IRB CONSIDERATIONS

It may be useful to think of genetic research as being carried out on a continuum comprising four stages: (1) pedigree studies (to discover the pattern of inheritance of a disease and to catalog the range of symptoms involved); (2) positional cloning studies (to localize and identify specific genes); (3) DNA diagnostic studies (to develop techniques for determining the presence of specific DNA mutations); and (4) gene therapy research (to develop treatments for genetic disease at the DNA level).

Unlike the risks presented by many biomedical research protocols considered by IRBs, the primary risks involved in the first three types of genetic research are risks of social and psychological harm, rather than risks of physical injury. Genetic studies that generate information about subjects' personal health risks can provoke anxiety and confusion, damage familial relationships, and compromise the subjects' insurability and employment opportunities. For many genetic research protocols, these psychosocial risks can be significant enough to warrant careful IRB review and discussion. The fact that genetic studies are often limited to the collection of family history information and blood drawing should not, therefore, automatically classify them as "minimal risk" studies qualifying for expedited IRB review.

Pedigree Studies

When investigators attempt to document and study the natural history of an inherited disease, condition, or characteristic, they do so by identifying individual members of families presenting the disease, condition, or characteristic and obtaining information about them and the other members of their family. The result is a pedigree analysis, which, in addition to tracing the natural history of a disease and documenting the range of symptoms involved, may also reveal information about family members that individual members may not have known about previously (e.g., the existence of previously unknown relatives or the presence of stigmatizing diseases, such as mental illness). It may also reveal information about the likelihood that individual members of the family either are carriers of genetic defects or will be affected by the disease.

Subject Recruitment and Retention. The familial nature of the research cohorts involved in pedigree studies can pose challenges for ensuring that recruitment procedures are free of elements that unduly influence decisions to participate. The very nature of the research exerts pressure on family members to take part, because the more complete the pedigree, the more reliable the resulting information will be. For example, revealing who else in the family has agreed to participate may act as an undue influence on an individual's decision, as may recruiting individuals in the presence of other family members. (Both would also constitute a breach of confidentiality. The problem of confidentiality will be dealt with later in this Section.)

Recruitment plans, some of which are described here, can attempt to address these problems; each approach has its own strengths and weaknesses. One strategy is to use the proband as the point of contact for recruiting. This approach insulates families from pressure by the investigator, but presents the risk that the proband may be personally interested in the research findings and exert undue pressure on relatives to enroll in the study. Furthermore, the proband may not want to act as a recruiter for fear that other family members will then know that he or she is affected by the disease. Another approach is direct recruitment by the investigator through letters or telephone calls to individuals whose identity is supplied by the proband. Direct recruitment by the investigator may, however, be seen as an invasion of privacy by family members. (Similar issues arise in epidemiologic research. See Guidebook Chapter 4, Section E.) A third approach is to recruit participants through support groups or lay organizations. Adopting this strategy requires investigator and IRB confidence that these organizations will be as scrupulous in their own efforts to protect subjects as the investigator would be. A fourth possibility is to contact individuals through their personal physicians. Prospective subjects contacted by their physician may, however, feel that their health care will be compromised if they do not agree to participate. In the end, the IRB must ensure that the recruitment plan minimizes the possibility of coercion or undue influence [Federal Policy §___.116].

In contrast to inappropriate pressure placed on prospective participants to join the study is the possibility that a subject may agree to participate out of a misguided effort to obtain therapy. The purposes of the research and how subjects will or will not benefit by participation must be clearly explained. (See discussion below on informed consent).

Investigators and IRBs need to consider each of these concerns in arriving at a recruitment strategy that protects these various interests.

Defining Risks and Benefits. Potential risks and benefits should be discussed thoroughly with prospective subjects. In genetic research, the primary risks, outside of gene therapy, are psychological and social (referred to generally as "psychosocial") rather than physical. IRBs should review genetic research with such risks in mind.

Psychological risk includes the risk of harm from learning genetic information about oneself (e.g., that one is affected by a genetic disorder that has not yet manifested itself). Complicating the communication of genetic information is that often the information is limited to probabilities. Furthermore, the development of genetic data carries with it a margin of error; some information communicated to subjects will, in the end, prove to be wrong. In either event, participants are subjected to the stress of receiving such information. For example, researchers involved in developing presymptomatic tests for Huntington Disease (HD) have been concerned that the emotional impact of learning the results may lead some subjects to attempt suicide. They have therefore asked whether prospective participants should be screened for emotional stability prior to acceptance into a research protocol.

Note that these same disclosures of information can also be beneficial. One of the primary benefits of participation in genetic research is that the receipt of genetic information, however imperfect, can reduce uncertainty about whether participants will likely develop a disease that runs in their family (and possibly whether they have passed the gene along to their children). Where subjects learn that they will likely develop or pass along the disease, they might better plan for the future.

To minimize the psychological harms presented by pedigree research, IRBs should make sure that investigators will provide for adequate counseling to subjects on the meaning of the genetic information they receive. Genetic counseling is not a simple matter and must be done by persons qualified and experienced in communicating the meaning of genetic information to persons participating in genetic research or persons who seek genetic testing.

Social risks include stigmatization, discrimination, labelling, and potential loss of or difficulty in obtaining employment or insurance. Changes in familial relationships are also social ramifications of genetic research. For example, an employer who knew that an employee had an 80 percent chance of developing HD in her 40s might deny her promotion opportunities on the calculation that their investment in training would be better spent on someone without this known likelihood. Of course, the company may be acting irrationally (the other candidate might be hit by a car the next day, or have some totally unknown predisposition to debilitating disease), but the risk for our subject of developing HD is real, nonetheless. One problem with allowing third-parties access to genetic information is the likelihood that information, poorly understood, will be misused. Likewise, an insurer with access to genetic information may be likely to deny coverage to applicants when risk of disease is in an unfavorable balance. Insuring against uncertain risks is what insurance companies do; when the likelihood of disease becomes more certain, they may refuse to accept the applicant's "bet."

Debate about the social policy implications of genetic information is vitally important and is occurring on a national and international level, but is not literally a concern for IRBs. The IRB's concern is, first, to ensure that these risks will be disclosed to subjects, and, second, to protect subjects against unwarranted disclosures of information.

See also Guidebook Chapter 3, Section A, "Risk/Benefit Analysis," and Chapter 3, Section B, "Informed Consent," for further discussion of these issues.

Privacy and Confidentiality Protections. Special privacy and confidentiality concerns arise in genetic family studies because of the special relationship between the participants. IRBs should keep in mind that within families, each person is an individual who deserves to have information about him- or herself kept confidential. Family members are not entitled to each other's diagnoses. Before revealing medical or personal information about individuals to other family members, investigators must obtain the consent of the individual.

Another problem that arises in genetic family studies that is also common in other areas of research involving interviews with subjects is the provision by a subject of information about another person. In pedigree studies, for example, the proband or other family member is usually asked to provide information about other members of the family. The ethical question presented by this practice is whether that information can become part of the study without the consent of the person about whom the data pertains. While no consensus on this issue has yet been reached, IRBs may consider collection of data in this manner acceptable, depending on the nature of the risks and sensitivities involved. It may be helpful, for example, to draw a distinction between information about others provided by a subject that is also available to the investigator through public sources (e.g., family names and addresses) and other personal information that is not available through public sources (e.g., information about medical conditions or adoptions).

IRBs should require investigators to establish ahead of time what information will be revealed to whom and under what circumstances, and to communicate these conditions to subjects in clear language. For example, if the pedigree is revealed to the study participants, family members will learn not only about themselves but about each other. The possibility that family members who did not participate might also learn of the pedigree data should not be overlooked. Subjects should know and agree ahead of time to what they might learn (and what they will not learn), both about themselves and others, and what others might learn about them. One approach would be never to reveal the pedigree to participating subjects. Many investigators record their pedigrees using code numbers rather than names. IRBs should note, however, that when a study involves a rare disease or a "known" family, the substitution of numbers for names does not eliminate the problem.

Even where the protocol calls for providing certain information to subjects, participants in genetic studies should be given the option of not receiving genetic information about themselves or others that they do not wish to receive. In genetic research, the potential for psychosocial harm accruing to persons who express a desire not to receive information gained through the study and the uncertainties surrounding the disease-predictive value of the early phases of contemporary genetic research is felt to outweigh benefits of required disclosure. (A possible exception involving circumstances where early treatment of genetically-linked disease improves prognoses is discussed in the section on identifying and deciphering genes, below.)

Data must be stored in such a manner that does not directly identify individuals. In general, except where directly authorized by individual subjects, data may not be released to anyone other than the subject. An exception to requiring explicit authorization for the release of data may be secondary research use of the data, where the data are not especially sensitive and where confidentiality can be assured. IRBs should exercise their discretion in reviewing protocols that call for the secondary use of genetic data. Furthermore, when reviewing a consent documents, IRBs should note agreements made by investigators not to release information without the express consent of subjects. Subsequent requests for access to the data are subject to agreements made in the consent process. For studies involving socially sensitive traits or conditions, investigators might also consider requesting a certificate of confidentiality. [See Guidebook Chapter 3, Section D, "Privacy and Confidentiality."]

Informed Consent. The information presented to subjects in the informed consent process should be as specific as possible. Subjects should be told both the known risks, as well as the uncertainty surrounding the risks of participation. Among the uncertainties is the likelihood that useful information will result from the study (it may not). Prospective participants often come into genetic studies with unrealistic expectations of how they will benefit from the study, and without an appreciation of low-probability risks that are not well-understood by anyone. To the extent possible, unrealistic expectations should be dispelled in the informed consent process.

The provision of relevant information should take place as a thoughtful discussion with prospective subjects. Through this process, subjects should be informed:

• about the kind of information they will be provided (e.g., that they will receive only information the investigator feels is significant and reliable, or that no genetic information will be provided) and at what point in the study they will receive that information;
• that they may find out things about themselves or their family that they did not really want to know, or that they may be uncomfortable knowing;
• that information about themselves may be learned by others in their family;
• whether information they learn or information generated about them during the study may compromise their insurability;
• that actions they may take as a result of their participation may expose them to risks (e.g., submitting insurance claim forms for reimbursement for costs of genetic counseling or procedures whose costs are not covered by the protocol);
• about what assurances can be given to protect confidentiality and what lack of assurance can be given;
• about the rights they retain and the rights they must give up regarding control over what can be done with tissue they donate (e.g., blood samples);
• what the consequences of withdrawal from the study will be; and
• of any costs associated with participation (including, for example, the cost of genetic and/or psychological counseling, if those costs will not be covered by the investigator or the institution).

Information should be given to subjects in clear language, suitable to their age, cultural background, and physical and mental capabilities. Accommodations should be made for persons with learning disabilities (as distinguished from persons who suffer diminished mental capacity). The consent process should take place in the subject's native language, through an interpreter, if necessary; consent documents should be translated into the subject's native language. The IRB should satisfy itself that great care will be taken by the investigator to ensure that prospective subjects fully understand the risks and benefits involved in participation.

Disposition of DNA Samples. When tissue samples are to be collected for later DNA analysis, numerous issues must be addressed by investigators and IRBs. Primary among them are through what mechanism samples should be collected, who can have access to the samples and for what purposes, who owns the DNA, and how incorrect genetic information (due, for example, to faulty laboratory analysis) can be corrected. The American Society of Human Genetics' Ad Hoc Committee on DNA Technology has published a set of Points to Consider on DNA banking and DNA analysis (1987), with which IRBs may wish to acquaint themselves. While not all of the Society's recommendations may be directly applicable to the IRB's concerns, it is worth noting the importance the Society places on appropriate counseling and limited access to familial genotypes.

The genetic information (and tissue samples, where applicable) collected under a research protocol are of continuing importance to the families involved in the research. An important question for IRBs to consider is what will happen to the data (and samples) when funding for the research ends. Particular attention should be paid to protecting the confidentiality of the data and obtaining consent from the participants for any use of the data (and samples) that is not strictly within the original uses to which the participants agreed.

Withdrawal from Participation. Attention should be paid to subjects' rights when they decide to withdraw from participation in the study. The federal regulations clearly require that subjects be free to withdraw from participation without penalty or loss of benefits to which they are otherwise entitled [Federal Policy §___.116(a)(8)]. What the regulations do not address, however, is how to treat data or tissue samples obtained from subjects who subsequently withdraw from the study. A similar question was addressed by the California Supreme Court in the Moore case [John Moore v. The Regents of the University of California (1990)]. While Moore constitutes binding legal authority only in California and has not, as of this writing, been adopted in other jurisdictions, the court's findings may be helpful for exploring possible approaches to handling the treatment of data and tissue samples when a subject withdraws from a genetic study.

In Moore, the California Supreme Court held that cell lines established from a donated sample are not the property of the person who donated the sample. Extrapolating to the broader context of genetic research generally, the underlying principle would be that withdrawal releases the subject from providing further information or tissue samples, and perhaps requires the removal of the subject's identity from all research records, but does not require the investigator to eliminate the resulting data from the study or to destroy the cell line.

In pedigree studies, for example, investigators may respond to a request to withdraw by removing all information about that person and his or her spouse and children from the pedigree, but it is not clear that removal of the information is required by the human subjects regulations or any other legal principle.

Secondary Use of Tissue Samples. Where a new study proposes to use samples collected for a previously conducted study, IRBs should consider whether the consent given for the earlier study also applies to the new study. Where the purposes of the new study diverge significantly from the purposes of the original protocol, and where the new study depends on the familial identifiability of the samples, new consent should be obtained.

Vulnerable Populations. IRBs should ensure that the investigator conduct the research with sensitivity to the specific mental and physical manifestations of the particular disorders being investigated. Depending on the disease, and, therefore, the likely presenting population, investigators should be prepared to communicate effectively and with sensitivity with persons who have physical limitations (e.g., deafness or blindness), learning disabilities, cognitive impairments, or any other life circumstance that may affect their participation (e.g., severe pain).

The nature of genetic research raises some special concerns when the research will involve children, physically or cognitively impaired persons, older persons, or any subject population likely to have special needs. Not only must the IRB ensure that their participation is fully voluntary and informed, IRBs must also be sure to evaluate the risks and benefits of the research as they apply to these special populations. The risk of participation for an adult differs from that of children; persons who suffer from diminished mental capacities may be subject to different risks than persons who do not. If children will be involved in the research, IRBs should seriously consider consulting with experts in child development and others knowledgeable about risks to children and families. Similarly, if physically or cognitively impaired persons will be involved in the research, IRBs should consider consulting with experts who can advise them on the special concerns their participation raises. Where applicable, 45 CFR 46 Subparts B, C, and D (pertaining to women, fetuses, prisoners, and children) must be followed. [See also Guidebook Chapter 6, Section C, "Children and Minors," Section D, "Cognitively Impaired Persons," Section G, "Terminally Ill Patients," Section H, "Elderly/Aged Persons," and Section I, "Minorities."]

The involvement of children in genetic research raises many concerns, including pressure brought by family members on the child to participate and the potential for harm that may result from disclosure of genetic or incidental information. Even seemingly harmless research may actually present serious risks of harm to children. For example, interviewing children for genetic research on psychological disorders, such as schizophrenia or depression, or on alcoholism may inadvertently convey information about family members (the child may well wonder why he or she is being asked about alcoholism in the family) or cause self-doubt or stigmatization on the part of the child. Furthermore, disclosures of data to third-parties may result in children being labelled or stigmatized as, for example, potential alcohol abusers. IRBs must look carefully at both the questions that will be asked of children and the information that will be directly conveyed to them to determine whether the research involves more than minimal risk. The advisability of including children in studies of untreatable, fatal disorders such as HD has been strongly questioned [MacKay (1984), p. 3].

IRBs should also consider the mental capacities of participants in genetic research. In some diseases, such as Alzheimer Disease, patients will suffer loss of mental capacity over a period of time. In addition, it is possible that a family member might be comatose or legally incompetent for reasons unrelated to the disease under study. Special attention should be paid to methods of ensuring voluntary consent by the subject or the subject's legally authorized representative [Federal Policy §§___.102(c), ___.116]. Under the regulations, a "legally authorized representative" is defined as "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" [Federal Policy §___.102(c)]. IRBs should pay particular attention to state and local laws relating to persons authorized to give permission for participation in research on behalf of prospective subjects, noting that such "proxy" consent to participation in research that does not involve a direct medical benefit may differ from consent to receive medical treatment. Where possible, the subject's assent should be sought; his or her dissent should be honored. [See also Guidebook Chapter 6, Section D, "Cognitively Impaired."]

In appropriate circumstances the IRB might consider granting waivers of consent or alteration of the consent process. [See MacKay (1984), pp. 3-4, and Levine (1986).] The federal regulations allow for waivers or alterations in the consent process where the IRB finds that: (1) the research involves no more than minimal risk; (2) the waiver or alteration will not adversely affect the rights and welfare of the subject; (3) the research could not practicably be carried out without the waiver or alteration; and (4) whenever appropriate, the subjects will be provided with additional pertinent information after participation [Federal Policy §___.116(d)]. Again, IRBs should carefully consider whether the research qualifies as "minimal risk."

Publication Practices. One final issue involving consent is the publication of research data. The publication of pedigrees can easily result in the identification of study participants. Where a risk of identification exists, participants must consent, in writing, to the release of personal information. Various authors have noted the problem of obtaining consent for the publication of identifying data, and have recommended that consent to the publication be obtained immediately prior to the publication, rather than as part of the consent to treatment or participation in research. [See, e.g., Rost and Cohen (1976) and Murray and Pagon (1984).] It is worth noting, however, that to address this concern, IRBs must also resolve the following questions: Who determines the risk of identification, and on what grounds? Who are defined as participants (is it everyone listed in the pedigree, some of whom have been contacted by investigators, some of whom have had information about them provided by a family member)?

While IRBs must be careful to avoid inappropriate restrictions on investigators' research publications, some evaluation of publication plans is important as part of the IRB's overall interest in preserving the confidentiality of research subjects. One approach for investigators to use in evaluating their publication plans might be to work in a step-wise fashion: First, is publication of the pedigree essential? If publication of the pedigree or other identifying data (e.g., case histories, photographs, or radiographs) is essential, can some identifying data be omitted without changing the scientific message? (The practice of altering data — such as changing the birth order and gender — is controversial, and no clear professional consensus yet exists as to whether this is an appropriate practice.) Finally, if the pedigree must be published, and if identifying data cannot be omitted in an appropriate manner without changing the scientific message, subjects must give their permission for publication of data that may reveal their identity.

Another concern about publication is the potential for publicity of the research results, and the exposure of participants to such publicity. Consent by individuals to such publicity does not resolve the question. Because genetic research involves families, the agreement of one subject to participate in releases of information to the media (including interviews and the like) has significant implications for other members of the family, particularly where the research is of a sensitive nature. IRBs should ensure that the investigator has addressed this possibility.

Expedited Review and Exemption from Review. The expedited review process is available for minimal risk research where the research activity is limited to one of a specified category (as published in the Federal Register), including the provision of blood samples [Federal Policy §___.110; Federal Register 46 (January 26, 1981): 8392]. In genetic studies that involve a blood draw, the additional psychosocial risks are likely to raise the risk beyond the "minimal risk" level allowable for expedited review. When an expedited review is requested, IRBs should review the question of minimal risk carefully.

With respect to exemption from review, the development of a pedigree through interviews with family members is likely to create identifying information, even where individuals will not be identified. Such research would not, therefore, qualify for exemption from review under the federal regulations [Federal Policy §___.101(b)(2)].

Identifying and Deciphering Genes

Research focusing on identifying the specific genetic component of a particular disease, condition, or characteristic relies upon DNA analysis of tissue samples taken from the members of families in which the condition appears. Many issues raised by pedigree analysis are relevant to this stage of research as well: pressure or coercion in recruiting subjects; informing prospective subjects of the possible harms; minimizing psychological harm through counseling and education; protection of confidentiality (which is particularly problematic when family members constitute the subject population); control over the use of DNA tissue samples; and protecting particularly vulnerable persons, all of which were discussed in the previous section. Additional issues include: determining when the data constitute "information;" additional risks presented by this stage of research (e.g., the possibility of incidental findings); and possible conflicts between subjects' rights and investigators' duties with respect to revealing the results of the study to subjects [i.e., telling subjects whether they (or their relatives) carry the defect, and the meaning of their status with respect to the likelihood of suffering from the disease or passing it along to their children].

Access to Data: Interim Findings. An issue that must be resolved prior to beginning any genetic study is who will have access to the data and the stage in the research at which they will have access. The issue of information transfer is vitally important in all genetic research, but particularly in the first three stages of investigation. A crucial question investigators and IRBs must address is whether (and which) interim findings will be communicated to subjects.

Experts disagree about whether interim or inconclusive findings should be communicated to subjects, although most agree that they should not (that only confirmed, reliable findings constitute "information"). Persons who oppose revealing interim findings argue that the harms that could result from revealing preliminary data whose interpretation changes when more precise or reliable data become available are serious, including anxiety or irrational — and possibly harmful — medical interventions. They argue that such harms are avoidable by controlling the flow of information to subjects and limiting communications to those that constitute reliable information. MacKay (1984), writing about the development of genetic tests, argues against revealing interim findings, contending that preliminary results do not yet constitute "information" since "until an initial finding is confirmed, there is no reliable information" to communicate to subjects, and that "even...confirmed findings may have some unforseen limitations" [p. 3]. He argues that subjects should not be given information about their individual test results until the findings have been confirmed through the "development of a reliable, accurate, safe and valid presymptomatic test" [pp. 2-3; see also Fost and Farrell (1990)]. Others have argued that all interim results should be shared with subjects, based on the principle of autonomy — that subjects have a right to know what has been learned about them.

These arguments are equally relevant at any of the first three stages of genetic research. IRBs should consider these arguments, weighing the possible harms and benefits. Investigators should determine, prior to initiation of the study, the point at which the data will be considered solid enough to be constitute information that should be provided to subjects. Investigators should further consider coding the data and separating the research records from individuals' medical records, so that neither the investigators nor the subjects may gain access to them [MacKay (1984), p. 3].

Reilly (1980) suggests that IRBs develop general policies governing the disclosure of information to subjects, to help make these determinations. He suggests that at least the following three factors be considered: "(1) the magnitude of the threat posed to the subject, (2) the accuracy with which the data predict that the threat will be realized, and (3) the possibility that action can be taken to avoid or ameliorate the potential injury" [p. 5]. IRBs should ask investigators to define three categories of disclosure: (1) "findings that are of such potential importance to the subject that they must be disclosed immediately;" (2) "data that are of importance to subjects..., but about which [the investigator] should exercise judgment about the decision to disclose....[i]n effect, these are data that trigger a duty to consider the question of disclosure;" and (3) "data that do not require special disclosure" [pp. 5, 12].

IRBs should consider whether the investigator's approach appropriately balances the risks and benefits involved in providing access to the data. Subjects should be told, as part of the consent process, whether, when, and what information they will receive. Any disclosures of genetic information should be accompanied by appropriate counseling by trained genetic counselors. However the IRB resolves this question, investigators should explain to prospective subjects the basis according to which they will decide which data will be disclosed to whom, and when those disclosures will be made.

Access to Data: The Subjects' "Right Not to Know." Subjects generally retain the right not to receive information about the results of a study that reveals their genetic status. A possible exception involves circumstances where early treatment of genetically-linked disease could improve the subject's prognosis. In such circumstances, investigators may have a duty to inform the subject about the existence of the genetic defect and to advise him or her to seek medical advice. [See, e.g., Andrews (1991).] (As of this writing, a legal duty of investigators to inform subjects about the existence of genetic defects has not been firmly established.)

Furthermore, the existence of a genetic defect that is linked to disease may have important implications for family members; can or should the confidentiality of subjects' data be compromised to allow other family members to be warned? The President's Commission (1983), addressed this question with respect to information generated from genetic screening. The Commission's discussion may also be relevant to information obtained as the result of genetic research, at stages that precede genetic screening. The Commission concluded that:

[the] ethical duty of [providing confidentiality] can be overridden only if several conditions are satisfied: (1) reasonable efforts to elicit voluntary consent to disclosure have failed; (2) there is a high probability both that harm will occur if the information is withheld and that the disclosed information will actually be used to avert harm; (3) the harm that identifiable individuals would suffer would be serious; and (4) appropriate precautions are taken to ensure that only the genetic information needed for diagnosis and/or treatment of the disease in question is disclosed [p. 44].

The Commission further advised that, to the extent possible, persons undergoing genetic screening should be asked to consent in advance to the disclosure of genetic information to relatives in the event that such useful information is discovered [pp. 43-44]. Whether a legal duty exists to warn relatives of possible genetic defects has not yet been established. [See Robertson (1992), pp. 92-94.]

Access to Data: Incidental Findings. IRBs should also ensure that investigators adequately deal with how they will handle incidental findings; that is, what will be done with genetic information that is learned during the course of the study that does not directly relate to the research. For example, in intergenerational pedigree analyses, questions of paternity or parentage can come up. DNA analysis will reveal information indicating that an individual's biological parents are not who he or she thought they were; blood typing may reveal similar information. DNA analysis may also reveal information about diseases or conditions other than the disease or condition under study. Prospective subjects should be informed during the consent process that the discovery of such information is possible. Appropriate counseling should be provided to educate subjects about the meaning of the genetic information they have received, and to assist them in coping with any psychosocial effects of participation.

Access to Data: Secondary Use. Investigators should also address secondary use of research data (e.g., by other investigators, or by themselves for different research purposes). Where secondary uses can be foreseen, consent to the use should be sought. Express consent to access to data for secondary uses should be obtained for sensitive data and for circumstances under which confidentiality cannot be assured.

Research on Genetic Testing

Testing individuals to determine the presence of genetic defects falls into four basic categories:

• Testing newborns to detect serious genetic diseases. The screening of newborns is considered to be of value to the extent that infants can benefit from early intervention. In the case of phenylketonuria (PKU), for example, a genetic disease for which a test is available, a special diet can prevent most of the serious effects of the disease (which include brain damage).
  

• Testing for carrier status to identify individuals whose genetic makeup includes a gene or a chromosome abnormality that might have serious health implications for their children. Carrier testing is usually requested by adults who have some indication that they may be carriers of a genetically-linked disorder (e.g., because they are members of an ethnic group known to have a high incidence of the disorder, because a relative has a genetic disease, or because a spouse knows that he or she is a carrier). Testing will provide such persons information about the risks of being a carrier and of passing on either the disease or abnormal genes to their children. For recessive diseases, for example, a carrier will pass on the disease to their children only if the other biological parent is also a carrier of the same defective gene.
  

• Prenatal testing is aimed at detecting the presence of genetic or chromosomal abnormalities in fetuses. Examination of the genetic makeup of the fetus is done through amniocentesis, chorionic villi sampling, blood sampling from the umbilical cord and blood samples from the mother.
  

• Risk assessment testing (sometimes referred to as "presymptomatic testing") determines the probability that a person will develop a genetically-linked disease at some point in the future. The degree of certainty with which risk assessment tests can predict the likelihood of disease differs depending on the disease. For some diseases the actual gene has been located, making tests more accurate than for diseases for which only a marker has been found. Further, some markers are more closely linked to the gene than are others, thereby having a more predictive quality than others.
  

Protocols involving genetic testing raise somewhat different issues, depending on whether the tests are under development or are already established as reliable. IRBs are concerned with research aimed at developing genetic tests.

The ethical issues raised by the various kinds of genetic testing largely concern the concept of autonomy or self-determination. Before consenting to undergo genetic tests, whether new tests that are being developed, or already-established genetic tests, subjects should fully understand what it is they are going to learn about themselves, what they are not going to learn about themselves, and how reliable the information will be. Subjects must have information on which to base their decisions whether or not to go ahead with the testing. When the research involves the development of a genetic test, however, the uncertainties involved make the consent process problematic: How does one adequately alert subjects to the psychosocial risks of testing when the point of the study is to try to help define those risks? Research on pre-test education in effect experiments with the informed consent process. Can subjects consent to research knowing that one of the risks is that they may not be adequately informed about what they are agreeing to? The federal regulations allow IRBs to approve consent procedures that do not include or that alter some or all of the elements of informed consent; one of the requirements is that the research must involve no more than minimal risk [Federal Policy §___.116(d)]. Research that involves deliberate withholding of information or deception is reviewed pursuant to those provisions. Even where it is permitted, purposeful nondisclosure of pertinent information is allowed only to the extent necessary to conduct the study (e.g., when disclosure of the information would affect the outcome of the study). Furthermore, subjects must consent to the nondisclosure; that is, they must be told that there is some relevant information about the study that they will not be told prior to consenting to participate. [See Levine (1986, p. 117) and discussion in Guidebook Chapter 3, Section B, "Informed Consent."] In genetic testing research, however, the nondisclosure is not purposeful; rather, the nature and extent of the psychosocial risks involved is simply unknown. IRBs must look carefully at such studies to ensure that subjects are adequately protected. Investigators should provide the IRB their assessment of unknown risks. Subjects should be informed, in clear, understandable language, of the possibility of undisclosed risks, including any information the investigator has about their possible nature and extent.

Research results should be communicated to the subject by someone who possesses the appropriate medical and counseling expertise with which to explain the meaning of the test results. That person should ensure that the subject comprehends the information that has been provided to him or her, regardless of the time that may be involved. Furthermore, it may be appropriate to provide counseling not just for the subjects themselves, but also for their families. Consent to involve family members, should the need arise, should be sought as part of the consent to be tested.

Smurl and Weaver (1987) have developed a set of proposed ethical guidelines for the clinical testing of risk assessment tests for HD. IRBs reviewing investigations of risk assessment genetic tests should find their recommendations helpful. Many of their recommendations follow the arguments set forth in the discussions in the Guidebook on pedigree analysis and identifying and deciphering genes.

The misuse of genetic information due to misunderstanding its meaning is a risk faced by all participants in genetic research. Investigators can minimize this risk by working to educate not only subjects, but also the medical profession and the public about genetic testing. The term "diagnostic" is often used, but the term does not really apply. Genetic tests identify risks rather than "diagnose" the presence of disease. Discrimination in employment or in obtaining insurance are two areas that are of major concern, particularly where the genetic trait is one that is thought to indicate a predisposition to diseases or conditions caused by exposure to environmental agents. Significant damage has been done by, for example, misperceptions about what it means to be a carrier of sickle cell trait. Persons who carry the sickle cell trait have been denied jobs or have been otherwise discriminated against. Education, together with protecting subjects against disclosure of genetic information, can help minimize the risk of discrimination.

Gene Therapy Research

Gene therapy attempts to treat genetic disease by altering an individual's cells. Gene therapy can involve treatment of either somatic (nonreproductive) cells or germline (reproductive) cells. Genetic changes made to somatic cells affect only the individual who has received treatment; genetic changes made to germline cells may be passed on to the patient's descendants. A distinction must be made between gene therapy designed to treat or eliminate disease or serious medical, psychological, or behavioral conditions (e.g., cystic fibrosis), and the "improvement" of human characteristics (e.g., height).

Gene therapy techniques involving somatic cells are aimed at curing genetic disease in individuals by inserting properly functioning genes into the individual's somatic cells [Walters (1989), pp. 220-221]. The approach for making genetic changes to germ line cells is to add new DNA to early embryos in an attempt to change the genes not only in the individual, but also the genes passed on to his or her progeny. Walters (1989) has described the process as follows:

In studies involving mice, for example, genes have been added to one-cell mouse embryos after the sperm had penetrated the egg but before the genetic material from the sperm and egg are joined within the same nucleus. If the experiment is successful, these added genes are then adopted by the embryo. As the embryo grows and the number of embryonic cells increases, the added genes become part of every new embryonic cell. Later, when the sperm or egg cells of the mouse develop, the added genes are included in approximately half of these reproductive cells. Thus, when the mouse reproduces, some of its progeny receive the added genes, and so on through the generations [p. 221].

After being reviewed and approved by the IRB and the local institutional biosafety committee, gene therapy protocols for research conducted at or sponsored by an institution that receives any support for recombinant DNA research from NIH must be reviewed by the Recombinant DNA Advisory Committee (RAC) at NIH. At present, the RAC will consider human somatic cell gene therapy protocols, but not germline cell gene therapy protocols. The process of review is as follows: The Human Gene Therapy Subcommittee conducts a public review of the protocol, then submits its recommendation to the RAC; if the RAC approves the protocol, it is forwarded to the director of NIH for final approval.

The RAC, through a Points to Consider Subcommittee, has established "Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA into Human Subjects." Among the ethical concerns that investigators must address are subject selection, informed consent, and privacy and confidentiality. Investigators must also justify the use of recombinant DNA techniques against alternative methodologies and delineate the risks and benefits of the research. A summary of the Points to Consider follows; IRBs would be well-served to follow a similar line of inquiry when reviewing protocols that involve the transfer of recombinant DNA into human subjects.

The RAC Points to Consider. The following points should be addressed by all protocols involving somatic cell gene therapy:

A. The proposed research should be fully described.

1. Where recombinant DNA will be used for therapeutic purposes:

a. Why is the disease a good candidate for gene therapy?

b. After reviewing the natural history and range of expression of the disease (including the available objective and/or quantifiable measures of disease activity), are the usual effects of the disease predictable enough to allow for meaningful assessment of gene therapy?

c. What is the therapeutic goal of the research: to prevent all manifestations of the disease, to halt the progression of the disease after symptoms have begun to appear, or to reverse manifestations of the disease in seriously ill persons?

d. What alternative therapies exist? In what groups of patients are these therapies effective? What are their relative advantages and disadvantages as compared with the proposed gene therapy?

2. When recombinant DNA will be transferred for nontherapeutic purposes:

a. Into what cells will the recombinant DNA be transferred? Why is the transfer of recombinant DNA necessary for the proposed research? What questions can be answered by using recombinant DNA?

b. What alternative methodologies exist? What are their relative advantages and disadvantages as compared to the use of recombinant DNA?

B. The research design and anticipated risks and benefits should be described.

1. A full description of the methods and reagents to be employed for gene delivery and the rationale for their use should be provided to the IRB (a list of specific points to be addressed is provided in the Points to Consider).

2. Previous pre-clinical studies, including risk-assessment studies, that support the investigator claims about safety and effectiveness should be described. The investigator should explain why the model chosen is the most appropriate (a list of specific issues to be addressed is provided in the Points to Consider).

3. The treatment to be administered to patients and the diagnostic methods that will be used to monitor the success or failure of the treatment should be described, including any relevant previous clinical studies using similar methods that have been performed (specific issues to be addressed are provided in the Points to Consider).

4. Any potential benefits and hazards to persons other than the patients should be described.

5. The qualifications of the investigator(s) and the adequacy of the clinical facilities should be given.

C. Methods for patient selection should be described, including the numbers of patients, the recruitment procedures that will be used, the eligibility criteria that will be used (both exclusion and inclusion criteria), and how the investigator will select among eligible patients if it is not possible to include all who desire to participate.

D. Methods for obtaining informed consent should be described. Where the study involves pediatric or mentally handicapped patients, investigators should describe the procedures for seeking the permission of parents or guardians, and, where applicable, the assent of each patient (in keeping with the requirements of 45 CFR 46). In particular, investigators should address:

1. How the major points covered in A-C will be disclosed to potential participants in understandable language;

2. How the innovative character and the possible (including theoretically possible) adverse effects of the experiments will be discussed with patients; how the potential adverse effects will be compared with the consequences of the disease; and what will be said to convey that some of these adverse effects, if they occur, could be irreversible;

3. How the financial costs to the subject of the experiment and any available alternatives will be explained to the patients;

4. How patients will be informed that they may be subjected to media attention as a result of participating; and

5. How patients will be informed about the irreversible consequences of some of the procedures; about any adverse medical consequences that might occur if they withdraw from the study once it has begun; and about any preconditions to participation, such as their willingness to cooperate in long-term follow-up and autopsy in the event of a patient's death following gene transfer.

E. Measures that will be taken to protect the privacy of patients and their families and for maintaining the confidentiality of research data should be described.

IRB Considerations. The potential risks associated with gene therapy may weigh against the involvement of human subjects in gene therapy trials. As Walters (1989) has described it:

There are clearly some risks and some unknowns associated with even this simplest type of gene therapy [somatic cell gene therapy]. For example, it is not presently possible to control where the retroviral vectors will "touch down" when they reach the nuclei of the patient's...cells. In other words, currently-available vectors are unguided missiles. There is some concern among researchers that the vectors may disrupt properly-functioning genes and therefore kill some cells or, more seriously, that the vectors may activate some previously dormant cancer-causing genes. It is also possible that the domesticated retroviral vectors will recombine with other DNA or other viruses and so recapture their native capacity to produce more retroviruses and to infect large number of cells [p. 222].

IRBs need to consider the risks and benefits of gene therapy carefully, and, if a protocol is approved, ensure that subjects will be thoroughly informed of the risks and benefits involved in the procedure. It must be made clear to subjects that the investigation has both a therapeutic intent and the goal of acquiring scientific knowledge. Investigators should be careful not to raise unrealistically the hopes of the subjects and their families [Fletcher (1985) p. 298].

Protocols involving children are subject to the special provisions of 45 CFR 46 Subpart D. IRBs should pay particular attention to protecting children, including obtaining assent from child-participants, wherever possible. IRBs may want to consider using a consultant, an IRB member, or a "group consent auditor" to oversee the consent process, ensuring that the child's best interests have been carefully considered [Fletcher (1985), pp. 298-99]. Fletcher argues that IRBs should refrain from allowing the hopeless situation of subjects to overshadow the consideration of acceptable risk. He concludes that "even if the degree of risk does not approach the level of 'dangerous'...[d]esperation about [a] child's condition is not a sound premise for experimental gene therapy. Children in imminent danger of death should not be selected as subjects for the first trials" [p. 297]. [See also Guidebook Chapter 6, Section C, "Children and Minors."]

Special attention should also be paid to the possibility of mental impairment. [See Guidebook Chapter 6, Section D, "Cognitively Impaired."]

POINTS TO CONSIDER

1. Does the proposed study population comprise family members? Has the appropriateness of various strategies for recruiting subjects (e.g., recruiting by the proband or other family members, by the investigator, through support groups, or through prospective subjects' personal physicians) been considered? Does the proposed strategy for recruiting subjects sufficiently protect prospective subjects from the possibility of coercion or undue influence?

2. Does the investigator plan to use the proband or the proband's clinical medical records as a source of research data about other persons (e.g., other family members)? If so, must their consent be obtained before their data can be included, or is the permission of the person providing the information sufficient?

3. Has the investigator established clear guidelines for disclosure of information, including interim or inconclusive research results, to the subjects? Will subjects be informed, in clear language, about what information they are entitled to receive at what point in the research? Will subjects receive an explanation of the meaning of the information they receive?

4. Will family members be protected against disclosures of medical or other personal information about themselves to other family members? Will they be given the option not to receive information about themselves? Will limits on such protections be clearly communicated to subjects, including obtaining advance consent to such disclosures (e.g., when family members will be warned about health risks)?

5. Will the possible psychological and social risks of genetic research be adequately considered in the consent process? Will appropriate counseling be provided, both as part of the consent process and when communicating test or other research results to subjects?

6. Will subjects be informed about the possibility that incidental findings may be made (e.g., paternity, diseases, or conditions other than the one(s) under study)?

7. Will the data be protected from disclosure to third parties, such as employers and insurance companies? Will the data be stored in a secure manner? Will the data be coded so as to protect the identity of subjects? Is a request for a certificate of confidentiality appropriate?

8. Does the investigator plan to disclose research findings to subjects' physicians for clinical use? Are such plans appropriate? Will the possibility of such disclosures be discussed with and consented to by prospective subjects?

9. Will vulnerable populations (e.g., children, persons with impaired mental capacities) be adequately protected? Under what circumstances can a research subject serve to grant permission to involve a minor child or an incapacitated adult in a study?

10. Have adequate provisions been made for protecting against misuse of tissue samples (e.g., confidentiality, obtaining consent for any use not within the original purpose for which the samples were collected)? What agreements with subjects are necessary to use stored materials for new studies or for clinical diagnoses?

11. Have adequate provisions been made for the treatment of data and tissue samples in the event of subject withdrawal from the study?

12. Do the investigator's publication plans threaten the privacy or confidentiality of subjects? Has adequate consideration been given to ways in which subjects' privacy and confidentiality can be protected (e.g., providing for consent to publication of identifying information)?

13. Have the RAC's Points to Consider for gene therapy protocols been considered?

Some of the questions arising from the conduct of large pedigree studies were addressed at an NIH workshop jointly sponsored by the National Center for Human Genome Research (NCHGR) and the Office for Protection from Research Risks (OPRR) in October of 1992. For further information on the availability of the papers presented at the workshop (listed in "Suggestions for Further Reading," below), contact:

Dr Eric T. Juengst
National Center for Human Genome Research
National Institutes of Health
Building 38A, Room 617
Bethesda, MD 20892
Tel: (301) 402-0911

Dr. Joan P. Porter
Office for Protection from Research Risks
National Institutes of Health
Building 31, Room 5B63
Bethesda, MD 20892
Tel: (301) 496-7005

APPLICABLE LAWS AND REGULATIONS

Federal Policy for the protection of human subjects

Federal Policy §___.116 [Informed consent]

45 CFR 46 Subpart D [DHHS: Additional protections for children involved as subjects in research]

Federal, state, and local laws or regulations governing confidentiality of information

Federal, state, and local laws or regulations pertaining to insurance

There are currently no laws or regulations specifically governing the involvement of human subjects in genetic research, but the following guidelines may be useful:

U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. "Federal Guidelines for Recombinant DNA Molecule Research." 51 Federal Register (May 7, 1986): 16958.

U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. "Recombinant DNA Molecule Research, Proposed Actions under Guidelines; Notice." 50 Federal Register (August 19, 1985): 33462-33467.

U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. Recombinant DNA Advisory Committee. Points to Consider Subcommittee. "Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA into Human Subjects." Recombinant DNA Technical Bulletin 12 (No. 3, September 1989): 151-170.

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I. ALCOHOL AND DRUG RESEARCH

INTRODUCTION

Alcohol and drug research focuses on use, abuse, and dependence on abuse-liable substances, and may or may not involve the administration of an abusable substance. It may seek to investigate physiological responses to alcohol or drugs, or may be aimed at the treatment of alcohol or drug abuse. Treatment protocols may be behavioral or biomedical, including the administration of medications.

DEFINITIONS

Abuse-liable: Pharmacological substances that have the potential for creating abusive dependency. Abuse-liable substances can include both illicit drugs (e.g., heroin) and licit drugs (e.g., methamphetamines).

IRB CONSIDERATIONS

Research on alcohol or drug use raises special concerns for IRBs because the research often involves the administration of abuse-liable substances. Further, subjects' capacity to provide informed consent is often compromised. Institutionalization may also have an impact on the prospective subject's ability to choose freely to participate in research.

Other issues IRBs need to consider are the selection of subjects and confidentiality. With respect to confidentiality, federal, state, and local laws regarding criminal behavior must be considered, because legal requirements may impinge on the ability of the researcher to guarantee confidentiality. Finally, researchers may face ethical problems with the study design, such as the morality of giving alcohol to alcoholics, or the problems associated with studies that include placebo arms.

The National Advisory Council on Alcohol Abuse and Alcoholism (the Council) has issued guidelines entitled Recommended Council Guidelines on Ethyl Alcohol Administration in Human Experimentation (1989). Many of the recommendations apply equally well to studies involving abuse-liable drugs. The Council's recommendations contain a series of questions and answers about research involving alcohol administration to human subjects, and should be consulted by IRBs reviewing protocols involving alcohol- or drug-related research.

Risk/Benefit. A number of issues raised by alcohol and drug research focus on considerations of risk and benefit. Where alcohol or drugs will be administered to subjects, IRBs should consider, for example, whether the subjects are drug or alcohol abusers, and whether participation of the proposed populations is likely to expose the subjects to harm [see the Recommended Council Guidelines (1989), pp. 5-6]. Investigators must adequately assess the potential for toxicity, and make provisions for clinical care of subjects where it will likely be needed. Further, the need for access to medical backup services (i.e., the presence of a nurse or physician during conduct of the research, or the availability of a physician "on call") should be considered.

Other risks presented by some drug or alcohol research are those inherent in self-administration of abuse-liable substances. IRBs should consider such risks, including the possibility that subjects may self-administer an increasing amount of the drug to levels higher than those to which they are accustomed, and the possible harms that might result.

Where the study has a placebo arm, investigators need to consider the various effects the use of placebos might have and provide mechanisms for dealing with them so that subjects are adequately protected. For example, in a study in which subjects are told that the investigational agent blocks the effect of an abuse-liable drug, a subject, believing herself not to be in the placebo arm, might self-administer sufficiently large doses of the drug to fatally overdose. Investigators should be prepared to address this issue (e.g., through informed consent, monitoring, use of an in-patient subject population, or other means).

Adequate provisions must be made to eliminate the risk of drug or alcohol impairment before the subject leaves the research site.

The Council Guidelines describe investigators' obligations to facilitate the entry of alcoholics who are current, active drinkers into treatment programs [p. 6]. The Guidelines go on to point out that where potential subjects "have completed the initial phase of treatment and progressed into rehabilitation or recovery," their involvement in research in which alcohol will be administered requires "extremely strong scientific justification and risk/benefit assessment" [p. 6]. Further, Council policy holds that "it is considered inappropriate to administer alcohol to any recovering alcoholic who is abstinent and living a sober life in the community" [p. 6].

In addition to the risk/benefit questions discussed here, the Council Guidelines also consider such issues as the age of subjects, the involvement of alcohol-naïve subjects, deception or incomplete disclosure, medical and psychological evaluation of subjects prior to participation, and follow-up of subjects.

Incentives for Participation. IRBs should consider whether any remuneration offered to subjects for their participation is appropriate. Any remuneration (e.g., money, food, lodging, or medical care) should be commensurate with the burden of participation, and should not be such that it constitutes an undue inducement or is coercive.

The possible involvement of drug or alcohol abusers in drug and alcohol research has led some investigators not to offer any remuneration to their subjects for fear of unfairly inducing their participation. Many potential participants are unemployed or otherwise economically disadvantaged, so that concern over this issue is appropriate. Nonetheless, to assume that any remuneration given to alcohol and drug abusing constitutes an undue influence is also unfair. IRBs should consider this issue carefully.

Informed Consent. In drug and alcohol research, concerns about the consent process focus on determining the competence of subjects to consent to the research and effectively communicating the information necessary to obtain informed consent. With respect to competence, IRBs should ensure that competence is assessed rather than assumed. Because there are no generally accepted standards for determining competence to consent to research, the IRB plays an important role in assessing the researcher's proposed procedures. IRBs should take an active part in helping researchers formulate appropriate criteria and procedures, taking into consideration the degree of risk presented. The same or similar considerations as those discussed Guidebook Chapter 6, Section D, "Cognitively Impaired," would apply, noting, however, that the capacity to consent to research may fluctuate, depending on the subject's state of inebriation.

The Council recommendations on competency to consent state that:

due consideration should be given to the cognitive, physiologic and motivational states of the individuals in terms of their ability to fully understand the context of the informed consent. Individuals who are severely intoxicated or in a confusional withdrawal state are unable to give true informed consent. Alternatively, a blood alcohol concentration (BAC) of zero for the potential subject may not be a required prerequisite, depending upon cognitive capabilities of the individual at that time. If there is a question of a potential subject's ability to give meaningful informed consent, an independent clinician, ethical consultant, or uninvolved third party with appropriate qualifications may be asked to evaluate this ability [p. 4].

In drug research, the lack of physical measures for levels of drugs means that investigators must rely (as must alcohol researchers, in many instances) on clinical judgments based on other indications of mental competence (e.g., through evaluating the prospective subject's ability to converse or observing his or her motor skills).

The consent document must use language that is understandable to the subject population, including ethnic sensitivities. Further, the Council states its belief that "it [is] appropriate that every informed consent form should indicate that the drug, alcohol, is a toxin and a reinforcing agent which may cause changes in behavior, including repetitive or excessive consumption. Such a statement would appropriately acknowledge that alcohol is not an innocuous substance, and that everyone who drinks alcohol is at some risk" [p.4].

Investigators should be aware of federal, state, and local laws regarding criminal behavior, and any possible reporting requirements, whether they relate to criminal activity or other issues, such as HIV serostatus (see Guidebook Chapter 5, Section F, "AIDS/HIV-Related Research"). They should give the IRB evidence that they have considered these requirements and provide a means of dealing with them. The IRB should seek legal advice if necessary. The consent document should explain any limits on the investigator's ability to provide confidentiality of the data, including any required reporting to law enforcement or health authorities. [See also discussion of certificates of confidentiality below and in Guidebook Chapter 3, Section D, "Privacy and Confidentiality."]

Subject Selection. The question of subject selection also requires IRB attention. Drug- or alcohol-dependent individuals should not be taken advantage of. As the Council states, researchers must "avoid using subjects merely because of their easy availability, low social or economic status, or limited capacity to understand the nature of the research." Furthermore, IRBs should ensure that the proposed subject population is appropriate in terms of "age, sex, familial or genetic background, prior alcohol use, other drug use, and general medical and psychological condition, including, if appropriate, alcoholism recovery status." IRBs should consult the Council's recommendations, which describe these issues in greater detail.

IRBs must take into consideration the fact that the subject population of alcohol abusers and users of illicit drugs might include a significant number of adolescents. The protocol must address this issue. If subjects who are not adults participate, the additional protections for of 45 CFR 46 Subpart D apply. [See Guidebook Chapter 6, Section C, "Children and Minors."]

Privacy and Confidentiality. Records indicating alcohol abuse or illicit drug use are of an obviously sensitive nature, and must be provided appropriate confidentiality. Methods for assuring adequate protection of the privacy of subjects and the confidentiality of the information gathered about them (including the fact of participation in a drug or alcohol treatment program) should also be described by the investigator. Individually identifiable information that is "sensitive" should be safeguarded; requests for the release of such information to others, for research or auditing, should be allowed only when continued confidentiality is guaranteed.

To protect data against compelled disclosure, investigators may request a certificate of confidentiality from an appropriate federal official [42 CFR 2 and 2A]. For example, the directors of the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse are authorized to grant such protection for research on mental disorders or the use and effects of alcohol and other psychoactive drugs.

IRBs and investigators should note, however, that certificates of confidentiality protect research data from compelled disclosure; they do not cover voluntary disclosures (e.g., reporting of communicable diseases or suspected child abuse). The consent document should not, therefore, promise that "no information will ever be released," but should clearly spell out what can and cannot be released.

For information on certificates of confidentiality, contact:

National Institute on Alcohol Abuse and Alcoholism

Dr. Fulton Caldwell
National Institute on Alcohol Abuse and Alcoholism
16C-05 Parklawn Building
5600 Fishers Lane
Rockville, MD 20850
Tel: (301) 443-0796

National Institute on Drug Abuse

Ms. Jacqueline R. Porter
National Institute on Drug Abuse
10-42 Parklawn Building
5600 Fishers Lane
Rockville, MD 20850
Tel: (301) 443-2755

Cmdr. Lura S. Oravec
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A-55
Rockville, MD 20850
Tel: (301) 443-6071

National Institute of Mental Health

Dr. Anthony Pollitt
National Institute of Mental Health
9-97 Parklawn Building
5600 Fishers Lane
Rockville, MD 20850
Tel: (301) 443-4673

Other health research

Mr. John P. Fanning
Office of Health Planning and Evaluation
Public Health Service
740G Humphrey Building
U.S. Department of Health and Human Services
Washington, DC 20201
Tel: (202) 690-7911
Fax: (202) 690-6603
BITNET: JFANNING%PHSHHH7@NIHCU
INTERNET: JFANNING%PHSHHH7@CU.NIH.GOV

For further discussion of certificates of confidentiality, see Guidebook Chapter 3, Section D, "Privacy and Confidentiality."

IRB Membership. IRBs that regularly review research involving vulnerable subjects are required by DHHS and FDA regulations to consider including among their members one or more individuals who are knowledgeable about and experienced in working with those subjects [45 CFR 46.107; 21 CFR 56.107]. In addition, the IRB must be sure that additional safeguards are in place to protect the rights and welfare of these subjects [45 CFR 46.111(b); 21 CFR 56.111(b)].

For Further Information. Investigators and IRB members wishing to discuss drug research involving human subjects should contact:

Cmdr. Lura S. Oravec
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A-55
Rockville, MD 20850
Tel: (301) 443-6071

POINTS TO CONSIDER

1. Does the IRB's membership include sufficient expertise for reviewing the protocol?

2. Will the subject's drug or alcohol dependency create a deficient mental status which will preclude the subject's continuing ability to consent to participation in research? Will prospective subjects be in either a state of intoxication or withdrawal when approached to consent to participation? What mechanisms are proposed for evaluating subjects' competence to consent? Are they adequate?

3. Have additional safeguards been implemented to minimize risks (e.g., pregnancy tests or procedures for ensuring that subjects cannot leave the research site while intoxicated)?

4. Are there federal, state, or local laws regarding criminal behavior or reporting requirements that must be considered? How will they be dealt with? Will prospective subjects be informed of any reporting requirements?

5. Have the investigators provided for maintaining subjects' privacy and confidentiality? Should the investigators obtain a certificate of confidentiality to protect against compelled disclosure of their data?

6. Are adolescents potential participants? Have the additional requirements of 45 CFR 46 Subpart D been met? [See Guidebook Chapter 6, Section C, "Children and Minors."]

APPLICABLE LAWS AND REGULATIONS

Federal Policy for the protection of human subjects

Federal Policy §___.116 [Informed consent]

21 CFR 50.20 and 50.25 [FDA: Informed consent]

45 CFR 46 Subpart D [DHHS: Additional protections for children involved as subjects in research]

Federal, state, and local laws governing disclosure or reporting of criminal behavior (e.g., use of illicit drugs)

Federal, state, and local laws governing confidentiality of information

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SUGGESTIONS FOR FURTHER READING

A. Introduction

• Brett, A., and Grodin, M. "Ethical Aspects of Human Experimentation in Health Services Research." Journal of the American Medical Association 265 (No. 14, April 10, 1991): 1854-1857.
• Daedalus: Proceedings of the American Academy of Arts and Sciences 107 (No. 2, Spring 1978). "Limits of Scientific Inquiry." Special issue devoted to this theme.
• Drew, Clifford J., and Hardman, Michael L. "Ethical Issues in Conducting Research." In Designing and Conducting Behavioral Research, edited by Clifford J. Drew and Michael L. Hardman, pp. 29-48. New York: Pergamon Press, 1985.
• Fredrickson, Donald S. "Biomedical Research in the 1980s." New England Journal of Medicine 304 (No. 9, February 26, 1981): 509-517.
• Imber, Stanley D. et al. "Ethical Issues in Psychotherapy Research: Problems in a Collaborative Clinical Trials Study." American Psychologist 41 (No. 2, February 1986): 137-146.
• Kelman, Herbert C. "Research, Behavioral." In Encyclopedia of Bioethics (Vol. 4), edited by Warren T. Reich, pp. 1470-1481. New York: The Free Press, 1978.
• Kravitz, Richard. "Serving Several Masters: Conflicting Responsibilities in Health Services Research." Journal of General Internal Medicine 5 (No. 2, March/April 1990): 170-174.
• Lind, Stuart E. "The Institutional Review Board: An Evolving Ethics Committee." The Journal of Clinical Ethics 3 (No. 4, Winter 1992): 278-282. See also commentary in the same issue by Troyen A. Brennan ("Researcher as Witness," dealing with health services research, pp. 308-309).
• Macklin, Ruth. "The Paradoxical Case of Payment as Benefit to Subjects." IRB 11 (No. 6, November/December 1989): 1-3.
• Mahler, D. Mark. "When to Obtain Informed Consent in Behavioral Research: A Study of Mother-Infant Bonding." IRB 8 (No. 3, May/June 1986): 7-11.
• Marshall, Patricia A. "Research Ethics in Applied Anthropology." IRB 14 (No. 6, November/December 1992): 1-5.
• Robertson, John A. "The Scientist's Right to Research: A Constitutional Analysis." Southern California Law Review 51 (1978): 1203-1279.
• Sieber, Joan E. "On Studying the Powerful (or Fearing to Do So): A Vital Role for IRBs." IRB 11 (No. 5, September/October 1989): 1-6.
• Sieber, Joan E., and Stanley, Barbara. "Ethical and Professional Dimensions of Socially Sensitive Research." American Psychologist 43 (No. 1, January 1988): 49-55.
• Sieber, Joan E., ed. The Ethics of Social Research: Surveys and Experiments. New York: Springer-Verlag, 1982.
• Sieber, Joan E., ed. The Ethics of Social Research: Fieldwork, Regulation, and Publication. New York: Springer-Verlag, 1982.
• Stanley, Barbara. "Ethical Considerations in Biological Research on Suicide." In Psychobiology of Suicidal Behavior, edited by J. Mann and M. Stanley, pp. 42-46. New York: New York Academy of Sciences, 1986.
• U.S. Congress. Office of Technology Assessment. Assessing the Efficacy and Safety of Medical Technologies. Washington, D.C.: U.S. Government Printing Office, 1978.
• U.S. National Academy of Sciences. Behavioral and Social Science Research: A National Resource. Washington: National Academy Press, 1982.
• VandenBos, Gary R., Guest Editor. "Psychotherapy Research." American Psychologist 41 (No. 2, February 1986). Entire volume is devoted to this topic.
• Webb, Eugene J.; Campbell, Donald T.; Schwartz, Richard D.; and Sechrest, Lee. Unobtrusive Measures: Nonreactive Research in the Social Sciences. Chicago: Rand McNally, 1966.

• Cowan, Dale H. "Scientific Design, Ethics and Monitoring: IRB Review of Randomized Clinical Trials." IRB 2 (No. 9, November 1980): 1-4.
• Curran, William J. Rights and Responsibilities in Drug Research. Washington: Medicine in the Public Interest, Inc., 1977.
• Friedman, Lawrence, and DeMets, David. "The Data Monitoring Committee: How It Operates and Why," IRB 2 (No. 4, April 1981): 6-8.
• Friedman, L.F.; Furberg, C.; and DeMets, D. Fundamentals of Clinical Trials. Boston: Wright-PSG, 1981.
• Nightingale, Stuart. "Drug Regulation and Policy Formulation." Milbank Memorial Fund Quarterly 59 (No. 3, Summer 1981): 412-444.
• Ruse, Michael, and De Vries, Andre. "At What Level of Statistical Uncertainty Ought a Random Clinical Trial to be Interrupted?" In The Use of Human Beings in Research, edited by Stuart F. Spicker, Ilai Alan, Andre de Vries, and H. Tristam Engelhardt, Jr., pp. 189-225. Boston: Kluwer Academic, 1988.
• Sheps, Mindel C. "Problems in Clinical Evaluation of Drug Therapy." Perspectives in Biology and Medicine 5 (No. 3, Spring 1962): 308-323.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. "Guideline for the Monitoring of Clinical Investigations," January 1988.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. General Consideration for the Clinical Evaluation of Drugs. Washington, D.C.: U.S. Government Printing Office, 1977. HEW Publication No. (FDA) 77-3040. (Under revision.)

• Bjune, Gunnar, and Arnesen, Øyvind. "Problems Related to Informed Consent from Young Teenagers Participating in Efficacy Testing of a New Vaccine." IRB 14 (No. 5, September/October 1992): 6-9.
• Bjune, Gunnar, and Gedde-Dahl, Truls W. "Some Problems Related to Risk-Benefit Assessments in Clinical Testing of New Vaccines." IRB 15 (No. 1, January/February 1993): 1-5.
• Porter, Joan P.; Glass, Marta J.; and Koff, Wayne C. "Ethical Considerations in AIDS Vaccine Testing." IRB 11 (No. 3, May/June 1989): 1-4.
• Sawyer, Leigh A.; Katzenstein, David A.; and Quinnan, Gerald V. "Regulatory Concerns Regarding AIDS Vaccine Development." AIDS and Public Policy Journal 3 (No. 3, Summer 1988): 36-45.
• U.S. Congress. Office of Technology Assessment. A Review of Selected Federal Vaccine and Immunization Policies. Washington, D.C.: U.S. Government Printing Office, 1979.
• U.S. Congress. Office of Technology Assessment. Compensation for Vaccine-Related Injuries. Washington, D.C.: U.S. Government Printing Office, 1980.
• U.S. Department of Health, Education and Welfare. Public Health Service. National Center for Health Services Research. Office of the Assistant Secretary for Health. Estimated Economic Costs of Selected Medical Events Known or Suspected to be Related to the Administration of Common Vaccines: Final Report. Washington, D.C.: U.S. Government Printing Office, 1979.
• U.S. Department of Health, Education and Welfare. National Immunization Work Groups. Reports and Recommendations. McLean, Va.: J.R.B. Associates, 1977.
• U.S. Department of Health, Education and Welfare. Centers for Disease Control. Immunization Practices Advisory Committee (ACIP). "Recommendations on Poliomyelitis Prevention." Morbidity and Mortality Weekly Reports, November 22, 1979, p. 510.
• Voller, A., and Friedman, H. New Trends and Developments in Vaccines. Baltimore, MD: University Park Press, 1978.
• Weibel, R.E. et al. "Studies in Human Subjects of Polyvalent Pneumococcal Vaccines." Proceedings of the Society for Experimental Biology and Medicine. 156 (No. 1, October 1977): 144-150.

D. Medical Devices

• Annas, George J. "Made in the U.S.A.: Legal and Ethical Issues in Artificial Heart Experimentation." Law, Medicine and Health Care 14 (Nos. 3-4, September 1986): 164-171.
• Heath, Erica. "Information Sought about 'Significant Risk' Decisions." IRB 3 (No. 2, February 1981): 11.
• Holder, Angela. "The FDA's Final Regulations: IRBs and Medical Devices." IRB 2 (No. 6, June/July 1980): 1-4.
• Kennedy, Robert S. "Clinical Investigations With Medical Devices." Journal of the American Medical Association 245 (No. 20, May 22/29, 1980): 2052-2055.
• Kyper, C. "The 510(k) Route to the Marketplace." MD&MI (January 1982).
• Ryan, Mary Kay. "Research Involving Medical Devices." In Human Subjects Research: A Handbook for Institutional Review Boards, edited by Robert A. Greenwald, Mary Kay Ryan, and James E. Mulvihill, pp. 107-123. New York: Plenum Press, 1982.
• Swazey, Judith P.; Watkins, Judith C.; and Fox, Renee. "Assessing the Artificial Heart: The Clinical Moratorium Revisited." International Journal of Technology Assessment in Health Care 2 (No. 3, July 1986): 387-410.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. Bureau of Medical Devices. Investigational Device Exemptions Manual. Washington, D.C.: U.S. Government Printing Office, June 1992. DHHS Publication No. (FDA) 92-4159.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. Center for Devices and Radiological Health. "Highlights of the Safe Medical Devices Act of 1990." August 1991 (mimeo).
• U.S. Department of Health, Education and Welfare. Food and Drug Administration. Bureau of Medical Devices. All You Ever Wanted to Know About Medical Devices But Were Afraid to Ask, 3d ed. Washington, D.C.: U.S. Government Printing Office, August 1990. DHHS Publication No. (FDA) 90-4173.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. "Guidance to Significant and Nonsignificant Risk Device Studies." FDA IRB Information Sheets, February 1989.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. "IRBs and Medical Devices." FDA IRB Information Sheets, February 1989.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. Center for Devices and Radiological Health. An Introduction to Medical Device Regulations. Washington, D.C.: U.S. Government Printing Office, 1987. DHHS Publication No. (FDA) 87-4222.
• U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. Center for Devices and Radiological Health. Office of Device Evaluation. Guidance Document on Significant and Nonsignificant Risk Device Studies. Washington, D.C.: U.S. Government Printing Office, 1986.

• Alazracki, Naomi. "Evaluating Risk from Radiation for Research Subjects." IRB 4 (No. 1, January 1982): 1-3.
• Bolsen, Barbara. "CT Scanning of the Brain: A Revolution in Only Eight Years." Journal of the American Medical Association 246 (No. 23, December 11, 1981): 2667-2669, 2675.
• Crawford-Brown, D.J. "Truth and Meaning in the Determination of Radiogenic Risk." IRB 5 (No. 5, September/October 1983): 1-5, 12.
• Huda, Walter, and Scrimger, John W. "Irradiation of Volunteers in Nuclear Medicine." The Journal of Nuclear Medicine 30 (No. 2, February 1989): 260-264. Comment in Journal of Nuclear Medicine 30 (No. 12, December 1989): 2062-2063.
• Lyman, James D. Nuclear Terms: A Glossary, 2d ed. Oak Ridge, Tenn.: U.S. Atomic Energy Commission, Office of Information Services, 1974.
• Masse, Francis X., and Miller, Tracy. "Exposure to Radiation and Informed Consent." IRB 7 (No. 4, July/August 1985): 1-4. Includes description of the biological effects of ionizing radiation and examples of radiation risk statements appropriate for inclusion in the risk section of informed consent statements.
• U.S. Congress. House. Committee on Energy and Commerce. Subcommittee on Energy Conservation and Power. American Nuclear Guinea Pigs: Three Decades of Radiation Experiments on U.S. Citizens. [Report, Committee Print.] Washington: U.S. Government Printing Office, November 1986.
• U.S. National Research Council. Committee on the Biological Effects of Ionizing Radiations (BEIR III). "The Effects on Populations of Exposure to Low Levels of Ionizing Radiation," Washington, D.C.: National Academy Press, 1980.
• Veatch, Robert M. "The Ethics of Research Involving Radiation." IRB 4 (No. 1, January 1982): 3-5. Reprinted in The Patient as Partner: A Theory of Human-Experimentation Ethics, Chapter 18. Bloomington and Indianapolis: Indiana University Press, 1987.

• Ackerman, Terrence F. "Protectionism and the New Research Imperative in Pediatric AIDS." IRB 12 (No. 5, September/October 1990): 1-5.
• American Psychological Association. Committee for the Protection of Human Participants in Research. "Ethical Issues in Psychological Research on AIDS." IRB 8 (No. 4, July/August 1986): 8-10.
• Arvino, Andrew, and Lo, Bernard. "To Tell or Not to Tell: The Ethical Dilemmas of HIV Test Notification in Epidemiologic Research." American Journal of Public Health 79 (No. 11, 1989): 1544-1548.
• Barry, Michele. "Ethical Dilemmas with Economic Studies in Less-Developed Countries: AIDS Research Trials." IRB 13 (No. 4, July/August 1991): 8-9.
• Bayer, Ronald. "The Ethics of Research on HIV/AIDS in Community-Based Settings." AIDS 4 (No. 12, December 1990): 1287-1288.
• Bayer, Ronald; Levine, Carol; and Murray, Thomas H. "Guidelines for Confidentiality in Research on AIDS." IRB 6 (No. 6, November/December 1984): 1-9.
• Byer, David P. et al. "Design Considerations for AIDS Trials." New England Journal of Medicine 323 (No. 19, November 8, 1990): 1343-1348.
• Carter, Michele; McCarthy, Charles R.; and Wichman, Alison. "Regulating AIDS Research on Infants and Children: The Moral Task of Institutional Review Boards." Bridges 2 (No. 1/2, Spring/Summer 1990): 63-73.
• Christakis, Nicholas A.; Lynn, Lorna A.; and Castelo, Aduato. "Case Study — Clinical AIDS Research that Evaluates Cost Effectiveness in the Developing World." IRB 13 (No. 4, July/August 1991): 6-7.
• Christakis, Nicholas A. "The Ethical Design of an AIDS Vaccine Trial in Africa." Hastings Center Report 18 (No. 3, June/July 1988): 31-37.
• Corey, Lawrence, and Fleming, Thomas R. "Treatment of HIV Infection — Progress in Perspective." New England Journal of Medicine 326 (No. 7, February 13, 1992): 484-486.
• Culliton, B.J. "Human Experimentation: AIDS Trials Questioned." Nature 350 (No. 6316, March 28, 1991): 263.
• Curran, William J. "AIDS Research and 'The Window of Opportunity.'" New England Journal of Medicine 312 (No. 14, April 4, 1985): 903-904.
• DeJarlais, Don C., and Friedman, Samuel R. "AIDS Prevention Among IV Drug Users: Potential Conflicts Between Research Design and Ethics." IRB 9 (No.1, January/February 1987): 6-8.
• Dubler, Nancy Neveloff, and Sidel, Victor W. "On Research on HIV Infection in Correctional Institutions." Milbank Quarterly 67 (No. 2, 1989): 171-207.
• Dubler, Nancy Neveloff. "Treating Research Subjects Fairly." IRB 8 (No. 5, September/October 1986): 7-9.
• Freedman, Benjamin. "Placebo-Controlled Trials and the Logic of Clinical Purpose." IRB 12 (No. 6, November/December 1990):1-6.
• Freedman, Benjamin. "Equipoise and the Ethics of Clinical Research." New England Journal of Medicine 317 (July 16, 1987): 141-145.
• Gray, Joni N., and Melton, Gary B. "The Law and Ethics of Psychosocial Research on AIDS." Nebraska Law Review 64 (No. 4, 1985): 637-688.
• Hamburg, Margaret A., and Fauci, Anthony S. "AIDS: The Challenge to Biomedical Research." Daedalus 18 (Spring 1989): 19-39.
• Jones, James H. "The Tuskegee Legacy: AIDS and the Black Community." The Hastings Center Report 22 (No. 6, November/December 1992): 38-40.
• Jonsen, A.R. "The Ethics of Using Human Volunteers for High-Risk Research." Journal of Infectious Diseases 160 (No. 2, August 1989): 205-208. Comment by Tacket and Edelman, "Ethical Issues Involving Volunteers in AIDS Vaccine Trials," Journal of Infectious Diseases 161 (No. 2, February 1990): 356.
• Landesman, Sheldon M. "Against the Option Not to be Informed of HIV Status." IRB 8 (No. 5, September/October 1986): 9.
• Leikin, Sanford L. "Immunodeficiency Virus Infection, Adolescents, and the Institutional Review Board." Journal of Adolescent Health Care 10 (November 1989): 500-505.
• Levine, Carol. "Women and HIV/AIDS Research: The Barriers to Equity." IRB 13 (No. 1-2, January-April 1991): 1-17.
• Levine, Carol. "Children in HIV/AIDS Clinical Trials: Still Vulnerable after All These Years." Law, Medicine and Health Care 19 (No. 3-4, Fall/Winter 1991): 231-37.
• Levine, Carol. "Has AIDS Changed the Ethics of Human Subjects Research?" Law, Medicine and Health Care 16 (No. 3-4, Fall/Winter 1988): 167-173.
• Levine, Carol; Dubler, Nancy Neveloff; and Levine, Robert J. "Building a New Consensus: Ethical Principles and Policies for Clinical Research on HIV/AIDS." IRB 13 (No. 1-2, January/February 1991):1-17.
• Levine, Robert J. "The Use of Placebos in Randomized Clinical Trials." IRB 7 (No. 2, March/April 1985): 1-4. Comment by Arthur Schafer, p. 4.
• Macklin, Ruth, and Friedland, Gerald. "AIDS Research: The Ethics of Clinical Trials." Law, Medicine and Health Care 14 (No. 5-6, December 1986): 273-280.
• Mariner, Wendy K. "New FDA Drug Approval Policies and HIV Vaccine Development." American Journal of Public Health 80 (No. 3, March 1990): 336-341.
• Martin, Judith M., and Sacks, Henry S. "Do HIV-Infected Children in Foster Care Have Access to Clinical Trials of New Treatments?" AIDS and Public Policy Journal 5 (No. 1, Winter 1990): 3-8.
• Melton, Gary B. et al. "Community Consultation in Socially Sensitive Research: Lessons from Clinical Trials of Treatments for AIDS." American Psychologist 43 (No. 7, July 1988): 573-581.
• Merigan, Thomas C. "You Can Teach an Old Dog New Tricks: How AIDS Trials are Pioneering New Strategies." New England Journal of Medicine 323 (No. 19, November 8, 1990): 1341-1343.
• Meyers, Karin, and Dunton, Alan W. "Case Study: Applying 'An Ethical Framework' to a Proposed HIV Antibody Screening Program." IRB 10 (No. 1, January/February 1988): 6-8.
• Nolan, Kathleen. "AIDS and Pediatric Research." Evaluation Review 14 (No. 5, October 1990): 464-481.
• Novick, Alvin. "Noncompliance in Clinical Trials: I. Subjects." AIDS and Public Policy Journal 5 (No. 2, Spring 1990): 94-96.
• Novick, Alvin. "Clinical Trials with Vulnerable or Disrespected Subjects." AIDS and Public Policy Journal 4 (No. 2, 1989): 125-130.
• Novick, Alvin. "Some Ethical Issues Associated with HIV Vaccine Trials." AIDS and Public Policy Journal 3 (No. 3, Summer 1988): 46-48.
• Novick, Alvin. "Why the Burdensome Knowledge Need Not Be Imposed." IRB 8 (No. 5, September/October 1986): 6-7.
• Novick, Alvin. "At Risk for AIDS: Confidentiality in Research and Surveillance." IRB 6 (No. 6, November/December 1984): 10-11.
• Perry, Samuel W. "Pharmacological and Psychological Research on AIDS: Some Ethical Considerations." IRB 9 (No. 5, September/October, 1987): 8-10.
• Porter, Joan P.; Glass, Marta J.; and Koff, Wayne C. "Ethical Considerations in AIDS Vaccine Testing." IRB 11 (No. 3, May/June 1989): 1-4.
• Richman, Douglas D. "Public Access to Experimental Drug Therapy: AIDs Raises Yet Another Conflict between Freedom of the Individual and Welfare of the Individual and Public." Journal of Infectious Diseases 159 (No. 3, March 1989): 412-415.
• Sawyer, Leigh A.; Katzenstein, David A.; and Quinnan, Gerald V. "Regulatory Concerns Regarding AIDS Vaccine Development." AIDS and Public Policy Journal 3 (No. 3, Summer 1988): 36-45.
• Sieber, Joan E., and Sorensen, James L. "Conducting Social and Behavioral AIDS Research in Drug Treatment Clinics." IRB 14 (No. 5, September/October 1992): 1-5.
• Spiers, Herbert R. "Community Consultation and AIDS Clinical Trials, Part I." IRB 13 (No. 3, May/June 1991): 7-10.
• Spiers, Herbert R. "Community Consultation and AIDS Clinical Trials, Part II" IRB 13 (No. 4, July/August 1991): 1-6.
• Spiers, Herbert R. "Community Consultation and AIDS Clinical Trials, Part III." IRB 13 (No. 5, September/October 1991): 3-7.
• Thomas, S.B., and Quinn, S.C. "The Tuskegee Syphilis Study, 1932-1972: Implications for HIV Education and AIDS Risk Education Programs in the Black Community." American Journal of Public Health 81 (No. 11, November 1991): 1498-1505.
• U.S. Department of Health and Human Services. Public Health Service. "U.S. Public Health Service Consultation on International Collaborative Human Immunodeficiency Virus (HIV)." Reprinted in Law, Medicine and Health Care 19 (No. 3-4, Fall/Winter 1991): 259-263.
• Valdiserri, Ronald O.; Tama, Geraldine Maiatico; and Ho, Monto. "The Role of Community Advisory Committees in Clinical Trials of Anti-HIV Agents." IRB 10 (No. 4, July/August 1988): 5-7.
• Veatch, Robert M. "Drug Research in Humans: The Ethics of Nonrandomized Access." Clinical Pharmacy 8 (No. 5, May 1989): 366-370.

• American Medical Association. Council on Scientific Affairs. "Xenografts: Review of the Literature and Current Status." Journal of the American Medical Association 254 (No. 23, December 20, 1985): 3353-3357.
• Arras, John D., and Shinnar, Shlomo. "Anencephalic Newborns as Organ Donors: A Critique." Journal of the American Medical Association 259 (No. 15, April 15, 1988): 2284-2285.
• Bailey, Leonard L. "Organ Transplantation: A Paradigm of Medical Progress." The Hastings Center Report 20 (No. 1, January/February 1990): 24-28.
• Beauchamp, Tom L., and Childress, James F. Principles of Biomedical Ethics, 3d ed. New York: Oxford University Press, 1989.
• Caplan, Arthur L. "Is Xenografting Morally Wrong?" Transplantation Proceedings 24 (No. 2, April 1992): 722-727.
• Caplan, Arthur L. "Ethical Issues Raised by Research Involving Xenografts." Journal of the American Medical Association 254 (No. 23, December 20, 1985): 3339-3343.
• Caplan, Arthur L. "Ethical and Policy Issues in the Procurement of Cadaver Organs for Transplantation." New England Journal of Medicine 311 (No. 15, October 11, 1984): 981-983.
• Carney, Bridget. "Bone Marrow Transplantation: Nurses' and Physicians' Perceptions of Informed Consent." Cancer Nursing 10 (No. 5, October 1987): 252-259.
• Cowan, Dale; Kantorowitz, Jo Ann; Moskowitz, Jay; and Rheinstein, Peter H., eds. Human Organ Transplantation: Societal, Medical-Legal, Regulatory, and Reimbursement Issues. Ann Arbor, MI: Health Administration Press, 1987.
• Diethelm, Arnold G. "Ethical Decisions in the History of Organ Transplantation." Annals of Surgery 211 (No. 5, May 1990): 505-520.
• Fost, Norman. "Organs from Anencephalic Infants: An Idea Whose Time Has Not Yet Come." The Hastings Center Report 18 (No. 5, October/November 1988): 5-10.
• Gil, Gideon. "The Artificial Heart Juggernaut." The Hastings Center Report 19 (No. 2, March/April 1989): 24-31.
• Holder, Angela Roddey. "The Minor as Research Subject or Transplant Donor." In Legal Issues in Pediatrics and Adolescent Medicine, 2d ed., by Angela Roddey Holder, pp. 146-178. New Haven, CT: Yale University Press, 1985.
• Levine, Robert J. Ethics and Regulation of Clinical Research. 2d ed. Baltimore: Urban and Schwarzenberg, 1986.
• Lind, Stuart E. "The Institutional Review Board: An Evolving Ethics Committee." The Journal of Clinical Ethics 3 (No. 4, Winter 1992): 278-282. See also commentary in the same issue by John B. Dossetor ("An Ethics Issue for Cadaver Renal Transplantation," p. 309-311).
• McCarthy, Charles R. "The Role of the Institutional Review Board in Research Relating to Human Organ Transplantation." In Human Organ Transplantation: Societal, Medical-Legal, Regulatory, and Reimbursement Issues, edited by Dale H. Cowan et al., pp. 90-95. Ann Arbor, MI: 1987.
• Moore, Francis D. "The Desperate Case: CARE (Costs, Applicability, Research, Ethics)." Journal of the American Medical Association 261 (No. 10, March 10, 1989): 1483-1484.
• Moore, Francis D. "Three Ethical Revolutions: Ancient Assumptions Remodeled Under Pressure of Transplantation." Transplantation Proceedings 20 (No. 1, Supp. 1, February 1988): 1061-1067.
• Reemtsma, K. "Ethical Aspects of Xenotransplantation." Transplantation Proceedings 22 (No. 3, June 1990): 1042-1043.
• Robertson, John A. "Patient Selection for Organ Transplantation: Age, Incarceration, Family Support, and Other Factors." Transplantation Proceedings 21 (No. 3, June 1984): 3397-3402.
• Shewmon, D. Alan et al. "The Use of Anencephalic Infants as Organ Sources: A Critique." Journal of the American Medical Association 261 (No. 12, March 24/31, 1989): 1773-1781.
• Shewmon, D. Alan. "Anencephaly: Selected Medical Aspects." The Hastings Center Report 18 (No. 5, October/November 1988): 11-19.
• Singer, Peter A. et al. "Ethics of Liver Transplantation with Living Donors." New England Journal of Medicine 321 (No. 9, August 31, 1989): 620-622.
• Starzl, Thomas E. "Ethical Problems in Organ Transplantation: A Clinician's Point of View." Annals of Internal Medicine 67 (No. 3, September 1967): 32-36.
• Transplant Policy Center. Ethics and Social Impact Committee. "Anencephalic Infants as Sources of Transplantable Organs." The Hastings Center Report 18 (No. 5, October/November 1988): 28-30.
• U.S. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Implementing Human Subjects Regulations. Washington, D.C.: U.S. Government Printing Office, 1981.
• Walters, James W., and Ashwal, Stephen. "Organ Prolongation in Anencephalic Infants: Ethical and Medical Issues." The Hastings Center Report 18 (No. 5, October/November 1988): 19-27.

• American Association for the Advancement of Science-American Bar Association National Conference of Lawyers and Scientists and the American Association for the Advancement of Science Committee on Scientific Freedom and Responsibility. The Genome, Ethics and the Law: Issues in Genetic Testing. Washington, D.C.: American Association for the Advancement of Science, 1992.
• American Society of Human Genetics. Ad Hoc Committee on DNA Technology. "DNA Banking and DNA Analysis: Points to Consider." American Journal of Human Genetics 42 (No. 5, May 1988): 781-783. Adopted October 9, 1987.
• Anderson, W.F. "Human Gene Therapy: Scientific and Ethical Considerations." Journal of Medicine and Philosophy 10 (No. 3, August 1985): 275-277.
• Anderson, W.F., and Fletcher, John C. "Gene Therapy in Human Beings: When is it Ethical to Begin?" New England Journal of Medicine 303 (1980): 1293-1296.
• Andrews, Lori B. "Legal Aspects of Genetic Information." The Yale Journal of Biology and Medicine 64 (No. 1, January/February 1991): 29-40.
• Appelbaum, Paul S., and Rosenbaum, Alan. "Tarasoff and the Researcher: Does the Duty to Protect Apply in the Research Setting?" American Psychologist 44 (No. 6, June 1989): 885-894.
• Australia. National Medical Council. Report on Ethics in Epidemiological Research. Canberra: Australian Government Publishing Service, 1985.
• Baum, Rudy M. "Genetic Screening: Medical Promise Amid Legal and Ethical Questions." Chemical and Engineering News 67 (August 7, 1989): 10-16.
• Beauchamp, Tom L., and Childress, James F. Principles of Biomedical Ethics, 3d ed. New York: Oxford University Press, 1989. See especially pp. 333-342.
• Billings, Paul R. "Brewing Genes and Behavior: The Potential Consequences of Genetic Screening for Alcoholism." In Banbury Report 33: Genetics and Biology of Alcoholism, pp. 333-350. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1990.
• Bishop, Jerry E., and Waldholz, Michael. "The Search for the Perfect Child." The Wall Street Journal, 19 March 1986, p. 30.
• Bloch, M., and Hayden, M. R. "Opinion: Predictive Testing for Huntington Disease in Childhood: Challenges and Implications." American Journal of Human Genetics 46 (1990): 1-4.
• Brody, Howard. "Ethics, Technology, and the Human Genome Project." The Journal of Clinical Ethics 2 (No. 4, Winter 1991): 278-281.
• Busch, David B. et al. "Recontacting Subjects in Mutagen Exposure Monitoring Studies." IRB 8 (No. 6, November/December 1986): 1-4.
• Capron, Alexander M. "Which Ills to Bear?: Reevaluating the 'Threat' of Modern Genetics." Emory Law Journal 39 (Summer 1990): 665-696. See Sections III-IV.
• Collins, Francis S. "Medical and Ethical Consequences of the Human Genome Project." The Journal of Clinical Ethics 2 (No. 4, Winter 1991): 260-267.
• DeGrazia, David. "The Ethical Justification for Minimal Paternalism in the Use of the Predictive Test for Huntington's Disease." The Journal of Clinical Ethics 2 (No. 4, Winter 1991): 219-228.
• Dorozynski, Alexander. "Privacy Rules Blindside French Glaucoma Effort." Science 250 (April 1991): 369-370.
• Emory Law Journal 39 (No. 3, Summer 1990). The entire issue is devoted to issues in genetics and the law.
• European Parliament. "Resolution on the Ethical and Legal Problems of Genetic Engineering." Resolution of March 16, 1989. Official Journal of the European Communities 17.4.89, pp. C 96/165-170. Reprinted (slightly abridged) in Bulletin of Medical Ethics 57 (April 1990): 8-10.
• Fletcher, John C. "Ethical Issues In and Beyond Prospective Clinical Trials of Human Gene Therapy." Journal of Medicine and Philosophy 10 (No. 3, August 1985): 293-309.
• Fletcher, John C.; Berg, Kare; and Tranoy, Knut Erik. "Ethical Aspects of Medical Genetics: A Proposal for Guidelines in Genetic Counseling, Prenatal Diagnosis and Screening." Clinical Genetics 27 (No. 2, February 1985): 199-205.
• Fost, Norman, and Farrell, Philip M. "A Prospective Randomized Trial of Early Diagnosis and Treatment of Cystic Fibrosis: A Unique Ethical Dilemma." Clinical Research 37 (No. 3, September 1989): 495-500.
• Fost, N. and Cohen, S. "Ethical Issues Regarding Case Reports: To Publish or Perish the Thought." Clinical Research 24 (1976): 269-273.
• Friedmann, Theodore. "The Evolving Concept of Gene Therapy." Gene Therapy 1 (1990): 175-181.
• Glover, Jonathan. "Questions About Some Uses of Genetic Engineering." In Contemporary Issues in Bioethics, edited by Tom Beauchamp and LeRoy Walters, pp. 525-535. Belmont, CA: Wadsworth Publishing Co., 1978.
• Goldstein, David J., ed. Genetics for the Medically Oriented: Medical Genetics Core Book. Indianapolis: Indiana University School of Medicine, Medical Genetics, 1983.
• Gordis, Enoch; Babakoff, Boris; Goldman, David; and Berg, Kate. "Finding the Gene(s) for Alcoholism." Journal of the American Medical Association 263 (No. 15, April 18, 1990): 2094-2095.
• Hayden, Michael R. "Predictive Testing for Huntington Disease: Are We Ready for Widespread Community Implementation?" American Journal of Medical Genetics 40 (1991): 515-517.
• Hayes, Catherine V. "Genetic Testing for Huntington's Disease — A Family Issue." New England Journal of Medicine 327 (No. 20, November 12, 1992): 1449-1451.
• Holtzman, Neil A. et al. "The Effect of Education on Physicians' Knowledge of a Laboratory Test: The Case of Maternal Serum Alpha-Fetoprotein Screening." The Journal of Clinical Ethics 2 (No. 4, Winter 1991): 243-247.
• Holtzman, Neil A. Proceed with Caution: Predicting Genetic Risks in the Recombinant DNA Era. Baltimore: Johns Hopkins University Press, 1989.
• Howe, Edmund G., III; Kark, John A.; and Wright, Daniel G. "Studying Sickle Cell Trait in Healthy Army Recruits: Should the Research Be Done?" Clinical Research 31 (No. 2, April 1983): 119-125.
• Huggins, M. et al. "Ethical and Legal Dilemmas Arising During Predictive Testing for Adult-Onset Disease: The Experience of Huntington Disease." American Journal of Human Genetics 47 (1990): 4-12.
• International Committee of Medical Journal Editors. "Statements from the International Committee of Medical Journal Editors." Journal of the American Medical Association 265 (No. 20, May 22/29, 1991):2697-2698. Requiring the informed consent of patients when a risk of identification in published descriptions of research exists.
• Karson, Evelyn and Anderson, W. French. "Prospects for Gene Therapy." In The Unborn Patient: Prenatal Diagnosis and Treatment, 2d ed., edited by Michael R. Harrison, Mitchell S. Golbus and Roy A. Filly, pp. 481-494. Philadelphia: Saunders, 1991.
• Kolata, Gina. "Genetic Screening Raises Questions for Employers and Insurers." Science 232 (April 16, 1986): 317-319.
• Lappe, Marc; Gustafson, James M.; and Roblin, Richard. "Ethical and Social Issues in Screening for Genetic Disease." New England Journal of Medicine 286 (No. 21, May 25, 1972): 1129-1132.
• Levine, Robert J. Ethics and Regulation of Clinical Research. 2d ed. Baltimore: Urban and Schwarzenberg, 1986.
• Lewis, Ricki. "Genetic-Marker Testing: Are We Ready for It?" Issues in Science and Technology 4 (No. 1, Fall 1987): 76-82.
• MacKay, Charles R. "The Physician as Fortune Teller: A Commentary on 'The Ethical Justification for Minimal Paternalism.'" The Journal of Clinical Ethics 2 (No. 4, Winter 1991): 228-238.
• MacKay, Charles R. "Ethical Issues in Research Design and Conduct: Developing a Test to Detect Carriers of Huntington's Disease." IRB 6 (No. 4, July/August 1984): 1-5.
• Meissen, Gregory H. et al. "Understanding the Decision To Take the Predictive Test for Huntington Disease." American Journal of Medical Genetics 39 (No. 4, June 15, 1991): 404-410.
• Milewski, Elizabeth A., comp. "Discussions on Human Gene Therapy." Recombinant DNA Technical Bulletin 9 (No. 2, June 1986): 88-130. Compilation of excerpts from meetings of the National Institutes of Health's Recombinant DNA Advisory Committee and its working groups on human gene therapy and viruses.
• Milewski, Elizabeth A. "Development of A Points to Consider Document for Human Somatic Cell Gene Therapy." Recombinant DNA Technical Bulletin 8 (No. 4, December 1985): 176-180.
• Miller, Bruce. "Autonomy and Proxy Consent." In Alzheimer's Dementia: Dilemmas in Clinical Research, edited by Vijaya L. Melnick and Nancy N. Dubler, pp. 239-263. Clifton, NJ: Humana Press, 1985.
• Milunsky, Aubrey, and Annas, George J., eds. Genetics and the Law, III: Proceedings of the Third National Symposium on Genetics and the Law, Boston, 1984. New York: Plenum Press, 1985.
• Murray, Jeffrey C., and Pagon, Roberta A. "Informed Consent for Research Publication of Patient-Related Data." Clinical Research 32 (No. 4, October 1984): 404-408.
• Murray, Thomas H. "Warning: Screening Workers for Genetic Risk." Hastings Center Report 13 (No. 1, February 1983): 5-8.
• Nolan, Kathleen, and Sevenson, Sara. "New Tools, New Dilemmas: Genetics Frontiers." Hastings Center Report (October/November, 1988): 40-46.
• Quaid, Kimberly A. "Predictive Testing for HD: Maximizing Patient Autonomy." The Journal of Clinical Ethics 2 (No. 4, Winter 1991): 238-240.
• Reilly, Philip. "When Should an Investigator Share Raw Data with the Subjects?" IRB 2 (No. 9, November 1980): 4-5, 12.
• Reilly, Philip. Genetics, Law and Social Policy. Cambridge, Mass.: Harvard University Press, 1977.
• Riis, Povl and Nylenna, Magne. "Patients Have a Right to Privacy and Anonymity in Medical Publication." Journal of the American Medical Association 265 (No. 10, May 22/29 1991): 2720.
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Chapter V: Research: An Overview