reminders that IRB approval is about to expire. Sometime prior to the expiration of IRB approval, investigators will receive a request to complete a progress report for continuing review by the IRB. It is an investigator's responsibility to complete the continuing review request, submit it back to the IRB in a timely manner prior to the end of the current IRB approval period.

 

If a protocol's approval expires before the IRB completes its review, the investigator must stop all research procedures. When stopping the research could subjects at risk, the investigaor should contact the IRB immediatgely to obtain aproval to continue treating subjects on that study.

 

Amendments and Modifications

All amendments and modifications to a study need IRB approval before they are implemented. If the investigator wants to change anything in the research that would impact the subjects, such as recruitment procedures, key personnel, inclusion/exclusion criteria, research procedures, the informed consent document / process, or data elements collected, the investigator must obtain IRB review and approval prior to implementation of the changes. The only exceptions are changes necessary to immediately protect subjects' safety, as noted in 21 CFR 56.108(a)(4) and 56.115(a)(1). If an investigator is unsure about reporting changes to the IRB, he/she should call the IRB office and ask for guidance. The IRB office can also provide investigators with instructions for submitting a request to modify an IRB-approved research.

 

Reports of Unanticipated Problems / Adverse Events / Noncompliance to the IRB

Federal reporting requirements for IRBs, investigators, and funding sponsors are confusing. Consequently, IRBs tend to develop their own idiosyncratic reporting requirements, based upon their interpretation of both FDA and OHRP guidance. This poses some difficulty for investigators because if the project is funded, the sponsor may have reporting requirements that differ from the IRB policy and procedures.

 

At a minimum, to ensure compliance, the investigator is responsible for:

1.Determining the IRB requirements for reporting with respect to what needs to be reported, when it should be reported, and the procedure for submitting the report.

2.Setting up systems to ensure that reportable events are identified and submitted to the IRB in a timely manner.

 

Examples of the type of events that may be reportable include:

•An unanticipated problem which may be defined as any unexpected event that affects rights, safety or welfare of subjects. The event could be physical such as an adverse drug experience or adverse device effect. The event could also involve some harm or risk (i.e. breach in confidentiality or harm to a subject's reputation).

•Serious adverse event which may be defined as a death, life-threatening adverse drug or device experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent disability/incapacity, or a congenital anomaly/birth defect.

•Protocol exceptions which may be defined as enrollment of a research subject that fails to meet protocol inclusion/exclusion criteria.

•Protocol deviation which may be defined as a departure from the protocol as approved by the IRB for a single subject.

•Data and Safety Monitoring Plan or Board summary reports.

•Complaints concerning subject rights submitted by subjects or concerned parties, family members, or study personnel.

 

The IRB will use the reports to assess whether the risks/benefit ratio is still reasonable, whether changes in the informed consent document or study procedures are needed, or whether re-consent is necessary. IRB requirements for reporting vary regarding what should be reported, when the reports should be submitted, and the format of the reports. Check with your IRB to determine its specific requirements.

 

Additional Reporting Requirements

Besides the IRB, the Principal Investigator (PI) has a variety of entities to which he/she is responsible for reporting. Minimum reporting requirements for each entity are:

 

Entity	PI Reporting Requirements
Research Subject	While it might not be considered reporting in the strictest sense, the informed consent process is a report to the potential subject about the research, both before the research begins and on an ongoing basis throughout the study. Also, if new information becomes available during the research that might impact the subject's willingness to participate, an investigator is obligated to provide the subject with that information. This information will also need to be reported to the IRB. The IRB office can provide guidance on how additional information should be reported.
Institution	Most institutions have reporting lines set up so that the investigator makes reports to the IRB and it falls upon the IRB to keep the institution informed. However, check with the local IRB to make sure that the investigator does not have direct responsibility for reporting incidents to the institution.
Sponsor	Adverse events should be reported immediately to the sponsor. Investigators should also check with the sponsor about proposed changes that might be made to the study, based on the adverse event that has occurred or preliminary findings. The sponsor also should be told about serious or ongoing noncompliance in a study.
FDA	Adverse events should be reported directly to FDA if the research is PI-initiated (without external sponsorship) and falls under the FDA's purview.
DSMB	If your project has a Data Safety and Monitoring Board, check your DSMB plan for reporting requirements.

 

Record Keeping

The signed informed consent document is one of the most critical research records the investigator needs to obtain and keep. It provides verification that the research was explained to the subject and that the subject understood and voluntarily agreed to participate in the research study. Investigators are responsible for retaining signed consent documents, IRB correspondences, and research records for at least 3 years after the completion of the research activity. However, local institutional policy or sponsoring agency requirements may dictate that records be kept longer. Check with the sponsor and IRB office to make sure that the minimum 3 years retention requirement meets their needs.

 

The FDA regulations specify unique document retention requirements for FDA regulated studies [see 21 CFR Part 312.62 (c)]. These requirements must be met for FDA-regulated studies.

 

Other Regulations and Regulatory Groups

Funding and Regulatory Agencies

Depending upon the nature of your research and the agency that funds your research there are a number of other regulations, policies and procedures that may need to be considered. Below is a brief description of selected regulations, regulatory bodies, and funding agencies that may oversee your research. Funding agencies and /or your local IRB offices can also provide guidance on whether any additional requirements apply to a research activity.

 

Funding Agency / Regulatory Agencies	General Regulations
DHHS The Department of Health and Human Services (DHHS) is responsible for one group of human subjects federal regulations.	The DHHS 45 Code of Federal Regulations (CFR) Part 46 applies to all human research submitted to or funded by Department of Health and Human Services [http://www.hhs.gov/] and is applied to all human research by most large institutions. Subparts include: Subpart A: Basic Federal Policy for the Protection of Human Subjects Subpart B: Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research Subpart C: Additional Protections for Prisoners Subpart D: Additional Protections for Children
NIH The National Institutes of Health include funding agencies that provide federal funding for biomedical research. NIH requires grantees conducting certain types of clinical research studies to have either data safety monitoring plans and/or data safety and monitoring boards. In general NIH policy requires that a Data and Safety Monitoring Board be established for all phase III randomized clinical trials.	(1) NIH Policy for Data and Safety Monitoring [http://grants.nih.gov/grants/guide/notice-files/not98-084.html]. (2) Policy for the National Cancer Institute for Data and Safety Monitoring of Clinical Trials [http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page2]. (3) Essential Elements of a Data and Safety Monitoring Plan for Clinical Trials Funded by the National Cancer Institute [http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page3]. (4) Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials [http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html].
OHRP The Office for Human Research Protections is the DHHS oversight body that provides guidance to IRBs and investigators conducting human subject research.	OHRP Policy and Assurances guidelines, regulations, ethical principles, IRB Guide Book, OHRP/OPRR Reports, FAQs, and other materials relevant to the protection of human research subjects are available from the Office for Human Research Protections Website [http://www.hhs.gov/ohrp].
FDA The Food and Drug Administration oversees the use of all drugs, devices, biologics, etc. including their use in research with human subjects.	The Food and Drug Administration (FDA) [http://www.fda.gov/] has numerous regulations directly impacting informed consent. See Guidance documents [http://www.fda.gov/opacom/morechoices/industry/guidedc.htm], information sheets [http://www.fda.gov/cber/infosheets.htm] and regulations indirectly impacting IRBs and investigators [http://www.fda.gov/oc/oha/IRB/toc.html].
ICH/GCP. International Conference on Harmonization / Good Clinical Practices.	Human subject research that is conducted in international settings may have additional requirements that must be met such as, International Conference on Harmonization [http://www.ich.org/UrlGrpServer.jser?@_ID=276&@_TEMPLATE=254] / Good Clinical Practices [http://www.fda.gov/oc/gcp/default.htm]
Department of Education.	Research that is funded by the Federal Department of Education [http://www.ed.gov/index.jhtml] may have additional requirements that must be met.
Department of Veterans Affairs.	Research involving human subjects recruited from or conducted in a Veterans Affairs [http://www.va.gov/] facility must also meet the requirements as set forth in the VA Manual 1200.5
Other Federal Agencies.	Each federal agency may have additional policies, procedures, requirements, etc. that must be applied to research involving human subjects. Examples are the Department of Defense [http://www.defenselink.mil/], Department of Energy [http://www.energy.gov/engine/content.do?BT_CODE=DOEHOME], and National Science Foundation [http://www.nsf.gov/].

 

Assurance Requirements

HHS human subject protection regulations and policies require that any institution engaged in non-exempt human subjects research conducted or supported by HHS must submit a written assurance of compliance to OHRP. The Federalwide Assurance (FWA) is the only type of new assurance accepted and approved by OHRP. FWAs also are approved by the Office for Human Research Protections (OHRP) for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (also known as the Common Rule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

 

An assurance of compliance is a written document submitted by an institution (not an Institutional Review Board) that is engaged in non-exempt human subjects research conducted or supported by HHS. Through the assurance, an institution commits to HHS that it will comply with the requirements set forth in the regulations for the protection of human subjects at 45 CFR part 46.

 

IRB Registration

Both the FDA and DHHS now require IRB registration.

 

Each IRB that is designated by an institution under an assurance of compliance approved for federalwide use by the Office for Human Research Protections (OHRP) under §46.103(a) [http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.103(a)] and that reviews research involving human subjects conducted or supported by the Department of Health and Human Services (HHS) must be registered with HHS.

 

Additionally, any IRB in the U.S. that reviews research that is regulated by the FDA must be registered.

 

All IRB registrations are completed through OHRP’s website.

 

Contact the IRB office to:

•Ensure the organization is registered with OHRP if federal dollars are funding the research.

•Obtain the Federal Wide Assurance (FWA) or Multiple Project Assurance (MPA) number. Alternatively, this information can be found on the OHRP Website.

•Determine FWA requirements for multi-site research activities.>

 

Informed Consent

 

Content Author

 

Diane Paul MS, RN

National Comprehensive Cancer Network.

 

 

Internet Resources and References:

•Code of Federal Regulations for the Protection of Human Subjects in Research, U.S. Department of Health and Human Services, 1998, 21 CFR Part 50 ( http://www.access.gpo.gov/nara/cfr/waisidx_98/21cfr50_98.html) and 45 CFR Part 46 (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.htm).

•U.S. Food and Drug Administration, Information Sheets [Online] Guidance for Institutional Review Boards and Clinical Investigators, 1998. (www.fda.gov/oc/ohrt/irbs/faqs.html)

•National Cancer Institute, Informed Consent [Online]. Available: http://cancertrials.nci.nih.gov.

•Klimaszewski, A.D., Anderson, S., Good, M. (2000). Informed Consent. Manual for Clinical Trials Nursing. 213-219.

 

Introduction

There is consensus regarding the importance of informed consent. Informed consent is how you show respect to research subjects, and it is mandated by the *Code of Federal Regulations (CFR) to:

 

•Protect human subjects/volunteers.

•Ensure that potential study subjects clearly understand the benefits and risks associated with their participation in a study.

•Provide the potential study subjects with all information needed to reach a decision on whether or not to participate in a research study.

 

*The Code of Federal Regulations (CFR) is published in the Federal Register, a publication of the Federal Government that codifies the general and permanent rules of executive departments and agencies. There are 50 titles that represent broad areas subject to federal regulation. The CFR is updated once each calendar year and is issued on a quarterly basis.

 

The purpose of this module is to provide a basic understanding of informed consent and the process of obtaining informed consent. By the end of the module you will be able to:

 

•Describe the requirements for complying with informed consent regulations.

•Describe the process for obtaining informed consent.

•Describe the regulations for waiving informed consent.

 

Informed Consent Requirements

General Requirements

The framework for informed consent can be found in The Code of Federal Regulations 45 CFR 46.116(a) and 21 CFR Part 50.25(a). Legally appropriate informed consent will include the following elements:

 

•Information that the study involves research.

oAn explanation of the purposes of the research.

oThe expected duration of the subject's participation.

oA description of the procedures to be followed.

oIdentification of any procedures that are experimental.

•A clear description of the risks or discomforts to the subject. Such description must:

oBe accurate and reasonable.

oReview any risks related to procedures and tests relating solely to research and any tests that carry a risk of morbidity/mortality.

oInform the subject of previously reported adverse events.

•A description of the benefits to the subject or to others.

•A disclosure of any alternative procedures or treatments that may be advantageous to the subject, thus giving the subject a full range of available options. When appropriate, a statement that supportive care with no additional disease specific treatment is an alternative.

•A description explaining how the institution/investigator will maintain confidentiality of records. Statement should include full disclosure and description of approved agencies (i.e., FDA, OHRP) and/or other designated parties that may access the records.

•For research involving more than minimal risk, an explanation should describe:

oWhether there will be any compensation.

oWhether there will be any medical treatment offered and who will bear the financial responsibility for treatment if injury occurs, and, if so, how and to what extent.

oWhere the subject may obtain further information.

•The specific office, name, and telephone number (s) of whom to contact for further information regarding the research subjects' rights, the research study, or for research-related injury.

•A statement that participation is voluntary, that refusal to participate involves no penalty or loss of benefits to which the person is otherwise entitled, and that the subject may discontinue at any time.

 

Additional Requirements

 

In addition, if relevant to the research, legally effective informed consent will also include the following elements, outlined in The Code of Federal Regulations 45 CFR 46.116(b) and 21 CFR 50.25(b):

 

•A statement that the procedure may involve unforeseeable risks.

•When appropriate, include a statement that the research could involve unforeseeable risks to the embryo or fetus or to the subject if the subject is or becomes pregnant.

•A description of circumstances under which the subject's participation may be terminated by the investigator without the subject's consent.

•A description of any additional costs to the subject that may result from participation in the research.

•A clear statement of the consequences of a subject's decision to withdraw from the research, and, if so, how to withdraw safely.

•A statement that significant new findings developed during research which may relate to the subject's willingness to continue will be provided to the subject. Also describe the process whereby subjects will be notified of significant new findings.

•A description of the approximate number of subjects that will be involved in the study.

 

Regulatory Groups

Compliance with informed consent regulations is regulated by the:

 

•Food and Drug Administration (FDA), Title 21, Code of Federal Regulation, Part 50 (21CFR50)—see Module 12.

•Office for Human Research Protections, Title 45, Code of Federal Regulations, Part 46 (45CFR46).

•Study institution's Institutional Review Board.

 

Obtaining Informed Consent

Obtaining informed consent involves:

 

•Providing information to the subject.

•Ensuring the subject understands by answering questions the subject may have.

•Obtaining the voluntary agreement of the subject to participate in the study.

 

Providing Information

Guidelines for providing information include:

 

•Advertising cannot be coercive or make false promises or claims.

•The information should be communicated in a manner and language that is clear and understandable, be communicated in an organized fashion, and allow for questions the subject may have to be answered.

•The information communicated should not use exculpatory language either in the written consent or in discussions about the research. No informed consent, whether oral or written, may include any exculpatory language through which the subject is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence. --- 45 CFR 46.116

•Procedures to screen potential subjects for eligibility must protect the rights and welfare of prospective subjects.

 

Ensuring Understanding

Guidelines for ensuring understanding include:

 

•Proving consent in a language that is understandable to the subject or his/her representative.

•Providing non-English speaking subjects a translated informed consent document that is accurate as determined by the IRB.

•If a translator is used, providing a written translation of the consent document is still required. (Some IRBs allow use of a short form translation of the IRB consent document [see 45 CFR 46.117 (b)(2)])

•Giving the person enough time to think about their research before consenting to research study participation

 

Obtaining Voluntary Agreement to Participate

Legally effective informed consent shall:

 

•Be obtained from the subject or the subject's legally authorized representative.

•Be obtained under circumstances that provide the subject with an opportunity to consider whether or not to participate and that minimize coercive influences.

•Not include any language through which the subject is made to waive or appear to waive any of his/her legal rights or any language that releases the investigator, sponsor, or institution from liability for negligence.

 

Coercive tactics such as inappropriate financial or other rewards cannot be used. Illiterate English-speaking subjects can "make their mark" on the informed consent document, as long as it is consistent with applicable state laws.

 

Special Challenges

Language Issues

The consent process should be conducted in the language spoken by the subject, and the consent form should be translated into that language. An IRB may require independent confirmation of the accuracy of the translation. Subjects who are not literate in their language must have an interpreter present to explain the study to the subject and translate questions and answers between the subject and investigator.

 

Cultural Issues

Issues other than literacy may affect comprehension. For example, in some cultures it may be considered rude to ask questions of an investigator researcher, or rude to decline what is perceived of as a request for a favor. In these circumstances, the questions of who conducts the consent process and how it is explained become even more important.

 

Regulations for Waiving Informed Consent

Sometimes, under specific circumstances with IRB approval, informed consent can be waived.

 

DHHS Regulations for Waivers

The DHHS (45 CFR 46.116) allows an IRB to waive or change the requirements for informed consent under two sets of circumstances:

 

1.Government Projects
and

2.General Waivers and Alterations.

 

Government Projects

If the research/project is approved and/or conducted by state or local government and is meant to study/evaluate:

 

•A program to benefit the public.

•Procedures under those programs.

•Alternatives to those programs or procedures.

•Changes in payment methods or levels for the services of those programs.

•The research could not practicably be carried out without the waiver.

 

General Waivers and Alterations are permissible if the IRB determines that:

•The research involves no more than minimal risk to subjects.

•The waiver or alteration will not adversely affect the rights and welfare of the subjects.

•The research could not practicably be carried out without the waiver or alteration.

•Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

 

FDA Regulations for Exceptions from Informed Consent Requirements

The FDA 21 CFR 50.23 and 21 CFR 50.24 provide exceptions to the requirement for informed consent under the following circumstances:

 

•In situations where requirements for exception from informed consent are met for emergency research (21 CFR 50.24).

•In life-threatening conditions involving an individual subject where requirements for an exception from informed consent are met and include documentation of all of the following:

oThe investigator, with the concurrence of another physician, believes the situation necessitates the use of a test article (i.e., an investigational drug, device, or biologic).

oThe subject and/or legally authorized representative is unable to communicate consent (FDA definition of Legally Authorized Representative: an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research).

oThere is insufficient time to obtain consent.

oNo alternative exists that will provide an equal or better chance of saving the subject's life.

 

Waiver of Signed Consent/Use of Oral Consent

Signed consent may be waived and oral consent used under the following circumstances:

 

FDA

The FDA allows waiver of documented informed consent (21 CFR 56.109(c)[1]) when study participation presents minimal risk to the subject and the research involves no procedures requiring consent outside the context of participation in a research study. The IRB may require the investigator to provide the subject with written materials about the research.

 

When obtaining consent from a legally authorized representative (LAR) who is not able to provide signed consent in person, it is acceptable to send the informed consent document to the LAR by facsimile and conduct the consent interview by telephone when the LAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and return the signed document to the clinical investigator by facsimile.

 

DHHS

According to DHHS (45 CFR 46.117), an IRB may allow waiver of a signed consent document in either of the following circumstances:

 

•The consent would be the only link between the research and the subject and the principal risk to the subject would be due to a breach of confidentiality, and each subject will be asked if they want consent to be documented.

•Study participation presents minimal risk of harm to the subject and the research involves no procedures requiring consent outside the context of participation in a research study.

•The investigator may be required by the IRB to provide a written summary about the research to the subject if either of these methods is used.

 

See Internet Resources and References

 

Is Telephone Consent From a Legally Authorized Representative Appropriate?

FDA

Verbal approval does not satisfy the 21 CFR 56.109(c) requirement for a signed consent document, as outlined in21 CFR 50.27(a). However, it is acceptable to send the informed consent document to the legally authorized representative (LAR) by facsimile and conduct the consent interview by telephone when the LAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and return the signed document to the clinical investigator by facsimile.

 

See the for links to FDA information about informed consent.

 

DHHS

See 45 CFR 46.117

 

Social and Behavioral Research for Biomedical Researchers

 

Content Authors

 

Deborah Dickstein, MPH

Seattle, Washington

 

Celia Walker, MA

Colorado State University

Fort Collins, Colorado

 

Helen McGough, MA

University of Washington

Seattle, Washington.

 

Introduction

This part of the training program will:

 

•Characterize social and behavioral research, presenting the most likely and typical risks.

•Extend the basic concepts of human subjects protection to these situations for biomedical researchers.

 

What is social/behavioral research (SBR)?

Social and behavioral research (identified in this module by the acronym "SBR") refers broadly to research that deals with human attitudes, beliefs, and behaviors. Biomedical and clinical researchers often incorporate SBR goals and methodologies into their physiological research. SBR is often characterized by data collection methods such as questionnaires, interviews, focus groups, direct or participant observation, and non-invasive physical measurements. Examples of the ways biomedical researchers use these techniques in their research include health histories, quality of life assessments, family pedigrees, and outcomes studies.

 

SBR data collection methods often used by biomedical researchers.

Typical SBR data collection methods include:

 

•Questionnaires (written questions) or interviews (oral questions, either by phone or in person). These may be open-ended or fixed-answer with pre-established categories such as a Likert scale. Medication diaries and behavior logs are actually special forms of open-ended questionnaires. Some biomedical researchers may also use standardized questionnaires such as intelligence tests or psychiatric diagnostic assessments.

•Opinion data and other oral data from key informant interviews, focus groups, or group discussions. Biomedical researchers may use these data collection methods to provide qualitative data to develop or support a hypothesis.

•Direct observation of behavior and interactions. This may involve a pre-coded form for noting observations, or recording (audio-, video-, or other) of actual behavior.

•Data already collected for other purposes, such as records from education, health care, social service programs, employment, and insurance coverage. These kinds of data are often used by health researchers in outcomes studies and epidemiological studies or as adjuncts in clinical or basic science research.

•Non-invasive physiological measurement, such as skin impedance and pupil dilation as reflection of emotional arousal or attention. Although these are considered physiological measures, they are often used by social and behavioral researchers to document the physiological components of behavior.

 

Examples of biomedical researchers use of social/behavioral research methodologies.

•Descriptive or exploratory research involving detailed observation, often in the real world, and often of a culture, family, group, or individual. Records-based research that does not involve direct contact with subjects can be included in this category. Examples include:

oCollection of family pedigrees for genetic studies.

oDescription (from videotaping of family interactions) of the behavioral effects of drugs or devices.

oEpidemiology of farm accidents from an analysis of state workers' compensation and medical records.

•Evaluation of existing programs of care, service, and education. Distinguishing between program evaluation and research can be difficult. If the intent of the data collection is to contribute to "generalizable" knowledge, or if the results are going to be applied outside of the setting or population, the activity is usually classified as research. If the results stay entirely in-house and are used for administrative purposes only, many institutions do not consider it research. Examples include:

oExamination of the impact of a computer-generated information sheet given to people picking up asthma medications from a pharmacy.

oEvaluation of on-call nursing services for the elderly living at home.

oAssessment of the effectiveness of a manufacturer's marketing strategies.

•Comparison of competing types or programs of information, education or treatment. These research projects usually randomize participants between experimental and standard approaches, sometimes with a third, control group. Examples include:

oMassage versus education for low back pain.

oDiet versus diet plus coached exercise for control of diabetes.

oA new medication vs. a standard and widely used medication vs. talk therapy for treatment of depression.

•Experimental manipulations of belief, attitude, emotion, or behavior, that affects subjects in ways that would not occur in their normal experience outside the research setting. Research of this type typically comes from academic areas such as psychology, communication, speech and hearing, or education, as well as nursing or medicine. If deception is employed, additional consent issues become important and must be addressed. Examples of these kinds of studies include:

oCreating emotional stressors to measure cortisol levels.

oUse of placebo in clinical drug trials.

oEvaluating virtual reality as a means for pain management.

 

Risks and benefits unique to SBR

The risks of harm associated with SBR are different from those associated with traditional biomedical research.

 

•They may include psychosocial stress and discomfort, disruption of personal and family relationships, economic, and even political harms that may result from identifiable data falling into the wrong hands. Stress and discomfort may result from being asked personal questions, from being deceived, or from being subjected to research procedures designed to manipulate emotions, feelings, and thoughts.

•They may be less predictable, more subjective and variable, and less remediable than physiological harms. For example, it is more difficult to predict how an individual will respond to answering a question about childhood sexual abuse than to predict an individual's reaction to having blood drawn. Questions about certain behavior, attitudes, and beliefs may result in "inflicted insight." This can cause distress from learning something about oneself that one would not have learned without having taken part in the study.

•They may be more dependent on socio-cultural factors than physiological harms. For example, collecting demographic information from illegal immigrants may be more risky than collecting the same information about citizens.

 

Reporting adverse events or reactions is as important in SBR as in any other human subjects research. Check with your local IRB to make sure that you understand these reporting requirements.

 

Managing and Minimizing Risks of Harm from SBR

•Data management.

oMany risks of SBR are the result of breaches of confidentiality involving sensitive data. Coding data, securing the master list linking the code to the subject identifier, maintaining the data in a secure environment, or de-linking data from identifiers can minimize risks resulting from breach of confidentiality.

•Debriefing.

oIf distress or deception must be experimentally induced, as in some psychological and physiological measurement research, the research design usually requires withholding certain information from the consent process in order to obtain unbiased results. After they have completed participation, it is important to provide this information to subjects from whom it was withheld, and to provide an opportunity for subjects to express their concerns and ask questions about the research.

oStrategies to accomplish this might include:

Debriefing subjects with a description of what really happened.

Explaining why the research could not otherwise be conducted.

An apology.

oIf possible, researchers should debrief the subjects while they still have an opportunity to withdraw their data should they feel offended and not wish to continue participation or have their data excluded.

•Adequate informed consent.

oMaking sure that potentially disturbing experiences and questions are identified during the consent process before the subject agrees to participate can minimize the likelihood that subjects will experience stress and discomfort.

 

Key Points about Informed Consent

 

•The statement "there are no risks" should not be used. Although some SBR might have no physical risks, it is always necessary to consider whether there is a possibility (even if not a high likelihood) of emotional/psychological risk, loss or breach of confidentiality or stigmatization.

•Describe the content of questions, interview topics, etc., and give specific examples of the MOST personal, sensitive, or distressing questions that will be asked. Sometimes it is appropriate to reassure subjects that there is no "right" or "wrong" answer.

•State that participants have the right to refuse to answer any question for any reason. This statement should not impute to subjects a specific sensitivity or emotional state (e.g., it should not say, "You have the right to skip any questions that make you uncomfortable").

•It may be difficult to advise subjects about emotional distress without increasing the likelihood of experiencing it. This is a judgment call that needs careful consideration in wording of consent forms.

•If recordings are used, the consent should state that subjects have the right to review and delete recordings that will be kept indefinitely or shared outside of the research team.

•If focus groups are used, subjects should be reminded that the identities of fellow participants and the information exchanged are confidential.

 

Records Based Research

 

Content Author

 

Judy Matuk, M.S.

Stony Brook University

Stony Brook, New York USA

 

This module was revised and adapted from the original module authored by:

 

Barbara Young, Ph.D.

Group Health Cooperative

Seattle, Washington USA

 

Acknowledgement: The author would like to thank Dr. Bruce Gordon and Ms. Ada Sue Selwitz for their editorial review of this module.

 

Introduction

Researchers can make important advances in the fields of education, medicine, psychology, and public policy without any in-person interaction with human subjects. Rather, hypotheses can be posed and answered by analysis of documented information in various types of paper or electronic records, including, e.g., medical, motor vehicle, criminal justice, or school records.

Each person conducting scientific research based on records should:

 

•Understand the specific risks to human subjects associated with such research;

•Ensure that the research protocol specifies procedures that minimize those risks;
And

•Obtain all required approvals (institutional, state, federal, and international, if applicable) prior to conducting the research.

 

Before collecting information from records for purposes of research, an investigator should consult with:

 

(a) the Institutional Review Board (IRB) Office at his/her own institution to determine the type of review required, if any;

(b) the applicable administrator at the institution where the actual records are owned or maintained to ensure ability to access them for research purposes;

 

In addition, the researcher needs to determine if there are other regulations impacting the record- review. Examples include the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule for medical records research, or the Family Educational Rights and Privacy Act (FERPA) for student education records.

 

LEARNING OBJECTIVES

After completing this module, the learner will be able to:

 

•Discuss the risks associated with conducting records-based research;

•Identify the types of review that apply to records-based research.

 

Risks of Records-Based Research: Privacy and Confidentiality

Risks associated with records-based research stem from possible invasion of privacy and breaches of confidentiality, i.e., the possibility that disclosure of the information could reasonably place the subject at risk of criminal or civil liability and/or be damaging to the subject's financial standing, employability, or reputation.

 

Privacy can be defined in terms of having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) or information about oneself with others. In the context of research, privacy risk pertains primarily to the methods used to obtain information about subjects. Whereas privacy risks are obviously very low in studies when a subject actually consents to providing personal information, they are much higher, in records-based research, when information is obtained for research purposes without the consent of subjects.

 

Confidentiality pertains to the actual treatment of the personal information once it is obtained. In other words, now that the researcher has obtained private information, how will it be used, stored, and reported in a way that is consistent with the manner under which it was originally obtained from the individual? Information from public records, and information obtained under a relationship of trust, as in doctor-patient relationship, will require different considerations for protecting confidentiality.

 

Records-based research must balance the possible benefits of answering important research questions with the possible risks of using information about individuals, especially if information is used without their consent.

 

You can imagine the consequences to an individual if information provided to their medical doctor about their drug addiction was revealed to law enforcement officials, or their mental illness was revealed to an employer. The IRB carefully reviews the procedures that are described by the investigator to protect the confidentiality of the information being accessed, including identification of all individuals or groups who may also be able to access that information. For example, a University’s audit office, or a research sponsor may require access to the information to ensure that the research activity is being conducted appropriately.

 

Minimizing Risks

There is an ethical and regulatory responsibility to minimize the risks to subjects of research.

 

The risks of invasion of privacy can be minimized through by obtaining informed consent from subjects (even, perhaps, before their records are accessed to determine their eligibility). However, for a variety of reasons, obtaining informed consent may be impracticable, or may compromise the goal or the research, or may actually put the subject at greater risk. In these circumstances, the IRB may waive the necessity for informed consent if specific regulatory criteria are met:

 

•The research involves no more than minimal risk; and

•The risks and welfare of the subjects will not be adversely affected by the waiver; and

•The research could not practicably be carried out without the waiver of consent; and

•When appropriate, the subjects will be provided with pertinent information after participation.

 

The risks of breach of confidentiality associated with records-based research are necessarily tied to how identifiable and how sensitive the requested information is. If the information is recorded without identifiers, the sensitivity of the information is less of a concern. If the information is both identifiable and sensitive, methods to protect confidentiality must be carefully considered by the investigator, and reviewed by the IRB. Therefore, in considering the research hypothesis, the investigator must assess how important it is to be able to associate the individual with his/her information in research records.

 

Whenever possible, and to the greatest extent possible, de-identified or anonymous information should be recorded.

 

Assuming the research cannot be conducted anonymously, the following questions speak to protection of the collected information. Based on an investigator’s answers, an IRB will carefully assess whether possible risks from breaches of confidentiality have been minimized:

 

•What kind of identifiable information, if any, will be collected?

•Who will have access to the identifiable information?

•Where will the identifiable information be kept?

•What kinds of codes or encryption will be used to separate research data from subject identifiers?

•How will limitations on access be ensured?

•How will research staff persons be trained about privacy and confidentiality?

•How long will identifiable information or linkages to personal identifiers be kept?

•For data being transmitted physically and/or electronically, what encryption methods will be used?

•What procedures will be used for disposal/destruction of identifiers and research documents, once no longer required?

 

Certificates of Confidentiality

 

For studys in which identifiable, sensitive information is being accessed (HIV status, history of alcoholism, mental illness, etc), the investigator may obtain protection from subpoena of his/her records by receiving a study specific Certificate of Confidentiality from the NIH.. For more information, visit: http://www.nih.gov/grants/oprr/humansubjects/guidance/cert-con.htm

 

What type of review is required for records-based research?

Record-based research can fall into one of four types of review. To identify the appropriate type of review the following four questions should be considered:

 

•Do the activities meet the Federal definition of “human subject research”?

•Is the research eligible for exemption from the Federal regulations?

•Is the research eligible for expedited review under the Federal regulations?

•Does the record-based research need review by the full convened IRB?

 

Some institutions have criteria more stringent than the federal guidance, so the information provided in this specific section may not describe policies and procedures at the investigators own institution. Check with your IRB office to find out how your institution makes such determinations.

 

Do the activities meet the Federal definition of “human subject” research?

Record–based research activities may not meet the Federal definition of “human subjects” research. A human subject is “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information.”

 

To apply this definition, the individual designated by the institution to make this decision, will consider:

 

•Do the records involve living individuals?

•Were the records collected specifically for this research project through intervention or interaction with the individual?

•Can the investigator readily ascertain the identity of any of the individuals either directly or indirectly through coding systems?

 

The investigator should check with the IRB to determine who has the authority to make this decision whether the research constitutes “human subjects” research, or whether the institution policy is more stringent.

 

If the research involves coded private information, the Office of Human Research Protection has issued additional guidance [insert link to “OHRP Guidance on Research Involving Coded Private Information or Biological Specimens”]

 

Is the research eligible for exemption from the Federal regulations?

Record-based research may be exempt if:

 

•The information is existing (ie, on the shelf) at the time the exemption is requested, AND

•the sources of information are publically available (ie, any person can obtain the data), or the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects, i.e., although the researcher may actually see identifiers while reviewing the data set, they cannot record any of them in any research record, or data collection instrument.

 

The Office of Human Research Protections (OHRP) recommend that researchers not determine if their research qualifies as exempt. Rather, the institution should designate an applicable institutional official (or the IRB) to conduct this review. Institutions may have internal rules and policies in addition to the federal regulations that will determine whether to grant this exemption.

 

Is the research eligible for expedited review under the Federal regulations?

Record-based research may qualify for expedited review if the research activity:

 

•poses no more than minimal risk of harm or discomfort to the subjects AND

•is described in one of the expedited review categories: (http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm). Records-based research that is eligible for expedited review generally falls under Category 5, “Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis).”

 

The expedited category 5 described above differs from the exemption existing record category. The exemption category applies only to retrospective research; the expedited category applies to prospective as well as retrospective research.

 

Does the record-based research need review by the full convened IRB?

If the human research does not qualify for exemption or expedited review, then it must undergo full review by the IRB at a convened meeting.

 

When Health Information is Involved: The Federal Privacy Law

When records-based research requires access to individually identifiable (“protected”) health information, additional requirements of the federal Health Insurance Portability and Accountability Act (HIPAA) must be met. This includes the need for written authorization from the patient, above and beyond informed consent requirements under the Common Rule. Promulgated through the Office of Civil Rights (OCR), requirements under the Act vary depending on the type and number of identifiers that are being associated with the accessed health information. If most, but not all, mandated identifiers are removed (a “limited data set”), written patient authorization may not be required, provided there is a data use agreement between the investigator and the institution holding the medical records. If any more identifiers are added to the set, either written patient authorization is required, or a HIPAA Privacy Board (can grant a waiver of authorization based on similar criteria to those required for waiver of consent under 45 CFR 46. Health information that is completely ‘de-identified’ as defined under HIPAA, is not subject to the privacy law.

 

If you are conducting records-based research involving health information, you should review the "HIPAA and Human Subjects Research" module for more information about HIPAA requirements to which your research may be subject.

 

Conclusion

Although there is no direct interaction with human subjects in record-based research, there may be risks to those individuals who originally provided the information used in such activities. Those risks must be minimized, informed consent must be considered, and review and approval from your institution must be obtained, per local and/or federal regulations. Research involving identifiable health information requires compliance with additional federal requirements.

 

Genetic Research in Human Populations

 

This module was prepared by members of the CITI Genetics Workgroup: Elizabeth Bankert, Dartmouth College; Kenneth Goodman, University of Miami Ethics Programs; and Anil Sharma, IRB Company, Inc. It is based on a module originally written by Goodman.

 

Introduction

Thirty years ago, a drop of human blood provided information on blood chemistry and identified its source as falling into one of four blood groups. Today, in a pharmacogenomic world, that drop of blood identifies its source as a member of a large number of genetic subcategories; can, at least in principle, help predict the response to specific treatments; provides precious information about predisposition to disease; helps investigators study the role of genes in the etiology and mechanisms of disease; and, when stored in a biorepository, represents a valuable source of information for those whose research seeks deeper understanding of genotype-phenotype correlations. The availability of genetic information in that drop of blood represents one of the most exciting opportunities in the history of biomedicine. It also constitutes some of the most difficult challenges in the history of human subjects research. This module is intended to help researchers and IRBs sort through some of the implications of this new technology.

 

Section I: Varieties of genetic research

1. Genotyping and genome-wide association studies

The human genome consists of approximately 3 billion nucleotide bases, and the goal of determining its sequence was reached with the completion of the Human Genome Project in 2003. Determining the sequence of a genome, or a portion of a genome, of an individual is called “genotyping.” The analysis of DNA sequences and of variations between individuals’ nucleotides (that is, single nucleotide polymorphisms or SNPs) is enabling the science of personalized medicine. SNPs affect the development of disease and response to medication, and their analysis is the cornerstone of pharmacogenetics. Genetic research is increasingly a component of human subject trials. In addition to pointing the way to new generations of drugs and treatments, however, SNP analysis can be used to assess the risk of disease, determine (non-) paternity and predict individuals’ vulnerability to certain environments and substances.

 

In Genome-Wide Association Studies (GWAS), SNPs across the entire genome can be identified and associated with various maladies – and the likelihood of their development in population subgroups. An important tool in molecular or genetic epidemiology, GWAS and genotyping raise interesting issues related to management of information and of laboratory discovery.

 

Genotyping studies have long posed interesting and difficult challenges to the protection of confidentiality and privacy – including the “privacy” of population subgroups – and the consent process. These challenges are particularly important for IRBs to address. Federally supported GWAS must now de-identify and upload all data to central databases; these studies are tremendously expensive and data-sharing allows researchers to make maximum use of information.

 

2. Pharmacogenomics and pharmacogenetics

Pharmacogenetics is the study of how the genetic makeup on an individual may affect his/ her response to a particular drug. Pharmacogenomics is a science that examines the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict how a patient will respond to a drug. In general, pharmacogenetics is the study of various responses to drugs, and pharmacogenomics is the study of drug response in the context of the entire genome.

Pharmacogenomics is the key to personalized medicine; the use of knowledge about an individual patient's genetic make-up can influence the treatments, drugs, and doses physicians choose for that patient. An anticipated benefit of pharmacogenomics includes the development of more powerful drugs. This is the basis of personalized medicine.

As above, this research requires special attention to privacy and confidentiality, the role and scope of the valid consent process and the appropriate approach to and process for the secondary use of data and stored biological samples.

 

3. Biorepositories

Biorepositories have come to play an increasingly important role in genetic research. Nearly all research institutions maintain collections of biological material. The growth of pharmacogenetics and the goals of personalized medicine have accelerated the utility of these collections. Analysis of these materials, usually blood or biopsy specimens, pose important challenges for institutions, investigators and IRBs:

 

•How specific must consent be to permit research on stored samples?

•Do investigators have a duty to warn people who are the sources of samples of health risks?

•Who owns and should control biorepositories?

 

Despite their rapid growth and utility, governance of biorepositories remains one of the most interesting – and underaddressed – problems for investigators and institutions. The intersection of privacy and consent is especially significant, and points to additional challenges for managing data sharing and collaborative research. IRBs are increasingly needing to determine the adequacy of policies for de-identifying and re-identifying genomic data and samples. Moreover, some “bio”repositories have been rendered digital, and it is reasonable to infer that at least some and perhaps most future research will involve studies of the content of electronic data bases rather than that of sample tubes or of frozen sections.

 

Section II: Ethical Issues

Privacy and confidentiality of individuals and communities

The terms “privacy” and ”confidentiality” are not synonymous. Generally, ”privacy” refers to persons and “confidentiality” to information. If, for instance, one surreptitiously obtains a quantity of residual blood from hospital testing and analyzes it for cancer markers or mutations, then we should say that the blood source’s privacy has been violated. If, on the other hand, one were to sneak a look at the source's medical record and learn that she has breast cancer, her confidentiality has been breached.

 

For a number of reasons, including increased risk of bias, discrimination, and stigma, genetic privacy and confidentiality are sometimes thought to be more important than privacy and confidentiality in other kinds of research. Genetic information is, for these reasons, sometimes compared to information obtained from research involving sexually transmitted diseases, or psychiatric illnesses, in that hidden social behavior which the subject wishes to keep confidential may be revealed. This is, however, controversial, and there are strong arguments against what has been called “genetic exceptionalism.”

 

Investigators preparing to conduct genetic research must tell potential participants which entities and persons will have access to the data. This might include investigators at other institutions, corporate sponsors, a government, employers, etc. If information obtained during research will be placed in a patient’s medical record, this too must be disclosed. Subjects should also be told of the risks of others having access to his or her genetic information. Principal investigators must also discuss the risk of information being re-identified or accessed with future technology. Many of these risks are difficult to measure and, unlike the physical risks of traditional biomedical research, are often subtle, social and psychological.

 

Unlike most other kinds of health information, genetic information applies to or is about more than one person. Analyze genomes and you will learn something about a person’s parents, siblings, children, and others. This means that these individuals can lose privacy and/or confidentiality even if they are not the source of the specimen or of the information or topic being studied. For instance, confirming a genetic diagnosis of Huntington’s disease in a person also means that at least one of his or her parents carries this gene and is at risk of developing the condition. But the parent is not a subject in the research and did not consent to it. More broadly, it has been pointed out that genetic research can produce discoveries about entire subpopulations, some of which correspond to racial or ethnic groups. It has consequently been suggested that investigators and institutions must take seriously the concept of “group privacy” and take steps to include community members in the planning and management of genetic research, and the disclosure of research results.

 

Research that includes follow-up studies and attempts to identify clinical correlations requires that a subject’s unique information be linked to his/her genetic information. These links, in conjunction with particular aspects of research protocols, might be used to seek out or re-contact subjects in the future. These links and their uses must be disclosed to subjects at the start of the study.

 

For this and other reasons, many investigators seek to unlink or decouple personal identifiers from genetic information or biological specimens. Successful unlinking reduces or eliminates some threats to privacy and confidentiality. However, it is increasingly possible to take even “unlinked” information or samples and use “surrogate identifier ensembles” (demographic information, birth date, postal code, diagnostic code, etc.) to identify an individual. Some scholars question whether genetic samples can ever be completely “anonymized.”

 

It is important for institutions to consider policies surrounding the use of genetic information. These processes should address data collection and management, encryption, destruction of specimens and/or genetic information, and loss of data. Many institutions have adopted “trusted broker” (or “honest broker”) systems to oversee the flow of data from patient to investigator. (See Section IV, on “Stored biological samples.”)

 

Informed or valid consent

Ethical research on humans generally requires that three conditions be met. Subjects must be:

 

•Adequately informed,

•Free from coercion or undue influence, and

•Able, generally, to understand and appreciate the risks, potential benefits and alternatives of participating. This is sometimes called “competence” or “capacity,” where the former is usually reckoned to refer to a legal standard.

 

Note that the term “valid consent” is increasingly preferred to “informed consent” because it captures the fact that other criteria, in addition to adequate information, are needed to ensure the legitimacy of the process. There are many challenges in genetics research in fulfilling these conditions. For instance:

 

•In the case of traditional medical and behavioral research, it is difficult to determine how much information is adequate and, moreover, what level of complexity or detail is appropriate. This problem is magnified in genetics research.

•The informed consent process should describe the limitations of genetic testing: Testing alone cannot may not be able to verify (i) whether the individual will have symptoms of the disease or condition; (ii) the severity of symptoms; or (iii) the rate of disease progression.

•It is often unclear how to describe risks of harm to potential subjects. In genetics research, the risks are generally not physical but psychological, social, economic, etc., and these are sometimes more difficult to present and evaluate.

•In pedigree (studies involving family ancestry) and other studies, information collected might affect entire families, including members who do not wish to know or participate. If relevant, has considerations been given to these concerns in the consent process? Special precautions are needed to protect against or to manage pressure or coercion and to communicate risk. There is growing urgency to include genetic counseling in the consent process for this purpose.

•Is community consent required? How are individual autonomy and community consensus balanced in this process?

 

The consent process must take into account whether and when investigators will re-contact subjects. Options include:

 

•The samples will be unlinked from subjects’ identifying information and researchers will not inform subjects of any results. If subjects are interested in obtaining genetic information about themselves, they can then be advised to be tested independent of the research. Note that if a sample is successfully unlinked or anonymized, it might be impossible for the source of the sample to withdraw from research (his or her sample cannot be found to remove it). This constitutes one of the few exceptions to the rule that research participants must always be allowed to withdraw from studies.

•If re-contact is possible but not planned, subjects should be so informed, for the same reason.

•If re-contact is planned—perhaps to measure subsequent clinical correlations—disclosure is crucial for those who might not want to know their genetic status.

 

Researchers and research ethics reviewers should address the issue of clinically suspicious or significant incidental findings, and whether and how they will be communicated to subjects. Incidental findings can be of great interest to subjects, and a comprehensive consent process should make clear whether such findings will be disclosed. Indeed, the case could be made that risks associated with the disclosure of significant incidental findings are among the most interesting and difficult in genetics and genomics research.

 

In general, the following should be disclosed to prospective subjects during the consent process:

 

•The purpose of the research, in lay language.

•How the specimens will be stored and who will have access to them or the information they contain.

•Whether subjects will be re-contacted later with information about the study findings or their individual results.

•Whether the samples or genetic information have a code that can be linked to the identity of individual subjects. If a link to identifiers is retained, the sample/information is not anonymous.

•Whether the researchers will use specimens to develop commercial products or assays, and whether the subject will be able to share any financial gain from these products.

 

Section III: Legal and Regulatory Issues

 

In the United States, the passage of the Genetic Insurance Nondiscrimination Act (GINA) in 2008 (http://www.genome.gov/24519851) provided, at least in principle, sweeping protections for patients and subjects. GINA prohibits discrimination in health care insurance and employment based on genetic information. However, the law admits a number of exceptions, and there is extensive debate about whether the law enforcement mechanisms are adequate to its anti-discrimination intent. The extent to which GINA changes or reduces the risks of participation in genetic or genomic research should arguably be included in the consent process.

Individual states have laws related to genetic testing for diagnostic, prognostic, or research purposes. These laws vary in their scope and intent. Some state laws explicitly require consent for genetic testing of any sort. Some do not explicitly address research. It is of great importance that investigators and their institutions be familiar with state laws, governing procedures, and disclosures for research and other purposes. Research should follow the more restrictive regulation, be it at the state, provincial, or national level.

 

NIH regulations require the following:

 

•The data submission is consistent with all applicable laws and regulations, as well as institutional policies;

•The appropriate research uses of the data and the uses that are specifically excluded by the informed consent documents are delineated;

•The identities of research participants will not be disclosed to the NIH GWAS data repository; and

•An IRB and/or Privacy Board, as applicable, review and verify that:

oThe submission of data to the NIH GWAS data repository and subsequent sharing for research purposes are consistent with the informed consent of study participants from whom the data were obtained;

oThe investigator’s plan for de-identifying datasets is consistent with the standards outlined in the policy;

oThe risks to individuals, to their families, and to groups or populations associated with data submitted to the NIH GWAS data repository have been considered; and

oThe genotype and phenotype data to be submitted were collected in a manner consistent with 45 C.F.R. Part 46.

 

Section IV: Stored biological samples

 

Research on stored biological samples allows investigators to conduct studies long after subjects have completed all research procedures – and in some cases even if they were not research subjects before. It is helpful to think of research on stored samples as of two kinds:

 

•Retrospective, in which investigators use blood, tissue, etc. from pre-existing collectionsor biorepositories

•Prospective, in which investigators obtain samples to create new collections

 

If the research is retrospective, and if adequate steps are taken to prevent identification of the individual subjects, genetic research can often proceed without an IRB requiring that individual subjects provide valid consent. The scientific benefits of such research can be great and may outweigh the customary requirement of obtaining informed consent from all sources of stored biological samples. However, IRBs must scrutinize such waivers of consent carefully.

 

Even if federal regulations may permit research on existing samples without consent, an IRB may determine that consent is necessary if the cohort is small, the health condition or trait is stigmatizing, and there are concerns about maintaining confidentiality. If it is possible to re-contact individuals who were the sources of specimens, the following issue needs to be considered:

 

Suppose you have received IRB approval to study banked tissue without obtaining the consent of subjects. Your protocol meets the federal criteria for waiver of consent. Now imagine that you discover a medically important mutation in the sample belonging to patient XYZ. You do not know who XYZ is, or even if he/she is alive. But you can find out XYZ’s identity because the sample is linked to patient records with a code number. Should you use the link to find and warn XYZ? What if XYZ does not want to know of this condition, and you tell him/her anyway? What if he/she would want to know and you do not tell him/her? What about XYZ’s children? Is there a duty to warn or inform them? Laws and regulations do not usually address these difficult ethical issues.

 

IRBs face knotty challenges when investigators seek permission to bank or archive biological specimens for future, unspecified research. If investigators want to bank tissue but are unable to say what it will be used for, it is difficult to obtain valid consent at the time of recruitment, as subjects must know the purpose of the research in order to decide whether to consent to it.

 

It is possible to inform prospective subjects that their tissue will be banked for future, unspecified research, but this is increasingly difficult. Will the samples be used for research in cancer genetics or behavioral genetics? Will results be analyzed by race or ethnicity? Will the results be used to develop commercial products? These are all questions that prospective subjects increasingly want answered before they consent to participate in research.

 

Indeed, the secondary use of tissues or the information they contain is emerging as one of the greatest challenges of genetic and genomic research. Researchers must consider all potentially relevant analyses of genetic information, so that subjects can be as fully informed as possible.

 

The growth of bioinformatics or computational genomics makes it clear that, in the near future, the concern will not be so much with stored biological samples but with digitalized samples—electronic data that can be stored, transmitted, and analyzed with new ease and power. The use of this technology may also provide a process for contacting research subjects. Thus, IRBs might wish to consider the role of stepped consent/re-consent as part of the consent process.

 

If human genetic material is to be placed into a biorepository or data bank as part of an approved IRB protocol for unspecified research purposes other than that outlined in that protocol, a separate consent form obtaining approval of the source should be obtained. This is a controversial matter. Placement of human genetic material into a biorepository for future research could require the completion of an institution-specific data base development form which has been reviewed and approved by an institutional official (often the department chair) and filed with the IRB office. The genetic material, accompanied by a copy of the approved consent agreement, signed by the tissue source, can then be placed into the approved biorepository or data bank for unspecified future research purposes.

 

Conclusion

The genomic sciences have changed biomedical research. Concepts as fundamental as privacy and valid consent are now seen through lenses that have reshaped the ethical and legal duties of investigators and institutions to research participants. Indeed, it has been suggested that a regulatory environment crafted in the wake of Tuskegee is probably inadequate to the subtleties of genotyping and genome-wide association studies.

 

For those who believe the job of IRBs is to parse federal law and give thumbs up or down to individual projects, the genomic science revolution is likely a source of great consternation –the law barely contemplates that revolution. For those who regard IRBs as a grand exercise in applied ethics, then SNPs and GWAS offer exciting obligations to explore the protection of subjects in highly probabilistic sciences posing novel and complex new risks.

 

Put differently, the genetic and genomic sciences of the 21st century present opportunities both to fledge potentially exciting new treatments – and to underscore the unwavering importance of ethics in the service of shared values.

 

Research With Protected Populations-Vulnerable Subjects: A Definition

 

Content Author

 

David Forster, J.D., M.A.

Western Institutional Review Board

 

Introduction

The concept of subject vulnerability is important to research ethics and to regulatory compliance. DHHS regulation 45 CFR 46.111(b) and FDA regulation 21 CFR 56.111(b) require that "when some or all of the subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these subjects." The DHHS and FDA regulations, and International Conference of Harmonization (ICH) guidelines provide partial lists of subjects who should be considered vulnerable, but they do not provide a definition of vulnerable subjects or an explanation of the causes of vulnerability. The goal of this module is to provide an understanding of the concept of vulnerability and to discuss some of the characteristics of vulnerability.

 

Examples from DHHS and FDA Regulations

DHHS regulation 45 CFR 46.111(b) and FDA regulation 21 CFR 56.111(b) provides the following list of examples of vulnerable subjects: "children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons."

 

ICH Guideline 1.61

ICH guideline 1.61 provides the following list of vulnerable subjects:

 

•Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

•Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention.

•Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

 

The Concept of Vulnerability

The Belmont Report identifies three basic ethical principles essential to the review of research:

 

Respect for Persons, Beneficence, and Justice.

 

According to the Belmont Report,

 

"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."

 

Vulnerable subjects are those subjects with diminished autonomy. It is useful to further analyze the components of autonomy in order to understand which subjects have diminished autonomy.

 

Elements of Autonomy

Autonomy is generally broken down into two general elements in the bioethics literature. The first element is mental capacity, the ability to understand and process information. The second element is voluntariness, freedom from the control or influence of others. Therefore, subjects have full autonomy when they have the capacity to understand and process information, and the freedom to volunteer for research without coercion or undue influence from others.

 

Who Are The Vulnerable Subjects?

When a subject has limitations on either capacity or voluntariness, then the subject is vulnerable. Examples of subjects with a lack of capacity are children and the mentally disabled. Examples of subjects with a potential lack of voluntariness are subjects in emergency situations, subjects in hierarchical social structures, subjects who are economically or educationally disadvantaged, subjects who are marginalized in society, or subjects with fatal or incurable diseases.

 

 

Considerations about Vulnerability

Vulnerability often does not apply uniformly to a given research population. Some of the variables in vulnerability are provided below:

 

•Within any population of vulnerable subjects, individuals will have different levels of vulnerability.

•The level of vulnerability of an individual may change due to changes in capacity or in conditions affecting voluntariness. For instance, a subject with diminished capacity due to pain control medication may have lucid periods. It is the researcher's responsibility to systematically assess capacity to consent prior to and during the research activity.

•The IRB considers a hypothetical group of subjects, whereas the investigator interacts with actual subjects. Therefore, the investigator must take into account the actual vulnerability of a given subject and act accordingly in the consent process and in the conduct of the research.

 

To What Are Vulnerable Subjects Vulnerable?

Subjects who are vulnerable are more likely to have their rights abused in the following ways:

 

•Physical Control - Vulnerable subjects have been physically forced to participate in research at times. This represents a complete lack of voluntariness. A classic example is the use of prisoners of the Nazi Holocaust camps in research with an endpoint of subject death, such as the hypothermia studies. The subjects had no choice about whether or not to participate, and were under the complete physical control of the investigators. A recent example is a surgeon in California who kept a subject under anesthesia to perform research after clinically-required surgery, despite the subject's prior refusal to participate in the research.

•Coercion - The use of a credible threat of harm or force to control another person. An example of coercion is a nursing home resident who was forced to choose between participating in a research study or leaving the nursing home, as reported in the June, 2000, Office of the Inspector General Report OEI-01-97-00195, "Recruiting Human Subjects."

•Undue Influence - The misuse of a position of confidence or power to lead another to make a decision he would not otherwise have made. An example would be a physician's affirmative response to a patient's inquiry of whether the patient should enter a research study, when in fact the physician knows that participation in the study is not in the patient's best interest.

•Manipulation - Deliberate management of conditions or information in such a way as to lead another to make a decision he would not otherwise have made. Examples of information manipulation include lying, withholding information, and exaggeration.

 

Specific Classes of Vulnerable Subjects

There are several classes of vulnerable subjects, with varying degrees of potential vulnerability. These classes are discussed below, including the potential for control, coercion, undue influence, or manipulation.

 

•Children have a wide range of capacity depending on age, maturity and psychological state. There is potential for control, coercion, undue influence, or manipulation by parents, guardians, or investigators, particularly of young children.

•Embryos and Fetuses have absolutely no capacity and are under the direct control of the mother.

•Mentally Disabled Individuals have problems with capacity, which may be continuous or fluctuating, depending on the disability. In addition, they may have limitations on voluntariness because often they are institutionalized or hospitalized, are economically and educationally disadvantaged, and suffer from chronic diseases. As a result, they are potentially subject to control, coercion, undue influence, or manipulation.

•Emergency Situations create a situation where capacity and voluntariness is compromised. There are often limitations to capacity due to the emergency condition. There are often limitations on voluntariness due to time constraints or hospitalization. An example is research on heart attack medications, in which the subjects are asked to consent in the ambulance on the way to the hospital. There is potential for control, coercion, undue influence, or manipulation.

•Hierarchical Social Structures that confront hospitalized patients, nursing home residents, students, prisoners, military personnel, and some ethnic groups create situations where voluntariness can be compromised. There is potential for control, coercion, undue influence, or manipulation.

•Educationally Disadvantaged Subjects may have limitations on understanding of the study they will participate in, and may even be illiterate. The possibility exists for undue influence and/or manipulation.

•Economically Disadvantaged Subjects may be vulnerable due to a limitation on voluntariness. They may enroll in research only to receive monetary compensation (such as in Phase I drug studies), or they may enroll in research to obtain medical care they cannot otherwise afford. There is potential for undue influence or manipulation.

•Marginalized Social Groups may lack influence in society as a result of race, age, disease, or caste systems. These groups often do not have full access to social institutions such as the legal system. There is potential for control, coercion, undue influence, or manipulation.

•Individuals with Incurable or Fatal Diseases often have limitations on voluntariness, and in addition may have problems with capacity caused by disease or medications. These individuals may accept very high risks in desperation for a cure, even when there is little or no prospect of direct benefit.

 

Conclusion

DHHS and FDA regulations provide lists of potentially vulnerable subjects, and require the consideration of additional safeguards for vulnerable subjects, but do not provide a definition of vulnerability or an explanation of the causes of vulnerability. The goal of this module is to show that vulnerability arises from limitations on subjects' capacity or voluntariness, two essential elements of subject autonomy.

 

Research Involving Prisioners

 

Content Authors

 

Helen McGough, MA

The University of Washington

Seattle, WA

 

Introduction and Background

In 1976, the U.S. National Commission for the Protection of Human Subjects issued a report on the issues involved with performing experiments on prisoners. In 1978, the U.S. Department of Health and Human Services issued regulations addressing prisoners as a vulnerable research population (45 CFR 46 Subpart C [http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#subpartc]).

 

These regulations were developed as a result of the exploitation of prisoners to test drugs and medical devices during the middle decades of the twentieth century. For example, it is estimated that, until the early 1970's, nearly 90% of all new pharmaceuticals were first tested in prison populations (see article by T.J Wiegand MD [http://jmt.pennpress.org/strands/jmt/pdfHandler.pdf;jsessionid=0D996052DFC18992A558EC1D4CB4122A?issue=20070301&file=20070301_037_039.pdf]). This section addresses some of the important matters researchers should consider when they wish to study prisoners.

 

Why do prisoners need special protections?

The National Commission presented several reasons that supported special protections for prisoners as research subjects:

 

•The ability of prisoners to exercise free choice may be limited because their autonomy is restricted. They may be concerned about repercussions if they refuse to participate in the research.

•Confidentiality of participation and of data are difficult to maintain in a prison setting because privacy of inmates is severely limited and prison spaces may be subject to monitoring such as audio and visual recordings.

•Inducements offered by researchers to prisoners may create undue influence. Prisoners are paid low wages and have limited access to money. An inducement to participate may appear much more valuable to a prisoner than it would to a non-prisoner.

•Prisoners may represent a population of convenience for researchers rather than a truly representative or inclusive study population. Studies of medical products on prisoners are quicker and cheaper than doing these studies in a non-incarcerated clinical population because the confounding variables can be reduced.

•Prisoners may not realize benefits from participating in research that non-incarcerated subjects may be offered. Their options for health care, education, and social services are limited by virtue of their incarceration and social and economic status.

 

Who is a prisoner?

The word "prisoner" is defined in 45 CFR 46.303(c) as follows:

 

"A Prisoner means any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing."

 

Rough translation:

 

Prisoners are people who are being held in a jail, prison, or treatment facility or who have been convicted or are awaiting arraignment, trial, or sentencing. This includes those who are in hospitals, alcohol, and drug treatment facilities under court order. The definition applies to minors as well as to adults.

 

What kinds of research with prisoners are allowed?

The regulations allow prisoners to be involved in four categories of research:

 

Category 1: Studies of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects (examples of this kind of research might involve demographic studies of rates of incarceration or records-based studies of recidivism).

 

Category 2: Studies of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects (examples of this kind of research might involve confidential surveys of prisoners regarding food service or educational opportunities).

 

Category 3: Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) and

 

Category 4: Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well being of the subject. (Examples of this kind of research might include studies on alternative sentencing or clinical trials of cancer therapies that do not involve assignment to placebo.)

 

Most studies in categories 3 and 4 may proceed only after the Secretary of DHHS has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice in the Federal Register of the intent to approve such research.

 

OHRP has to be notified about the research in all categories if the study is funded by DHHS. The only exception for DHHS secretary approval appears to be in category 4 if the study holds out potential benefits for prisoner-subjects and does not include the possibility of assigning them to a placebo or no treatment condition.

 

What does the IRB have to do in order to review research involving prisoners?

A majority of the IRB members (excluding prisoner members) must have no association with the prison(s) involved, apart from their membership on the Board.

 

At least one member of the IRB must be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity. If a research project is being reviewed by more than one IRB only one IRB must satisfy this requirement. Suitable individuals could include prison chaplains, prison psychologists, prison social workers, or other prison service providers; persons who have conducted advocacy for the rights of prisoners; or any individuals who are qualified to represent the rights and welfare of prisoners by virtue of appropriate background and experience.

 

What must the IRB determine in order to approve research involving prisoners?

The IRB must determine that:

 

•The research under review falls into one of the categories of research allowed under Section 46.306(a)(2).

•Any benefits to the prisoner which may result from being in the research, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, do not impair his or her ability to weigh the risks of the research against the benefits in the prison environment.

•The risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers.

•Procedures for the selection of subjects within the prison are fair to all prisoners and control subjects must be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project.

•The study information is presented in language which is understandable to the subject population.

•Parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on his or her parole.

•Adequate provisions have been made for follow-up examination or care, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact.

 

What if an already enrolled subject becomes a prisoner?

The regulatory protections are applicable to all prisoner-subjects, regardless of their status at the time of enrollment in a study. OHRP does not require immediate suspension of research activities when a subject becomes a prisoner. Rather, OHRP recommends that:

 

1.Investigators inform the IRB immediately upon learning that a subject has entered prison.
AND

2.The IRB review the protocol "at the earliest opportunity" to determine whether continued participation in the research is appropriate under the regulations.

 

See OHRP Guidance on Approving Research Involving Prisoners [http://www.hhs.gov/ohrp/humansubjects/guidance/prisoner.htm].

 

Subjects involved in research on practices "which have the intent and reasonable probability of improving the health or well-being of the subject" are eligible to continue their participation with absolutely no interruption, as are subjects involved in the other categories described in the regulations.

 

Research Involving Minors

45 CFR 46 Subpart D

 

Content Author

 

Bruce Gordon MD,

The University of Nebraska Medical Center

Omaha, NE

 

Introduction

Major objectives are:

•Describe the major historical events that influenced how research with children as subjects is currently conducted.

•Identify problems with research involving children that may violate ethical standards.

•Understand the assent and informed consent requirements on different types of studies involving children.

•Understand the current efforts by the FDA to ensure the inclusion of children in studies on the safety and efficacy of new drugs.

 

Historical Events that have Influenced Research on Children.

Early Medical Experiments

In the 18th century, a number of early "medical experiments" involved the immunization of children. They were deemed good subjects because they had no prior experience with the disease and they were convenient or in close proximity to the investigator. Edward Jenner tested the first smallpox vaccine on his own son, and then on 48 children in an almshouse. The orphans were then infected with smallpox to determine efficacy. Early American pediatrician Benjamin Waterhouse tested an initial shipment of vaccine by vaccinating his own children, then exposing 3 of them to smallpox patients.

 

The nineteenth century saw growth in a wide range of institutions for children (orphanages, foundling homes, hospitals), reflecting growing public concern for the welfare of children. As these institutions became more common, the health needs of institutionalized children encouraged pediatric experimentation, and these institutions provided ideal conditions for these experiments. Alfred Hess, the medical director of Hebrew Infant Asylum in New York, used his charges to conduct seminal experiments on the anatomy and physiology of digestion, on pertussis, mumps, and varicella immunizations, and on nutritional deficiencies. He insisted that "conducting experiments in an asylum is ideal because it approximated the conditions insisted on in studying experimental infection in animals but which could rarely be controlled in a study of infection in man."

 

Some of these experiments were of benefit to the children involved. For example, Louis Pasteur conducted large scale tests of new diphtheria antitoxin in 1893-4 in children in Paris orphanages. Others were less beneficial or dangerous to children. Karl von Ruck tested a "TB vaccine" on 262 children in a Baptist orphanage in North Carolina. Experiments in guinea pigs (performed after the large scale human tests) subsequently showed that the "vaccine" increased the risk of developing TB.

 

Growing Concern

The latter half of the 19th century saw the rise of the Anti-vivisection movement. Primarily opposed to use of live animals for medical research, the movements also opposed medical experimentation in charity hospitals, and especially in the use of children as research subjects. The Antivivisectionist press exposed the Rockefeller Institute studies of lutein for the diagnosis of syphilis in 1912. Control subjects for these trials included 46 normal children between 2 and 8 years of age.

 

Between 1914 and 1920 Alfred Hess and Mildred Fish conducted studies on etiology of scurvy during which they withheld orange juice from institutionalized infants until they developed hemorrhages associated with scurvy. Similar studies performed to determine etiology of rickets. When the details of these studies became public, journalist and social reformer Konrad Bercovici wrote "no devotion to science, no thought of greater good to the greater number, can for an instant justify the experimenting on helpless infants, children pathetically abandoned by fate and entrusted to the community for their safeguarding. Voluntary consent by adults should, of course, be the sine qua non of scientific experimentation"

 

National Research Act (1974)

Research excesses (including research on hepatitis using mentally retarded children at Willowbrook in the 1950s and 1960s) culminating in the exposé of the PHS syphilis experiments, led to the passage of the National Research Act in 1974.

 

The Act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Among the charges of the commission was to "identify the requirements for informed consent to participation in biomedical or behavioral research by children." The Commission report on Research Involving Children was published in 1977, and largely translated into regulations as 45 CFR 46 (subpart D), "Additional Protections for Children as Research Subjects."

 

National Commission Report and Federal Regulations

The National Commission report described a "sliding scale" for research involving children. Research was to be classified according to the risk and the direct benefit to the child. As the risk-benefit relationship of the research became less favorable, additional protections were to be imposed. These categories were translated into sections 45 CFR 46.404, 405, 406 and 407 of subpart D of the DHHS Regulations. Research involving minors must fit into one of these categories to be approvable by the IRB.

 

See Appendix for summary of National Commission's Analysis of Problematic Issues Involving Children as Research Subjects.

 

Assent and Permission in the Federal Regulations

For a child to participate in research, permission of one or both parents is required, and in most cases, assent of the child is also needed. "Assent" means a child's agreement to participate in research. Mere failure to object should not be construed as assent. However, not all children are capable of assent, due to their age, maturity, and psychological state. IRBs are responsible for making the decision when assent is an absolute requirement.

 

Waiver of consent or assent is also allowed, as per the requirements of 45 CFR 46.116(d). This only applies to studies approvable under 45 CFR 46.404, as will be seen below, since these studies involve no more than minimal risk to the subjects.

 

Categories of Allowable Research

Research involving no greater than minimal risk (46.404)

To be approvable under 45 CFR 46.404, research must present no more than minimal risk to the subject. Minimal risk is defined as "the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or routine medical or psychological examination, of healthy children." Note that minimal risk is weighed against a standard of the life of a healthy child.

 

Minimal risk procedures might include:

•Venipuncture, bagged urine collection.

•Chest radiograph.

•Psychological tests.

•Classroom observation.

 

No direct benefit to the child is needed for research to be approvable under 45 CFR 46.404. The permission of one parent and the assent of child are required.

 

Examples of research projects potentially approvable under 46.404 include:

•A study to determine the relationship between maternal age and head circumference at birth. Measurement of head circumference is part of the normal newborn examination, and is therefore minimal risk.

•A study to determine the incidence of asymptomatic proteinuria in school age children. The research involves the analysis of a voided urine collection, which is minimal risk.

 

Research involving greater than minimal risk but presenting the prospect of direct benefit (46.405)

Research that presents greater than minimal risk to the subject may be approvable under 45 CFR 46.405 if it holds the potential for direct personal benefit to the child. The benefit must balance or outweigh the risks, and the risk-benefit relationship must be at least as favorable as that seen with standard care. As in the previous section, the permission of one parent and the assent of the child are usually required. However, if the research holds out a prospect of direct benefit to the child which is not available outside the research, the consent of the parent is sufficient; that is, assent of the child, though desirable, is not an absolute requirement.

 

An example of a research project potentially approvable under 46.405 is:

•A pilot study of a shorter duration of antibiotic treatment for uncomplicated otitis media. The potential benefit associated with the shorter duration of treatment is reduced cost, increased compliance, and a reduced rate of antibiotic related diarrhea. The risk associated with the shorter duration of therapy is a higher likelihood of treatment failure.

 

The risks associated with this research appear to be greater than minimal, but there is the prospect of direct benefit to the child (reduced cost, increased compliance, and a reduced rate of antibiotic related diarrhea). If the IRB decides that the potential benefits balance or outweigh the risks, and the risk-benefit relationship is as favorable as that seen with standard care, this research would be approvable under 46.405.

 

Research involving greater than minimal risk and no prospect for direct benefit (46.406)

Research involving greater than minimal risk and no prospect for direct benefit to the subject may be approvable under 45 CFR 46.406. Under this section, the risks associated with the research must satisfy certain specific criteria:

 

•The risks must be no more than a "minor increase" over minimal risk. No definition of "minor increase is provided in the Federal Regulations. According to the National Commission "...while [minor increase] goes beyond the boundaries of minimal risk, it poses no significant threat to the child's health or well being." Interventions that might constitute a minor increase include:

oCatheterized urine collection

oSkin biopsy or bone marrow biopsy

oMRI scan with sedation

oSensitive survey

•Risks must be commensurate with those inherent in the subject's actual medical situation. According to the National Commission, "the requirement of commensurability of experience should assist children who can assent to make a knowledgeable decision about their participation in research, based on some familiarity with the procedure and its effects…"

•The research must be likely to yield knowledge of vital importance about the child's disease or condition.

 

To participate, the permission of both parents and the assent of the child are required.

 

An example of a research project potentially approvable under 46.406 is:

•A study to determine the clinical relevance of a new technique to quantitate minimal residual disease (MRD) during therapy for acute lymphoblastic leukemia in children. The study requires one additional bone marrow aspirate be performed during the course of treatment. Therapy for the subject will not be altered based on the results of the assay. However, if it can be shown that the presence of MRD predicts poor outcome, in the future, patients with MRD can receive more intensive treatment and increase their chance of cure.

 

It can be argued that the risk of a bone marrow aspirate in a normal child is only a minor increase over minimal risk. Further, the risk appears commensurate with risks inherent in the subject's actual medical situation, and the research may yield knowledge of vital importance about the child's disease (leukemia). Therefore, this research may be approvable under 46.406.

 

Research otherwise not approvable (46.407)

Research not approvable under any of the previous sections, but which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health and welfare of children, may still be approvable. The research must be reviewed by a panel of experts appointed by the Secretary of DHHS. The research must be conducted in accordance with sound ethical principles. The assent of subjects and permission of parents must be obtained.

 

Inclusions of Wards (e.g., Foster Children)

Remembering the exploitation of orphans as subjects of medical research, the National Commission also specifically addressed the inclusion of wards of the state. They noted that it is important to "learn about the effects of the settings in which children who are wards of the state may be placed ... in order to improve the care that is provided for such children." Further, they thought it important to avoid embarrassing these children by excluding them from research in which their peers in a school, camp or other group setting might be participating. To these ends, the commission notes that the IRB should "evaluate the reasons for including wards of the state as research subjects and assure that such children are not the sole participants in a research project unless the research is related to their status as orphans, abandoned children, and the like."

 

45 CFR 46.409, reflecting the National Commission report, restricts the involvement of wards in research that is greater than minimal risk and without direct subject benefit (research approvable under 46.406). Wards may only be enrolled in such research if the research is related to their status as wards, or is conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards. Further, the regulations require that each child have an advocate appointed who has the background and experience to act in, and agrees to act in, the best interests of the child, and who is not associated in any way with the research, the investigators, or the guardian organization. It is important to note that the IRB has the responsibility to appoint the guardian and not the investigator.

Other Guidelines on the Inclusion of Children in Research Involving Human Subjects

NIH Guidelines

Although the adoption of subpart D marked a high point in the protection of children, there were concerns that children would also be denied the potential benefits of medical research. In 1977 the American Academy of Pediatrics agreed that children capable of providing assent have the right to refuse research participation. However, the Academy also pointed out that exclusion of children from drug studies was more unethical than clinical testing, and could lead to devastating results.

 

The antibiotic chloramphenicol was released in the 1950s without adequate testing in infants and children. As use of the drug became more common, reports of a serious and often fatal reaction called the Grey Baby Syndrome surfaced. This reaction was related to slow clearance of the drug in infants as compared to adults, due to deficiency in hepatic glucuronyl transferase in infants. Similarly, though less devastating, widespread use of tetracycline in children was subsequently shown to be associated with dental dysplasia.

 

Nonetheless, children continued to be excluded from drug testing. A survey of the 1991 Physician's Desk Reference showed that 81% of listed drugs contained language disclaiming use in children or restricting use to certain age groups.

 

In March 1998, the NIH published Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, to answer some of these concerns. The guidelines state "... children must be included in all human subjects research conducted or supported by the NIH unless there are scientific or ethical reasons not to include them". Possible justifications for the exclusion of children from NIH Funded studies include:

 

•The research topic is irrelevant to children.

•Knowledge sought is already available in children or will be obtained from another ongoing study.

•A separate age-specific study is warranted and preferable, or

•Insufficient data are available in adults to determine potential risks in children.

 

In addition, the NIH Guidelines state that "inclusion of children must be in compliance with all applicable subparts of 45 CFR 46"

 

For more details see NIH Policy and Guidelines on the Inclusion of Children as Participant in Research involving Human Subjects [http://grants.nih.gov/grants/guide/notice-files/not98-024.html].

 

FDA Guidance and Regulation

In 2001, in response to the Children's Health Act of 2000, the FDA adopted Additional Protections for Children in Clinical Investigations (21 CFR 50 subpart D). These regulations are largely equivalent to the HHS regulations at 45 CFR 46 subpart D.

 

The FDA has also attempted to answer concerns regarding the exclusion of children, by taking a "carrot and stick" approach. The Best Pharmaceuticals for Children Act (2002) extends marketing exclusivity for pharmaceutical companies who test new drugs in children. The Pediatric Research Equity Act (2004) enables FDA to require testing of drugs for pediatric use.

 

Summary

Early medical experiments involving children, especially institutionalized children, lacked sound ethical research practices. Growing public concern over the exploitation of children led to movements aimed at protecting the rights of children and resulted in the establishment of ethical standards and federal regulation. The National Research Act for the Protection of Human Subjects in Biomedical and Behavioral Research established the National Commission. The National Commission Report provides a "sliding scale" classifying research according to the risk and the direct benefit to the child, and provides the requirements for assent and informed consent for participation in research involving children. Specific requirements are:

 

 

Research involving no greater than minimal risk (46.404) requires the permission of one parent and the assent of the child

 

Research involving greater than minimal risk but presenting the prospect of direct benefit (46.405) requires:

•The benefit must balance or outweigh the risks.

•The risk-benefit relationship must be at least as favorable as that seen with standard care.

•Permission of one parent.

•Assent of the child, unless the research holds out a prospect of direct benefit to the child which is not available outside the research.

 

Research involving greater than minimal risk and no prospect for direct benefit (46.406) requires:

•The risk is only a minor increase over minimal risk.

•The risks are commensurate.

•The research will likely yield knowledge of vital importance.

•Permission of both parents.

•Assent of the child.

 

Review the Appendix Materials.

 

Appendix for Biomedical Module 9

Research Involving Minors (45 CFR 46 Subpart D)

 

National Commission’s Analysis of Problematic Issues Involving Children as Research Subjects

 

The National Commission identified crucial questions regarding research involving children:

 

•Who should decide about children’s participation in research?

•On what basis should this decision be made?

•Benefit to the child?

•Benefit to others?

•Is non-therapeutic research on children ever justified?

 

"Consent"

The National Commission agreed that parents cannot give true "consent" - only a competent person can do this for himself. But parents can and should be respected in their role as persons responsible for the child’s welfare. Further, children cannot give true "consent" - they are incapable legally and may be incapable of sufficient comprehension. But this does not mean they should have no say regarding participation. Instead of "consent", then, the National Commission substituted the concepts of "assent" and "permission."

 

Assent and Permission

Children don’t give consent, they give assent. "Assent" means a child’s affirmative agreement to participate in research. The National Commission recommended that the age where assent is required should be at the discretion of the IRB. Further, the National Commission suggested that the assent of the child should not be an absolute requirement. Assent, they recommended, should not be required for minors to participate in studies which hold out the potential for direct benefit to the child if therapy is not available outside the research setting.

 

Parents don’t give consent, they give "permission". Permission means the "the agreement of the parents to the participation of their child in research." The National Commission recommended that permission be required from one (or both) parents.

 

Non-therapeutic research

With regard to the participation of children in non-therapeutic research, the National Commission accepted the value of this type of research. They asserted that the issue of involvement of children in non-therapeutic research should be faced on practical grounds based on risk rather than theoretical grounds or ethical absolutisms. The National Commission suggested that is was "groundless and imprudent" to restrict children from participating in research with risks no greater than those that occurred in their daily lives, thus introducing the concept of "minimal risk."

 

References

 

Grodin M, Glantz L (eds): Children as Research Subjects. Science, Ethics and Law. Oxford University Press, New York, 1994.

 

Lederer SE: Subjected to Science. Human Experimentation in America Before the Second World War. Johns Hopkins University Press, Baltimore, 1995.

 

DHEW (OS)77-0004 (Washington D.C.: U.S. Government Printing Office, 1977), reprinted in Jonsen A (ed): Source Book in Bioethics. Georgetown University Press, Washington D.C., 1998.

 

NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

 

Research Involving Women of Childbearing Potential, Pregnant Women and Fetuses

 

Content Author

 

Bruce Gordon MD

The University of Nebraska Medical Center

 

Ernest Prentice Ph.D.

The University of Nebraska Medical Center

 

Introduction and Background

Women as subjects of research

Historically, in order to avoid harm to a developing fetus in an unsuspected pregnancy, women of childbearing potential have been excluded from biomedical research. For example, 1977 FDA Guidelines exclude women of childbearing potential from early phase drug trials. In the late 1980s and early 1990s, recognizing that as a consequence of this "protection", women were being denied the benefits of research, women's groups began advocating strongly for expanded access. In 1988, the FDA issued guidelines that called for safety and efficacy profiles for women as part of all new drug applications, and in 1993, eliminated restrictions on women of childbearing potential participating in all phases of drug development. In 1994, the NIH issued guidelines requiring the inclusion of women in research. The NIH concluded that the only justification for exclusion of non-pregnant women of childbearing potential was compelling evidence that inclusion would be inappropriate with respect to the health of the subjects, or to the purpose of the research.

 

Pregnant women and fetuses as subjects of research

Since the 1930s, biomedical researchers in the US have used ex utero fetal tissue as an object of experimentation, including production and testing of vaccines, propagation of human viruses and testing of biological products. The 1954 Nobel Prize for Medicine was awarded to researchers who utilized human fetal kidney tissue cell lines to grow poliovirus in culture. In the early 1970s, however, the great societal debate over Roe v. Wade prompted Congress to charge the newly established National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to report on research using the human fetus.

 

The Commission report, submitted in July 1975, formed the basis for DHHS (then DHEW) regulations 45 CFR 46 subpart B (Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization). In 2001 DHHS issued modifications to subpart B, now entitled "Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research".

 

Research Involving Pregnant Women or Fetuses (46.204)

Subpart B generally allows research involving pregnant women or fetuses only if appropriate studies on animals and non-pregnant individuals have been completed. In addition, if the research is not intended to meet the health needs of the mother or the fetus, the risk to the fetus must be minimal. Subpart B does not give specific guidance regarding the definition of "minimal risk" in this context. In any case, the risk to the fetus must be minimized to the greatest extent possible.

 

To minimize the possibility that involvement in research will influence a mother's decision to terminate a pregnancy, subpart B also excludes investigators from any decisions as to the timing, methods or procedures used to terminate a pregnancy, or determining the viability of the fetus at the termination of the pregnancy. Research involving pregnant women and fetuses may be conducted only if consent is obtained from the mother, or from both parents, after she/they have been fully informed regarding the possible impact of the research on the fetus. If the research has the prospect of direct benefit to the mother or has minimal risk to the fetus, only the mother's consent is needed. If the research has the prospect of direct benefit only to the fetus then consent of both the mother and father are required. The father's informed consent also need not be secured if his identity or whereabouts cannot reasonably be ascertained, he is not reasonably available, or the pregnancy resulted from rape or incest.

 

Requirement for Mother’s Consent

Recognizing that research involving the fetus also affects the mother, the Federal Regulations require the mother’s consent, even if the research is intended to have a health benefit for the fetus. It is important to distinguish here between research performed to meet the health needs of the fetus, and fetal therapy of proven value. In the case of unproven (research) interventions, the mother’s refusal is binding. Only in the case of fetal therapy of proven value may the objection of the mother be overruled, and then only in limited circumstances and by action of the court.

 

Research Involving Neonates (46.205)

After a fetus is delivered, it is termed a neonate (newborn). Neonates of uncertain viability, or non-viable neonates may also be subjects of research regulated by subpart B. Viability is defined as the ability of the fetus to survive, given the benefit of available medical therapy, to the point of independently maintaining heart beat and respiration. Using this definition, it is clear that "viability" is a moving target.

 

Neonates of uncertain viability may be involved in research only if there is no added risk to the fetus, or the purpose of the research is to enhance the possibility of survival of the particular fetus to the point of viability. Consent of legally competent mother or father, or either parent's legally authorized representative is needed.

 

If a fetus is determined to be non-viable after delivery, it may only be involved in research if the vital functions of the fetus will not be artificially maintained, no experimental activities which of themselves would terminate the heartbeat or respiration of the fetus will be employed, there will be no additional risk to the neonate and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means. Consent of legally competent mother and father is needed.

 

If a fetus is determined to be viable after delivery it is a child, and research involving that viable newborn is governed by subpart D (Additional Protections for Children as Research Subjects).

 

Research Involving the Dead Fetus, Fetal Material, or the Placenta (46.206)

Subpart B does not directly regulate research involving the dead fetus, stating only that these research activities shall be conducted in accordance with any applicable Federal, State or local laws. In most states the use of tissue from dead fetuses for research purposes would fall under the Uniform Anatomical Gift Act (UAGA), which requires consent of parents. However, some states specifically ban research that involves aborted fetuses, or their organs, tissues or remains.

 

Research involving fetal material for transplantation, and utilizing embryos produced by in vitro fertilization for the generation of human embryonic stem cell lines have been subject to additional restrictions.

 

Group Harms: Research with Culturally or Medically Vulnerable Groups

 

Content Author

 

Helen McGough, MA

The University of Washington

 

Introduction

Sometimes researchers involve people in their research who do not belong to a federally protected group (i.e., prisoners, pregnant women, fetuses, or children), but who are nevertheless vulnerable to harms from participating in research. In some cases, the harms may fall, not necessarily on the subjects of the research, but on the group as a whole, including those who did not take part in the research itself. The purpose of this section is to provide examples of situations in which groups of people may be harmed and to describe some things researchers can do to reduce their risks of harm.

 

By the end of this module you will be able to:

•Describe some distinct groups or communities of people who are vulnerable.

•Identify examples of research that have harmed groups.

•Identify strategies that researchers can take to reduce the risk of group harms.

 

What do we mean by "groups" or "communities?"

In this module we use the terms "groups" and "communities" in a variety of ways. Sometimes people are members of ethnic or racial groups (such as, African-American, Hispanic, or Bantu), religious groups (such as, Islamic, Taoist, or Christian Scientist), or groups described by geographic location (such as, New Yorker, Parisian, or New Zealander), by occupation (such as, agricultural worker, physician, or teacher), or by physical condition (such as, diabetic, sight-impaired, or cancer patient). One person may belong to more than one of such groups. People may choose to describe themselves as members of groups, or may be assigned membership into these groups by others.

 

What do we mean by vulnerability?

Because of their special position in society, some groups may be at increased risk of suffering harm that may result if individual members of the group take part in research. Generally, these groups include those that have suffered and continue to suffer discrimination (such as African-Americans, American Indians, and Alaska Natives), those who may have less access to education, social services, and health care (such as groups with low socio-economic status), and those who may be behaviorally or politically stigmatized (such as commercial sex workers, injection drug users, or members of religious cults). Although members of the group may be harmed as a result of taking part in research, group harms result when many or all of the group members are harmed, including those who did not consent to being research subjects.

 

Such harms may include stigmatization, loss of status, genetic determinism, and violation of cultural or group norms and values.

 

Examples of how research has harmed groups in the past

Although some studies that have resulted in harms to groups were poorly designed, even well-designed studies can have consequences for members of specific groups that could have been avoided. What follows are examples of studies that have had negative impacts on groups of people who were not necessarily study subjects:

 

•Publication of results of research conducted in Ashkenazi Jewish families contributed to the misperception that Jews are more prone to genetic defects and diseases. There was concern in the Ashkenazi Jewish community that this information would lead to health and life insurance discrimination, even for those who did not undergo genetic testing (Phillips KA, Warner E, Meschino WS, Hunter J, Abdolell M, Glendon G, Andrulis IL, Goodwin PJ., "Perceptions of Ashkenazi Jewish breast cancer patients on genetic testing for mutations in BRCA1 and BRCA2," Clin Genet. 2000 May;57(5):376-83).

•Publication of the results from a study of alcoholism among Alaska Native residents of Barrow, Alaska contributed to stigmatization of this group of Alaska natives (Klausner, S. and Foulks, E. (1982). Eskimo Capitalists: Oil, alcohol and social change. Montclair, NJ: Allenheld and Osmun). This is an example of a situation in which groups were stigmatized and the economic situation of a city suffered because of conclusions drawn from a research study.

•Various studies purporting to study the intelligence of various racial groups (Herrnstein, R.J. and Murray, C. (1994). The Bell Curve: Intelligence and Class Structure in American Life, A Free Press Paperbacks Book) have resulted in stigmatization of these groups. Many of these studies were poorly designed and resulted in inappropriate characterizations of members of racial groups.

 

What steps can researchers take to minimize these risks of group harms?

There are several actions that researchers can take to reduce the risks of group harms.

 

•Community consultation: Researchers should work with the community of interest to make sure that potential harms are recognized and understood, and that the study is designed to provide benefits to the community.

•Collaborative IRB review: Some groups (such as tribes, retirement communities, and school districts) have their own ethical review process for research. Researchers should work with the local ethics review body to make sure that the group's approval is obtained.

•Plan on-going consultation: Researchers should work with the group to make sure that group leaders are provided with accurate information about the research as it progresses and changes. Researchers must anticipate that their research may have to change or even stop in order to minimize potential harms.

•Plan disclosure of research results ahead of time: Most group harms result from inappropriate disclosure of research results. Working with the group so that the members are informed about how the research results will be disclosed and what the implications of disclosure may be will reduce the possibility of harms resulting to the group as the research is published or presented.

 

Researchers must evaluate whether or not their research could result in group harms and, if this is a possibility, take appropriate steps to minimize this risk.

 

FDA Regulated Research

 

Content Authors

 

Susan Kornetsky MPH

Children's Hospital, Boston

 

David G. Forster JD, MA, CIP

Western IRB

 

Gary L. Chadwick PharmD, MPH, CIP

The University of Rochester

 

Introduction

The U.S. Food and Drug Administration (FDA) regulates drugs, biologics, and devices used in the diagnosis, mitigation, treatment, or prevention of diseases. This training module addresses FDA-regulated clinical research and the responsibilities of investigators, IRBs, and sponsors when they participate in a study of an FDA-regulated product.

 

FDA Review

The FDA conducts a thorough review of drugs, biologics, and medical devices for safety and effectiveness before granting approval for marketing. Before a product is marketed, the sponsor submits an application for approval by the FDA. This application contains a proposed "package insert" which may also be referred to as "labeling". This insert summarizes what the FDA has determined to be a safe and effective use of the product. The FDA bases its approval decision upon bioresearch data generated and reported to the FDA by the sponsor to support the marketing approval of a product. These data are collected by the sponsor during clinical research conducted under an IND (Investigational New Drug application) or an IDE (Investigational Device Exemption).

 

Drugs and Biologics

IND

Research involving a drug or biologic that has not yet reached the marketplace or that studies a new use of the marketed product requires an IND (21CFR 312). A sponsor develops a research protocol, which is then evaluated by the Food and Drug Administration. A sponsor can be a drug company, a cooperative group, or even an individual physician. After careful review, the FDA will allow human studies to proceed if it determines that the risk of exposure to the drug is reasonable. This determination is based upon:

 

•Data from prior animal or human testing.

•Methods of manufacturing.

•Plans for testing and reporting significant toxicities.

•A well-developed clinical research plan that minimizes risks to the subjects.

 

Investigational Use of a Marketed Drug

Investigators may want to use an approved product in the context of clinical studies. When the principal intent of the investigational use of the product is to develop information about safety or efficacy, an IND may be required. However the clinical investigation of a marketed drug does not require an IND if the following conditions are met:

 

•The data will not be used to support a new indication, new labeling, or change in advertising.

•The research does not involve a route of administration/dosage level or subject population that significantly increases the risks of the drug product.

•The research is conducted in compliance with IRB review and informed consent requirements.

•The research is conducted in compliance with requirements for promotion and sale.

 

(21CFR312.2(b))

 

Exemption from IND submission requirements does not mean exemption from IRB review and approval or from informed consent from subjects. The FDA should be consulted if there are any changes.

 

FDA Form 1572

•Investigators participating in drug and biologic studies subject to the IND regulations MUST sign Form 1572 [http://www.fda.gov/opacom/morechoices/fdaforms/cder.html].

•Form 1572 outlines the commitments that must be made by the investigator(s) regarding the conduct of the study.

•Form 1572 must list co-investigators who will be administering the drug or separate forms need to be submitted for these individuals.

•Form 1572 must list the IRB of record for that study site.

 

(21CFR312.53)

 

"Off Label" Use of Drugs, Devices, and Biologics

Good medical practice and the best interests of a patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and judgment. If physicians use products for an indication not listed in the approved labeling, they have the responsibility to be well informed and to base the proposed use on scientific rationale and medical evidence.

 

Use of a marketed product in this manner when the intent is practice of medicine does not require the submission of an IND or IDE. However, an individual institution may under its authority require oversight for this practice such as review by a Medical Practice or Pharmaceutics and Therapeutics Committee (21CFR312.2(d)).

 

Devices

The Definition of a Medical Device

A medical device is any health care product that does not achieve its primary intended purpose by a chemical interaction or by being metabolized. Medical devices include surgical lasers, sutures, pacemakers, and diagnostic aids such as reagents and test kits for in vitro diagnosis.

 

The Medical Device Amendments of 1976

The Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990 provide the regulatory framework for medical device development, testing, approval, and marketing. Manufacturers who wish to market a new medical device may need to submit a pre-market notification to the FDA. Some medical devices are exempt from the pre-market approval process. If the device is not exempt, FDA determines whether the device is substantially equivalent (21CFR807.81(a)(1)) to similar devices marketed before the 1976 amendment. These devices are often referred to as 510K devices (21CFR807.92). If the new device is not substantially equivalent, the company may need to demonstrate safety and efficacy in a pre-market approval application, which could include clinical trials.

 

Investigational Device Exemption (IDE)

An investigational device is a medical device that is undergoing clinical trials to evaluate safety and effectiveness. The IDE regulations specify how to conduct these clinical trials (21CFR812.2). The regulations require that devices be classified as "significant risk" or "non-significant risk" devices. The sponsor often first makes this classification, but the IRB must agree with the determination. The risk determination should be based on the proposed use of the device and not on the device alone.

 

Significant Risk (SR) Devices

A significant risk device presents a potential for serious risk to the health, safety, or welfare of the subject and it:

 

•Is intended to be implanted into a human;

•Is used in supporting or sustaining human life;

•Is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise prevents impairment of human health;
or

•Otherwise presents serious risk to health, safety, and welfare of a subject.

 

(21CFR812.3(5)(m))

 

The sponsor must submit an IDE application to the FDA (21CFR812.20). There is no specific form for this purpose, but the regulations list elements required in the application. The trial cannot begin until FDA grants an IDE and the IRB grants approval for the study. By definition, a study with a significant risk device poses more than minimal risk to the human subjects and requires full IRB review.

 

Non-Significant Risk (NSR) Devices

A non-significant risk device, by default, does not meet the criteria of significant risk. It is considered to have an approved IDE application (i.e., no application is filed with the FDA), and is studied without FDA oversight if the sponsor complies with certain FDA requirements such as monitoring, record-keeping, and properly labeling the investigational device. The IRB must agree that the study meets the criteria for non-significant risk. The clinical trial of a non-significant risk device requires IRB approval, informed consent, and proper study monitoring and it must meet all other regulatory compliance requirements.

 

INFORMED CONSENT

Elements of informed consent are found in the FDA regulations at 21 CFR 50.25.

 

Informed Consent Waiver

Elements of informed consent are found in the regulations at 21 CFR 50.25

 

The FDA 21 CFR 50.23 and 21 CFR 50.24 provide exceptions to the requirement for informed consent under certain circumstances:

 

•In situations where requirements for exception from informed consent are met for emergency research (21 CFR 50.24).

•In life-threatening conditions involving an individual subject where requirements for an exception from informed consent are met. More specifically, FDA regulations (21 CFR 50.23) permit exception for informed consent in life-threatening situations where:

oThe investigator, with the concurrence of another physician, believes the situation for the human subject is life-threatening and necessitates the use of a test article (i.e., an investigational drug, device, or biologic).

oThe subject and/or legally authorized representative is unable to communicate consent. The FDA indicates that a Legally Authorized Representative is "An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research."

oThere is insufficient time to obtain consent.

oNo alternative exists that will provide an equal or better chance of saving the subject's life.

 

Is Oral Consent Appropriate?

The FDA allows waiver of written documentation of informed consent (i.e., consent of the subject is obtained, but the subject does not have to sign a consent document):

 

•When study participation presents minimal risk of harm to the subject

•And when the research involves no procedures requiring written documentation of consent outside the context of participation in a research study.

 

With a waiver of written documentation of consent, the consent of the subject or the subject's legally authorized representative is still required. The IRB may require the investigator to provide the subject with written materials about the research. (21CFR56.109)

 

Emergency Use of an Investigational Biologic, Drug, or Device

Investigators and IRBs may be confronted with the need to use an unapproved investigational drug or device in an emergency situation. In these circumstances, review by a full IRB may not be feasible because of the emergent nature of the problem. When this happens attention must be given to the IND/IDE requirements, informed consent, and IRB procedures. Please note that regulations exist-21 CFR 50.23-for unplanned emergency use (Regulations also exist for "planned" emergency research and can be found at 21 CFR 50.24).

 

The Definition of Emergency Use

Emergency use is the use of an investigational drug or device with a human subject in a life-threatening situation or in which no standard acceptable treatment is available and there is not sufficient time to obtain IRB approval. Life-threatening means that the likelihood of death is high unless an intervention interrupts the process. It also applies to a condition that is immediately and severely debilitating and that causes irreversible morbidity such as blindness or paralysis. (21CFR56.102(d))

 

IND/IDE Requirements for Emergency Use

If an individual patient does not meet the criteria for an existing protocol or an approved protocol does not exist, the usual procedure is for the physician to contact the manufacturer and determine if the drug can be made available for an "emergency use" under the company's IND. If there is no IND, the FDA may authorize the manufacturer to allow the drug to be used in advance of an IND submission or if the company agrees to provide the product, the physician can contact FDA, explain the situation, and obtain an emergency IND to permit shipment of the drug (21CFR312.36). If there is no IDE, the physician may use the device and notify FDA of its use after the fact. The physician should obtain an independent assessment from another physician and informed consent, however, before emergency use of the device occurs.

 

IRB Review Requirements for Emergency Use

In an emergency use situation the FDA permits an exemption from prior review and approval by an IRB (21CFR56.104c). For emergency use of devices, concurrence of the IRB chair is required before the use takes place. However, individual institutions may have a variety of policies to handle this situation. For example, the investigator may be required to notify the IRB office when an emergency use is being considered. Contact your local IRB office for further information. DHHS regulations do not prohibit an investigator from using any investigational or approved drug or device in an emergency situation for the clinical care of a patient. However, the information collected from the patient in whom the drug or device has been used should not be considered research data. IRB review and approval is required in all circumstances if the investigator wishes to use the data for research purposes.

 

Informed Consent Requirements for Emergency Use

In accordance with FDA regulations (21CFR50.23(a)), investigators are required to obtain informed consent from the subject or legally authorized representative unless both the investigator and uninvolved physician certify in writing that:

 

•The life threatening condition necessitates the use of the test article (i.e., an investigational drug, device, or biologic).

•There is an inability to communicate with or obtain informed consent.

•There is no time to obtain consent from a legal representative.

•There are no alternatives to provide equal or greater benefit.

 

After an Investigational Drug or Device has been used in an Emergency

Subsequent use of the investigational product at the institution should have prospective IRB review and approval. If the IRB was not notified before the investigational drug or device was used in an emergency situation, the IRB should be notified per institutional policy or within 5 working days (21CFR50.23(c)). The FDA and sponsor should be notified as necessary.

 

Further information on emergency use of investigational devices can be found at the FDA's Guidance on IDE Policies and Procedures page [http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm].

 

RESPONSIBILITIES

Sponsor Responsibilities

A "sponsor" may be an individual, a private company, an institution or other organization that is responsible for the initiation and conduct of a study involving a drug, device, or biologic. Investigators may assume this responsibility in addition to their role as investigator. Often these are called "investigator-initiated" studies. The sponsor's responsibilities include:

 

•Selecting clinical investigators qualified by training and experience.

•Informing and qualifying investigators by obtaining their commitment to supervise the study, follow the protocol, and obtain consent.

•Monitoring the conduct of the study by auditing documentation and conducting site visits.

•Completing regulatory filings related to the IND or IDE, adverse events, amendments or revisions, progress reports, withdrawal of IRB approval, and final reports.

•Controlling the distribution, tracking, and dispensation of the regulated products.

 

Investigator Responsibilities

Investigator responsibilities include:

 

•Ensuring IRB approval for the study is obtained before any subjects are enrolled.

•Ensuring that informed consent is obtained in accordance with FDA regulations.

•Ensuring that the investigation is conducted according to the investigational plan and applicable regulations.

•Administering the drug or using the device only in subjects under the investigator's supervision or under the supervision of a recognized sub-investigator.

•Maintaining adequate records of the dispensation of the drug or device.

•Returning unused materials at the end of trial.

•Preparing and maintaining adequate case histories and signed informed consent documents.

•Maintaining correspondence with the IRB and the sponsor to make sure that both have reviewed protocol amendments, recruitment materials, investigator brochures.

•Retaining records in accordance with regulations.

•Providing progress, safety, final and financial disclosure reports.

•Notifying the sponsor if IRB approval is withdrawn.

•Comply with International Conference on Harmonization (ICH) guidelines, if applicable. See Conference on Harmonization for ICH guidance [Submodule].

 

Inspections and Audits

The Bioresearch Monitoring Program of the FDA conducts routine, "not for cause," and "for cause" audits of IRBs, clinical investigators, and sponsors. The purpose of this monitoring is to ensure the quality and integrity of data submitted to FDA for regulatory decisions and to protect human subjects. The FDA may conduct on-site reviews of IRBs, research sites, pharmacies, manufacturing sites, etc. The FDA may also inspect, review, and copy records associated with the research.

 

 

21 CFR Part 11

21 CFR Part 11 Electronic Records; Electronic Signatures; Final Rule, often referred to as Part 11, was published May 20, 1997 and was intended to enable the use of electronic documents in the regulatory process for drugs and devices. Part 11 specifies processes that must be in place assuring that electronic documents and signatures are equivalent to paper documents and handwritten signatures.

 

For systems to comply with 21 CFR Part 11, a number of requirements must be met. For example:

 

•Computer systems utilizing electronic records and signatures must ensure accuracy, reliability, and consistent performance. Standard operating procedures (SOPs), audits, testing and training are required.

•Computer systems must use and maintain secure, computer-generated, time-stamped audit trails independently recording the date and time of entries and actions that create, modify, or delete electronic records.

•Computer systems must use system checks ensuring that only those individuals authorized to use the system are allowed access to the system (and access only those parts of the system they have authorization to use), alter records, and perform operations.

•Procedures must be established to ensure that records are retained for a duration of time, in an appropriate format, and to meet FDA requirements at a minimum [21CFR56.115(b), 312.57, 312.62 and 812.140].

 

In 2003, FDA clarified the application of Part 11 and limited the scope of its enforcement [www.fda.gov]. Under this narrower interpretation, FDA generally would not consider Part 11 to apply when computer systems are used to generate paper printouts of electronic records, and those paper records meet all the FDA requirements.

 

 

The FDA plans to publish a revised rule updating and clarifying the Part 11 requirements and the FDA's scope of enforcement. Until then, investigators and IRBs should check with their information technology (IT) support personnel (and as appropriate, sponsors) to ensure that either Part 11 compliance is maintained, or that Part 11 does not apply.

 

References:

•21 CFR Part 11 Electronic Records; Electronic Signatures; Final Rule

•Guidance for Industry: Part 11, Electronic Records; Electronic Signatures Scope and Application

 

Submodule: FDA Regulated Research: ICH for Investigators

 

Content Authors

 

David G. Forster JD, MA, CIP

Western IRB

 

Gary L. Chadwick PharmD, MPH, CIP

The University of Rochester

 

ICH for Investigators

1. INTRODUCTION: What is ICH?

The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use, commonly referred to as the International Conference on Harmonization (ICH) is an attempt to streamline the process for developing and marketing new drugs internationally. The ICH is comprised of representatives from the pharmaceutical industry and the regulatory bodies of the United States, Japan and the European Union. In addition, observers include Canada, the European Free Trade Area, and the World Health Organization.

 

 

The ICH has established several international standards of Good Clinical Practice (GCP) for the development of pharmaceutical products. The guideline that primarily affects investigators in the daily practice of clinical research is E6, "ICH Harmonized Tripartite Guideline: Guideline for Good Clinical Practice." The E6 guideline has 8 parts:

 

1.Glossary.

2.Principles.

3.IRBs.

4.Investigator.

5.Sponsor.

6.Protocol and amendments.

7.Investigator's brochure.

8.Essential documents.

 

The initial basis for drafting the E6 guidelines was the U.S. FDA regulations for the protection of human subjects (21 CFR 50 and 56).

 

II. LEGAL STATUS

After the guidelines were finalized, several countries adopted them as law. In the United States, however, the FDA adopted the ICH only as guidance (Federal Register, Vol. 62, No. 90, May 9, 1997, pages 25691-25709). Therefore, the ICH guidelines do not have the force of law in the United States and are not regulations. In the Federal Register Notice, FDA stated that the ICH guideline "does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both."

 

Therefore, compliance is voluntary, but as with any published FDA guideline compliance is considered part of good clinical practice.

 

For sponsors, the advantage of complying with the ICH guidelines is that the FDA and equivalent government agencies in other countries will consider studies conducted in accordance with the ICH guidelines to meet the regulatory requirements of the drug approval processes for all of these countries. Increasingly, sponsors want investigators to meet the ICH requirements. However, certain requirements of ICH are not included in FDA or HHS regulations. Therefore, investigators need to be aware of the differences between ICH and FDA regulations so that they can fully comply with the ICH requirements when requested by sponsors.

 

III. DIFFERENCES BETWEEN ICH GUIDELINES AND U.S. REGULATIONS

The ICH E6 guidelines generally agree with the FDA regulations for IRBs, investigators and informed consent, but there are a few areas in which the ICH guidelines have requirements that go beyond either FDA or HHS (Common Rule) requirements. It is important for investigators to know what these differences are so that the investigator can comply with ICH when requested by a sponsor. References below are either to the ICH E6 guidelines or to the FDA regulations at 21 CFR parts 50 or 56.

 

1. Investigator to Obtain IRB Assurance that the IRB is in Compliance with ICH.

One of the requirements of the ICH guideline is that "the sponsor obtain from the investigator/institution . . .[a] statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations." (ICH section 5.11). Oftentimes, sponsors will approach IRBs directly to obtain this statement, but some sponsors will request that the investigator obtain the statement from the IRB and then forward it to the sponsor.

 

2. Confidentiality of Medical Records

ICH has broader requirements than FDA or HHS concerning notice to subjects about potential access to identifiable research records by third parties.

 

•ICH 4.8.10 states that the informed consent should indicate that the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access.

 

•ICH 5.15.2 states that the sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.

 

•FDA regulations (50.25(a)(5)) state only that in seeking informed consent, the following information shall be provided to each subject:. . . (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.

 

Thus, ICH allows broader access to research records and to otherwise confidential medical records. Some subjects have complained about the extent of this access. Most consent forms currently permit access to research records by sponsors, and most investigators and subjects are not troubled by this. However, access by foreign regulatory agencies to research records and to subject's medical records is problematic for some investigators and subjects. Investigators must decide if they want to comply with ICH and agree to this access to subject medical records, and also must clearly disclose this information to subjects during the informed consent process.

 

3. Signature by Person Conducting the Consent Discussion

•ICH 4.8.8 states that prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.

•The FDA regulations only require the signature of the subject and the date the subject signed the consent form (50.27(a)).

 

To assure compliance with this requirement, the investigator should include a signature line labeled "person conducting informed consent discussion." This line should not be labeled "Investigator's Signature," unless the investigator is always the person who obtains consent.

 

4. Subject Receipt of a Signed and Dated Copy of the Consent Form

•ICH 4.8.11 requires that the subject or the legally authorized representative (LAR) receive a copy of the signed and dated written informed consent form.

•The FDA regulations allow subjects to receive either a signed or unsigned copy. (FDA Information Sheet "Frequently Asked Questions," September 1998, page 11). To be in compliance with ICH guidelines, the investigator should include a statement in the consent form that the subject will receive a signed and dated copy of the consent form. Persons obtaining consent must then ensure that this procedure is followed.

 

5. Assent of Children and Mentally Disabled Adults

•ICH 4.8.12 requires that when a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject's legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject's understanding and, if capable, the subject should assent, sign and personally date the written informed consent.

•HHS regulations, and FDA regulations, require that children assent to research unless there is an appropriate reason for waiving assent. However, neither FDA nor HHS regulations specifically require that incapacitated adults assent to research participation. To meet the ICH requirement, the investigator needs to have a policy for getting assent, whenever possible, from decisionally impaired adult subjects. This policy must account for the fact that often decisionally impaired adults will not be able to assent, due to a complete lack of capacity. In those situations, the consent of the legally acceptable representative is the only requirement.

 

6. Impartial Witness for Illiterate Subjects

•ICH 4.8.9 states that if a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects is read and explained to the subject or the subject's legally acceptable representative, and after the subject or the subject's legally acceptable representative has orally consented to the subject's participation in the trial, and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject's legally acceptable representative.

oThe ICH definition of "impartial witness", found at section 1.26, is, "A person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial, who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject."

•The FDA addresses the documentation of informed consent for illiterate subjects by allowing the use of a short form consent document and a written summary for oral presentation (50.27(b)(2)).

Thus, the ICH guideline goes beyond the FDA regulations in requiring that the witness be impartial and specifying to what the witness should attest.

 

The investigator will need to consider how to document the signature of the impartial witness, as most consent forms for drug studies do not routinely include such a signature block. This can best be worked out with the investigator's IRB. If an investigator expects illiterate or blind subjects to enroll in studies on a regular basis, then there should probably be a signature block on the consent forms for an impartial witness, with the explanation that the signature block is only to be used "when necessary."

 

7. Elements of Consent

A few of the ICH guideline requirements for elements of informed consent go beyond the FDA requirements, and would need to be included by the IRB for studies that are intended to meet ICH requirements.

 

Alternative Treatments

•ICH 4.8.10(i) requires an explanation of "the alternative procedure (s) or course (s) of treatment that may be available to the subject, and their important potential benefits and risks." Most sponsors, investigators and IRBs have not included the benefits and risks of alternative treatments in consent forms, as consent forms are already long and difficult to understand. This is an area where many sponsors and IRBs decide to limit their compliance with ICH. However, the investigator should explain the risks and benefits of alternative treatments to subjects when the information is necessary for the subject's full understanding and exercise of autonomy.

 

Probability of assignment to each study arm in a study.

•The FDA regulations (50.25(a)(1)) state that the consent form must include: "A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental."

•ICH 4.8.10(c) states in addition that the informed consent should include: "The trial treatment (s) and the probability for random assignment to each treatment."

 

This difference can be addressed by including a description of each arm of the study in the consent form, and including a statement about the likelihood of receiving each of the study arms.

 

Description of subject's responsibilities.

•ICH 4.8.10(e) requires an explanation of "The subject's responsibilities." Some investigators include this information as part of the procedures section of the consent form.

 

Statement of no benefit

•ICH 4.8.10 requires an explanation of "The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this." Many investigators customarily include this information in the consent form.

Prorated payment in the consent form

•ICH 4.8.10(k) states that "anticipated prorated payment, if any, to the subject for participating in the trial" must be included in the consent form.

•While not an FDA requirement, prorated payment is addressed in the FDA Information Sheet entitled "Payment to Research Subjects," and it is common practice for IRBs and investigators in the United States to include in consent forms.

 

8. Non-therapeutic Trials

The following two ICH sections address non-therapeutic research and the requirements for consent. These issues are not specifically addressed in the FDA regulations.

•ICH 4.8.13 Except as described in ICH 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no anticipated direct clinical benefit to the subject) should be conducted in subjects who personally give consent and who sign and date the written informed consent form.

•ICH 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:

oThe objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally.

oThe foreseeable risks to the subjects are low.

oThe negative impact on the subject's well-being is minimized and low.

oThe trial is not prohibited by law.

oThe approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable opinion covers this aspect.

 

Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed. The ICH requirements for inclusion of subjects in non-therapeutic trials are straightforward. To comply with ICH requirements, investigators should ensure that subjects without capacity are not used for non-therapeutic trials, except as described above.

 

9. Investigator Notification to Subject's Primary Physician

•ICH section 4.3.3. states that it is recommended that the investigator inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.

•There is no equivalent to this requirement under FDA regulations. Investigators should have a policy in place to address this notification requirement. It can be included in the consent form so that the subject's choice about the notification is documented in the consent form.

 

10. IRB Responsibilities

There are several differences between the FDA and ICH regarding the responsibilities and duties of the IRB.

 

Documents the IRB must review.

The ICH provides a list of documents that the IRB should review, and IRBs routinely review most of the materials listed. Compliance with ICH requires reviewing all the listed materials.

 

•ICH 3.1.2 The IRB/IEC should obtain the following documents:

oTrial protocol(s)/ amendment(s).

oWritten informed consent form(s) and consent form updates that the investigator proposes for use in the trial.

oSubject recruitment procedures (e.g., advertisements).

oWritten information to be provided to subjects.

oInvestigator's Brochure (IB).

oAvailable safety information.

oInformation about payments and compensation available to subjects.

oThe investigator's current curriculum vitae and/or other documentation evidencing qualifications

oAny other documents that the IRB/IEC may require to fulfill its responsibilities.

•The FDA regulations do not specifically list in one place what documents an IRB should review. FDA requires the IRB to review the consent form (56.109(b)), and 56.115(a) requires the IRB to keep "copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents."

 

Review of Changes in Research

•ICH 3.3.7 states that "The IRB/IEC should [specify] that no deviations from, or changes of, the protocol should be initiated ... without prior IRB/IEC written approval." ICH 4.5.3 adds that "Investigators should document and explain any deviations from the approved protocol."

•FDA regulations (56.108(a)(4)) requires review of changes in research. However, review of deviations is not required by FDA, and the ICH 4.5.3 requirement is quite burdensome when applied literally. Investigators should clarify with sponsors and their IRB whether and how this requirement will be satisfied.

 

IV. CONCLUSION

In the U.S., compliance with the ICH E6 guidelines is voluntary for investigators in that it is not federal regulation. For research institutions that conduct clinical trials of drugs, however, pharmaceutical sponsors often insist that the ICH requirements be met. Investigators should assess their level of compliance and decide if ICH requirements can be met without compromising subject protections or institutional values.

 

Research and HIPAA Privacy Protections

 

Author

 

Reid Cushman, Ph.D.

University of Miami Ethics Programs and UM-Miller School of Medicine

 

Acknowledgments

The author would like to thank the following persons for their editorial and content review of this module, and for work on prior versions: Evelyn Bital (UM), Anita Cava (UM/CITI), Joey Casanova (UM), Amanda Coltes-Rojas (UM), Ken Goodman (UM/CITI), Karen Hansen (UW/CITI) and Sally Mann (CITI).

 

Introduction

Protections for health information are required by Federal laws and regulations. Every state also has its own requirements. So do private certification organizations, such as the Joint Commission [http://www.jointcommission.org/]. If you have access to persons’ identifiable health information for any purpose, it is required that you know how to protect it. If you use such health information for human subjects research, you need to know the specific limitations that apply to that activity, notably those imposed by HIPAA.

 

Researchers have long been acquainted with meeting federal standards for the protection of human subjects, since these rules have been in place for many decades. As discussed in other modules, most biomedical and behavioral research in the US is subject to the DHHS-codified "Common Rule" (45 CFR 46) and/or the analogous regulations of the FDA (21 CFR 50, 56). The Common Rule and FDA protections focus on the rights, safety and welfare of research subjects, including such matters as informed consent and appropriateness of risks relative to benefits. They also include attention to research subjects' privacy and the confidentiality of research information.

 

HIPAA's relatively new data-focused protections, which took effect starting in 2003, supplement the Common Rule and FDA protections; they are not a replacement. Protocol reviews using Common Rule/FDA criteria by IRBs remain as before, including aspects related to data protection. As will be discussed, IRBs may have the responsibility of addressing HIPAA’s additional requirements in their reviews when those apply; or some responsibilities may be given to another kind of body that HIPAA permits (a Privacy Board) or to an institutional official that HIPAA requires (a Privacy Officer).

 

Where a state’s data protection laws and regulations extend to research subjects’ data, these too generally remain in effect. HIPAA for the most part defers to state data protections that are more stringent than its own. HIPAA also generally leaves unaffected the data protection requirements that may be imposed by institutional certification bodies, such as the Joint Commission. Data protection requirements from these various sources are generally congruent in their focus on assuring the confidentiality, integrity and availability of data for treatment, payment, health care operations and other legitimate purposes such as research. HIPAA sets the federal floor for such data protections.

 

Learning objectives

By the end of this module you should be able to describe or explain:

 

•HIPAA’s additional privacy protections for individually identifiable health data that is used for human subjects research, including authorizations, accountings of disclosures, etc.

•Situations where full HIPAA privacy protections are required, and those which can qualify for waivers, alterations or exemptions with more limited requirements.

•The responsibilities of investigators and institutions for meeting these privacy requirements, and for appropriate data security protections that are necessary to protect privacy.

 

HIPAA’S REGULATORY SCOPE

HIPAA’s protections focus on individually identifiable health information, which HIPAA defines as information in “any form or medium” that “[r]elates to the past, present, or future physical or mental health or condition of an individual; the provision of health care to an individual; or the past, present, or future payment for the provision of health care to an individual.”

 

HIPAA’s protections reach only a subset of individually-identifiable health information – formally called protected health information or simply “PHI” – created in or by what HIPAA calls covered entities. Covered entities include individual health providers, health provider organizations, health plans, and health information clearinghouses that engage in electronic health care transactions. (Sometimes determining covered entity status is easy; sometimes it’s complex. See these HHS decision tools. [https://www.cms.gov/apps/hipaa2decisionsupport/]) HIPAA’s protections for PHI extend to non-U.S. citizens’ information as well.

 

Some identifiable health information obviously arises outside of covered entities, and so is not covered by HIPAA. But you must check with your organization’s privacy authorities before you assuming your situation falls outside HIPAA’s scope. More on that below.

 

What kinds of users and uses are covered?

HIPAA’s regulations set requirements for use and disclosure of PHI by covered entities, and by extension on all members of a covered entity’s workforce that have contact with PHI. Covered entities must also establish contractual requirements for data protection on business associates (and by extension on the workforce of business associates) that perform functions using PHI on the covered entity’s behalf.

 

Researchers may be covered entities if they are also health care providers, or be part of the workforce of a covered entity otherwise. If so, they are directly affected by the HIPAA’s research rules. Researchers who meet neither of these conditions are still indirectly affected by HIPAA rules if a covered entity is the source of their data and that data meets the definition of PHI.

 

HIPAA’s rules on use and disclosure are generally “purpose-based” – that is, the intended use sets the rules more than the type of data itself. The research rules discussed here are different than those for, say, treatment or payment for treatment (relatively liberal), or for marketing or fundraising (relatively strict). A few types of data, such as psychotherapy notes do receive special protection under HIPAA. State laws often have many categories of data with special protections, with which you should be familiar (or be in contact with an organizational official who has that knowledge).

 

What constitutes “research”?

HIPAA defines research as any “systematic investigation, including research development, testing, and evaluation, designed to develop and contribute to generalizable knowledge.” Not all kinds of research-like activity are included in this definition. For example:

 

•Quality assessment and improvement activities, including outcomes evaluation and development of clinical guidelines or protocols, fall under the category of health care operations under HIPAA – provided the primary aim is not obtaining generalizable knowledge.

•Activities that aim primarily for generalizable knowledge of population health can fall into the category of public health activity under HIPAA.

 

As with the covered entity status, a determination by an organization's IRB, privacy official or legal counsel is usually required to designate an activity as "not research" and therefore subject to different HIPAA rules. It’s always a good idea to check with one of these authorities before you assume anything about what requirements apply. (And remember what HIPAA excludes may not be excluded under Common Rule/FDA rules, nor under your state’s laws.)

 

Who enforces HIPAA's protections?

A covered entity may choose to rely on an IRB to assess compliance with both the FDA/Common Rule requirements and the HIPAA research requirements. Alternatively, HIPAA provides that covered entities may create a Privacy Board to handle some research-related issues, notably determinations about eligibility for waivers, alterations and exemptions from authorization processes (about which more below). A covered entity may also leave some decisions about compliance with the research provisions of HIPAA to its designated Privacy Officer. An example might be a determination about whether a particular use or disclosure application needs Privacy Board/IRB review.

 

Research subjects, like patients generally, have recourse to the Department of Health and Human Services’ Office for Civil Rights (OCR) in the event they are not satisfied with an institution’s protective efforts. OCR can levy fines or leverage the federal court system for serious violations. Recent changes in HIPAA by the HITECH Act also permit states’ Attorneys General to pursue HIPAA violations in state courts. It should be noted that the already substantial civil and criminal penalties for HIPAA violations were increased by the HITECH Act, and can be applied against both organizations and individuals.

 

As with any other planned activity related to health data, research must be mentioned in the Privacy Notices that HIPAA requires be provided by covered entities to their patients/customers. The Notice must include the ways in which data subjects may register complaints and report problems, either locally or with federal authorities.

 

HIPAA RESEARCH RULES

If the data in question meet the definition of PHI and are being used for purposes that fall within its definition of research, HIPAA generally requires explicit written authorization from the data subject for research uses. However, HIPAA provides several alternatives that can bypass such authorizations:

 

•Waiver or alteration of the authorization requirement is granted by an IRB/Privacy Board because of minimal risk, and other criteria are met.

•Research is used solely for activities preparatory to research, and certain representations are obtained from the researcher.

•Only deceased persons’ information is used, and certain representations are obtained.

•Only de-identified data is involved, by meeting set criteria or with independent validation of de-identification (a.k.a., “anonymization”).

•Research is conducted with limited data set under an approved data use agreement.

•It is “grandfathered” research where all legal permissions were in place before HIPAA took effect.

 

Each of these is described in the sections below.

 

Waivers and alterations of authorization requirement

An organization's IRB or a Privacy Board may determine that a waiver or alteration of the authorization requirement is appropriate, if the following criteria are met. These conditions are modeled on the conditions for a waiver of informed consent in the Common Rule.

 

Use or disclosure of the PHI involves no more than minimal risk to the privacy of the research subjects, based on the following elements:

 

•An adequate plan to protect any data identifiers from improper use and disclosure.

•An adequate plan to destroy data identifiers at the earliest opportunity consistent with conduct of the research (unless there is a health or research justification for retaining the identifiers, or such retention is otherwise required by law).

•Adequate written assurances that the PHI will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research project or for other research for which the use or disclosure of PHI would be permitted by HIPAA.

•The research could not practicably be conducted without the PHI.

•The research could not practicably be conducted without the waiver.

 

More about what counts as a "data identifier" is provided in the sections below on limited data sets and de-identified data.

 

Activities preparatory to research, decedents’ information exceptions

HIPAA provides for two more exceptions to the authorization requirement for identifiable data:

 

•Where the PHI will be used solely for reviews preparatory to research (e.g., for protocol development) and will not leave the covered entity.

•Where the PHI refers solely to deceased persons (the covered entity may ask for documentation of death of all data subjects).

 

In each case, the researcher must make a written or oral representation to the IRB or Privacy Board that such access is necessary for the research purposes.

 

Covered entities may determine their own processes for approval of the "representations" related to waivers, alterations and exceptions. The process may be analogous to "expedited review" under the FDA/Common Rule, and not require a full IRB or Privacy Board approval. It is not, however, a determination a researcher can (or should) make on his or her own. Aside from the HIPAA issues, preparatory research activities involving human subjects must be reviewed as research unless otherwise exempt under Common Rule criteria.

 

De-identified data

A researcher may use fully de-identified information without any authorization. As the name implies, de-identified information must have all direct and indirect identifiers removed, to eliminate – or at least make highly improbable – re-identification using statistical techniques. De-identified information is no longer considered PHI, because it is no longer individually identifiable. (Under the Common Rule, use of de-identified data is no longer considered human subjects research.) De-identification may be asserted on the basis of certification by a “person with appropriate knowledge” of statistical techniques who has analyzed the data set. Or a researcher may use the “safe harbor” method of removing 18 types of identifying element specified in the HIPAA regulations. In either case, the covered entity must have no actual knowledge that re-identification is possible by linking to other known data sets.

 

Limited data sets and data use agreements

Alternatively, a covered entity may disclose PHI in a limited data set (LDS) to a researcher who has entered into an appropriate “data use agreement.” An LDS must have all direct identifiers removed; however, it may still include information that could “indirectly” identify the subject using statistical methods. As you’d expect, the identifying elements that must be removed are similar to those for de-identified data, but with less restrictiveness on geographic specificity (addresses), data subject age and other dates, and other types of identifiers (16 instead of 18 types must be removed).

 

The data use agreement for an LDS must delineate the permitted uses and disclosures of such information by the recipient, consistent with the purposes of research; limit the persons that can use or receive the data; and require the recipient to agree not to re-identify the data or contact the individuals. (For more details, see the LDS link above.)

 

Grandfathered research

If all informed consents and other legal permissions required at the time were in place before HIPAA took effect (April 2003 in most cases), and have not changed since, no new HIPAA authorization is required. Obviously, this is no longer a commonly used pathway to bypass authorizations.

 

Minimum necessary uses and disclosures

Uses and disclosures of data for research that are allowed to bypass the authorization requirement are still subject to the minimum necessary standard – that is, the uses/disclosures must be no more than the minimum required for the described research purpose. A covered entity may rely on a researcher's documentation – or the assessment of an IRB or Privacy Board – that the information requested is the minimum necessary for the research purpose.

 

By contrast, research information obtained using an authorization is not bound by the minimum necessary standard – on the theory that the data subject has given explicit permission for whatever information access the research team deems to be necessary. But be aware that while HIPAA may not require a minimum necessary justification at all times, the IRB’s evaluation of risks and burdens on human subjects arguably does.

 

Disclosure accounting

Among the rights that HIPAA confers on data subjects is the right to an accounting of disclosures made by the covered entity. Disclosures for research that are allowed to bypass authorization, with the exception of those in an LDS, are subject to this accounting requirement. (Formally, under HIPAA: A “disclosure” occurs only when PHI is communicated to an outside person or entity, including another covered entity. By contrast, a “use” occurs when the data does not leave the covered entity.)

 

Where the study involves more than 50 subjects’ records, the disclosure accounting requirement can be met by the covered entity providing data subjects with:

 

•A list of all protocols for which their PHI may have been disclosed, along with the timeframe for those disclosures.

•The purpose of those protocols, and the types of PHI sought.

•The researcher's name and contact information for each study.

 

Covered entities must assist subjects in contacting investigators when they have questions about a disclosure or any other aspects of the protocol.

 

Where fewer than 50 records are involved, the listing must be more specific and detailed, commensurate with the requirements for other kinds of PHI disclosure accounting. Covered entities may still choose to impose more detailed reporting requirements for research, even on larger studies. (DHHS “encourages” providing more detail, but does not require it.)

 

Disclosure accounting is not required for disclosures made under authority of an authorization on the theory that the data subjects are aware of what they have authorized. Neither is accounting required for disclosures to the data subject directly about him/herself. Nor, as noted, is it required for an LDS disclosure. De-identified information isn’t PHI anymore, so disclosing it isn’t a “disclosure.”

 

While HIPAA may not require it, many organizations will require that investigators maintain logs of all disclosures from research data collections as a security measure, even “disclosures” to other persons within the covered entity. Electronic data storage will increasingly offer this capability cheaply and automatically; older collections will require manual logging.

 

Characteristics of authorizations

If a research activity meets none of the bypassing criteria above, an authorization is required. When they are required, authorizations must be:

 

•In "plain language" so that individuals can understand the information contained in the form, and thus able to make an informed decision.

•Executed in writing, and signed by the research subject.

 

HIPAA authorizations are normally required to have an explicit expiration date. In the context of research, it is sufficient to specify an expiration “event” – such as “the end of the study.” Or a research authorization can have no expiration date at all, though this absence must be clearly indicated.

 

As with FDA/Common Rule requirements for informed consent, there are many format and content specifications for a HIPAA research authorization. Researchers are strongly urged to rely on standard models rather than creating their own authorization form. Most organizations will already have a standard document available; check with your IRB, Privacy Board or Privacy Officer.

 

HIPAA authorizations cannot normally be combined with other types of documents (such as a Privacy Notice). However HIPAA research authorizations can be combined with any other legal permission related to the study, including another authorization or a Common Rule/FDA informed consent, provided one does not mix authorizations where treatment is conditioned on signing the authorization with ones where it is not. (HHS is currently considering whether to change this last restriction, to allow “compound” authorizations of any kind.) If there are multiple documents that limit information use or disclosure, the most restrictive one applies.

 

DHHS has noted that it may be advisable – though not required – for a research authorization to include:

 

•How PHI obtained for a research study may be used and disclosed for treatment, payment and health care operations. (Note that research-related treatment can be conditioned on provision of a research authorization. However, treatment unrelated to the research cannot.)

•Information about sources of funding for the study and payment arrangements for investigators. Consistent with general recommendations about informed consent, any information that might be "material to the potential subject's decision-making" should be included.

 

Revocations of authorizations

Like other kinds of HIPAA authorizations, those for research may be revoked by the subject at any time, provided that the revocation is in writing. Revocation of an authorization is not valid to the extent that the covered entity has taken actions relying on it, such as in the provision of prior treatment. And such revocations may be limited “as necessary to maintain the integrity of the research study.” This last qualification would, for example, permit the continued use and disclosure of already-gathered data (e.g., for subsequent statistical analyses, adverse event reporting, or any disclosures required by law). It would not, however, allow new data to be collected or used.

 

Recruiting into research

It is still permissible under HIPAA to discuss recruitment into research with patients for whom such involvement might be appropriate. This common practice is considered to fall within the definition of treatment, at least when the conversation is undertaken by one of the patient's health care providers.

 

Remember, however, that a data subject’s information cannot generally be disclosed to a third party (even another care provider) without an authorization from the individual or an approved waiver, alteration or exception to authorization. HHS guidance on HIPAA has reaffirmed that recruitment activities can qualify as a “preparatory to research” activity that would allow a researcher to identify prospective research participants and then contact them for purposes of seeking their authorization. However, the PHI used for this purpose should not leave the covered entity during this activity.

 

As noted previously, preparatory activities are considered research and subject to IRB review unless exempt. And the “preparatory to research” exception itself must be approved prior to using it. Most IRBs have policies and procedures about recruitment contacts, pre-screening, enrollment, post-enrollment screening and dis-enrollment that stem from a mix of Common Rule, FDA and HIPAA requirements. You must contact appropriate authorities at your organization to determine what’s required for your circumstances. Don’t assume.

 

"Retrospective" research

As electronic health data collections grow in scale and scope it is an increasingly common practice to “browse” them, looking for interesting patterns that could translate into research possibilities. Indeed, bio-repositories of tissue and data created just for this purpose are increasingly common, and the scope and scale of such repositories grows every day. (Retrospective analysis of paper charts hasn’t gone away either.) HHS has reiterated in its guidance that use or disclosure of PHI for retrospective research studies may be done only with patient authorization or a waiver, alteration or exception determination from an IRB or Privacy Board. It shouldn't be difficult to meet one of the criteria for most efforts of this kind. For example, initial in-house examinations may be qualified as “preparatory to research,” and subsequent waivers of authorization requested on grounds of minimal risk with the required protection of any identifiers. (HHS is now considering whether to make it easier to construct HIPAA authorizations, and Common Rule informed consents, that include permission for collection of data into repositories for unspecified future research.) But this sort of data mining is considered research, even if you are “just looking around” in a casual way. You cannot proceed on your own without the approval of an IRB, Privacy Board or other designated governing entity.

 

SUMMARY

Although the specifics are lengthy, the net administrative burden that HIPAA adds to existing Common Rule/FDA regulations is generally not a large one. Compared to protocol approval generally – and the details of informed consent particularly – a HIPAA authorization is relatively easy. And, as noted, there are several pathways around the authorization requirement. To approve a study under the Common Rule/FDA requirements, IRBs have long been required to determine that there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. Where investigators are meeting those requirements, HIPAA should change very little beyond the additional “paperwork.”

 

As noted, HIPAA applies to covered entities and the PHI that originates in or by them. Research conducted by organizations that do not qualify as such, using data that does not derive from any covered entity source, are not reached by HIPAA. In such cases, the requirements of the Common Rule/FDA remain as protections for human subjects’ privacy and other interests. The issue then is not “PHI” but what the Common rule defines as identifiable “private information.”

 

Efforts to meet the Common Rule/FDA and HIPAA regulations' privacy requirements are only part of the researcher’s task. HIPAA also has a Security Rule that complements its Privacy Rule. The Security Rule requires that PHI collections receive appropriate information security protections for as long as they exist. Clinical data more typically enjoy the security of an organized medical records system, particularly with the growing commonality of integrated electronic systems. Research data are too often stored in hodge-podges of computer- and paper-based records with inadequate attention to security. Hence all persons involved in a research protocol who have access to the associated data must be competent in the basic information security practices appropriate for the context. Devices and media on which research data are stored must be appropriately protected while in production, and appropriately cleaned or destroyed when no longer needed. If you don’t know how to do that, find a resource at your organization that does. In addition to a Privacy Officer, HIPAA requires designation of a security official, who should be able to help.

 

Here are the key points:

 

•HIPAA privacy protections supplement those of other federal regulations (viz., the Common Rule and FDA), state law, and certification/accreditation requirements.

•HIPAA protects identifiable health information from covered entities. Not all identifiable health information is protected health information (PHI).

•Under HIPAA, research activity using PHI generally requires authorization. However, there are several alternatives that allow bypassing the authorization requirement.

•Minimum necessary standards, disclosure accounting requirements, and the characteristics of authorizations (when required) must be understood by researchers when HIPAA applies.

•If you're unsure about the particulars at your organization or have questions, consult with your organization's IRB, Privacy Board or privacy official. For data security issues, consult with your organization’s security official.

 

ADDITIONAL READING

The Department of Health and Human Services has created a series of excellent “fact sheets” that focus of different aspects of HIPAA’s impact on research. Most are available in HTML, PDF and RTF formats.

 

•Clinical Research and the HIPAA Privacy Rule (June 2004) [http://privacyruleandresearch.nih.gov/clin_research.asp]

•Health Services Research and the HIPAA Privacy Rule (May 2005) [http://privacyruleandresearch.nih.gov/healthservicesprivacy.asp]

•Institutional Review Boards and the HIPAA Privacy Rule (July 2004) [http://privacyruleandresearch.nih.gov/irbandprivacyrule.asp]

•Privacy Boards and the HIPAA Privacy Rule (September 2003) [http://privacyruleandresearch.nih.gov/privacy_boards_hipaa_privacy_rule.asp]

•Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule (July 2004) [http://privacyruleandresearch.nih.gov/pr_02.asp]

•Research Repositories, Databases, and the HIPAA Privacy Rule (January 2004) [http://privacyruleandresearch.nih.gov/research_repositories.asp]

 

The University of Miami has a Privacy/Data Protection web site includes materials on HIPAA in a glossary of HIPAA terms [http://privacy.med.miami.edu/glossary/index_hipaa.htm].

 

REFERENCES

The Health Insurance Portability and Accountability Act of 1996 (HIPAA), Public Law 104-191, 21 August 1996. Regulations promulgated under HIPAA are grouped into Rules, the most prominent of which is the Privacy Rule. See Standards for the Privacy of Individually Identifiable Health Information, which became effective on 14 April 2001. For most individuals and organizations covered by the Privacy Rule (“covered entities”) the effective date was 14 April 2003. Smaller entities were given an additional year to comply. Of equal importance is the so-called Security Rule, which specifies administrative, physical and technical safeguards for protected health information (PHI) in electronic form. The Privacy Rule and Security Rule regulations are codified in the Code of Federal Regulations at 45 CFR 160 and 164.

 

The American Recovery and Reinvestment Act of 2009 (ARRA, a.k.a., “the Stimulus Bill”), Public Law 111-5, 17 February 2009. Title XIII of ARRA has the subtitle Health Information Technology for Economic and Clinical Health Act (HITECH Act); this part of ARRA contains most of the provisions related to electronic health care information. See sections 13401ff.

 

See 45 CFR 164.514(b). In addition to removal of the specified identifiers, the covered entity must have no actual knowledge that the information could be used alone or in combination with other data to determine individuals’ identity. The 18 are:

 

1.Names

2.All geographic subdivisions smaller than a State, including street address, city, county, precinct, zip code, and their equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly available data from the Bureau of the Census:

(a)The geographic unit formed by combining all zip codes with the same three initial digits contains more than 20,000 people; and

(b)The initial three digits of a zip code for all such geographic units containing 20,000 or fewer people is changed to 000.

3.All elements of dates (except year) for dates directly related to an individual, including birth date, admission date, discharge date, date of death; and all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages and elements may be aggregated into a single category of age 90 or older;

4.Telephone numbers;

5.Fax numbers;

6.Electronic mail addresses;

7.Social security numbers;

8.Medical record numbers;

9.Health plan beneficiary numbers;

10.Account numbers;

11.Certificate/license numbers;

12.Vehicle identifiers and serial numbers, including license plate numbers;

13.Device identifiers and serial numbers;

14.Web Universal Resource Locators (URLs);

15.Internet Protocol (IP) address numbers;

16.Biometric identifiers, including finger and voice prints;

17.Full face photographic images and any comparable images; and

18.Any other unique identifying number, characteristic, or code.

 

See 45 CFR 164.514(e). For a limited data set, relative to a de-identified data set, the no. 2 restriction on geographic information is relaxed to require removal of street addresses and PO boxes numbers, but not town or city, state, or zip code; the no. 3 restriction on dates is eliminated, as is the no. 18 restriction on unique identifiers not otherwise listed.

 

Financial Conflicts of Interest in Research Involving Human Subjects

 

Content Author

 

Robin N. Fiore, Ph.D.

Florida Atlantic University

 

1. Introduction

There is currently no comprehensive regulatory approach to reporting and managing conflicts of interest. Although the Public Health Service (PHS) has had regulations regarding financial conflicts of interest since 1995 and the Food and Drug Administration (FDA) has had regulations requiring financial disclosure for investigators since 1998, by and large, conflict of interest regulations, guidelines and policies have been oriented around the need to ensure good science. However, recent, high profile, adverse events involving researchers with significant financial interests in the outcomes of their studies have increased concerns about risks that financial conflicts of interest pose to the wellbeing of individuals who agree to participate in human subjects research. There is a growing consensus among investigators, regulators, and the public that existing guidelines have failed to deal adequately with problems associated with conflicts of interest and that additional measures are required to ensure the validity of research and protect human subjects.

 

The following two views represent a continuing, fundamental disagreement about the nature of the conflicts of interest:

 

•"Conflicts of interest are ubiquitous in academic life, indeed all professional life; conflicts of interest can never be eliminated. Moreover, the existence of conflicts of interest has to be accepted and not equated with scientific misconduct." (Korn 2000)

 

•"Financial conflicts of interest are not inherent to the research enterprise. They're entirely optional - unlike intellectual or personal conflicts of interest to which they're often compared." (Angell 2000)

 

On the first view, conflicts of interest are inescapable; what matters is whether professional misconduct actually ensues. On the second view, failing to forgo financial interests that pose conflicts is itself a form of research misconduct. Thus, proposed remedies vary, depending on which of these views is accepted. Nevertheless, the need to manage conflicts of interest cannot await consensus on this underlying dispute. Individual investigators and their institutions must cooperatively address the ethical challenges presented by financial conflicts of interest.

 

This module has the task of describing an issue that is under debate and in transition. It begins with a general discussion of conflicts of interest and the related ethical concerns that arise in the context of research involving human subjects. Subsequent sections summarize current reporting and disclosure requirements for investigators, and discuss the latest (May 2004) Federal guidance on the management of conflicts of interest.

 

2. What is a Conflict of Interest?

Professionals have a conflict of interest when their interests or commitments compromise their judgments, compromise their research reports, or compromise their communications to research subjects, participants, patients, and/or clients. (NHRPAC 2001). Conflicts of interest are of two major types (Rodwin 1993):

 

1.Conflicts between the professional's personal or financial interests and the interests of a subject/participant, patient or client.

2.Conflicts that involve competing loyalties, to two or more subjects, patients or clients. Alternatively, the conflict may be between a subject/participant, client or patient and a third party to whom the professional owes contractual duties, for example, sponsors of research, insurance companies, employers, etc.

 

The term competing interest rather than conflict of interest is preferred by some as a way of lessening any implicit sense of misconduct. Nevertheless, it is non-controversial that significant conflicts of interest increase the likelihood that professionals will abuse their trust. Law and professional ethics routinely require the avoidance of conflict of interest situations as a way of guarding against wrongful acts. Scientific misconduct is not always associated with conflicts of interest; but conflicts of interest increase the chance of scientific misconduct (Bodenheimer 2000). The approach taken in this module is to follow legal usage and distinguish conflicts of interest from actual breaches of obligation (Rodwin 1993).

 

As used here, conflict of interest describes a relationship, commitment or interest that constitutes a moral hazard i.e., something that has the likelihood of producing a moral error. In contrast, a breach of obligation describes an actual violation of a moral or legal duty. These include: violations of norms of professional scientific conduct, violations of human rights, neglect of professional role-related fiduciary responsibilities, and failure to acknowledge the existence of conflict of interest situations.

 

Adopting the distinction between conflicts of interest and breaches of obligation can ease defensiveness in disclosing and discussing the existence of conflicts of interest since their acknowledgment would not be an admission of wrongdoing. Clearly, distinguishing between circumstances that may influence conduct and actual misconduct avoids the error of referring to potential conflicts of interest. It also avoids what most commentators regard as an unhelpful differentiation between having a conflict of interest and (merely) having the appearance of a conflict of interest (Erde 1996).

 

In sum, a conflict of interest is best understood as an objective fact situation in which there is increased potential for harm or wrongdoing as a result of compromised independence.

 

2.1 Financial Conflicts of Interest

The paradigm conflict of interest is financial interest. To be sure, non-financial (or only indirectly financial) forms of bias can pose serious risks to research and to human safety and dignity, but regulations and institutional oversight are primarily oriented to financial conflicts of interest. Significant financial interests must be disclosed to institutional officials and be appropriately managed [Title 42 CFR, Section 50, Parts 604 and 605]. A "significant financial interest," according to the PHS, is one that that could directly and significantly affect the design, conduct, or publication of research and thus bear on issues of human subjects protection. While the PHS defines "significant" in terms of a monetary threshold of a $10,000 interest or 5% ownership in an entity that would reasonably be affected by research. Neither PHS nor FDA spells out types of financial interests that may be held; each grantee institution must develop guidance, policies and mechanisms for reporting and managing conflicts of interest.

 

Financial interests include, but are not limited to:

 

•Compensation from employment (by other than grantee institution).

•Paid consultancy, advisory board service, etc.

•Stock ownership or options.

•Intellectual property rights (patents, copyrights, trademarks, licensing agreements, and royalty arrangements).

•Paid expert testimony.

•Honoraria, speakers' fees.

•Gifts.

•Trips.

 

Proprietary interests (intellectual property rights and equity) are of particular concern, not only because they offer potentially enormous financial rewards, but also because financial gain depends on the study outcome. (Note that investigators may have interests in competitor products not under study and have a conflict of interest despite having no direct financial association in a particular study.) The worry is that if researchers have a stake in the success of commercial ventures, their judgment and objectivity in the conduct of research may be affected - consciously or unconsciously - to the detriment of research subjects' wellbeing.

 

The goal of protecting human subjects is the best guide to determining whether a financial interest is ethically significant or not.

 

Basic questions that help reveal significant financial conflicts of interest are:

 

•Is compensation affected by the outcome of the research?

•Does a financial relationship suggest, to a reasonable person, that the investigator or institution would prefer one study outcome rather than another?

 

For additional questions to be considered in determining the significance of specific financial relationships see the 2004 Final Guidance [http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf].

 

3. What are the ethical concerns relating to conflicts of interest in research?

There are two important ethical concerns relating to conflicts of interest: the preservation of sound science and the protection of human subjects. Each is discussed separately below, however, they are integrally related. Robust protection of human subjects - and those who use the products of science - depends on ensuring the soundness of research.

 

3.1 Preservation of Sound Science

Conflicts of interest pose a threat to scientific integrity by introducing forms of bias that affect the enterprise of science itself. First, financial relationships among investigators, academic research centers and private industry create incentives to serve commercial interests rather than the advancement of scientific knowledge. For example, sponsors may seek to restrict publication, citing protection of proprietary information, in order to avoid advancing the work of competitors. They may conceal negative study findings by maintaining control of publication, or avoid disclosing adverse events and side effects to the public (though these are disclosed to the FDA). Restricted or partial publication increases the cost of clinical progress and can jeopardize the health of future study subjects and future patients. It also impedes or disrupts the work of other scientists whose work would otherwise improve, build on or impeach prior investigations.

 

Secondly, the soundness of study results can be profoundly influenced by study design decisions: treatments to be tested, e.g., placebo control or active control, favorable and adverse endpoints, the characteristics of eligible and ineligible participants, stopping or modifying a trial, and so on (Brody 1996) . Without an investigator's being aware of it, conflicts of interest may influence the design and conduct of research in ways that render study results unsound, with the potential to misinform the practice of many physicians and to affect the health of patients. Thirdly, the availability of capitation payments - fees paid by study sponsors to physicians for each patient enrolled in a study - may increase the likelihood that basic science research will be less attractive to researchers and institutions than projects with more immediate application preferred by commercial sponsors. To the extent that capitation payments exceed actual overhead costs, the excess or "profit" benefits the investigator and/or the institution by providing a source of discretionary funds. Excessive capitation payments may serve as an inducement for researchers and research institutions to choose projects that are of interest to generous sponsors rather than alternatives that might be of more benefit to patients or society.

 

3.2 Protection of Human Subjects

As relationships between industry and academic medicine become increasingly more complex, clinicians may assume multiple roles of physician, investigator, sponsor, and sometimes, institutional official, and institutional review board (IRB) member as well. The primary role, however, must be that of fiduciary. A fiduciary is a person trusted with acting on behalf of others for their benefit, or in the public interest. Compromised loyalties are inconsistent with acting as a fiduciary. Professionals with fiduciary responsibilities must avoid interests (or roles) that pose a hazard to the welfare of those for whom they are responsible.

 

Human subject recruitment in industry-sponsored trials conflicts with the fiduciary role. Investigators, sponsors, grantee institutions, and physicians in private practice all stand to benefit by a patient's participation in research. Since studies must enroll a sufficient number of subjects to obtain funding, there is an inevitable conflict between potential subject/participant interests and those of investigators. The concern is that investigators - under pressure to recruit - may undermine the consent process by misrepresenting the research or inappropriately influencing patients to participate. The most objectionable financial arrangements in clinical research involve "trading in patients" or their medical information. For example, the practice of paying finders' fees to physicians for enrolling their patients is rightly regarded as ethically equivalent to fee splitting (Lind 1990). According to The American Medical Association, "it is unethical to for physicians to accept payment solely for referring patients to research studies" [Opinion 6.03]. Other recruitment techniques, such as naming private-practice physicians as co-investigators, or retaining them as consultants in order to gain access to their patients, increase the likelihood that financial considerations may influence clinical judgment with respect to whether patients are benefited by being enrolled in a study.

 

4. What are the current requirements applicable to individual investigators?

Before beginning a study, individual investigators are required to disclose financial interests that may be affected by the outcome of research to designated institutional officials. Institutions are required to report the existence of conflicts of interest - but not substantive details - to PHS funding agencies and to take steps to reduce, eliminate or manage conflicts of interest [Title 42 CFR, Section 50: Parts 603 and 604].

 

The FDA requires sponsors and individual investigators to report certain financial arrangements as part of marketing applications for drugs, biologics and medical devices [Title 21CFR, Section 54; Part 4].

 

4.1 Institutional Assurance

The regulations state that information regarding financial conflicts of interest should be obtained from all investigators according to institutional policies and procedures. Thus, research institutions are formally responsible for developing and communicating a process for reviewing, authorizing and monitoring arrangements that present conflicts of interest. However, the specifics are left up to each institution, and vary widely. A national survey of academic medical centers reported that the responsibility for conflict of interest policies tends to be distributed among several administrative units, so investigators are advised to make sure they are in compliance with all of their institution's policies relating to conflicts of interest (GAO 2001). In the event that investigators fail to comply with conditions or restrictions imposed to manage conflicts of interest, the institution must report the delinquency and how it is being handled. Improperly managed conflicts of interest can result in the PHS suspending funding to the offending grantee. The PHS may also require the institution to ensure that investigators disclose the conflicting interest in each public presentation of the results of research [Title 42 CFR Section 50: Parts 604-606].

 

5. What is the impact of the 2004 Guidance on current requirements?

On May 12, 2004, the Department of Health and Human Services (DHHS) published final guidance for IRB's Investigators, research institutions and others entitled "Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection". The Final Guidance [http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf] has now been published. The 2004 final document states that it "does not change any existing regulations or requirements, and does not impose any new requirements." It applies to research conducted or supported by HHS or regulated by the FDA and replaces earlier "draft interim guidance." Guidance documents are often used by Federal agencies to augment existing regulations without triggering the cumbersome statutory rule-making process. It is probably right to regard this draft guidance a statement of "best practices" and to incorporate its recommendations into current policies and procedures. The 2004 guidance defines a "conflicting financial interest" as "a financial interest related to a research study that will, or may reasonably be expected to create a bias." It continues to rely on institutional assurance rather than prescription. While clearly anticipating that IRB's and investigators will take more active roles in ensuring that financial interests do not compromise the protection of research subjects, it stops short of prescribing, the approach taken in earlier guidance documents.

 

As a general guideline, the 2004 Guidance states that the Belmont principles − respect for persons, beneficence, justice − should not be undermined by financial interests. In particular:

 

•IRBs should consider whether management of conflicts of interest adequately protects subjects, or actions are required.

•IRBs should determine the level of detail to be provided to subjects regarding sources of funding, funding arrangements, financial interests of parties involved, financial interest management actions, etc.

 

6. What are the primary strategies for eliminating, reducing and managing conflicts of interest?

The primary strategies for managing conflicts of interest are disclosure and prohibition. A number of influential professional societies, researchers and institutions have advocated a total ban on paid consultancies and equity holdings in entities related to their research; some have recommended barring investigators from investments in fields in which they are conducting research. Less drastic approaches include:

 

•Peer review of the study design.

•Independent oversight of the research.

•Insulating investigator from knowledge about the impact of financial interests through blind-trust type devices.

•Insulating the subject/participant from the influence of financial considerations on professional judgment by having an investigator with a conflict abstain from problematic aspects of the study.

•Disclosure of the financial interest to subjects on the consent form.

 

6.1 Disclosure and Consent

Although nearly all research institutions have the requisite policies calling for investigators to disclose "significant financial interests" to designated institutional officials, fewer than 10% of institutions in a national survey required disclosure to funding agencies or to journals; only 1% required disclosure to IRB's and/or subjects (McCrary et al. 2000) .Current PHS and FDA regulations are silent on what if any information about financial conflicts of interest ought to be shared with prospective research subjects. Critics of the current regulations argue that the failure to disclose financial conflicts of interest violates the ethical obligation to provide subjects and potential participants with information that is relevant to the choice to participate. Further, some argue that failure to disclose is fundamentally deceptive and that without complete information about the risks of participation, including the possibility that financial arrangements of the investigator might influence their judgment, consent is invalid. It is worth noting that the World Medical Association's 2000 revision of the Declaration of Helsinki now lists "sources of funding" as information that should be provided to subjects. Others have argued that disclosure merely confuses or disturbs subjects and does nothing to actually eliminate or reduce conflicts of interest. On this view, subjects are unlikely to be able to make effective use of information about conflicts of interest because they are, variously, mistaken about the nature of clinical trials, confused about relative and objective risk, or ill-informed about financial interrelationships among investigators, institutions and industry.

 

Rather than addressing the question of how much transparency is enough, the U.S. National Human Research Protections Advisory Committee (NHRPAC) has argued that research should not be allowed to proceed until the risk from "troubling financial relationships" has been reduced to a level below "significant" through appropriate management strategies. In that event, the consent form need only state, for example, that the review committee believes that there are no conflicts of interest that, taken together with the management strategies agreed to by the investigator, will influence the way the study will be conducted (NHRPAC 2001). Investigators should not rely on disclosure alone to do the work of protecting the rights and welfare of human subjects, as Dr. Greg Koski - the former Director of the Federal Office for Human Research Protections (OHRP) - acknowledged when he declared, "disclosure is not enough in most instances and, yet, at the same time openness is essential."

 

6.2 Prohibiting Problematic Financial Interests

The evidence is persuasive that investigators with financial ties to companies whose products they are studying are much more likely to publish studies favorable to those products (Bodenheimer 2000). Ideally, investigators should be paid on the basis of time and effort, not the outcome of trials. There is a fairly broad consensus in favor of prohibiting academic researchers and their families from having financial interests in companies sponsoring their research, in companies that manufacture a product or device being tested, and in companies that manufacture competing products. The difficulty is that the current regulatory approach that relies on individual research institutions to assure that conflicts of interest are managed cannot ensure a level playing field, i.e. that policies are consistent across institutions. Without binding regulations or voluntary agreements, institutions fear that they risk losing investigators to institutions with more lenient policies.

 

Some have recommended that prohibitions on stock ownership and stock options be imposed only on investigators who are responsible for sensitive elements of the study process: the selection of subject-participants, obtaining informed consent, and clinical management. Critics have responded that bias also may occur in the design of the study itself, and in the interpretation of study results, and so have endorsed broader prohibitions on the ownership of stock/stock options (Lo et al. 2000).

 

There is general agreement that the most problematic financial interests are equity holdings and paid consultancies. However, internal compensation to investigators and institutions from grants can be just as significant a source of conflicts of interest (Brody 1996). Since grants typically cover more than the marginal costs of research, anything that reduces grant funding, such as decisions to stop a trial early or failure to enroll enough patients with the consequent elimination of a center from a trial, have both financial and career implications.

 

An alternative to outright prohibition of "profit" that exceeds true direct and indirect costs - whether from excess capitation payments/enrollment bonuses or overhead - is to insulate the investigator from the surplus. An alternative suggested by The Institute of Medicine is that the excess be placed in a pool administered by the institution for all researchers, rather than allowing the investigator or the investigator's unit to appropriate it.

 

7. Conclusion

The goal of managing conflicts of interest is to minimize the extent to which the design and conduct of research is influenced - consciously or unconsciously - by financial considerations. However, merely complying with the letter of current conflict of interest regulations and institutional policies is unlikely to achieve the twin objectives of maximizing protection of human subjects and ensuring sound science. Responsible conduct of research calls for investigators to exercise their best judgment when entering into financial relationships that constitute conflicts of interest, to acknowledge non-financial biases, and to disqualify themselves when appropriate.

 

Reference List

 

Angell, M. (2000). Remarks. HHS Conference on Human Subject Protection and Financial Conflicts of Interest: August 16-17, 2000, NIH Campus, Bethesda MD.

 

Bodenheimer, T. (2000). Remarks. HHS Conference on Human Subject Protection and Financial Conflicts of Interest: August 16-17, 2000, NIH Campus, Bethesda MD.

 

Bodenheimer, T. (2000). Uneasy Alliance--Clinical Investigators and the Pharmaceutical Industry. New England Journal of Medicine 342(20): 1539-1544.

 

Brody, B. A. (1996). Conflicts of Interest and the Validity of Clinical Trials. In Conflicts of Interest in Clinical Practice and Research. J. Roy G. Spence, D. S. Shimm and A. E. Buchanan. New York, Oxford University Press: 407-417.

 

Erde, E. L. (1996). Conflicts of Interest in Medicine: A Philosophical and Ethical Morphology. In Conflicts of Interest in Clinical Practice and Research. J. Roy G. Spence, D. S. Shimm and A. E. Buchanan. New York, Oxford University Press: 12-41.

 

GAO (2001). Financial Conflicts in Biomedical Research: Report to the Ranking Minority Member, U.S. Senate Subcommittee on Public Health, Committee on Health, Education, Labor, and Pensions. Washington, DC, U.S. General Accounting Office: 1-39.

 

Korn, D. (2000). Conflicts of Interest in Biomedical Research. Journal of the American Medical Association 284: 2234-2237.

 

Lind, S. (1990). Finder’s Fees for Research Subjects. New England Journal of Medicine 323: 192-195.

 

Lo, B., L. E. Wolf, Berkeley, A. (2000). Conflict of Interest Policies for Investigators in Clinical Trials. New England Journal of Medicine 343: 1616-1620.

 

McCrary, S.V., Anderson, C.B., Jakovljevic, J., Khan, T., McCullough, L.B., Wray, N.P., Brody, B.A.. (2000). A National Survey of Policies on Disclosure of Conflicts of Interest in Biomedical Research. New England Journal of Medicine 343: 1621-1626.

 

National Human Research Protections Advisory Committee (2001). NHRPAC Recommendations on HHS’s Draft Interim Guidance on Financial Relationships in Clinical Research.

 

Rodwin, M. A. (1993). Medicine, Money and Morals: Physicians Conflicts of Interest, Oxford University Press.