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Protecting Human Research Subjects

Address correspondence to Roger L. Bertholf, Ph.D., Department of Pathology, University of Florida Health Science Center/Jacksonville, 655 West 8th Street, Jacksonville, FL 32209 USA; tel 904 244 5076, fax 904 244 4290, e-mail roger.bertholf{at}jax.ufl.edu.

	Abstract

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 
Respect for persons, beneficence, and justice are the cardinal principles that guide the ethical conduct of research on humans. Past abuses of human research subjects prompted medical organizations and governmental agencies to develop guidelines that ensure the protection of human research subjects. Human research funded by the U.S. government is strictly regulated, and Institutional Review Board approval of the experimental protocol is required prior to the award. Under limited circumstances, human research may be exempted from review, or review may be expedited. Research involving specimens submitted for pathological examination or diagnostic studies sometimes qualifies for these special categories of limited review. Academic pathologists and laboratorians should be aware of the regulations that apply to research on human subjects.

Keywords: Human research, Nuremberg Code, Belmont Report, Declaration of Helsinki

	Introduction

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 
Experimentation involving human subjects is an essential component of medical research. When human subjects are enlisted to participate in clinical research, they may be asked to take an experimental medication, submit to an unproven procedure, donate blood or tissue for analysis, or provide information about their lifestyle and personal habits. Some types of research involve potentially life-threatening medical interventions, whereas other studies may not even require contact between the investigator and the subject. Virtually every therapeutic modality in common use today was, at one time, experimental and unproven. A bone marrow transplant, coronary artery bypass graft, chemotherapeutic agent, magnetic resonance image, and radial keratotomy each was, at some point, performed for the first time on a human subject. Not all experimental procedures are ultimately successful, and the history of medical research includes a list of failures like bloodletting, thalidomide, xenotransplantation, mechanical hearts, and electro-convulsive therapy. Since the mid-nineteenth century, progress in medicine has relied on the scientific method, and the controlled clinical trial involving human subjects has become the dominant mechanism by which new therapies are tested and their efficacy demonstrated. In the mid-twentieth century, consideration was given to the rights and protection of human research subjects, and foundations were laid for the ethical conduct of medical research involving humans.

Although pathology is the most fundamentally scientific discipline in medicine, pathologists have enjoyed a special immunity in protection of human subjects, presumably owing to their historical role as consultants to the primary physicians and their absence from direct involvement in patient care. Post-mortem examinations and tissues submitted for histological examination do not generally fall under the legal definition of a human research subject, although there are circumstances in which some restrictions exist, for instance, with regard to the investigational use of blood, urine, and other body fluids submitted for laboratory tests. Pathologists who collaborate on federally funded research studies assume the same responsibility for human subject protections as the principal investigator does, and federal regulations require that anyone engaging in research involving human subjects be familiar with the essential protections that are assured by federal law.

	History of Human Research Protection

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 
Prior to the mid-twentieth century, little attention was paid to protecting human research subjects. Physicians often relied on personal experience or anecdotal reports to justify the selection of unconventional therapies. Experimentation was considered part of progressive medical care, and patients rarely questioned the recommendations of their physicians. Physicians, after all, have a Hippocratic obligation to "do no harm," and public trust and confidence in the medical profession extended to the ethical conduct of human research. Two events changed this perception: the Nuremberg Trials and the Tuskegee Syphilis Study.

The Nuremberg Code.  From November 1945 to October 1946, an International Military Tribunal was convened in Nuremberg, Germany, to adjudicate charges of war crimes filed on behalf of the USA, Britain, France, and USSR against 24 Nazi leaders and 6 Nazi organizations. Subsequent to this trial, an American military tribunal was convened in Nuremberg to hear charges against 23 German physicians and administrators. In the course of the Doctors’ Trial, as it was known, witnesses described horrific medical experiments using involuntary subjects, most of whom were imprisoned Jews, Poles, Russians, and Roma (Gypsies). The verdict (19 August 1947) included a section entitled "Permissible Medical Experiments," now called the "Nuremberg Code," that addressed fundamental issues on the use of human subjects in medical research.

The Nuremberg Code is the foundation upon which subsequent efforts to define and codify human research protections are based. Of 10 basic principles set forth in the Nuremberg Code, the first is: The voluntary consent of the human subject is absolutely essential [1]. The Nuremberg Code thereby established a key principle of human research (ie, that humans are entitled to choose whether or not to participate in a research study). The principle of beneficence was also introduced: The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature [1]. Beneficence simply means that any experiment involving human subjects should have a reasonable likelihood of producing meaningful and beneficial results. Human research subjects should not be exposed to risk when there is no foreseeable offsetting benefit. The Nuremberg Code stipulates that the risk to individuals participating in research should be minimized, and no experiment should be conducted for which there is reason to believe death or disabling injury may occur. Finally, the Code introduces the important notion of balancing risks against potential benefit: The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment [1]. In this principle, the Code acknowledges that some risk is unavoidable in human research, but requires that the risk be in proportion to the importance of the experimental results.

The ethical and humanitarian principles of the Nuremberg Code are the cornerstone of public policy regarding medical research on human subjects. The principles seem so obvious and sensible that it is difficult to imagine a time when they were not generally respected. The atrocities committed by the genocidal Nazi regime in the name of medical research, it might be argued, were an exception born of malignant antiSemitism. However, there are other examples where fundamental human rights were violated in the course of medical research.

The Tuskegee Syphilis Study.  In 1928, the U.S. Public Health Service, with financial backing of a private philanthropic foundation, initiated a program to test for and treat syphilis in African Americans residing in several areas of southern USA. The testing program found that 35–40% of African American men in Macon County, Alabama, were infected with Treponema pallidum. This was the highest incidence of syphilis in all the locations where testing was conducted. When the private sponsor experienced financial difficulty during the Great Depression and withdrew support, the Public Health Service could not afford to continue the treatment program. Dr. Taliaferro Clark, a Public Health Service employee, suggested that the study be continued in Macon County without treatment, in order to gather data on the natural progression of syphilis. Because of its ties with the African American community, the Tuskegee Institute was given funding by the Public Health Service to help recruit study volunteers. Since medical care was unavailable to many Macon County residents, the promise of free medical care was a considerable inducement for participation. The study subjects were provided with regular medical checkups, including transportation to the clinic and free meals. None of the subjects was told he had syphilis or that he would not be treated for the disease. A stipend towards burial expense was given to families in exchange for their consent to perform autopsies on study participants.

Treatment was withheld from participants in the Tuskegee Syphilis Study, even though the Public Health Service began treating syphilis with penicillin in 1943. Study subjects who moved from Macon County were tracked by the Public Health Service to ensure that no treatment was administered at other local health departments. Military doctors, at the covert insistence of USPHS officials, excluded several study participants who enlisted in the armed services from routine syphilis treatment. The study was discontinued in 1972 when a concerned Public Health Service researcher described the project to an Associated Press reporter who made the story public. Outrage over the disregard for the rights and welfare of Tuskegee Study subjects prompted Congressional action to ensure human research protections in publicly funded medical research. On 16 May 1997, President Clinton issued an official apology on behalf of the U.S. Government to the Tuskegee Study participants and their families.

The Tuskegee Syphilis Study illustrates the tragedy that can occur when ethical research principles, such as those enumerated in the Nuremberg Code, are not observed. Subjects volunteered to participate in the Tuskegee Study, but did so without any knowledge of the consequences of their participation. They were not made aware of the study design or informed about alternatives to participation. Since they were denied potentially helpful treatment, they assumed risk for which there was no offsetting benefit to them.

The Nuremberg Trials and the Tuskegee Syphilis Study were defining events in the evolution of human research protections. Other abuses of human subjects in medical research undoubtedly occurred, but these two incidents captured public attention and prompted private and governmental efforts to draft guidelines for the ethical conduct of human research.

Guidelines for research on human subjects.  The Nuremberg Code established fundamental principles of human research protections, but lacked specific guidance about how these principles could be observed in the practical conduct of medical research. Because of the circumstances under which it was produced, the Nuremberg Code did not contain the detailed language that is typical of a regulatory policy, and many questions were unanswered. What constitutes medical research? When is informed consent of the subject necessary, and under what circumstances should it be obtained? By what criteria is the scientific validity of the experiment to be judged, and who should make that judgment? How much risk to human subjects is acceptable? Can children consent to medical experiments? At least two efforts have been made to draft guidance documents for human research: the Declaration of Helsinki and the Belmont Report.

The Declaration of Helsinki.  The World Medical Association Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects were adopted at the 18th World Medical Assembly in Helsinki, Finland, in June 1964 [2]. The recommendations, commonly known as the "Declaration of Helsinki," have been revised several times, most recently in 1996. The Declaration expands on the principles in the Nuremberg Code and provides practical guidance for conducting human research. The Declaration was the first document to require that biomedical research involving humans conform to generally accepted scientific principles [2]. The Declaration specifies information that must be given to the subject before consent is obtained, including all foreseeable risks and discomforts, the fact that he or she may withdraw at any time, and a complete description of the study protocol.

The Declaration recognizes the potential for unintended coercion resulting from the physician/patient relationship, and recommends that under certain circumstances a physician other than the principal investigator obtain the subject’s consent. Procedures for obtaining consent when the subject is incapacitated, legally incompetent, or a child are also addressed. The Declaration of Helsinki introduced the notion of an independent committee to review research proposals and assess potential risks to human subjects—a harbinger of the modern Institutional Review Board.

The Declaration of Helsinki makes a distinction between biomedical research in which the aim is essentially diagnostic or therapeutic, and experimentation that is purely scientific and without direct diagnostic or therapeutic value to the subject. This important distinction corresponds roughly to the division between Phase 1 and Phase 2 clinical trials of new drugs.

Perhaps the most important and controversial principle espoused by the Declaration of Helsinki relates to medical research combined with professional care (clinical research): Every patient, including those of a control group, if any, should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists [2]. In this statement, the Declaration severely restricts the circumstances under which a placebo can be used. This recommendation has been criticized by researchers who believe it dilutes the statistical power of controlled clinical trials [3]. Some have interpreted it to imply that investigators are obligated only to provide the best available therapy, which in some underdeveloped countries means none, even though effective drugs may be available in more affluent countries.

The Belmont Report.  In response to Congressional hearings on the Tuskegee Syphilis Study, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established in 1974 to identify the basic ethical principles that should direct research involving humans. The Commission also was charged with developing guidelines to ensure research was conducted in accordance with those principles. The Commission held a meeting at the Smithsonian Institution’s Belmont Conference Center in 1976; from that meeting and subsequent deliberations, a document entitled Ethical Principles and Guidelines for the Protection of Human Subjects of Research was produced [4].

The Belmont Report has three sections. The first addresses the boundaries between medical practice and research and tries to answer the important question: What constitutes research, as opposed to clinical practice? The distinction is not always clear. Suppose, for example, that a physician begins prescribing a less expensive drug in order to determine whether his patients respond just as well as when given the more expensive alternative. The intent is to save patients money, not to advance medical science. The design is not controlled, so the study is unlikely to yield statistically valid data. The physician is merely exercising clinical and economic judgment by choosing among alternative therapies. This approach does not meet the criteria for research. If, however, the physician decides to randomly give the more expensive drug to half of his patients and the cheaper alternative to the other half so that he can statistically compare the responses of the two groups, then the exercise is research. The subjects are entitled to know that their therapy is being determined randomly for the purpose of testing a hypothesis. A colloquial rule is: "If you plan to publish the results, then it is research."

The Belmont Report’s second section establishes three basic ethical principles that should guide human research: Respect for persons, beneficence, and justice. Respect for persons requires that potential research subjects be sufficiently informed about the study so that they can make a knowledgeable decision whether to participate. The Report states that individuals should be treated as autonomous agents, and defines the characteristics of autonomy as follows: "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" [4]. The Report recognizes that individual autonomy must be respected, but states that individuals who have diminished autonomy are entitled to special protections. People with diminished autonomy include minors and those with mental incapacities, whose participation in research requires a careful consideration of the risk of harm and likelihood of benefit to them. Prisoners also have limited autonomy, and the Belmont Report points out their susceptibility to institutional coercion or undue influence.

The notion of beneficence, introduced in the Nuremberg Code, is the second basic ethical principle contained in the Belmont Report. The Report offers two general rules that express beneficent actions: (1) do no harm, and (2) maximize possible benefits and minimize possible harms [4]. These rules reinforce an overarching principle of ethical research involving humans that risks assumed by study participants be justified by potential benefits from the research. The benefits need not apply specifically to the study participants, although that is clearly desirable. The Report acknowledges that some research protocols cannot be designed in a manner that would directly benefit participants, and in those instances risks must be carefully weighed against the overall benefits to society.

The third basic ethical principle in the Belmont Report is justice. This principle is not directly addressed in either the Nuremberg Code or the Declaration of Helsinki. The principle of justice holds that benefits and risks of human research should be fairly distributed, ie, one group should not assume research risks for the benefit of another. The Report notes that society ordinarily allocates burdens and benefits by any of five formulations: (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 [4]. Just selection of research participants should be guided by these same formulations. Both the Nazi medical experiments on prisoners and the Tuskegee Study’s use of disadvantaged African American men living in rural areas illustrate violations of the principle of justice. In both cases, the population was selected not because of potential benefit to them, but for the convenience of researchers. Use of prisoners is severely restricted under the principle of justice, since it is necessary to demonstrate that the results of the research will benefit prisoners individually or as a group.

In its third section, the Belmont Report provides three requirements for application of its general principles to the conduct of research: informed consent, assessment of risks and benefits, and selection of subjects. The Report advises that the process of informed consent include complete disclosure of all known risks and anticipated benefits of the research, but addresses circumstances when information must be withheld from subjects in order for the research to be valid. For example, a study that depends on spontaneous responses might be compromised if participants are informed in advance of the hypothesis being tested. According to the Report, use of uninformed subjects is allowed only if: (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 disseminating research results to them [4]. Moreover, information provided to potential subjects should be comprehensible to them and presented in an orderly fashion so as not to confuse. Most importantly, consent must be obtained under circumstances that promote a free and voluntary choice. Physicians obtaining consent from patients must exercise great care not to influence, either deliberately or by virtue of their perceived authority, the decision of the patient whether to participate in a research study.

In assessing risks and benefits of research, the Report offers the following guidelines (some are paraphrased): (1) Brutal or inhumane treatment of human subjects is never morally justified, (2) Risks should be reduced to those necessary to achieve the research objective, (3) When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk, (4) When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated, and (5) Relevant risks and benefits must be thoroughly arrayed in documents used in the informed consent process [4].

Finally, the Belmont Report emphasizes the principle of justice in the selection of research subjects. The principle applies to both social and individual justice, the latter implying that every person should have equal opportunity to participate in research that may potentially benefit him or her. Social justice requires that benefits be reasonably accessible to the population from which research subjects are recruited.

The Belmont Report, the most comprehensive treatise to date on protection of human research subjects, is the basis for federal regulations on the conduct of government funded research.

	Federal Regulations

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 
Since 1966, the National Institutes of Health (NIH) has had a policy regarding the protection of human research subjects, but that policy did not have regulatory status until 1974 when the National Research Act was passed. Institutional Review Boards were established as part of the NIH policy. The National Research Act appointed the commission that created the Belmont Report. In response to recommendations contained in the Belmont Report, legislation in 1981 codified the Department of Health and Human Services (formerly the Department of Health, Education, and Welfare) rules and regulations on biomedical research using human subjects. The NIH regulations appeared in Title 45, Part 46 of the Code of Federal Regulations (45 CFR 46), and were revised in 1983 and 1991. Separate rules applying to clinical trials regulated by the Food and Drug Administration (FDA) are contained in 21 CFR Parts 50 and 56, and were originally adopted in 1980. There are minor differences between 45 CFR 46 and 21 CFR 50, but attention here will be given mostly to 45 CFR 46.

As part of the National Research Act, the Office for Protection from Research Risks (OPRR) was created within NIH and given oversight authority for NIH–funded research. OPRR was reorganized in 2000 as a Health and Human Services department-level agency, renamed the Office for Human Research Protections (OHRP). Within the past 10 years, the OHRP exercised its regulatory authority by suspending all federally-funded clinical research at several academic medical centers where incidents of non-compliance were revealed.

The Department of Health and Human Services regulations (45 CFR 46) comprise four subparts. Subpart A is called the "Common Rule" and includes most of the regulatory aspects of human research protections. The Common Rule defines research as "...a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge" [5]. This definition appears to exclude investigative activities that are intended to monitor and improve local policies and procedures associated with medical care, customarily called quality assurance. Measures such as utilization review, tumor boards, and grand rounds generally fall under the category of quality assurance activities and are not subject to IRB review because they do not contribute to knowledge that can be generalized. However, a retrospective review comparing mortality in patients undergoing alternative surgical treatments may qualify as research under federal rules, and thus require Insitutional Review Board review of the protocol.

Subparts B, C, and D of 45 CFR 46 provide special protections to pregnant women, fetal tissue research, prisoners, and children, respectively. Pregnant women often are excluded from participating in biomedical research since the risk to the unborn child cannot be determined. Use of fetal tissue in research has been the subject of intense political debate, and was under moratorium from 1988 to 1993, when a presidential memorandum allowed studies involving fetal tissue to proceed under certain restrictions. In August 2000, the NIH released guidelines for use of human pluripotent stem cells in research. Subpart C requires a prisoner representative on any Institutional Review Board that reviews research involving prisoners. Children are given protections under Subpart D, which requires that assent of minor subjects be obtained when possible. Institutional Review Board review of any study involving these special classes of subjects pays particular attention to the need to use these subjects. Unless their use is essential, these special classes of subjects ordinarily will be excluded from participation.

The Department of Health and Human Services requires that any institution receiving research grants from federal agencies provide assurance that research is conducted in compliance with 45 CFR 46 or 21 CFR 50. Large academic institutions that receive federal research funds typically meet this requirement by submitting a Multiple Project Assurance, which describes the institution’s strategy for protecting human research subjects, complying with federal regulations.

The National Bioethics Advisory Commission.  In 1995, by Executive Order 12975, President Clinton established the National Bioethics Advisory Commission (NBAC) and specified that its first priority is protection of the rights and welfare of human research subjects [6]. The Commission does not review research proposals, but advises the National Science and Technology Council and other federal agencies on issues related to ethical conduct of biomedical research. Recent reports by the NBAC include Ethical Issues in Stem Cell Research, Research Involving Human Biological Materials, Research Involving Persons with Mental Disorders That May Affect Decision Making, and Cloning Human Beings.

Of interest to pathologists are the NBAC recommendations concerning human biological materials. The NBAC affirms the exemption of unidentified (and, in most circumstances, unlinked) human tissues from Common Rule protections, and recommends that minimal risk research involving human biological materials be eligible for expedited Institutional Review Board review. Such review of the procedure in place to unlink specimens from subjects’ identities also is recommended by the NBAC. When identifiable biological materials are to be used, the NBAC recommends that the Institutional Review Board review the mechanisms in place to protect against inadvertent release of confidential medical information, and also recommends that a separate informed consent be obtained for storage and use of biological specimens. Most importantly, the NBAC recommends that minimal risk can be presumed if protection of confidentiality is adequate, and there is no inappropriate release of information to third parties, and provisions exist for patient and physician notification, should research findings merit such disclosure. The NBAC recommendations do not have regulatory force, but influence the adoption of federal policy concerning research on human subjects.

Pathology and human subjects protection.  Certain types of research are excluded from review under 45 CFR 46. These exclusions include, in addition to the quality assurance activities described above, many studies of instructional techniques or testing procedures, evaluation of public benefit programs, and taste and food quality surveys. One exclusion is particularly relevant to pathology: "Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available, or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects [5]." The exclusion of pathological and diagnostic specimens appears to exempt most, if not all, research activities that pathologists might pursue. However, there are two qualifications that must be met before the use of these materials can be exempted from Institutional Review Board review. First, the specimens must be in existence before the study is initiated. Retrospective examination of stored tissues may be exempt, but prospective collection of specimens for examination is not. It does not matter that the specimen is collected as part of normal clinical care; if the specimen is not in existence at the time the study begins, the research is not exempt from Institutional Review Board review. Second, data cannot be recorded in a manner that links the information to the patient from whom the specimen was obtained. Privacy is an important component of human research protections, and the regulations do not, in general, allow infringement on that privacy without obtaining prior consent. Research on pathological or diagnostic specimens is exempt only if it maintains the privacy (anonymity) of the subjects.

Within these two restrictions, most pathology research is exempted from Institutional Review Board review. Look-backs designed to reveal common histological findings, for example, are exempt as long as the data recorded by the investigator does not identify patients and cannot be linked to individuals. Correlation studies using surplus serum are usually exempt, with the same restriction. Reference range studies that require collection of blood from healthy individuals are not exempt. Special stains on interesting pathological specimens for investigative purposes are normally exempt. Depending on the institution’s Multiple Product Assurance, it may be necessary to submit these protocols to the Institutional Review Board to obtain a letter verifying their exempt status.

Non-exempt protocols do not necessarily receive full review by the Institutional Review Board, and may not require informed consent. The regulations recognize several categories of research that qualify for expedited review, which means that a vote of the full board is not required for approval. In order to qualify for expedited review, a protocol must involve no more than minimal risk to subjects. Minimal risk is an important criterion that the regulations define as follows: "...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" [5]. Collection of excreta, minimal amounts of blood by venipuncture, or nail and hair clippings, non-invasive diagnostic procedures not involving ionizing radiation, moderate exercise, and behavioral studies that are not manipulative or designed to cause stress all are minimal risk activities that qualify for expedited review. Minimal risk is a necessary, but not sufficient, condition for expedited review. In protocols that involve no risk at all to subjects and do not affect in any way the medical care that subjects receive, informed consent may be waived after expedited review. Any protocol that maintains the identity of the patient as part of the experimental data, however, will likely require informed consent of the subjects.

Mechanisms for ensuring confidentiality with regard to tissue and body fluid testing have been given more scrutiny since molecular methods for genetic testing have been developed. A genetic predisposition to an incurable disease can have profound impacts on an individual’s employability, insurability, and well-being. Many research studies include collection and storage of tissue for future testing, anticipating the development of techniques to identify clinically relevant genetic markers. Although tissue banking appears to be a prudent investigational measure, it produces an ethical dilemma: If the identity of the donor is maintained in order to obtain follow-up clinical data, the Institutional Review Board cannot adequately assess the risk to subjects from information that may be learned from unspecified future tests, and therefore cannot balance risks and benefits of the study. If, on the other hand, the researcher obtains extensive clinical and demographic information about the subject at the time the specimen is collected, so that follow-up is not necessary and the specimen can therefore be randomly coded, the information alone may be sufficient to link the individual to the specimen. Studies involving tissue banks and genetic testing ordinarily require special language in the informed consent document detailing the potential but uncertain risks associated with genetic information that may be revealed at a later date.

Privacy of health information has been addressed legislatively in the Health Insurance Portability and Accountability Act of 1996 (HIPPA), which was enacted to establish standards for the interchange of medical information between insurers and health care providers. The final rule was published in August 2000 [7]. Although HIPPA is primarily concerned with electronic transmission of health information between insurers and providers, its provisions apply to any identifiable health information that is stored or transmitted electronically. HIPPA allows use and disclosure of protected health information without individual authorization for several activities, including research, provided that certain individual rights are observed. These rights include written notification of information practices from health plans and providers, the right to inspect and obtain a copy of disclosed information and amend or correct information that is inaccurate or incomplete, and the right to receive an accounting of any instances where protected health information has been disclosed for purposes other than treatment, payment, or health care operations.

The use of human tissues to develop reagents or cell lines that may eventually lead to commercial products or applications is also addressed in the regulations. The informed consent document cannot include language that constitutes a waiver of any rights on the part of the research subject. It is acceptable to state that there are no plans to compensate or provide royalties to research subjects, but potential subjects cannot be asked to waive any claim on future profits resulting from the use of their tissue for commercial purposes, even though the courts have consistently denied the validity of such claims.

The broad areas covered by hospital consent forms for treatment or surgeries do not obviate the need to obtain consent for research. The specific elements required in an informed consent to participate in research are not uniformly part of medical "consent to treat" forms. Other information contained in a typical consent for medical treatment, such as billing information, a living will, designation of a responsible party, etc, may obscure the vital information related to the research protocol and thereby interfere with the patient’s ability to make an informed and independent decision whether to participate. It is possible that the patient will interpret consent to participate in research as a requirement for medical care, which is strictly forbidden by the regulations and on ethical grounds.

As of 1 October 2000, institutions are required to document that all investigators, as well as any research support staff, conducting federally-funded research involving humans are familiar with the regulations that apply to their research activities. The resources available for investigator education vary from one institution to another. The National Institutes of Health offers a web-based tutorial that covers the basic aspects of human research subject protections.

	Summary

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 
Use of pathological or diagnostic specimens for research is, under many circumstances, exempt from regulations that apply to human research subjects, but certain qualifications must be met. Investigations that involve pre-existing data or specimens are usually exempt, unless specific identifying information that may be traced to an individual patient is recorded. Prospective collection of data on pathological or diagnostic specimens ordinarily requires Institutional Review Board review, but may qualify for expedited review and a waiver of informed consent if the risk to donors is minimal or non-existent. There may be unforeseen risks associated with genetic testing of human tissue, and research studies that can potentially link results of such tests with individual donors warrant finer inspection of the disclosed risks to potential subjects.

	Internet Resources

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 
Most documents and regulatory material relevant to human research subjects protection are available on the Internet. The following are useful resources:

The Nuremberg Code: http://www.ushmm.org/research/doctors/Nuremberg_Code.htm.

The Declaration of Helsinki: http://www.wma.net/e/policy/17-c_e.html.

45 CFR 46: http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm.

21 CFR 50: http://www.fda.gov/oc/oha/IRB/toc10.html#AppendixB.

21 CFR 56: http://www.fda.gov/oc/oha/IRB/toc10.html#AppendixC.

Office of Human Research Protections: http://ohrp.osophs.dhhs.gov.

National Institutes of Health tutorial on human research: http://ohsr.od.nih.gov/cbt/cbt_index.html.

National Bioethics Advisory Commission: http://bioethics.gov.

Health Insurance Portability and Accountability Act of 1996: http://aspe.os.dhhs.gov/admnsimp.

	References

Top Abstract Introduction History of Human Research... Federal Regulations Summary Internet Resources References

 

1. US Government Printing Office. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Nuremberg, October 1946 - April 1949. US Government Printing Office, Washington, DC, 1949–1953.
2. World Medical Association. Human experimentation: Code of ethics of the World Medical Association, Declaration of Helsinki. Brit Med J 1964;2:177.
3. Rothman KJ, Michels KB, Baum M. Declaration of Helsinki should be strengthened. Br Med J 2000; 321:442–445.[Free Full Text]
4. Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. U.S. Government Printing Office, Washington, DC, (DHEW Publication OS 78-0012), 1978; pp 1–120
5. Federal Register: June 18, 1991; vol 56, no 117, pp 28003–28032.
6. Federal Register: October 5, 1995; vol 60, no 193, pp 52063–52065.
7. Federal Register: August 17, 2000; vol 65, no 160, pp 50312–50372.

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