Analysis and Proposed Actions Regarding the NBAC Report: Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity. Comments and Proposed Actions on Specific Recommendations

01/16/2001

  1. COMMENTS AND PROPOSED ACTIONS ON SPECIFIC RECOMMENDATIONS

    This section presents the WG’s comments on each of NBAC’s 21 recommendations using the order and titles from the Report. Most recommendations are addressed singly, but some are grouped together to facilitate discussion. Each section begins with the text of the recommendation, then presents the WG’s analysis, and concludes with the WG’s proposed action.

    1. Recommendations Regarding Review Bodies

      NBAC Recommendation 1: Institutional Review Board (IRB) Membership

      All IRBs that regularly consider proposals involving persons with mental disorders should include at least two members who are familiar with the nature of these disorders and with the concerns of the population being studied. At least one of these IRB members should be a member of the population being studied, a family member of such a person, or a representative of an advocacy organization for this population. These IRB members should be present and voting when such protocols are discussed. IRBs that only occasionally consider such protocols should involve in their discussion two ad hoc consultants who are familiar with the nature of these disorders and with the concerns of the population being studied; at least one of these consultants should be a member of the population being studied, a family member of such a person, or a representative of an advocacy organization for this population.

      Discussion

      The WG agrees with the principle, reflected in this NBAC recommendation, that IRB deliberations should include persons who are familiar with conditions that may affect decisionmaking capacity and with the concerns of the population being studied. [9] This principle is particularly important where research involves subjects who may be vulnerable to coercion or undue influence. The presence of these individuals on the IRB, particularly if able to represent the viewpoint and concerns of the population being studied, should contribute significantly to protecting subject rights and welfare.

      However, the WG does not endorse the specific recommendation that IRBs be required to include two members (or to engage two consultants) who are knowledgeable about mental disorders and the concerns of the population being studied. Such a specific requirement relative to decisional impairments might set a precedent that would not be practical to implement, especially with respect to other vulnerable categories of subjects. [10] Rather, the WG considers it preferable that IRBs be afforded the flexibility needed to address the underlying principle of the NBAC recommendation.

      The HHS regulations at 45 CFR §46.107(a) and FDA regulations at 21 CFR §56.I07(a) recommend that IRBs that regularly review research involving subjects with mental disabilities include “one or more individuals who are knowledgeable about and experienced in working with these subjects.” Nevertheless, the WG shares NBAC’s concern that more effective and consistent implementation of this regulation is needed, especially in research involving conditions that may affect decisionmaking capacity. [11]

      Proposed Action

      The WG proposes that the Office for Human Research Protections (OHRP) - which is the successor to the Office for Protection from Research Risks (OPRR) and is located in the Office of the Secretary, Office of Public Health and Science - working in consultation with FDA, develop and issue interpretive guidance for IRB review of research directed toward persons with mental or physical conditions that are associated with decisional impairment. The WG further recommends that OHRP consider incorporating the following elements in its guidance:

      1. That a diagnosis of mental disorder does not necessarily imply decisional impairment relative to research participation; and that certain physical disorders may result in a high likelihood of such impairment.

      2. That where an IRB regularly reviews research directed toward persons with conditions that are associated with decisional impairment, the IRB should include members who are familiar with such conditions and with the concerns of the population being studied.

      3. That where an IRB only occasionally reviews research directed toward persons with conditions that are associated with decisional impairment, the IRB should involve in its discussion consultants who are familiar with such conditions and with the concerns of the population being studied.

      4. That every effort should be made to include among the IRB members or consultants described in paragraphs 2 and 3 at least one person who has the background, experience, and willingness to serve as an advocate, specifically representing the viewpoint and concerns of the population being studied. Further,

        1. That, where appropriate, every effort should be made to engage, as advocates, members of the population being studied. Family members, organization representatives, or others may also serve as advocates where appropriate;

        2. That every effort should be made to ensure that subject advocate IRB members are present when the convened IRB discusses and votes on the proposed research; and

        3. That, where research is eligible for IRB review under expedited procedures, every effort should be made to include appropriate subject advocate IRB members or consultants in the review.

      NBAC Recommendation 2: Creation of a Special Standing

      Panel (SSP)The Secretary of the Department of Health and Human Services should convene a Special Standing Panel (SSP) on research involving persons with mental disorders that may affect decisionmaking capacity. The panel’s tasks should include:

      1. reviewing individual protocols that cannot otherwise be approved under the recommendations described in this report, that have been forwarded by IRBs to the SSP for its consideration. If the SSP finds that a protocol offers the possibility of substantial benefit to the population under study, that its risks to subjects are reasonable in relation to this possible benefit, and that it could not be conducted without the proposed population, then the SSP may approve the protocol if it is satisfied that all appropriate safeguards are incorporated Under no circumstance, however, should the SSP approve a protocol that reasonable, competent persons would decline to enter;

      2. promulgating guidelines that would permit local IRBs to approve protocols that cannot otherwise be approved under the recommendations described in this report. Such guidelines could suggest that a particular class or category of research, using specified research interventions with certain identified populations, could be considered by local IRBs without the need to resort to the SSP for further approval. Under no circumstances, however, should the SSP promulgate guidelines permitting IRBs to approve research that would enroll subjects who lack decisionmaking capacity in protocols that reasonable, competent persons would decline to enter.

        The SSP should have members who can represent the diverse interests of potential research subjects, the research community, and the public. The panel’s protocol approvals and guidelines should all be published in an appropriate form that ensures reasonable notice to interested members of the public.

        Those federal agencies that are signatories of the Common Rule should agree to use the SSP, and the SSP ‘s effectiveness should be reviewed no later than five years after inception.

      Discussion

      Under current regulations, IRBs have authority to approve protocols that present greater than minimal risk for decisionally impaired subjects, but promise substantial scientific benefit, when the risks are reasonable in relation to the potential benefits. Were IRBs to be stripped of this authority in the case of research that offers no direct medical benefit to subjects, as NBAC recommends (see Recommendation 12), the WG agrees that a mechanism would have to be created to allow acceptable protocols in this category to be conducted. The WG also agrees that guidelines could be valuable to IRBs reviewing protocols that pose moderate risks but require participation by subjects whose decisional capacity maybe impaired, in order for the IRBs to understand, prevent, or alleviate serious problems affecting persons with conditions that may affect decisionmaking capacity.

      However, the WG is not persuaded that the SSP is the appropriate mechanism to accomplish either of these functions. As noted in section All above, the WG has serious concerns about the feasibility of the SSP review process in the absence of an intermediate risk category under which IRBs may approve protocols without involvement of a national-level panel.

      Even if the envisioned regulatory framework were modified to include an intermediate category of risk, implementation would be inadvisable prior to full consideration of its similarities and differences with respect to the current regulations. For example, whereas the envisioned SSP would have authority to approve or disapprove protocols, the national-level review panels currently provided for in HHS regulations to oversee certain research involving pregnant women (Subpart B), prisoners (Subpart C), and children (Subpart D) [12] are ad hoc panels that advise the Secretary. Further, preempting the ability of IRBs to approve certain protocols not only would require rulemaking but also would create a precedent that could have an impact well beyond this area. [13] Moreover, since NBAC is currently conducting a comprehensive review of human subject protections, any significant regulatory changes in this areas would be premature until NBAC’s further findings and recommendations are available.

      NBAC intended the SSP “to provide some genuine flexibility to respond to new knowledge and to create greater uniformity of understanding” in an area of disagreement about how to achieve the proper balance between advancing knowledge and protecting vulnerable subjects. (Report at p. 55). The WG agrees that both of these goals are important but notes that two IRBs reviewing similar . protocols may appropriately come to different conclusions because of local differences - as where one IRB is considering more restrictive State laws or is more confident about the investigator’s sensitivity to decisional impairment issues. Whether establishing a national panel with approval authority is the proper way to balance concerns about uniformity and flexibility in this area requires a more thorough public discussion.

      Proposed Action

      As outlined in the discussion following Recommendations 10-12, the WG proposes that the Department solicit additional public input on whether, and how, a national-level panel should be implemented to protect the rights and welfare of human research subjects whose conditions are associated with decisional impairment.

    2. Recommendations Regarding Research Design

      NBAC Recommendation 3: Appropriate Subject Selection

      An IRB should not approve research protocols targeting persons with mental disorders as subjects when such research can be done with other subjects.

      Discussion

      The WG agrees with NBAC’s intent; this recommendation is consistent with the “basic ethical principles” of respect for persons, beneficence and justice -- as identified in the Belmont Report by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In particular, the recommendation applies the justice principle to subject selection. These principles are currently embodied in the HHS regulations in §46.111 (a)(3) and the FDA regulations in §56.111(a)(3): “Selection of subjects is equitable:... the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.”

      The WG shares NBAC’s view that it is inappropriate to engage in research persons who are decisionally impaired simply because, for example, their condition provides investigators easier access to subjects who are unlikely to object. Due consideration must be given to the appropriateness and scientific value of conducting the proposed research with subjects who can provide informed consent. However, this recommendation should not be interpreted to preclude specific categories of research with persons who are decisionally impaired even when that research is possible with those who can consent but is likely not to be scientifically practical or sufficient. Some research that literally “can be done with other subjects” and sometimes should be done first with other subjects, cannot be conducted equally well with subjects who can provide informed consent in those instances where crucial information cannot be obtained without the participation of the same types of subjects who are ultimately going to receive the intervention or otherwise benefit from the research. Investigators and IRBs must carefully weigh the appropriateness of recruiting persons with decisional impairment in studies in terms of both the scientific question and subject concerns.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, develop and issue interpretive guidance clarifying how these concerns should be addressed within the existing regulations.

      NBAC Recommendation 4: Justifying Research Design and Minimizing Risks

      Investigators should provide IRBs with a thorough justification of the research design they will use, including a description of procedures designed to minimize risks to subjects. In studies that are designed to provoke symptoms, to withdraw subjects rapidly from therapies, to use placebo controls, or otherwise to expose subjects to risks that may be inappropriate, IRBs should exercise heightened scrutiny.

      Discussion

      The WG agrees that “investigators should provide IRBs with a thorough justification of the research design they will use, including a description of procedures designed to minimize risks to subjects.” NBAC has rightly called attention to the importance of considering research design. Although current regulations do not explicitly require investigators to justify their research designs, the information is necessary for IRBs to make the determinations required under §46.111(a)(1)-(2) of the HHS regulations and 21 CFR §56.111(a)(1)-(2) of the FDA regulations. The IRB must ensure that risks to subjects “are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk” and “are reasonable in relation to anticipated benefits, if any, to subjects and the importance of the knowledge that may reasonably be expected to result.” Since the investigator is in the best position to provide justification for the research design, the regulation implicitly requires the investigator to provide this information.

      The WG is concerned, however, that some may mistakenly read the last sentence of Recommendation 4 together with some of the accompanying text as implying that protocols designed to provoke symptoms, to withdraw subjects from therapies, or to use placebo controls are inherently unethical. These designs may sometimes expose subjects to heightened risk and, therefore, warrant greater scrutiny by IRBs, rigorous justification by investigators, and particularly close attention to the subjects in the study. However, they are not inherently unethical; and the WG does not agree with the possible implications stemming from the use of the word “otherwise” in the second sentence. It should also be appreciated that study designs that are inadequate to provide useful information are unethical. [14]

      The WG also agrees that IRBs should ensure that all research designs are justified by a positive risk-benefit analysis and that subjects will be fully informed of the risks involved, including those stemming from assignment to a placebo group in clinical research. “An analysis of each case depends on the validity of standard treatment, on the seriousness of the disease, the burden of the intervention, and some fundamental value questions about whether the risks are worth the possible benefits.” [15] As NBAC points out, it may be worthwhile to remind IRBs that they are required to make these determinations and to minimize risks as fully as possible for all research covered by the HHS and FDA regulations, especially research involving vulnerable populations.

      Proposed Action

      The WG proposes that OHRP, working closely with FDA on matters of study design, issue such additional interpretive guidance as it considers necessary to implement this Recommendation in accordance with the foregoing discussion.

      NBAC Recommendation 5: Evaluating Risks and Benefits

      Investigators should provide IRBs with a thorough evaluation of the risks and potential benefits to the human subjects involved in the proposed protocol. The evaluation of risks includes the nature, probability, and magnitude of any harms or discomforts to the subjects. The evaluation of benefits should distinguish possible direct medical benefits to the subject from other types of benefits.

      Discussion

      The WG strongly supports this recommendation. Although current regulations do not explicitly require investigators to provide this information, the information is necessary for IRBs to carry out their obligations under §46.111 of the HHS regulations and §56.111 of the FDA regulations - i.e., that risks to subjects (1) be minimized and (2) be reasonable in relation to (a) the anticipated benefits, if any, and (b) the importance of the knowledge that may reasonably be expected to result. In the text following the recommendation, NBAC recognizes that the requirements are implicit in the regulations: “This recommendation reaffirms what is already in the federal regulations....”: (Report at p. 56). [16] IRBs typically request this information. Thus, the recommendation seems to promote the efficient operation of IRBs. As the text following the recommendation emphasizes, “The assessment should include consideration of the particular procedures proposed and their relationship to the specific conditions of the individuals who may be involved as study subjects.” (Report at p. 56).

      Although the investigator is required to provide risk assessment information, the recommendation does not excuse the IRB from making its own independent assessment and evaluation as to whether the protocol should be approved under the Department’s regulations and guidelines. As NBAC notes, “IRBs should be alert to the possibility that researchers and subjects may not evaluate the risks and benefits of a particular study in the same way.” (Report at p. 56). Participation of “individuals who are knowledgeable about and experienced in working with these subjects,” in accordance with §46.107(a) of the HHS regulations and §56.107(a) of the FDA regulations, may assist the IRB in making its independent assessment. See above regarding Recommendation 1.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, issue such additional interpretive guidance as it considers necessary to implement this Recommendation.

    3. Recommendations Regarding Informed Consent and Capacity

      NBAC Recommendation 6: Informed Consent

      No person who has the capacity for consent may be enrolled in a study without his or her informed consent. When potential subjects are capable of making informed decisions about participation, they may accept or decline participation without involvement of any third parties.

      Discussion

      The WG fully supports this recommendation. Informed consent is the bedrock principle that makes the enterprise of human research permissible. Soliciting informed consent respects the research subject’s autonomy. It also enables the subject to make an informed choice about the risks and benefits of research. Informed consent is a cornerstone of the HHS and FDA regulations.- This recommendation is consistent with those regulations. See 45 CFR § 46.111(a)(4) and § 46.116 (except where the IRB may waive consent, “no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative”) and 2I CFR §56.111 (a)(4) and §50.20, respectively. To be legally effective, consent by the subject requires that the subject have the capacity to consent; conversely, decisionmaking by the subject’s surrogate is effective only when the surrogate is legally authorized to provide consent under State law and the subject lacks capacity to consent.

      NBAC noted and the WG agrees that, where the existing regulations permit waiver of informed consent, this recommendation does not negate that waiver.

      Proposed Action

      No action is needed.

      NBAC Recommendation 7: Objection to Participation in Research

      Any potential or actual subject’s objection to enrollment or to continued participation in a research protocol must be heeded in all circumstances. An investigator, acting with a level of care and sensitivity that will avoid the possibility or the appearance of coercion, may approach people who previously objected to ascertain whether they have changed their minds.

      Discussion

      The WG agrees with this recommendation. Under the HHS and FDA regulations, participation by subjects is voluntary, and subjects may discontinue participation at any time. 45 CFR §46.116(a)(8) and 21 CFR §50.25(a)(8). Thus, investigators must heed a subject’s objection to participation that is articulated in any manner. Similarly, investigators must heed a subject’s objection to any intervention or procedure in the protocol. It is important to determine carefully whether the subject is objecting to a particular procedure in a study or to participation altogether. If the former, it may be possible to continue the study without the particular procedure, or if not, to re-approach the subject with care, as NBAC suggested. Investigators and IRBs must minimize the risk of coercion or undue influence before and throughout the trial, particularly in approaching vulnerable subjects, who previously objected, to ascertain whether they have changed their minds. 45 CFR §46.111(b) and 21 CFR §56.111(b). Guidance clarifying the right of individuals with decisional impairment to object to participation may be helpful to investigators and IRBs.

      Further, the WG emphasizes that investigators must take care to minimize risks to any subject who is withdrawing from the study. Moreover, if at any time there is ambiguity regarding the subject’s willingness to participate, investigators must err on the side of subject safety and autonomy.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, issue such additional interpretive guidance as it considers necessary to implement this recommendation.

      NBAC Recommendation 8: Assessing Potential Subjects’ Capacity to Decide about Participating in a Research Protocol

      For research protocols that present greater than minimal risk an IRB should require that -an independent, qualified professional assess the potential subject’s capacity to consent. The protocol should describe who will conduct the assessment and the nature of the assessment. An IRB should permit investigators to use less formal procedures to assess potential subjects’ capacity if there are good reasons for doing so.

      Discussion

      The WG recognizes that accuracy about the subject’s capacity to provide informed consent is a prerequisite to respect for persons and to compliance with the HHS and FDA regulations. [17] Adopting this recommendation would create a strong presumption that IRBs should require formal capacity assessment for all greater than minimal risk research in this area, although NBAC notes that IRBs may forego requiring a capacity assessment “if there are good reasons for doing so.” However, a requirement, even a presumption, that capacity must be assessed is problematic.

      Under the regulations, obtaining valid informed consent from a subject necessarily requires that the subject have capacity under both the law of the jurisdiction and the regulations. See 45 CFR §46.116(a) and 21 CFR §50.20 (“no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject”). Determining that the subject has capacity and can give legally effective consent is primarily the responsibility of the investigator, who must also apply the local standard to avoid liability exposure for treatment without informed consent. Under the current regulations, the IRB is also responsible; for it must determine that the investigator’s protocol satisfies State and Federal informed consent requirements. See 45 CFR §46.11I (a)(4) & (b) and 21 CFR §50.I11 (a)(4) & (b).

      NBAC recommends that a formal capacity assessment be required in almost all cases, rather than at the IRB’s discretion. Although the WG recognizes the importance of accurate capacity assessment, requiring a formal assessment would be problematic and premature for a number of reasons. As NBAC recognizes, most persons with mental disorders that may affect decisional capacity in fact have decisional capacity. The same is true of other conditions associated with decisional impairment. Thus, a requirement, even a presumption, that capacity be formally assessed would often be unnecessary, and the WG is concerned it could contribute to the lingering stigmatization of persons with mental disorders. [18] Moreover, the need to ensure that the subject has capacity to consent is not unique to this area and thus will have wider implications. [19]

      Requiring a formal capacity assessment is also problematic and premature because there are no known, accurate, and validated capacity assessment instruments for clinical care, let alone research participation. There is also no consensus regarding the professional qualifications necessary to perform capacity assessments. Determining whether the person performing the assessment can be “independent” is also problematic if he or she is paid by the researcher or is otherwise affiliated with the institution; IRBs would need to have a clearer definition before this requirement could be implemented. Moreover, the standard for legal capacity to consent must be determined under local laws, which are not uniform. When crucial issues are unresolved -- such as who should perform the assessment, what is the proper assessment instrument, and according to what standard for capacity, it would be inappropriate for the Department to require formal capacity assessments.

      Under the current regulations, IRBs remain responsible for determining that every protocol satisfies State and Federal informed consent requirements and are given the authority to impose any additional safeguards they deem necessary, including a formal capacity assessment. [20] In selecting the appropriate safeguards, the IRB may consider the potential subjects’ condition, the degree of impairment, the complexity of the protocol, the degree of risk involved, the research design, the phase(s) of the research when capacity is most at issue, and the IRB’s assessment of the investigator’s ability to provide accurate and ethical capacity assessment. Especially given the many unsettled factors in current capacity assessment practices, the WG concludes that IRBs should continue to have discretion to determine in each case whether capacity assessments or other safeguards are warranted.

      However, the WG recognizes that there is substantial room for improvement in the way that IRBs handle the informed consent process. Working with subjects whose decisionmaking capacity may be impaired is an additional complication to adequately addressing informed consent. Thus, ensuring the adequacy of informed consent in general is crucial to protecting vulnerable subjects.

      The WG agrees with NBAC’s recommendation that NIH support research to expand knowledge about the most appropriate methodologies for assessing decisionmaking capacity so they may become available to researchers. NIH has already taken several steps to increase research and prioritize studies focused on human subject issues. See Appendix B.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, issue such additional interpretive guidance as it considers necessary to enhance the way in which investigators and IRBs address the informed consent process, in general, as well as when decisional impairment is an issue.

      NBAC Recommendation 9: Notifying Subjects of Incapacity Determinations and Research Enrollment

      A person who has been determined to lack capacity to consent to participate in a research study must be notified of that determination before permission may be sought from his or her LAR to enroll that person in the study. If permission is given to enroll such a person in the study, the potential subject must then be notified. Should the person object to participating, this objection should be heeded.

      Discussion

      The WG agrees with the principles embodied in this recommendation but would emphasize them differently. Respect for persons includes a potential subject’s right to object to a determination that he or she lacks capacity, to object to the proposed involvement of third parties, and to object to any participation in research. [21] Belmont Report at § C.1. Whether or not the person has the capacity to give informed consent, he or she is entitled to object, without the involvement of third parties, to participation or continuation in research. This right to object is implemented in current regulations, 21 CFR 50.25(a)(8). [22] Providing a potential subject with notice and opportunity to object to a determination that may lead to unwanted involvement by others or enrollment in research by another is a necessary prerequisite to showing respect for persons and therefore crucial to these rights.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, issue such additional interpretive guidance as it considers necessary to implement this recommendation.

    4. Recommendations Regarding Categories of Research

      Recommendations 10-12 are discussed together.

      NBAC Recommendation 10: Research Protocols Involving Minimal Risk

      An IRB may approve a protocol that presents only minimal risk, provided that:

      1. consent has been waived by an IRA pursuant to federal regulations; or

      2. the potential subject gives informed consent; or

      3. the potential subject has given Prospective Authorization, consistent with Recommendation 13, and the potential subject’s LAR gives permission, consistent with Recommendation 14; or

      4. the potential subject’s LAR gives permission, consistent with Recommendation 14.

      NBAC Recommendation 11: Research Protocols Involving Greater than Minimal Risk that Offer the Prospect of Direct Medical Benefit to Subjects

      An IRB may approve a protocol that presents greater than minimal risk but offers the prospect of direct medical benefit to the subject, provided that:

      1. the potential subject gives informed consent; or

      2. the potential subject has given Prospective Authorization, consistent with Recommendation 13, and the potential subject’s LAR gives permission, consistent with Recommendation 14; or

      3. the potential subject’s LAR gives permission, consistent with Recommendation 14. The research must also comply with Recommendations 7, 8, and 9.

      NBAC Recommendation 12: Research Protocols Involving Greater than Minimal Risk Research that Do Not Offer the Prospect of Direct Medical Benefit to Subjects

      An IRB may approve a protocol that presents greater than minimal risk but does not offer the prospect of direct medical benefit to the subject, provided that:

      1. the potential subject gives informed consent; or

      2. the potential subject has given Prospective Authorization, consistent with Recommendation 13, and the potential subject’s LAR gives permission, consistent with Recommendation 14; or

      3. the protocol is approved by the panel described in Recommendation 1, or falls within the guidelines developed by the panel, and the potential subject’s LAR gives permission, consistent with Recommendation 14.

      The research must also comply with Recommendations 7, 8, and 9.

      Discussion

      The WG agrees with the principle, reflected in NBAC’s Recommendations 10, 11, and 12, that additional safeguards are warranted when research is directed toward subjects with mental or physical conditions that are associated with decisional impairment. This principle is consistent with current requirements of the HHS regulations at 45 CFR §46.111(b) and the FDA regulations at 21 CFR §56.111(b).

      However, as detailed in the next section on Recommendation 13, the WG believes that widespread execution of Prospective Authorizations for research is unlikely. Moreover, the large number of proposed protocols that Recommendation 12 would require to be reviewed by the SSP could make this recommendation impractical to implement. (See analysis in section A.II.a above).

      The WG senses substantial polarity of opinion within the research and ethics communities regarding the involvement of subjects with decisional impairment in greater than minimal risk research that presents no prospect of direct benefit to the individual subject. Some have asserted that such research cannot be justified under any circumstances. Some have argued that certain important, greater than minimal risk research may be justifiable only in terms of “future benefits to others who have or will develop the condition or disorder” under study, or that prohibiting such research “would contribute to needless suffering.” (See, e.g., NIH, Interim - Research Involving Individuals with Questionable Capacity to Consent: Points to Consider, Appendix C). Others have asserted that certain non-treatment research (e.g., laboratory studies involving lumbar punctures or CT scans with contrast; population-based epidemiology studies), while presenting somewhat more than minimal physical, psychological, or social risk to subjects, may be justified if appropriate protections are provided to safeguard subjects’ rights and welfare. Still others question why NBAC limited its consideration to the prospect of direct medical benefit to subjects, especially with regard to non­medical research, without considering possible psychological or social benefits.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, solicit additional public comment regarding appropriate approval standards as a function of differing levels of risk in research directed toward subjects with mental or physical conditions that are associated with decisional impairment. The WG proposes in particular that a formal Federal Register solicitation request comment on appropriate mechanisms for ensuring needed protections; appropriate regulatory frameworks for characterizing informed consent and IRB approval requirements as a function of differing levels of risk; and acceptability of certain overarching principles.

      1. With respect to mechanisms, the solicitation could invite comment on at least three alternatives:

        1. best practice consensus building
        2. OHRP/FDA guidance; and
        3. rulemaking;
      2. With respect to the regulatory frameworks for review of research protocols that would involve decisionally impaired subjects but offer no prospect of direct benefit to them, the solicitation could invite comment on at least three alternative approaches:
        1. leaving discretion with the cognizant IRB - in accord with current regulations and guidance such as the NIH “Points to Consider” (Appendix C);
        2. establishing a regulatory structure similar to that used in the children’s regulations, 45 CFR 46.406 - i.e., introducing a concept such as “minor increment above minimal risk”; authorizing IRBs, with appropriate guidance, to approve research protocols in this risk category as well as the “minimal risk” category, but requiring that IRBs defer to a national-level panel regarding research protocols that present “more than a minor increment above minimal risk”; and
        3. establishing the regulatory structure recommended by NBAC in the Report.
      3. With respect to overarching principles, the solicitation could invite comment on at least the following candidates:
        1. Additional safeguards are needed for all HHS-conducted, HHS-supported, or HHS-regulated research that is directed toward subjects with mental or physical conditions that are associated with decisional impairment.
        2. Additional safeguards that should be considered include: the use of independent consent monitors, independent assessment of the subject’s capacity to consent, advance research directives or prospective research authorizations, waiting periods, and special communication techniques. In general, safeguards should be commensurate with the degree of risk, the nature of the risk, the complexity of the research, and the degree of the subjects’ impairment.
        3. For all research involving subjects with mental or physical conditions that are associated with decisional impairment, any subject’s objection to any research procedure or intervention or to participation in research should be honored.
        4. Minimal risk research should be permitted if (a) the legally effective informed consent of the subject or the subject’s LAR is obtained, or (b) informed consent requirements may be waived in accordance with Subpart A of 45 CFR Part 46.
        5. Greater than minimal risk research that presents the prospect of direct benefit to the individual subject should be permitted if (a) the relation of the anticipated benefit to the risk is at least as favorable to the subject as that presented by available alternative approaches; and (b) the legally effective informed consent of the subject or the subject’s LAR is obtained. In determining whether a protocol presents a prospect of direct benefit to the subject, the IRB may consider medical, psychological, social, or other benefits that it deems relevant and meaningful.
        6. Greater than minimal risk research that presents no prospect of direct benefit to the individual subject should be permitted if (a) the legally effective informed consent of the subject or the subject’s LAR is obtained; (b) the research only presents experiences that are (i) likely to be identical to, or reasonably equivalent to, experiences inherent in the target population’s actual medical, dental, psychological, social, or educational situation; and (ii) consistent with accepted professional standards relative to the target population; (c) appropriate additional safeguards are included to protect the rights and welfare of the subjects; and (d) the research is likely to yield important generalizable knowledge about the subject’s disorder or condition.
        7. Other research or classes of research presenting greater than minimal risk without- - prospect of direct benefit to the individual subject should be permitted if the Secretary, after consultation with a panel of experts, determines that (a) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of persons with mental or physical conditions that arc -associated with decisional impairment; (b) the research will be conducted in accordance with sound ethical principles; and (c) the legally effective informed consent of the subject or the subject’s LAR will be obtained.
    5. Recommendations Regarding Surrogate Decisionmaking

      NBAC Recommendation 13: Prospective Authorization

      A person who has the capacity to make decisions about participation in research may give Prospective Authorization to a particular class of research if its risks, potential direct and indirect benefits, and other pertinent conditions have been explained. Based on the Prospective Authorization, an LAR may enroll the subject after the subject has lost the capacity to make decisions, provided the LAR is available to. monitor the subject’s recruitment, participation, and withdrawal. The greater the risks posed by the research protocol under consideration, the more specific the subject’s Prospective Authorization should be to entitle the LAR to permit enrollment.

      Discussion

      The WG agrees that an advance directive for research, such as NBAC’s “Prospective Authorization,” where permitted by State or other applicable law, can be extremely useful in some circumstances. For example, a valid Prospective Authorization may be useful and feasible if executed prior to enrollment in a protocol during which decisionmaking capacity may become impaired or by a person who has been diagnosed with a degenerative disorder, such as Alzheimer’s disease.

      However, the recommendation will not prove useful to most subjects whose conditions are associated with decisional impairment. First, individuals who have never had capacity will be unable to execute a Prospective Authorization.

      Second, it is unlikely that Prospective Authorizations will be executed by a significant number of individuals. Most States authorize advance directives for end-of-life medical care (such as a living will or a durable power of attorney), yet few individuals use them, even though most patients are informed of this option and provided with forms by their health care facilities. Since individuals would be more motivated to indicate preferences regarding end-of-life care than to indicate preferences regarding involvement in research without direct benefit, Prospective Authorizations will seldom play a role in this area of research.

      Finally, because of the degree of specificity suggested in the recommendation’s explanatory text, it is extremely unlikely that a validly executed Prospective Authorization will be effective, except for those executed immediately before the subject’s enrollment in a protocol. Due to scientific progress, research designs and interventions are constantly evolving; consequently, the ability to predict the attendant risks and benefits will diminish over time.

      The WG agrees with NBAC that autonomous choices, made while capable, to cover future periods of mental impairment or incapacity should be respected. When a loss of decisional capacity is foreseeable, investigators should encourage subjects to consider how their wishes regarding research may be carried out; and IRBs should consider the necessity of this safeguard. Any advance directive rejecting a research intervention must be heeded. With regard to advance directives to participate in research, investigators must observe local laws regarding their validity and effect. [23]

      All or nearly all the States recognize the right of individuals with capacity to have their wishes regarding health care carried out after a loss of capacity, particularly where the wishes are formalized in an advance directive. However, the WG is not aware of any State that has recognized the validity of an advance directive for research. It would be helpful to IRBs, investigators and subjects if the States addressed the issue of advance directives for research. Until then, Federal action regarding such a Prospective Authorization would not be productive; although, as addressed below in connection with Recommendation 17, ascertaining the wishes of subjects for whom impairment of capacity is foreseeable may be beneficial.

      Proposed Action

      The WG proposes that the Secretary make the States aware of NBAC’s Recommendations and our proposed actions and encourage the States to consider them, by sending copies of NBAC’s Report and this Analysis to the States’ Attorneys General.

      Recommendations 14-16 are discussed together.

      NBAC Recommendation 14: Legally Authorized Representatives

      An LAR may give permission (within the limits set by the other recommendations) to enroll in a research protocol a person who lacks the capacity to decide whether to participate, provided that:

      1. the LAR bases decisions about participation upon a best estimation of what the subject would have chosen if capable of making a decision; and

      2. the LAR is available to monitor the subject’s recruitment, participation, and withdrawal from the study; and

      3. the LAR is a person chosen by the subject, or is a relative or friend of the subject.

      NBAC Recommendation 15: Expansion of the Category of Legally Authorized Representatives and of the Powers Granted under Statutes for Durable Powers of Attorney (DPA) for Health Care

      In order to expand the category of LARs:

      1. an investigator should accept as an LAR, subject to the requirements in recommendation 14, a relative or friend of the potential subject who is recognized as an LAR for purposes of clinical decision making under the law of the state where the research takes place.

      2. states should confirm, by statute or court decision, that:

        1. an LAR for purposes of clinical decision making may serve as an LAR for research; and

        2. friends as well as relatives may serve as both clinical and research LARs if they are actively involved in the care of a person who lacks decisionmaking capacity.

      NBAC Recommendation 16: State Legislation Regarding Advanced Directives for Research

      States should enact legislation, if necessary, to ensure that persons who choose to plan for future research participation are entitled to choose their LAR.

      Discussion

      The WG agrees with NBAC that determining who may serve as an LAR and how the LAR should make decisions is important to research involving persons whose conditions are associated with decisional impairment. The current regulations recognize and implement the principle that State law controls on the issue of who may provide consent for a decisionally-impaired individual to participate in research. [24] The NBAC recommendations also appear to recognize this principle, but it is not clear that NBAC accounted for all the potential conflicts between State law and Federal requirements or for the State-Federal coordination problems inherent in its recommendations.

      Recommendation 14 suggests an amendment to the regulations that would define “Legally Authorized Representative” to include “a person chosen by the subject, or [who] is a relative or friend of the subject,” and those who may serve as surrogate decision-makers for health care. In the absence of a valid and effective Prospective Authorization, NBAC’s framework would extend the authority of LARs to enroll subjects only to minimal risk research or to research where there is a prospect of direct benefit, unless the protocol has been approved by the SSP of Recommendation 2. Otherwise, where research involves greater than minimal risk and does not hold out the prospect of. direct benefit, the authority of the LAR would apparently extend only to permitting continued enrollment or withdrawing the subject. It is not clear how these recommendations would relate to State laws, which may be more or less restrictive.

      Because issues surrounding the authority of a surrogate to act on behalf of another are the province of State law, investigators must comply with both local law and the Federal regulations. [25] There are no potential conflicts or coordination problems so long as Federal requirements are in addition to State law requirements, or vice versa. However, if the State and Federal requirements are discordant, researchers would face the dilemma of jeopardizing their Federal funding or subjecting themselves to potential liability under State law. Recommendation 14(B), referring to the LAR’s availability to monitor the subject’s participation in the research, could be implemented in addition to State law requirements. However, 14(A) and (C) propose Federal requirements that may be contrary to State law. ‘This is apparently recognized in Recommendation 15(B), in which NBAC recommends that State law be amended to be consistent with Recommendations 14(C) and 15(A). Except for Recommendation 14(B), implementing NBAC’s recommendations as Federal requirements for LARs would be dependent upon action by the States.

      Recommendations 15 and 16 are not directed to the Department. However, as NBAC recognized, State laws would have to change in order for the other recommendations regarding LARs to be operational. Not all States have addressed the issue of who may act as an LAR in the absence of an advance directive. Those that have addressed the issue have only identified LARs for making health care treatment decisions.

      However, the WG notes that one State that has tried to address research involving persons with decisional impairment, including LAR issues, has now abandoned that effort. Maryland’s Assistant Attorney General recently wrote a letter stating that the “effort at finding common ground must be reckoned a failure.” “With some opponents damning the bill as unacceptably onerous and others as unacceptably weak, committee, approval would have been most unlikely. Therefore, our effort to pursue this legislation has ended. The legal status quo, unsatisfactory as it is will remain.” [26]

      Despite such potential difficulties, it would be helpful to IRBs, investigators and subjects if the States addressed the issue of research LARs both under, and in the absence of, advance directives.

      Proposed Action

      The WG proposes that the Secretary make the States aware of NBAC’s recommendations and our proposed actions and encourage the States to consider them, by sending copies of NBAC’s Report and this Analysis to the States’ Attorneys General.

      NBAC Recommendation 17: Involving Subjects’ Family and Friends

      For research protocols involving subjects who have fluctuating or limited decisionmaking capacity or prospective incapacity, IRBs should ensure that investigators establish and maintain ongoing communication with involved caregivers, consistent with the subjects’ autonomy and with medical confidentiality.

      Discussion

      The WG agrees that - when a research protocol involves a subject with fluctuating decisionmaking capacity, limited decisionmaking capacity, or prospective decisionmaking incapacity - anticipatory discussions among the subject, the investigator(s), caregiver(s), and/or other concerned parties could contribute materially to the subject’s safety and welfare during the course of the research. The WG agrees further that, when fostering such discussions, investigators and IRBs are obliged to be mindful of the subject’s autonomy, the confidentiality of information, and the requirements of applicable statutes. [27]

      The WG does not endorse the specific recommendation that IRBs be required to “ensure that investigators establish and maintain ongoing communication with involved caregivers.” [28] (Emphasis added). In view of the inherent difficulty of achieving a consensus on the definition of such core concepts as “involved caregiver” and “consistent with the subject’s autonomy and medical confidentiality,” development of an effective regulatory requirement seems likely to involve a challenging and possibly protracted rulemaking process. Moreover, implementation of requisite procedures to ensure that appropriate communication is established and maintained would impose new burdens of effort, time, and costs upon IRBs at a time when many of them frequently are hard-­pressed to discharge their current functions.

      The WG believes that, where the subject might be expected to lose decisionmaking capacity during the research, temporarily or permanently, investigators should solicit the subject’s preferences regarding communications with, and involvement of, caregivers or other concerned parties prior to commencement of the study. Under 45 CFR §46.111(b) and 21 CFR § 56.111(b) an IRB may so require, if it determines that safeguard is warranted for a particular protocol.

      Proposed Action

      The WG proposes that OHRP, working in consultation with FDA, issue such additional interpretive guidance as it considers necessary to implement this recommendation in accordance with the foregoing discussion.

    6. Recommendations Regarding Education. Research, and Support

      NBAC Recommendation 18: Reviewing and Developing Educational Materials Regarding Research

      Professional associations and organizations should develop (or review their existing) educational materials pertaining to research involving persons with mental disorders to ensure that they are adequate to inform the health care community and the public of ethical issues related to the involvement of such persons as research subjects, and to convey the importance of measures to ensure that their rights and we fare are adequately protected

      Discussion

      This recommendation is not directed at the Department. However, the WG endorses this recommendation for all conditions that may cause decisional impairment and commends it to these associations and organizations for consideration.

      Proposed Action

      No Departmental action is needed.

      NBAC Recommendation 19: Expanding Knowledge about Capacity Assessment and Informed Consent

      The National Institutes of Health (NIH) should sponsor research to expand understanding about decisionmaking capacity, the best means for assessing decisionmaking capacity, techniques for enhancing the process of informed consent, and the possible roles of surrogate decision makers in research. It should sponsor research to evaluate the risks of various research interventions, and the attitudes of potential subjects toward the prospect of participating in research. Particular attention should be paid to attitudes toward participating in research of greater than minimal risk that does not offer the prospect of direct medical benefit to subjects. These data may be of particular value to the panel described in Recommendation 2.

      The NH should ensure that proposals for training grants and center grants include appropriate provisions for training and technical assistance in the issues discussed in this report. Where appropriate, NIH and OPRR should consider using consensus development conferences or workshops to advance discussion of these issues.

      Discussion

      The WG agrees with NBAC on the need for research and training in the area of human subject protections in general and the area of protecting vulnerable subjects in particular. The NIH appreciates NBAC’s acknowledgment of its support for research and training in informed consent, research ethics, and issues associated with decisional impairment. HHS is currently conducting many activities that address the concerns outlined in this recommendation.

      One of the most important of the activities in this area is the NIH Program Announcement on Research on Ethical Issues in Human Studies, which was released March 31, 1999 (PA NUMBER: PA-99-079) and is ongoing. This PA is designed to encourage empirical studies that are expected to fill many gaps in our knowledge and understanding of the complex ethical issues that arise when involving human participants in research. Some possible research topics include:

      Evaluate the cognitive ability required to comprehend, appreciate, and reason in order to consent to specific experimental procedures and risks; to differentiate between research and standard treatment; and to distinguish between discretionary and obligatory activities (e.g., quid pro quo add-on studies or wraparound studies).

      Develop and test new means of sustaining autonomy to be used in situations of declining or loss of capacity, means can include current yet untested advance directives for research and consent programs for organ donation (e.g., durable power of attorney, proxy, legally authorized representative).

      Investigate how potential participants weigh risks and benefits, e.g., what factors would lead individuals to participate in studies that present significant risk with little or no prospect of direct benefit.

      Apply existing knowledge from cognitive, behavioral, social, and educational fields to develop practical, reliable, valid, and efficient methods and instruments for assessing capacity to comprehend, appreciate and/or reason in a research setting, especially when individuals with cognitive, psychiatric, and developmental disorders are involved; the focus should be on functional abilities rather than on clinical diagnosis.

      Some additional NIH research and training activities are highlighted below. Details on these and other NIH and CDC activities can be found in appendix B.

      Research Activities

      NIH/DOE/VA Request for Applications on Informed Consent to identify and validate methods for improving the informed consent process in scientific research..

      The National Institute on Deafness and Other Communication Disorders Working Groups on (1) Considerations for Developing and Implementing Genetic Diagnostic Tests for Hereditary Hearing Impairment and Other Communication Disorders (December 1998) and (2) Communicating Informed Consent to Individuals- Who Are Deaf or Hard-of Hearing (May 1999).

      Clinical Center Department of Clinical Bioethics.

      ORWH/NCI/NAPBC/PRIM&R/ARENA Meeting, “Informed Consent and IRB Review: A Model for Review and Discussion.”

      Training Activities

      NIH/CDC/HRSA/AHCPR/SAMHSA Mentored Scientist Development Award in Research Ethics-Program Announcement

      National Institute of Mental Health “Investigators Guide.” Informed Consent Working Group [1997-99].

      NIMH “Participants Guide to Clinical Mental Illness Research.”

      Office of Intramural Research/NIH Committee on Scientific Conduct and Ethics.

      In addition, the WG is aware that the OHRP is initiating an aggressive effort to educate research investigators, IRB members, and relevant staff. OHRP will work closely with HHS agencies to ensure that all personnel involved in the conduct or administration of research receive appropriate training related to human subject protection and informed consent, including issues related to capacity assessment.

      Proposed Action

      The WG proposes that the Secretary charge the Director of NIH to determine and take whatever additional action is needed in this area.

      NBAC Recommendation 20: Institute of Medicine Review of Research Studies

      The Department of Health and Human Services should contract with the Institute of Medicine (IOM) to conduct a comprehensive review and evaluation of the nature and extent of challenge, washout, and placebo controlled studies with subjects with mental disorders that may affect decision making.

      Discussion

      The WG agrees with NBAC that these study designs may expose subjects to additional risk and therefore warrant heightened scrutiny. Data, guidelines and other resources may be helpful to investigators, IRBs, and others reviewing research supported by the Department, who must determine when these study designs are justifiable. The WG notes that the National Institute of Mental Health (NIMH) has already taken substantial steps regarding these concerns. In December 1998, NIMH sponsored a workshop on “Medication Discontinuation and Symptom Challenge Designs,” bringing together scientists, bioethicists, consumers, family advocates, HHS regulatory staff, and Congressional staff Based on this, the National Advisory Mental Health Council created a special Council Workgroup on Human Subject Research to consider “fundable” grant applications involving potentially problematic human protection issues. This group, acting since July 1999 via the Council, has had a substantial effect on assuring that risk/benefit evaluations, informed consent, and clinical safeguards are properly considered. The NIMH is also involved in discussions regarding the appropriate use of placebo controls, access by research participants to useful clinical information after a clinical trial, and other key issues.

      The NIMH will continue to take steps to better safeguard human research volunteers upon whom clinical research depends - both to monitor studies and to anticipate emerging issues in research involving potentially vulnerable populations. In addition, OHRP will work with all components of the Department to enhance protections for human subjects.

      Proposed Action

      The WG proposes that the-Secretary charge the Director of NIH, in consultation with the OHRP Director and the FDA Commissioner, to determine and take whatever additional action is needed in this area.

      NBAC Recommendation 21: Increased Funding to Support Necessary Protections of Human Subjects

      Compliance with the recommendations set forth in this report will require additional resources. All research sponsors (government, private sector enterprises, and academic institutions) should work together to make these resources available.

      Discussion

      The WG recognizes that IRB burdens continue to expand and agrees that IRBs need additional resources to support them in protecting human subjects. This recommendation has been made by the Office of the Inspector General (OIG), [29] others, and now NBAC. The OIG concluded that “[a]s they have for about 25 years, IRBs continue to provide vital protections for human subjects,” [30] but found them to be vulnerable for a number of reasons, particularly the dramatic increase in IRB workloads, [31] while “staffing levels and budgets have remained the same at many IRBs.” In addition, “[m]anaged care cost pressures have constrained the time that IRB members have to devote to reviewing protocols.... With limited personnel and few resources, IRBs are hard pressed to give each review sufficient attention.” [32] Thus, the OIG recommended that IRBs be provided with sufficient resources to be able to effectively carry out their function.” [33]

      The WG agrees with NBAC’s recommendation. Some institutions have increased support for IRBs, but “[m]any IRBs are not sufficiently supported by their institutions.” [34] Not all institutions may have the ability to increase funding to IRBs without causing detrimental effects elsewhere within the institution.

      IRBs reviewing protocols from commercial sponsors are free to request full reimbursement of the costs of IRB review, although this opportunity appears to be underutilized. Institutions conducting Federally-sponsored research are able to seek reimbursement for IRB expenditures through indirect cost payments that are a regular part of research awards.

      Proposed Action

      The WG proposes that the Department continue to work with awardee institutions to increase the financial support available to IRBs.


[9] The Emergency Research Regulations provide precedent for the mode of consultation envisioned by NBAC; see 21 CFR §50.24(a)(7): “consultation ... with representatives of the communities in which the clinical investigation will be conducted and from which subjects will be drawn.”

[10] See endnote 19 re: subpart B proposal.

[11] If the IRB determines that including such individuals is necessary to protect the subjects, then HHS and FDA regulations (45 CFR §46.111(b) or 21 CFR §56.111(b)) seemingly require their inclusion.

[12] Under 45 CFR §46.407, parents or guardians are permitted to enroll a child in research that presents more than a minor increase over minimal risk, provided that, after the Secretary consults a panel of experts and allows for public review and comment, the Secretary finds that “the research presents a reasonable opportunity to further understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children” and that “the research will be conducted in accordance with sound ethical principles.”

[13] Moreover, public discussion is also warranted by existing disagreements on whether persons with decisional impairment may be involved under any circumstances in any research having greater than minimal risk and no prospect of direct benefit - even with review by a national panel.

[14] Report at p. 9 (“respectful treatment begins with soundness in research design, which is the sine qua non for ethical research involving human subjects”). Also see Office for Protection from Research Risks (OPRR) - IRB Guidebook, Ch. IV - Considerations of Research Design, Part A: “Me value of research depends upon the integrity of study results .... [I]f a research study is so methodologically flawed that little or no reliable information will result, it is unethical to put subjects at risk or even to inconvenience them through participation in such a study.”

[15] See, e.g., testimony/statement of Dr. Norman Fost before the Pediatric Advisory Subcommittee, a Subcommittee of the FDA Anti-infective Drugs Advisory Committee, Ethical Issues Day I, November 15, 1999.

[16] NBAC also intends the recommendation to facilitate the IRB’s determination of risk levels.

[17] At least one State appeals court has suggested that the same constitutional requirements that must be observed before the involuntary administration of anti-psychotic drugs also apply to enrolling children, or adults who lack capacity, in greater than minimal risk research without benefit to the subject. T.D. v. N. Y. Office of Mental Health, 650 N.Y.S.2d 173 (N.Y. Appellate Division 1996). Those requirements include notice to the subject, or a surrogate, and the opportunity to object at a judicial or an administrative hearing to both the capacity determination and the intervention. On appeal, New York’s highest court disapproved of the appeal court’s foray into constitutional analysis after it had already determined that the regulations were invalid on the narrower legal grounds that the promulgating body had no authority to issue those regulations. T.D. v. N. Y. Office of Mental Health, 91 N.Y.2d 860, 690 N.E.2d 1259 (1997). As a result, the intermediate court’s constitutional analysis carries no legal weight; the higher court did not weigh in on the substance of the constitutional analysis.

[18] For example, the self-esteem of subjects who become aware that their capacity is being questioned may suffer. Even if the assessment is handled in a confidential and sensitive manner, the fact that the subject’s capacity has been assessed may have implications outside the research protocol; for example, the subject may be asked on a job or security application if his or her capacity has ever been tested or questioned.

[19] As an example see, in response to comments received on the proposed changes to Part B, HHS noted the following:

The Department notes that ensuring that information is understood and checks for understanding tailored to particular situations are not precluded by the regulations, nor are they unique to research with pregnant women. Subpart A affords IRBs the opportunity and the authority to ensure the adequacy of informed consent and protections by imposing additional requirements or monitoring the research or consent process.

[20] The HHS regulations at 45 CFR §46.111(b) and FDA regulations at 21 CFR § 56.111(b) already require that research involving subjects with mental disabilities include additional safeguards to protect the rights and welfare of those subjects. Some other safeguards available to IRBs include: requiring modification of the informed consent process so as to empower the subject to decide whether to enter or continue in a research study, requiring that LARs be educated about the research in order to better perform their duties, and monitoring of the consent process or the research. Another issue not settled by NBAC’s recommendation is when capacity assessments most be performed, particularly when capacity is expected to fluctuate over time. The IRB may determine that an ongoing safeguard such as monitoring would be more effective than discrete capacity assessments.

[21] See also endnote. 17.

[22] In fact, the FDA further recognized the importance of this right in the emergency research regulations. “If a legally authorized representative or family member [of a subject who lacked capacity at the time of the emergency] is told about the clinical investigation and the subject’s condition improves, the subject is also to be informed as soon as feasible.” 21 CFR §50.24(b).

[23] Some states may permit LAR’s, even in the absence of a Prospective Authorization, to enroll subjects in certain types of research based on substituted judgment.

[24] The regulations define the term “legally authorized representative” to mean “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.” 45 CFR § 46.102(c) and 21 CFR §50.3(1).

[25] Sections 46.116 and 50.20 provide that, except as otherwise provided in 45 CFR Part 46 or 21 CFR Part 50, respectively, no investigator may involve a human being as a subject in research covered by the regulation, “Unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.” (Emphasis added).

Guidance on consent by a legally authorized representative is provided in “Interim-Research Involving Individuals with Questionable Capacity to Consent: Points to Consider” (http://grants.nih.gov/grants/policy/questionablecapacity.htm) under the heading “Use of a Surrogate.” This statement was developed to assist IRBs and clinical investigators in protecting research participants who are, may be, or may become decisionally impaired by NIH in consultation with a broad array of experts on, and participants in, clinical research, bioethics, mental health, substance abuse, and age-related conditions, as well as agencies and groups concerned about clinical research and human subject protections. According to the statement, “where permitted by law, individuals with impaired capacity may have a family member or other legally authorized representative serve as a surrogate for research decisions, with this role documented during the consent process.” The surrogate should make research decisions based on substituted judgment whenever possible. Otherwise, best interest standards are to be used if the values of the individual are not known or cannot be given legal effect. The statement also emphasizes the importance of surrogates receiving some education about their own role and the cognitive and health status of the research participant, as well as about the study in which the participant may be involved.

[26] Letter of Maryland Assistant Attorney General Jack Schwartz to Gary Ellis (February 7, 2000).

[27] A number of findings of the Surgeon General’s Mental Health Report, are particularly relevant:

State and Federal laws protect the confidentiality of health care information but are often incomplete because of numerous exceptions which often vary from state to state. Several states have implemented or proposed models for protecting privacy that may serve as a guide to others.

States, consumers, and family advocates take differing positions on disclosure of mental health information without consent to family caregivers. In states that allow such disclosure, information provided is usually limited to diagnosis, prognosis, and information regarding treatment, specifically medication.

When conducting mental health research, it is in the interest of both the researcher and the individual participant to address informed consent and to obtain certificates of confidentiality before proceeding. Federal regulations require informed consent for research being conducted with Federal funds.

****

Until the stigma associated with mental illnesses is addressed, confidentiality of mental health information will continue to be a critical point of concern for payers, providers, and consumers.

Executive Summary, page xviii.

[28] An issue of some controversy in mental health is whether families should be provided information regarding their adult child in certain circumstances....

Family advocates often take the position that a family in a caregiving role should have access to some types of information whether or not the individual specifically has consented to the disclosure, because it is necessary to play a caregiving role (Lefly, 2000). Advocates for consumer-recipients often argue that consent should be required, because the right to confidentiality belongs to the recipient of services, and because there may be intrafamily conflicts that could be exacerbated by the release of information to family members.

Surgeon General’s Mental Health Report Chapter 7 at ___.

[29] OIG, Institutional Review Boards: A Time for Reform (OEI-01-97-00193) June 1998, at p. 4.

[30] Id

[31] The IRBs studied “reported average increases of 42 percent in initial reviews during the past 5 years, with the result that some of them are reviewing more than 2,000 protocols. At the same time, these IRBs are being deluged with adverse event reports from the multi-center trials they oversee.” Id at p.5.

[32] Id at 6. “The resources we refer to are, above all, the human resources represented by staff and board members, but also space, computers, and other elements essential to an efficient and effective IRS.” Id. at p. 19.

[33] Id. at p. 19.

[34] OIG, Institutional Review Boards: Promising Approaches (OEI-01-97-00191) June 1998, at p. 1.

View full report

Preview
Download

"nbac.pdf" (pdf, 171.03Kb)

Note: Documents in PDF format require the Adobe Acrobat Reader®. If you experience problems with PDF documents, please download the latest version of the Reader®