Ethics and Regulation in Organ Procurement Research

http://www.medscape.com/viewarticle/447480_2

Ethics and Regulation in Organ Procurement Research

from Progress in Transplantation

Development of Ethical and Regulatory Guidelines

A series of scandals in the 1960s underscored the need to develop a formal system for protecting the rights and welfare of human subjects.^[1] These revelations culminated in the public disclosure of the Tuskegee syphilis study.^[2] Designed to characterize the natural history of syphilis, the study was begun in 1932 and continued for 40 years. It involved 399 poor, black men in Macon County, Ala, who were told only that investigators were studying "bad blood." Subjects underwent annual medical examinations, including blood withdrawal and occasional lumbar punctures. Even after the introduction of modern antibiotics, the study continued without offering treatment to the subjects. In response to the public outrage, in 1974 Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission was charged with developing substantive and procedural guidelines for the operation of IRBs, as well as special rules for research in vulnerable populations. The recommendations of the Commission provided the basis for the current federal rules implemented in the early 1980s for the protection of human subjects.^[3] At present, 15 federal agencies subscribe to the so-called "Common Rule" (subpart A of 45 CFR 46) that formulates the basic rules for the operation of IRBs and the review of research with human subjects^[4].

In its deliberations, the National Commission identified 3 basic moral principles that should guide the conduct of research with human subjects.^[5] The principle of respect for personal autonomy requires that investigators facilitate the capacity of subjects to deliberate about and act in accord with their own values and goals. Various rules derive from this principle, including the requirements to secure the informed consent of subjects or their legally authorized representatives, to respect the privacy of subjects, and to protect the confidentiality of information about them gathered in the research context. These rules share the common feature of allowing persons to decide in accord with their own values and goals when they want to participate in research and the conditions under which they are willing to share information about themselves with investigators.

The second basic requirement is the principle of beneficence or concern for the welfare of subjects. Numerous rules also derive from this principle, including the requirements that the risks to subjects be minimized, that the risks of nontherapeutic interventions not be serious, and that therapeutic procedures used in research not be known to have a less favorable risk-benefit ratio than alternative treatments available to subjects.

The third basic principle relates to justice or fair treatment of subjects. This principle requires that the benefits and burdens of participation in research be distributed in a manner that all persons have an equal opportunity to pursue their life plans vis-à-vis one another. One rule deriving from the principle of justice is that vulnerable groups in the population should not be unduly exposed to the burdens of participation in research. Another important rule is that all groups should have access to clinical trials that may offer the prospect of direct benefits to subjects not available out-side the research setting. Finally, justice requires that the healthcare needs of particular population groups, such as children or elderly persons, not be ignored in the conduct of medical research.

Moreover, the National Commission endorsed the view that the application of these fundamental principles should not be left to the private judgment of individual investigators.^[6] It recognized that investigators have professional interests in the development of generalizable knowledge, which may skew their evaluation of the importance of research goals and, more importantly, the judgment of whether the risks to subjects are justified by the anticipated benefits of the re-search. This principle of independent review of re-search proposals has also been widely endorsed by professional societies in published guidelines for the ethical conduct of research with human subjects.^[7-9]

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Ethics and Regulation in Organ Procurement Research

from Progress in Transplantation

Applicability of Federal Regulations

An important question is whether research activities conducted by OPOs are subject to federal regulatory oversight. According to section 101(a) of the regulations,^[4] federal rules apply only to research involving human subjects "conducted, supported or otherwise subject to regulation" by federal agencies that adhere to the Common Rule. In addition, institutions that conduct such research must assure the Office for Human Research Protections of the Department of Health and Human Services that they will provide equally stringent oversight of other human research activities. Applying the federal rules to all studies usually satisfies the latter requirement, even if particular protocols are not supported or regulated by federal agencies. However, if no research activities of an OPO are supported or regulated by a federal agency that is a signatory to the Common Rule, there is no legal requirement to observe the federal rules, including the requirement for prior IRB review and approval.

Nevertheless, there are good policy reasons for conducting OPO research activities in accord with the federal rules. First, although OPOs do not typically receive federal funds to conduct human research, they do receive federal support for their ongoing service activities. Because federal funds are received for general service activities, it might be considered appropriate to observe federal standards for the review and conduct of human research. Second, because most human research in the United States is conducted in accord with the federal regulations, these requirements constitute the standard of practice for protecting human subjects. If OPO research is conducted using less rigorous standards for protecting the rights and welfare of human subjects, then oversight of such research might be claimed to fall below the current standard of practice. Third, OPOs depend for effective functioning on the trust and goodwill of organ donors and their families. One way to prevent the erosion of this trust is to voluntarily submit research proposals to the same level of review required by the federal regulations. This assures donors and families that protections for the rights and welfare of human subjects in OPO research are not less rigorous than the current standard of practice. Fourth, virtually all professional guidelines for the ethical conduct of human research endorse the independent review of research protocols as an essential mechanism for assuring that investigators implement appropriate protections for the interests of human subjects.

An important practical issue for OPOs is how to secure IRB review, because OPOs are not part of institutions with established IRBs. One approach is to negotiate a cooperative agreement with an IRB at a nearby academic institution to review proposals. Because OPOs engage in organ procurement services at these institutions, the establishment of a cooperative agreement may be viewed as a professional courtesy. Alternatively, a consortium of organ procurement agencies might consider establishing a central IRB to review research using human subjects conducted by its member organizations. Finally, OPOs might secure the services of a commercial IRB on a fee-for-service basis. Many private, nonacademic research institutions that do not possess the staff resources for maintaining a standing committee utilize commercial IRBs.

When OPO research activities are undertaken in multiple hospitals or other institutions, additional IRB review at the host institutions may be necessary. The IRB bylaws of host institutions will usually require that all research conducted in those facilities be reviewed according to the federal regulations. However, institutions that do not engage in federally supported research, such as many community hospitals, usually do not have IRBs and may not require any additional IRB review beyond that of the primary board utilized by the OPO.

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Ethics and Regulation in Organ Procurement Research

from Progress in Transplantation

IRB Review of OPO Research Activities

IRB review requires submission of protocols to assess the adequacy of protections for the rights and welfare of human subjects. The extent of IRB review and oversight of research proposals depends on the nature of the research activity and the level of risk to human subjects. The 3 levels of IRB review involve assignment of exempt status, expedited review, or full board review.

Exempt Studies

Some research activities involving little or no risk to human subjects may qualify for exempt status under federal regulations for the protection of human subjects. Federal guidelines require that an institutional officer other than the investigator determine the eligibility of studies for exempt status. Normally, a senior IRB member reviews a brief description of the proposed research to determine whether it qualifies for exempt status and whether informed consent is required. Once a study has been determined to be exempt, the IRB performs no further role in the oversight of the research activity.

There are several ways in which research studies conducted by OPOs might receive exempt status. The activities may not constitute "research" as defined in the federal regulations. According to section 102(d) of the Common Rule,^[4] "research" is defined as "a systematic investigation... designed to develop or contribute to generalizable knowledge." Systematic investigation utilized for internal program evaluation or quality assurance does not constitute " research" under this definition, because it is intended only to evaluate a particular program and to revise specific services of an OPO. The investigation in case 1 (Table 2) may receive exempt status because it is not intended to produce generalizable knowledge that could be used by many OPOs, but is undertaken only to evaluate the agency's new program. However, if an independent investigator undertakes a similar investigation to develop general advice about the usefulness of multi-lingual coordinators to service providers, then the activity is intended to produce generalizable knowledge and constitutes research as defined.

Investigations may constitute research, but qualify for exemption because they fail to involve "human subjects" as defined in the federal regulations.^[4] In the Common Rule, a "human subject" is defined as a "living individual" about whom data are gathered for re-search purposes. Research involving dead individuals is exempt from IRB oversight. In case 2 (Table 2), the human materials used in the investigation are organs from deceased donors and therefore the study may receive exempt status. The definition of "human subject" also does not apply when data do not contain "private identifiable information" or when the individual identity of persons cannot be "readily ascertained" by the investigator. Although there is some confusion about the meaning of "readily ascertained," it is generally agreed that it applies to data that come to the investigator in genuinely anonymous form, that is, when no remaining linkage can be made between the data and the individual identity of the persons whose data are used. If the OPO in case 1 sent general demographic data about donor families to a university investigator for statistical analysis, then the use of these data would not involve human subjects, because the linkage between the data and specific individuals could not be made by the investigator.

A third way studies may qualify for exemption is when they satisfy one of the formal exemption categories described under section 101(b) of the federal regulations.^[4] One category especially relevant to OPO research concerns the study of existing records, data, or specimens.^[10] Studies must satisfy 2 conditions in order to qualify for this exemption. The data used must already be in existence at the time the study is initiated. In addition, the information collected must be "recorded by the investigator in such a manner that the subjects cannot be identified, directly or through identifiers linked to the subjects." According to this regulation, records research is exempt provided that the investigator records the data on worksheets in such a fashion that the information can no longer be linked to identifiable individuals, even if the records from which the information is drawn contain individual subject identifiers. Thus, the study proposed in case 3 (Table 2) would qualify to receive exempt status.

Another category of exempt research frequently undertaken by OPOs involves interview or survey procedures. The federal regulations exempt such studies unless they involve recording the individual identity of subjects and the information gathered might, if publicly disclosed, place subjects at risk of criminal or civil liability or be damaging to their financial standing, employability, or reputation.^[11] In case 4 (Table 2), the proposed research may receive exempt status from the IRB provided that the surveys are administered to subjects without attaching their names or other individual identifiers. Even if the subjects' names were collected on the survey instrument, the study would remain exempt if nothing disclosed in their answers would place them at risk of harm.

Expedited Review of Studies

Studies that do not qualify for exempt status may be eligible for expedited IRB review. Studies may undergo expedited review if they involve no more than minimal risk and the research procedures fall into any of 9 categories eligible for expedited consideration. The expedited process requires only review and approval of the study by a senior IRB member. However, under the expedited review process, the IRB retains responsibility for continuing oversight of the progress of the research. In addition, informed consent is normally required for such studies.

One common type of study qualifying for expedited review involves analysis of data or records that, at least in part, will be collected prospectively after the study is initiated. For example, case 3 might be modified to compare data trends over the last 2 years with data to be collected from donors over the next 2 years. Because the study does not focus exclusively on data collected before the initiation of the study, it does not qualify for exempt status as in the original example. Other types of research procedures qualifying for expedited review involve simple blood draws, gathering physical data on subjects using noninvasive techniques, recording voice or video images, and most behavioral research interventions, provided that the procedures used do not expose the subjects to more than minimal risk.

Full Board Review

Evaluation of proposed research studies by the full IRB is reserved for studies that do not qualify for exempt status or expedited review, either because the procedures used are not covered in these categories of review or because the procedures involve more than minimal risk of harm to subjects. As with studies that qualify for expedited review, continuing IRB oversight on no less than an annual basis is required, and the informed consent of subjects is necessary, unless the studies qualify for waiver of consent under other provisions of the federal regulations. Intervention studies evaluating treatment procedures typically require full board review, as do studies involving nontherapeutic research procedures that pose more than minimal risk of harm for subjects. Because research conducted by OPOs typically do not involve such procedures, IRB review of such studies is not considered further.

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from Progress in Transplantation

Informed Consent in OPO Research Activities

Respect for the personal autonomy of research subjects is a basic moral principle guiding the conduct of human research. It constitutes the rationale for requiring the informed consent of prospective subjects or their legally authorized representatives. Informed consent is a process of disclosure by the investigator that enables prospective subjects or their representatives to determine whether the procedures, risks, and benefits of research participation accord with the subject's values, goals, and interests.^[12] The investigator must disclose those items of information that a reasonable person in the prospective subject's position would need to know in deciding about research participation. The process culminates in an understanding and voluntary decision by the subject or legally authorized representative. This process of negotiation and agreement must be carefully distinguished from the signing of the consent form. The latter action creates documentation that a prior consent negotiation and agreement has occurred, but is not itself the informed consent process.

The centrality of respect for autonomy creates a strong general presumption in favor of securing informed consent in human research. Nevertheless, this presumption may be overridden when studies cannot practicably be carried out without a waiver of informed consent and provision of a waiver will not seriously violate the rights and welfare of subjects. This situation occurs most often in research using existing specimens or medical records. Requiring informed consent might thwart the conduct of the research because recontacting all the subjects would be prohibitively expensive or because significant refusal rates would skew the analysis of the data.^[13] Moreover, there is usually little or no risk of harm to the interests of subjects, provided that the confidentiality of the materials is properly protected and their use does not violate the prior wishes or legal rights of the subjects. In these circumstances, informed consent may be waived.

This exception to the informed consent requirement represents a trade-off between the benefits of research for society and the interest of prospective subjects in exercising their autonomy. It reflects the judgment that the societal benefits of expanded knowledge are sometimes substantial enough to outweigh the obligation to secure informed consent. Nevertheless, respect for the autonomy of subjects is sufficiently important that the exception is restricted to situations in which the interests of the subjects are only modestly implicated and the research cannot be practicably undertaken without the waiver of informed consent. For example, large-scale studies of medical records to assess disease trends involve only a modest imposition on the privacy of individuals and could not be carried out if investigators were required to contact hundreds of former patients to secure their informed consent.

These general moral rules related to informed consent are applicable to the various categories of research activities discussed above. With respect to research studies that are exempt from IRB oversight, a common misconception is that the informed consent requirement also does not apply. This is not the intent of the federal regulations. In issuing its updated regulations in 1981, the Department of Health and Human Services noted specifically that in establishing categories of exempt research, it was not addressing the question of whether these research activities require informed consent.^[14] Rather, the designation of categories of exempt research was intended to free IRBs from continuing oversight of research activities that involve little or no risk to human subjects, so that IRBs could focus on studies that may pose more substantial risks. Thus, each category of exempt research must be evaluated to determine the appropriateness of informed consent.

The conditions for waiving informed consent are usually satisfied when studies do not involve "human subjects" as defined in the federal regulations. According to the regulations, "human subjects" are not involved when materials are drawn from deceased individuals or cannot be linked to identifiable living individuals. In these cases, the investigator is literally unable to seek the informed consent of the subjects. In the modified version of case 1, the investigator receives no data that can be linked to individual subjects, whereas in case 2 the organs used are derived from deceased individuals. Thus, informed consent is not required in these instances.

Another category of exempt studies involves the use of existing data or specimens, provided that the investigator records the research data in a manner that cannot be linked to individual subjects. In these cases, the only risk of harm to subjects derives from the possibility of unintended disclosure of confidential information. If identifiers are not copied from the raw data or specimens, this risk is low. Normally, the subjects have not expressed any prior wishes regarding the use of these materials. Often, it would be extremely expensive and time-consuming to find the subjects and to secure their agreement to participate in the study. Thus, in case 3, the conditions for waiving informed consent are satisfied.

The same conditions may not prevail, however, with regard to interview or questionnaire research. In this case, the investigator must interact with subjects to complete the data collection phase of the research activity. Because interaction must occur, it cannot be argued that there is some practical impediment to obtaining informed consent. Informed consent can be secured at the outset of the interaction. Even though interview activities usually involve no more than minimal risk to subjects, informed consent is required. In case 4, the conditions for waiver of consent are clearly not satisfied.

Unlike studies in the exempt category, the federal regulations establish the presumption that informed consent will be sought for studies that must undergo expedited or full board review by the IRB. The federal regulations also permit waiver of consent for such studies provided that the risk to subjects is minimal, participation will not adversely affect the welfare or rights of the subjects, the studies could not practicably be carried out without the waiver, and subjects will be provided with additional pertinent information after their participation.^[15] However, most studies that require expedited review involve some interaction or intervention with the subjects, thereby undermining any claim that it is not practicable to secure informed consent. Similarly, studies requiring review by the full IRB usually do not qualify for waiver of informed consent because they typically require interaction with the subjects and involve more than minimal risk.

Federal regulations specify the elements of consent information that must be disclosed to prospective subjects, so that each person has adequate information to deliberate about participating in the study (Table 3).^[16] These items include the study's purpose, procedures, risks and discomforts, benefits, alternative treatments, protections for the confidentiality of research data, the availability of compensation for research injuries, an explanation of whom to contact for questions about the research, and a statement that participation is voluntary and that nonparticipation or withdrawal will result in no loss of benefits to which the subject is otherwise entitled. The consent process must also be performed in such a way as to minimize the possibility of coercion or undue influence.

Although federal regulations do not stipulate required elements of information disclosure for exempt studies, the items specified in the federal regulations represent the types of information that a reasonable person would need to know in deciding about participation in research. However, some of these items may not always be relevant for exempt studies. For example, provision of information about the availability of compensation for injury is usually irrelevant to participation in survey research. Similarly, a discussion of alternative treatments that may be advantageous to the subject is not pertinent for such studies. It should also be emphasized that the extent of the disclosure may be appropriately tailored to the complexity of the study procedures and the risk of harm or discomfort to which subjects are exposed. For example, if a survey study does not involve recording the identity of subjects, then the informed consent disclosure does not need to describe special protections for confidentiality, but can merely point out that there are no risks related to confidentiality because personal identifiers will not be recorded.

Situations may arise in which future research is anticipated utilizing records, data, or specimens that are currently being collected, but specific studies have not yet been planned. These situations raise the question of the appropriate role of advance consent to later research use of individually identifiable records or specimens.^[17] When future research use of individually identifiable materials is anticipated, respect for the autonomy of persons requires that we inform them of potential research uses, so that they may determine whether use of their materials is consistent with their own values and goals. Failure to secure advance consent involves deception by omission, because persons are allowed to maintain their usual (but mistaken) assumption that the information gathered in the course of organ procurement will be used only for the purposes of the transaction. Moreover, waiver of advance consent cannot be justified even when the anticipated research will involve little risk to subjects, because there are no grounds for claiming that advance consent is somehow not practicable.

In general, advance consent to research use of records, data, or specimens should cover the same items of information appropriate to informed consent to participation in specific research studies. Although the information disclosed cannot be as specific as that describing a particular study, sufficient information can be provided to secure a valid consent to future re-search use of the materials being collected. For example, the purposes for which the future research will be done can be broadly outlined. The procedures to be used can be roughly sketched, such as what records might be utilized and the kinds of information that might be abstracted from them. The absence of anticipated benefits for the subjects themselves can be indicated. The provisions that will be established to protect the confidentiality of individually identifiable information can be described. Information about whom to contact to retract consent at a future date can be provided.

Two caveats about the use of advance consent are important. First, unless sufficient information is provided to enable a reasonable person to decide about the use of their materials in future research studies, advance consent cannot be considered valid. The statement in a general donor consent form that the donor family agrees to "future research use" of records or data may be considered unacceptable for 2 reasons. It does not provide enough information for a reasonable person to make a knowledgeable decision about future research. In addition, unless the agreement or refusal for the use of the materials in future research is separated from the general consent to donate organs, such consent cannot be considered to be adequately voluntary. Second, granting of advance consent cannot be considered blanket permission for all possible future research uses of the material. If a future study can be reasonably considered to fall outside the terms of the advance consent, then specific consent for that study should be sought unless the conditions for waiver of informed consent are satisfied.

http://www.medscape.com/viewarticle/447480_6

Ethics and Regulation in Organ Procurement Research

from Progress in Transplantation

Summary

OPOs continue to expand research activities involving human subjects. Basic moral principles for the conduct of research with human subjects have been carefully articulated and their application has been specified in federal regulations for the protection of human subjects. Although OPOs may not be required by law to observe these regulations, voluntary use of the regulatory framework will assure donors and their families that OPOs conduct human research according to current standards of ethical practice. Although many of the research activities conducted by OPOs may qualify for exempt status, this determination should be made by the IRB. Even when studies qualify for exempt status, there is a general moral presumption that the informed consent of prospective subjects will be secured unless the narrow conditions for waiver of informed consent are satisfied. Finally, when future research using records and data from donors or their families is anticipated, respect for autonomy requires that OPO personnel provide sufficiently detailed information to donors' families to permit knowledgeable advance consent.