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                Clinical Trials and Human Subject Protection

Clinical Trials and Human Subject Protection

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          Clinical Trials and Human Subject Protection
          Protection of Human Subjects; Informed Consent Part II 61 FR 51498Clinical Trials and Human Subject Protection Protection of Human Subjects; Informed Consent Part II 61 FR 51498
  
  	
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    Print21 CFR Parts 50, 56, 312, 314, 601, 812, and 814 [Docket No. 95N-0158] RIN 0910-AA60 DATE: Wednesday, October 2, 1996 **ACTION:** Final rule. **SUMMARY:** The Food and Drug Administration (FDA) is amending its current informed consent regulations to permit harmonization of the Department of Health and Human Services' (DHHS) policies on emergency research and to reduce confusion on when such research can proceed without obtaining an individual subject's informed consent. This regulation provides a narrow exception to the requirement for obtaining and documenting informed consent from each human subject, or his or her legally authorized representative, prior to initiation of an experimental intervention. The exception would apply to a limited class of research activities involving human subjects who are in need of emergency medical intervention but who cannot give informed consent because of their life-threatening medical condition, and who do not have a legally authorized person to represent them. FDA is taking this action in response to growing concerns that current rules are making high quality acute care research activities difficult or impossible to carry out at a time when the need for such research is increasingly recognized. **EFFECTIVE DATE:** These regulations are effective November 1, 1996. **FOR FURTHER INFORMATION CONTACT:**Glen D. Drew, Office of Health Affairs (HFY-20), Food and Drug Administration, Rockville, MD 20852, 301-443-1382. SUPPLEMENTARY INFORMATION: I. Background In the **Federal Register** of September 21, 1995 (60 FR 49086), the Secretary of Health and Human Services and the Commissioner of Food and Drugs proposed to amend FDA's current informed consent regulations to permit emergency care research. FDA proposed this action in response to growing concerns that current rules are making high quality acute care research activities difficult or impossible to carry out at a time when the need for such research is increasingly recognized. By permitting certain adequate and well-controlled clinical trials to occur that involve human subjects who are confronted by a life-threatening situation and who also are unable to give informed consent because of their medical condition, the agency expects the clinical trials to allow individuals in these situations access to potentially life-saving therapies and to result in advancement in knowledge and improvement of therapies used in emergency medical situations that currently have poor clinical outcome. FDA allowed 45 days for comment on the proposal of September 21, 1995. Written comments received in response to the proposal are on file in the Dockets Management Branch. Comments were received from clinical investigators, institutional review boards, patient advocacy groups, trade associations, professional societies, drug and medical device companies, and private citizens. The substantive comments received and FDA's responses are discussed below. Approximately 90 comments were received on the proposed rule. The vast majority of these comments supported the proposal, although many of these comments contained suggestions or requests for clarification. A number of the comments that supported the proposal came from organizations and associations representing large numbers of members. These included the Brain Injury Association, the National Stroke Association, the American Academy of Orthopaedic Surgeons, the Coalition of Acute Resuscitation and Critical Care Researchers, Applied Research Ethics National Association, Pharmaceutical Research and Manufacturers of America, Health Industry Manufacturers Association (HIMA), the American Academy of Pediatrics, the American Heart Association Emergency Cardiac Care Committee, the American College of Emergency Physicians, the American Medical Association, the American College of Cardiology, the Society of Critical Care Medicine, the National Association of EMS Physicians, the American College of Obstetricians and Gynecology, and the American College of Physicians. A number of the comments in favor of the proposal cited how it will facilitate research in this patient population, provide the necessary safeguards to ensure responsible and ethical research with protection of the human subjects, and ultimately speed the wide availability of products proven efficacious to individuals in life-threatening situations. For example, the American College of Physicians and the Project on Informed Consent of the University of Pennsylvania Center for Bioethics commented that they "applaud these proposed regulations as a much needed step in the advancement of vital emergency research with careful attention to the rights and welfare of human research subjects." The American Heart Association commented that "We are particularly pleased with the balance that appears to have been struck between the need for conducting high quality clinical research in an effort to develop better treatments for critically ill patients and the protection of human subjects." The American Medical Association commented that "The proposed rules are far superior to their inadequate antecedents in balancing the need for emergency research with respect for the paramount concern for patient safety, welfare and comfort." The Brain Injury Association commented that "* * * this rule is a major step towards increasing the available therapies and medical care available for those individuals who are critically ill or injured." The Coalition of Acute Resuscitation and Critical Care Researchers commented that "* * * this proposed rule is a significant step forward towards advancing the medical care of critically ill or injured patients for whom current therapies are unsatisfactory or unproven." The National Stoke Association commented that "* * * once in practice it will help to appropriately expedite study enrollments thus allowing for earlier study completion, analysis, and ultimately will speed the availability of those drugs proven efficacious to the one-half million people who suffer stroke each year." These comments are addressed in more detail in sections II and III of this document. Generally, the 16 comments opposed to the proposed rule were from individuals who were not convinced by the agency's description of the legal and ethical basis for the rule, and these comments concluded that informed consent should not be waived under any circumstances. Some of these comments suggested that the agency was proceeding hastily and under undue pressure from the research community. In section II of this document, we address the general comments first, followed by the more specific comments. II. General Comments *A. Need for the Rule* 1. One comment questioned the need for the rule and whether there were hard data documenting the number of[*51499]subjects eligible for these types of research activities who are lost to enrollment due to an inability to obtain informed consent from the subject or the subject's authorized representative. Another comment questioned the need for this rule based on the DHHS waiver granted in July 1995 for a hypothermia study, arguing that: (1) The waiver was not needed to complete a reasonable preliminary sample, (2) the criteria for participation were needlessly inclusive, (3) the investigator used questionable tactics to achieve waiver, (4) the provisions for oversight were inadequate, and (5) the provisions for monitoring were inadequate. This comment went on to discuss "the overarching considerations" for the rule, arguing that it is not in the subject's interest to prevent death in order to linger in a vegetative state; that the high percentage of families agreeing to continuing participation in the research after the fact demonstrates how ill-informed they are about the possibility of negative outcomes, e.g., prolonged vegetative state, dissipation of financial resources, court challenges to terminate life support; that subjects will be misenrolled in "an abundance" of life-threatening situations; that the rule does not address or provide for followup or special circumstances for terminating life support for "saved" individuals in these studies; and that it is not clear who will bear the cost and burden to sustain an individual who has been "saved" from a life-threatening medical condition by being on a research study. The preamble to the proposed rule extensively discussed why this rule is needed and why this limited class of research has been unable to proceed under existing requirements. The purpose of this rule is to permit the study of potential improvements in the treatment of life-threatening conditions where current treatment is unproven or unsatisfactory, in order to improve interventions and patient outcomes. It is not the goal of this rule to leave study subjects in vegetative states or to have any of the other negative outcomes outlined in the comments. The risks to patients of having these negative outcomes exist now with interventions that are unproven or unsatisfactory. If interventions are improved, patient outcomes will be improved. The possibility of worsened outcome or adverse reactions will be assessed before the clinical investigation begins by the IRB and during the investigation by the data monitoring committee that is required under the regulation. The regulations require the institutional review board (IRB) to ensure that risks to subjects are minimized and to determine that risks to subjects are reasonable in relation to anticipated benefits to subjects (see §56.111(a)(1) and (a)(2) (21 CFR 56.111(a)(1) and (a)(2)), respectively). The rule does not address the issue of terminating life support because this is dictated by State law and is implemented through such standard procedures as "do not resuscitate" orders. *B. Ethical Objections to the Rule* 2. Several objections to the proposed rule noted that the major protection from research risks remains informed consent and that without this procedure, potential abuse of research subjects will always remain unacceptably high; that it is unethical for patients who cannot consent to receive nonstandard care; that overriding individual autonomy and not obtaining informed consent is unacceptable; that therapeutic intent is not sufficient to obviate consent when there are no data or when there is uncertainty or disagreement. Some of these comments mentioned the recent report of the President's Advisory Committee on Human Radiation Experiments, in which radiation experiments without the subjects' consent are condemned as a wrongful use of persons as means to the ends of others; others mentioned examples from Nazi Germany, Stalin's U.S.S.R. and other totalitarian regimes. Some of these comments noted that it is particularly objectionable that there is no way to avoid involvement as a subject in this research if, as an individual, one objects to the research. The agency acknowledges that the waiver of informed consent is a serious matter. That is why it has developed a regulation that requires additional protections when informed consent is waived. The purpose of this rule is to ensure such protections. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research states in *The Belmont Report* that: Respect for persons incorporates at least two basic ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy. This rule, §50.24 (21 CFR 50.24) in part 50 (21 CFR part 50), can be invoked for emergency research in which it is not feasible to obtain informed consent from prospective subjects. As such, these subjects have diminished autonomy and are entitled to protection. *The Belmont Report* states that: The extent of protection afforded [to individuals with diminished autonomy] should depend upon the risk of harm and the likelihood of benefit. The judgment that any individual lacks autonomy should be periodically reevaluated and will vary in different situations. *The Belmont Report,* thus, states that: (1) Subjects with diminished autonomy are entitled to protection; (2) the extent of protection should depend upon the risk of harm and the likelihood of benefit; and (3) the judgment that any individual lacks autonomy should be periodically reevaluated. This regulation incorporates each of these principles. The regulation recognizes that subjects with diminished autonomy are entitled to protection. These additional protections include the requirements in the regulation for consultation with representatives of the communities from which the subjects will be drawn; public disclosure of the clinical investigation and its risks and expected benefits prior to initiation of the investigation; public disclosure of sufficient information following completion of the investigation to apprise the community and researchers of the results of the investigation; the establishment of a data monitoring committee to exercise oversight of the investigation; and, if consent is not feasible and a legally authorized representative is not available, providing an opportunity for a family member to object to a subject's participation in the investigation, if feasible within the therapeutic window. The regulation recognizes that the extent of protection should depend upon the risk of harm and the likelihood of benefit to the subjects. The regulation requires the IRB to find and document that appropriate animal and other preclinical studies have been conducted; that the information derived from those studies and related evidence support the potential of providing a direct benefit to the individual subjects; and that the risks associated with the investigation are reasonable in the light of what is known about the prospective subjects' medical condition, the risks and benefits of standard therapy, if any, and what is known about the risks and benefits of the proposed intervention or activity. The regulation recognizes that the judgment that any individual lacks autonomy should be periodically reevaluated. This is reflected in two requirements: (1) The IRB must review and approve informed consent[*51500]procedures and an informed consent document for use with subjects or their legal representatives in situations where use of such procedures and documents is feasible; and (2) at the earliest feasible opportunity, each subject (or a legally authorized representative or family member) will be informed of the subject's inclusion in the research, the details of the research, and that the subject (or representative or family member) may discontinue the subject's participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. In response to the comments that expressed concern about the ability of an individual to avoid involvement as a subject in this research, the agency thinks that the opportunity for individuals to express objections to the research may be optimized in a number of ways. Comments suggested making available medical bracelets that record refusal to participate in the research, and publicizing the existence of the bracelets; and excluding from participation those individuals with advance directives rejecting such research (most feasible for hospitalized patients). The agency encourages IRB's, investigators, and sponsors to work together to maximize the ability of individuals to prevent their inclusion in research to which they would object. The agency does not believe that this rule creates a situation that differs significantly from other emergency situations warranting intervention in that individuals in life-threatening situations are often unable to direct decisions concerning their health care and are, therefore, unable to consent or object to a particular treatment. Yet they are routinely treated by State-licensed medical practitioners. This inability to exercise autonomy is not unique to the subjects who will be eligible for this research-it is common to the majority of individuals who may be in these life-threatening situations. FDA thinks that the protections contained in this rule including IRB review, the requirements for obtaining informed consent when it is feasible, and for community consultation and disclosure will prevent unethical research from occurring. FDA expects these procedures involving waiver of informed consent to be used infrequently. As noted, the research carried out under such a waiver must present the potential of direct benefit to the individual subjects. It should be initiated only after appropriate animal and other preclinical studies have been conducted, and it is clear that the information derived from those studies and related evidence support the potential of direct benefit to the individual subjects. 3. One comment stated that the proposal violates the American Hospital Association's "Patient's Bill of Rights" to fully informed consent. The agency has reviewed the AHA's Patient's Bill of Rights and concludes that there is no conflict between this rule and that document. In particular, the agency notes that the Patient's Bill of Rights recognizes that an exception occurs "in emergencies when the patient lacks decision-making capacity and the need for treatment is urgent." 4. Another comment questioned the agency's discussion of respect for persons in the preamble to the proposal and the agency's supposed conclusion that if individuals capable of exercising their autonomy refuse to enroll in research, this justifies diminished protection to those individuals who lack the capacity for autonomous choice. This comment defined the informed consent doctrine as: (1) Promoting individual autonomy; (2) respecting human dignity; (3) encouraging professional self-scrutiny; (4) promoting rational decision making; (5) avoiding deceit and coercion; and (6) educating the public. It then concluded, that by exempting emergency research from informed consent, the agency was concluding that these values have no relevance to decisions made in the context of emergency research. This comment misrepresents the agency's discussion of the principle of respect for persons. In the preamble to the proposed rule, the agency described: [H]ow the principle of respect for persons incorporates two general rules of ethical behavior: (1) Competent individuals must be treated as autonomous agents * * *; and (2) persons whose autonomy is absent or diminished may participate in research only if additional protections are provided for them. (60 FR 49086 at 49093, September 21, 1995) This rule, in fact, incorporates the values described in the comment to the extent that they are relevant to decisions made in the context of emergency research. 5. A number of comments misinterpreted the agency's description of the principle of justice in the preamble to the proposed rule, and were offended by the idea that it is acceptable for a researcher to waive consent because if consent were requested, it would be refused. One comment suggested that the agency clarify that it meant that it is often easier to locate legal representatives from white populations than from minority populations, and for that reason if consent were required from a legally authorized representative, the requirement could prevent equitable numbers of minority patients from having the opportunity to participate in emergency research. The Indian Health Service recommended that the agency supplement its discussion of justice by adding the following: Waiving informed consent will increase justice only in communities or sub-communities with a low percentage of people who would refuse to participate if asked. Many minority or economically disadvantaged communities distrust research more, and have higher percentages of refusers, than white middle class communities; in such communities, the ethical principle of justice would favor maximizing self-determination (i.e., informed consent) over achieving high rates of participation. Justice would also require the public disclosure to and consultation with those communities as required in the Proposed Rule; if those communities do not agree to be sites, consideration should be given to doing the research elsewhere. The Indian Health Service, in supporting the intent of the rule, articulated two aspects of the problem: (1) Finding legally qualified surrogates for individuals who lack telephones, for example, which is a socioeconomic barrier; and (2) a surrogate's unwillingness to enroll a relative in the research, based on distrust of research and researchers. If certain communities have a higher prevalence of refusers than others, the ethical harm of inadvertently enrolling people in research against their will would fall on those communities with a higher prevalence of refusers. Thus, the Indian Health Service (IHS) concluded that while it may be appropriate to waive informed consent based on socioeconomic barriers, it is not appropriate to waive informed consent in communities in which there are lower rates of obtaining surrogate consent due to the unwillingness of surrogates, i.e., high refusal rates. Another comment noted that if the community in which an emergency research study is carried out has a large minority and lower income population, then the likelihood of the community agreeing prospectively to participate in the study would be small or nonexistent; ethically this would violate the principle of justice in that such communities would be unlikely to share the burdens and benefits of participation in such research. The agency's comments concerning justice, in the preamble to the proposed rule, concerned the ability of health care delivery personnel to locate legally authorized representatives. The agency agrees with the IHS articulation of the[*51501]two aspects of the problem. The agency would not consider writing a rule that would permit the waiver of informed consent in a situation where if consent were requested, it would be refused. Such an action would violate ethical principles. The agency has implicitly addressed the problem of a surrogate's unwillingness to enroll a relative in research through the rule's requirement for community involvement, including consultation with and disclosure to the community, and by providing that consent from the subject or the subject's legally authorized representative be obtained or an opportunity for a family member to object be provided when it is feasible. If an IRB decides that its community should not participate in research, the agency does not believe that decision would violate the principle of justice. Justice, in this context, requires only that the community have the opportunity to participate in the research if asked. *C. Harmonization* 6. A number of comments applauded the intent of FDA and DHHS to harmonize regulations in this area. Concern was expressed, however, that because FDA and DHHS did not propose regulations simultaneously, the two regulations may not ultimately be identical, thus thwarting a major objective of this endeavor. One comment expressed concern that the DHHS waiver might follow the specific project waiver for hypothermia research that was published in July 1995, that, according to the comment, was not sufficiently protective of subject rights. Another comment suggested that for studies that do not involve drugs or devices, DHHS develop an analogous mechanism to FDA's requirement that studies be submitted for agency review. Another comment suggested that the two sets of regulations not be in total harmony in this regard, because a greater degree of protection of subjects is necessary for studies of drugs and devices that are not yet FDA-approved, than for those involving drugs or devices that have received approval. One comment encouraged FDA and the Office for Protection from Research Risks (OPRR) to work together to ensure that current Multiple Project Assurances remain valid and not require renegotiation as a result of this rule. DHHS has committed to consistency between the FDA final rule and the Secretarial waiver of the DHHS regulations in all critical respects. Elsewhere in this issue of the **Federal Register** is the Secretarial waiver of the DHHS regulations for the protection of research subjects for emergency research. The agency notes that FDA's rule requires investigational new drug applications (IND's) and investigational device exemptions (IDE's) for all clinical investigations involving drugs and devices seeking an exception to the requirement for informed consent, including both those that have received marketing approval and those that have not. 7. Other comments asked for clarification as to whether the requirement contained in §50.24(d) would apply to studies that attempt to elucidate a pathophysiologic explanation (e.g., blood drawing studies); studies that use interventions of different techniques (e.g., two different methods of bystander CPR); research designed to explore basic pathophysiological mechanisms in emergency situations; studies to compare the timing of standard fluid administration for shock and surgical techniques; etc. If FDA's regulation did not apply, these comments asked if the DHHS "harmonized" regulation would apply to these studies and require prior DHHS review or whether some other agency would be responsible for prior review of the proposed research. These regulations are applicable only to clinical investigations involving products that are regulated by FDA. The DHHS regulations apply to research supported or conducted by the Department or conducted in an institution that has agreed to review all research, regardless of its funding source, in accord with the DHHS regulations. The "harmonized" regulations have compatible criteria; their basic requirements are in agreement. FDA includes terms specific to the type of research covered by FDA regulations (e.g., it uses the term clinical investigation instead of research). Both the DHHS and FDA recognize that there may be research that is neither regulated by FDA nor supported or conducted by DHHS; for that research, it is possible that neither regulation will apply. *D. Comment Period and Effective Date* Several comments opposed to the regulation objected to the 45-day comment period and the agency's proposal that the final rule will be effective upon publication. 8. One comment suggested that the effective date of the regulations should be 30 days after publication of the final rule. This comment noted that this research has been halted since mid-1993, that all parties will need time to develop adequate policies and procedures to comply with the new rule, and that distribution of the policy to those affected will take up to 30 days. The agency agrees with this comment and has made the effective date of the final rule 30 days after its publication in the **Federal Register**. The agency notes that the Secretarial waiver of the DHHS regulations, published elsewhere in this **Federal Register**, is also effective 30 days after its publication. IND's and IDE's that intend to invoke this rule may be submitted to the agency on or after its publication date and should include a description of how the clinical investigation proposes to meet the conditions of this regulation. These investigations cannot begin until the rule is effective, the agency has reviewed the investigation against the requirements contained in this final rule, a letter has issued to the sponsor advising the sponsor that the investigation may proceed, the investigation has been reviewed and approved by an IRB, and the community consultation and disclosure required by this rule have occurred. 9. Comments objecting to the 45-day comment period suggested that there was inadequate time to discuss the proposed changes in the regulation at length with a broader audience, that the IRB community is ill-informed about the proposed rule change and therefore the comment period should be extended, the issue revisited, and the rule reconsidered. One of these comments stated that the process leading to development of the rule was flawed and that it appears that the comment period is irrelevant, that no significant review of the basic issues will occur, and, thus, the rule is a fait accompli. As described in detail in the preamble to the proposed rule, the issues associated with this rule were debated at length at conferences, during FDA and NIH cosponsored Public Forum on Informed Consent in Clinical Research Conducted in Emergency Circumstances, at a congressional hearing, and in various articles. The agency received no formal request for a general extension of the comment period; instead, it received numerous thoughtful comments and has modified the proposed rule as a result of those comments. 21 CFR 10.40(b)(2) states that a proposed rule "* * * will provide 60 days for comment, although the Commissioner may shorten or lengthen this time period for good cause. In no event is the time for comment to be less than 10 days." In the proposed rule, the agency explained why the Commissioner determined that there was good cause to shorten the comment period from 60 to 45 days.[*51502] In order to encourage comments on this rule, the agency conducted a number of out-reach efforts to publicize publication of the proposal. The agency provided information on the proposed rule to national media and trade press contacts. The agency mailed copies of the proposal to all registrants at the January 1995 Public Forum on Informed Consent in Clinical Research Conducted in Emergency Circumstances and to over 1,000 IRB's and over 250 health professional organizations and consumer groups. FDA also distributed copies at workshops and at national meetings of IRB organizations. The agency invited consumer, health professional, and industry organizations to briefing meetings where the proposal was described and questions could be answered. The agency encouraged the submission of comments to the administrative record maintained by the Dockets Management Branch whenever possible. *E. Preemptive Effect* 10. In the preamble to the proposed rule, FDA requested comment on the need to preempt local and State regulations. The agency received a number of comments both for and against the need for preemption. Comments received that were opposed to preemption included the following: There is no legitimate (constitutional) over-riding Federal concern that requires the Federal Government to preempt local and State requirements; it is inappropriate to remove the ability of citizens to enact State and/or local laws that would require additional protections for research subjects, or to restrict the conduct of this type of research if citizens find it objectionable based on community standards; it is not logical to prohibit local action when the regulation itself emphasizes community involvement and deference to community standards. The IHS objected to Federal preemption because it would: (1) Counter the long-standing Federal policy not to place restrictions on tribal sovereignty; (2) be an unnecessary limitation, because retaining tribal sovereignty would have no measurable adverse effect on the nation or on emergency research as a whole; (3) give American Indian and Alaska Native (AI/AN) people and governments one more reason to distrust the Federal Government, because they would see the rule as putting AI/AN people at risk for the good of non-AI/AN people and communities; and give AI/AN people and governments one more reason to distrust research, because they would see the rule as overriding a patient's or family's desire not to participate in research-a desire more common in AI/AN communities than in white middle class communities. Other comments noted that the proposal did not recognize tribal sovereignty and that it undermines the tribal government's authority to implement stricter requirements for biomedical research conducted on persons residing in tribal jurisdictional boundaries. Comments noted that the tribal review process is in place to protect tribal members from unnecessary or undesirable research. Another comment opposed to preemption noted that the rule would preempt State and local laws for the minimum protections acceptable for emergency research involving waiver of informed consent; however, without preemption, it permits greater protections to be imposed at the State or local levels. One comment suggested that in lieu of preemption, FDA and IRB's should track how States, local, or tribal governments retain or amend their laws in response to public discussion by researchers with those governments and assess the various reactions after 3 years. Other comments supported the need for preemption in order to ensure national uniformity; to prevent or limit liability of universities, hospitals, IRB members, clinical investigators, and sponsors for failure to provide informed consent under State law or in the event of a poor subject outcome; and to enhance the ability to conduct valuable research with critically ill subjects. These comments stated that the subject protections included in the proposed regulation are substantial enough to justify Federal preemption of State and local law, and that current State laws (e.g., in the State of Florida) would preclude research that otherwise could be authorized by IRB's under these rules. Several comments supported the need for preemption, noting the difficulty caused by differing State laws that define who may serve as a legal representative or that are ambiguous on this issue. Another comment noted that without Federal preemption, Federal uniformity in the application of waiver of informed consent in a specific setting will not occur. This comment argued that Federal preemption would: (1) Forestall wasteful State court litigation to explore whether the scope of the privilege of emergency action without consent is consistent with the proposed Federal rule, and any related potential liability; and (2) implement congressional intent to create nationally uniform criteria for informed consent and research involving human subjects. The Coalition of Acute Resuscitation and Critical Care Researchers surveyed a number of State representatives regarding State regulations for informed consent for research and identification of surrogates. The results of that survey (with 19 States represented) indicate that there are very few States that have specific legal requirements pertaining to waiver of consent for research. The agency has carefully considered each of these arguments in support of, and opposed to, preemption of State law. The agency has concluded that it would be inappropriate to preempt State law at this time. Preemption of State law would prevent the application of State or local law that requires additional protections to research subjects and, as such, would be inconsistent with the existing Federal policy for the Protection of Human Subjects and the DHHS regulations (45 CFR 46); in addition, it would be inconsistent with the notion of community norms, upon which this regulation is based. *F. Followup/Reassessment* 11. One comment recommended that the implementation of this rule be assessed in 3 years and that any pending questions be addressed during the assessment. Another comment asked the agency to announce its intent to survey and analyze the experience with the rule following 3 years of implementation. The comment recommended that the rule encourage IRB's and researchers to track implementation information including: The number of times the researcher was able to contact legally authorized representatives within the allowed therapeutic window time period; problems with the documentation and procedures used for the consent process with those representatives; the percentage of subjects or legally authorized representatives who wanted to discontinue the intervention or to remove their data from the research database in the posthoc debriefing; problems with documents and procedures used to give the community the preresearch public information and the post-research information; and problems with the documents and procedures for consulting with community representatives. This comment suggested that this information be described both as seen by the IRB and by the experienced researcher. The agency agrees that it will be important to assess implementation of this rule and, thus, the agency intends to evaluate implementation of this rule[*51503]on an ongoing basis. The agency believes that a sponsor's IND or IDE and new drug application (NDA), product license application (PLA), or premarket approval application (PMA) should contain sufficient information under the agency's existing reporting and recordkeeping requirements for the agency to assess how well this rule is working without requiring additional information collection and recordkeeping by researchers and IRB's of their experiences under the rule. The agency, however, encourages IRB's, researchers, and sponsors to share their experiences under this rule, for example, in publications and at conferences, so that the research community and public can benefit from their experiences. The agency notes that for research that is regulated by FDA, although subjects, legally authorized representatives, or family members may elect to withdraw from continued participation in the clinical investigation, they may not remove previously collected data from the research database because it is critical that FDA obtain and be able to consider all data on a product's use in order to be able to determine its safety and efficacy. *G. Scope/Applicability* 1. Special Populations 12. One comment questioned the applicability of this rule to specific special patient populations. This comment recommended that FDA rule state that it does not apply to research involving prisoners or fetuses; and urged that the decision about its applicability to emergency research targeting pregnant women be made after the DHHS regulations have been revised and the 3 year period in which experience of implementing the rule will be obtained and analyzed. This comment recommended that pregnant women should not be excluded from emergency research. This comment also recommended that the rule state that it does not apply to children now; rules for pediatric emergency research should be developed by the end of the 3 year period of experience and assessment; and noted that the process of Secretarial waiver is available if an exception for a specific pediatric emergency protocol must be made before then. Taking a contrary view, the American Academy of Pediatrics stated that: * * * it is important that children be included in research protocols, including those on emergency treatments, so that the safety and efficacy of various treatment methods can be determined in a scientific manner. We believe that this proposed regulation will help to further that objective while protecting children as much as possible by requiring that a consent document be available in cases where surrogate permission can be obtained in a timely manner. The agency believes that it would be inappropriate to exclude any special subject population from this regulation. Moreover, for research regulated by FDA, a Secretarial waiver of the informed consent requirement may not be an option. Thus, the agency is not limiting the applicability of this regulation to exclude any special subject population. The agency notes that it is the general responsibility of the IRB, where some or all of the subjects are likely to be vulnerable to coercion or undue influence, to ensure that appropriate additional safeguards have been included in the clinical investigation to protect the rights and welfare of these subjects. (See 21 CFR 56.111(b).) The subject population covered in this rule is, in a sense, a particularly vulnerable population, by having no capacity to decide about medical treatments. The additional safeguards in the rule are included for this reason. 2. Existing Regulations 13. One comment asked the agency and DHHS, respectively, to explicitly state, when this rule is finalized, that FDA will retain §50.23(a) (21 CFR 50.23(a)) and the DHHS will retain 45 CFR 46.116(d). Both FDA and DHHS will retain these sections in the Code of Federal Regulations. These sections will continue to be useful in situations not otherwise covered by this regulation. 14. Another comment suggested that the regulations address compensation or medical treatment available in the event of unanticipated injuries or death. The agency agrees that it is important for all subjects in a clinical investigation to be provided with the basic information required by §50.25, including §50.25(a)(6) that requires that information be provided to each subject about whether any compensation and any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. As a result, the agency has modified §50.24(a)(6), previously numbered §50.24(a)(5), to make it clear that the IRB-approved informed consent document must be consistent with §50.25. The agency has also modified §50.24(b) to make it clear that when prospective informed consent cannot be obtained, the subject, or the subject's legally authorized representative or family member is to be informed, at the earliest feasible opportunity, of the subject's inclusion in the clinical investigation, the details of the investigation, and other information contained in the informed consent document. 15. A third comment requested the agency to retain two protections previously established by the agency that are not contained in the proposed rule: (1) That the intervention be in the health interest of the subjects; and (2) that an attempt to obtain informed consent be made and documented for enrolled research subjects by a physician unaffiliated with the research activity. The agency thinks that the concerns expressed by the first protection are addressed in §50.24(a)(3), which requires that participation in the research hold out the prospect of direct benefit to the subjects. The second protection is similar to that contained in §50.23(a), which requires, in effect, a second opinion from a physician who is not otherwise participating in the clinical investigation that the conditions for waiving informed consent are met. This protection is performed for the class of subjects in this research by the requirement in §50.24(a)(2) that a determination be made that obtaining informed consent is not feasible and that this determination receive the concurrence of a licensed physician who is either an IRB member or a consultant to the IRB, and who is not otherwise participating in the clinical investigation (§50.24(a)). The agency notes that §50.24(b) requires that at the earliest feasible opportunity, each subject is to be informed of the subject's inclusion in the clinical investigation, the details of the investigation and other information contained in the informed consent document. The agency also notes that under new §50.24(a)(5), the researcher is required to describe the efforts made to obtain informed consent and make this information available to the IRB at the time of continuing review. 3. Foreign Data 16. One comment noted that the rule was silent as to its potential impact on the acceptability of data generated in emergency research studies that are not subject to the proposed rule-i.e., studies conducted outside the United States and outside the scope of the IND and IDE regulations. This comment asked FDA to make it clear that such studies will continue to be considered acceptable in terms of providing evidence of safety and effectiveness and could be treated as pivotal trials, even though they may not meet some of the proposed requirements for the conduct[*51504]of emergency research. This comment stated that if this clarification is not consistent with the agency's intent, then the proposal effectively establishes a new, inappropriate standard concerning the adequacy of clinical studies for purposes of providing evidence of safety and effectiveness that would require specific notice-and-comment rulemaking. Sections 312.120 and 814.15 (21 CFR 312.120 and 814.15) describe the criteria for acceptance by FDA of foreign clinical investigations not conducted under an IND and IDE, respectively. In general, FDA accepts such clinical investigations provided they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community. FDA will accept such emergency research investigations provided that they meet the requirements of §312.120 and §814.15. This rule does not change the requirements of §312.120 and §814.15. 17. One comment noted that the International Conference on Harmonisation Draft Guideline on Good Clinical Practice (GCP) (60 FR 42948, August 17, 1995) states that "the rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over [the] interests of science and society." This comment suggested that the main argument for the proposed rule is for the benefit that the new drugs and devices will bring to science and society, rather then recognizing, as the GCP does, the value of the individual and subject rights. The agency disagrees that this rule is inconsistent with the ICH Draft Guideline and has emphasized in the preamble to this regulation that the basic rationale for this rule is that it holds out the prospect of direct benefit to the subjects. The agency is committed to protecting the rights of research subjects. In addition, FDA recognizes that this rule may also serve society by making available more drugs and devices for use in emergency, life-threatening situations. The agency notes that the draft GCP cited specifically acknowledges the need for waivers of informed consent in some circumstances. 4. Independent IRB's 18. One comment expressed concern about FDA's continued acceptance of reviews by "independent" IRB's. This comment questioned the ability of a nonlocal, independent IRB to have local insight and knowledge necessary for comprehensive review and continuing oversight, and suggested that unless there is monitoring of independent IRB's by OPRR, they should not be allowed to approve research under this rule. The agency received other comments asserting that independent IRB's are well-qualified to maintain the requisite oversight and responsibilities of emergency research trials and that independent IRB's can maintain ethical standards equivalent to dependent IRB's. As previously discussed in the preamble to the proposed rule, the agency thinks that independent IRB's can properly review this type of research. The agency thinks that duly constituted IRB's can ensure that the rights and welfare of research subjects are protected by fulfilling the requirements of part 56 (21 CFR part 56) and §50.24, including §50.24(a)(7) requiring public disclosure as well as consultation with the communities from which the subjects will be drawn. FDA anticipates that this type of research will usually be performed in an institution with an IRB. In that case, the IRB for the institution has the responsibility and authority to review all studies performed in the institution. This review responsibility may not be delegated to another IRB unless the institution and the IRB for the institution agree to the delegation and the agreement is documented in writing. 5. Conflicts with Statutes, the Constitution, and Other Standards 19. One comment stated that the rule conflicts with State common law-that is, a physician who performs research without obtaining consent for that research will be liable under common law for malpractice and battery, and is likely to lose his or her license. This comment stated that by adopting the proposed rule, FDA is overstepping its authority by attempting to regulate the practice of medicine and by attempting to override State law, and that FDA lacks the authority to permit anyone in the medical profession to practice without obtaining consent. FDA disagrees with the comment. This rule does not attempt to regulate the practice of medicine. Rather, as discussed more fully in the preamble to the proposed rule, FDA is regulating investigational products under the statutory authority contained in the Federal Food, Drug, and Cosmetic Act (the act). FDA also disagrees with the comment that FDA is overriding State law. As stated elsewhere in this preamble, FDA is not changing the existing Federal policy that recognizes the continuing validity of applicable State or local laws and regulations on human subject protections. With regard to physician liability for performing research under this regulation, FDA disagrees with the comment's blanket conclusion that physicians participating in such research are committing malpractice and battery. FDA notes that this rule does not override existing State and local laws and regulations that may apply to such research. Institutions wishing to participate in such research may wish to consult their attorneys regarding any State and local restrictions that preclude such research. As with other research, physician liability for activities engaged in during emergency research will vary from State to State because of different laws on human subject protections. FDA notes that an existing regulation §50.23 permits waiver of informed consent in certain limited emergency situations. FDA is unaware of any research conducted in accordance with that regulation that has resulted in physician liability for malpractice or battery. 20. One comment stated that the proposal violates Federal law under the Patient Self-Determination Act of 1990. FDA disagrees with the comment. The Patient Self-Determination Act of 1990 defines an advance directive as "a written instruction, such as a living will or durable power of attorney for health care, recognized under State law (whether statutory or as recognized by the courts of the State) and relating to the provision of such care when the individual is incapacitated." (42 U.S.C. 1395cc(f)(3).) That act imposes obligations on certain facilities (hospitals, skilled nursing homes, home health agencies, and hospice programs) participating in the Medicare program regarding advance directives. (42 U.S.C. 1395cc.) The Patient Self-Determination Act requires these facilities to give information to patients about their rights under State law to accept or refuse treatment and to make advance directives. These facilities also are required to document in the patient's medical records whether the patient has executed an advance directive and to ensure compliance with State laws on advance directives. The comment did not explain how he believed the rule violates the Patient Self-Determination Act; nothing in this rule prevents facilities from continuing to act in compliance with the requirements contained in that act. 21. Another comment questioned the validity of the claim in the proposal that "the proposed rule gives double weight to the statutory 'necessitates' criterion" because "(1) intervention is needed because of the medical condition, and (2) the collection of valid data is needed[*51505]because of the absence of proven satisfactory available treatment for the condition." This comment stated that the context of the "necessitates" clause makes it clear that what is necessary is the use of a device to preserve the life of the subject-that the relationship of necessity is between the intervention and the subject's condition. This comment stated that it is a perversion of the statutory language to claim that it uses "necessitates" to refer to the relationship between the collection of data and proven treatment. The comment noted further that randomly assigning subjects to a treatment that some researchers consider unsatisfactory and to a treatment researchers think may be an improvement is not necessitated by the subject's life-threatening condition and, further, a placebo can never be necessitated to preserve a subject's life. The agency agrees that the "necessitates" clause focuses on the relationship between the treatment and the subject's condition. The idea that an intervention using an investigational product is "necessary" may, at first, appear to be contradictory. It does not mean the product is safe and effective and that it must be given to everyone. Read this way the exception would apply to products that are not investigational and it would be irrelevant. The device amendments to the act are referring to an investigational intervention that is not known to be beneficial, and "necessitate" means that because available therapy is inadequate, potentially beneficial intervention is needed. Thus, there is no obligation to give everyone the investigational intervention despite the patient's need for some better treatment; it is possible to give only some subjects the intervention, leaving others to the care they would get were there no study. In the absence of an obligation to give every patient the investigational intervention, it is possible to consider other factors, such as the need to evaluate the intervention and learn from the exposure, which potentially may benefit the subject in the study, the community, and future patients with the disease. The critical and potentially difficult concept is that the intervention is given because the patient/subject needs it, yet enough is not known about the intervention to support giving it to everyone as therapy. It is clear, despite the uncertainty, that the investigational intervention is intended to be beneficial and that there is conceptual, preclinical, and possibly clinical (e.g., other settings, preliminary results) evidence that the hoped for benefits outweigh the potential risks, all of which leads the investigator (and the pertinent IRB) to hope for, even anticipate, benefit. Such anticipation is compatible with the state of clinical equipoise needed to allow a clinical investigation. Indeed, true neutrality is rarely present at the start of an investigation; in the absence of expectation that an intervention may represent an improvement, or a belief that a standard therapy might not work, there is little incentive to proceed. The experienced clinical investigator, however, also knows that expectations are not the same as knowledge and that disappointments are too common to ignore. Therefore, despite optimistic expectations, one can be in the state of equipoise needed to allow a clinical investigation to be conducted. In the current rule, addressing the special case of nonconsenting subjects, the agency is asking for more than the usual assurances that the investigational intervention is promising, and that accumulating results have not taken us all the way past equipoise (through the data monitoring committee's considerations). This extra assurance is necessary because it must be possible to state honestly that the intervention is for the patient's benefit, at least at the level of being promising, and is not a project only for pure science, future generations, or the community, although it will, of course, benefit those too. Therefore, if there are available only unproven or unsatisfactory therapies and appropriate animal and other preclinical studies support the potential of benefit to subjects from a new intervention, the agency thinks it can be said that the subject's condition "necessitates" alternative treatment. In the case under consideration, where the new intervention is not known to be of value, although it is promising and has been evaluated in animals and in less emergent settings, it is reasonable to randomize to a standard therapy not yet shown inferior to the new intervention. The subject receiving standard therapy is no worse off than if there had been no clinical investigation. 22. Another comment considered the rule contrary to the Nuremberg Code and to the U.S. Constitution; it stated that the agency's reliance on *Doe* v. *Sullivan* is inappropriate. Another comment suggested that the decisions of the U.S. Supreme Court in *Cruzan* v. *Director Mo. Department of Health*, and *Griswald* v. *State of Connecticut* present constitutional barriers to the proposal to eliminate the requirement of informed consent in biomedical research involving emergency conditions. This comment also analyzed an attorney's observations at the Public Forum with respect to State law and criticized the proposal for not addressing these. Another comment stated that the rule denies persons with disabilities equal protection under the law and their rights to due process in that it treats competent and incompetent patient-subjects in a distinct, unequal manner. FDA disagrees with these comments and with the assertions that the cases cited present constitutional barriers to the issuance of this rule. FDA strongly endorses the concept of informed consent. Obtaining informed consent is not always possible, however, as Congress has recognized in enacting amendments to the Act. Congress explicitly has authorized exceptions from the requirement for informed consent in research in limited situations. (See preamble to the proposed rule for a more detailed discussion of authority in the act for permitted exceptions from informed consent (60 FR 49086)). Unlike situations involving a failure to inform a competent person of the risks and consequences associated with participating in research (see *In Re Cincinnati Radiation Litigation*, 874 F. Supp. 796, 800-01 (S.D.Ohio 1995)), this rule seeks to maximize an individual's access to potentially beneficial drugs and devices at a time when, due to an emergency which causes incompetency, informed consent cannot be obtained. The issuance of this rule does not result in the automatic entry of an individual in a clinical investigation without informed consent. Rather, it contains important protections that must be met before such a clinical investigation may proceed. Decisions on whether an investigation may proceed will be made on a case-by-case basis by individual IRB's and need the concurrence of a licensed physician. Contrary to the comment's suggestion, the Supreme Court's decision in *Cruzan* v. *Director Mo. Department of Health* does not create a hurdle to the issuance of this rule. In *Cruzan* v. *Director Mo. Department of Health*, 497 US 261 (1990), the Supreme Court, in reviewing a Missouri statute which required clear and convincing evidence of an incompetent person's wishes as to whether or not life-sustaining treatment should be employed, balanced a State's interest in the preservation of life with an individual's wish to terminate life support rather than remain in a vegetative state. Unlike *Cruzan*, this rule focuses on the preservation of life when an individual's wishes are unknown. As in other emergency situations, where an individual is incompetent, if it is feasible to obtain informed consent from the individual's legally authorized[*51506]representative, then such consent should be obtained. FDA notes that it is possible that an individual may have previously issued advance directives on life-sustaining treatment. FDA believes that, where feasible, attempts should be made consistent with State law to identify the existence of such directives prior to enrolling an individual into a clinical investigation without informed consent. FDA recognizes, however, that in many life-threatening instances it may not be feasible to learn of the existence of any existing directives prior to taking potentially life-saving intervention and that in many instances, an individual may not have issued such advance directives. In such cases, FDA believes that interventions consistent with this rule are constitutionally permissible. *H. Clarifications* 23. HIMA noted that it was one of the organizations that endorsed the October 25, 1994, consensus document on Informed Consent in Emergency Research from the Coalition Conference of Acute Resuscitation and Critical Care Researchers. The agency acknowledges that HIMA endorsed the consensus document on Informed Consent in Emergency Research from the Coalition Conference of Acute Resuscitation and Critical Care Researchers. 24. HIMA also suggested that FDA recognize the diversity of opinion on "deferred consent" and its history of successful use from approximately 1980 until mid-1993, rather than simply disregard this concept as "post-hoc ratification" unworthy of "genuine" informed consent. FDA disagrees and thinks that its earlier rejection of "deferred" consent was appropriate. As described in the preamble to the proposed rule, posthoc ratification is not genuine consent because the subject or representative has no opportunity to prevent the administration of the test article, and cannot, therefore, meaningfully be said to have consented to its use. III. Specific Comments on the Proposed Regulation A discussion of the specific comments received in response to this proposal follows: *A. Definitions* 25. Four comments requested clarification of the proposed definition of family members in §50.3. Two comments questioned what one should do if there is disagreement among family members. One asked whether a family member could provide informed consent for emergency research if State law does not explicitly provide for consent from family members. Another questioned whether family members, even those who do not possess power of attorney for health care rights, can provide informed consent for emergency research under this rule. One individual suggested that it may be unwise to provide a new definition for such a familiar expression as "family member" and suggested that the phrase "any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship" be used in its place. Another comment commended the agency for including in its definition those individuals whose relationship resemble family relationships. One comment suggested that the hierarchy of the decision-making authority of family members should be clearly stated. This comment questioned whether one family member could overrule the decision of another and questioned whether all family members must agree. The agency thinks that it is appropriate to retain the phrase "family member" and its definition. The agency has specifically included family members under this rule because the opportunity for an available family member to object to a potential subject's participation in such a clinical investigation provides an additional and an important protection to these individuals. Otherwise, if consent from a subject or the subject's legally authorized representative were not feasible, the eligible individual could be enrolled into the investigation. Thus, by permitting a family member (even one who is not a legally authorized representative) to object to an individual's inclusion in the investigation, a further protection is provided to that individual. This rule has been modified to make clear that a family member must be provided an opportunity to object to the potential subject's participation, if feasible within the therapeutic window when obtaining informed consent from the subject is not feasible and a legally authorized representative is not available. The agency recognizes that this may not constitute legally effective informed consent if the family member is not a legally authorized representative under State law. FDA is not establishing a hierarchy of family members although an IRB may consider the need for creating a hierarchy in reviewing individual investigations. Under this rule only one family member would need to be consulted and agree or object to the patient's participation in the research. If family members were to disagree, the researcher and family members would need to work out the disagreement. 26. One individual, who was opposed to the entire rule, suggested that by not providing a definition of "emergency," FDA's quest for harmony and uniformity would be defeated by the various definitions provided by State law. He suggested that without such a definition, too much discretion is delegated to medical researchers and IRB's; that the agency will have little basis to monitor the activities carried out by these researchers; and that the exception will be used to exempt all emergency research from consent, even when it is feasible to prospectively identify and secure the consent of hospitalized individuals. Finally, he noted that the Health Care Financing Administration has issued regulations under the Emergency Medical Treatment and Active Labor Act which define the term "emergency medical condition;" this act's regulations link an emergency medical condition to the manifestation of "acute symptoms of sufficient severity * * * such that the absence of immediate medical attention could reasonably be expected to result in: (a) Placing the health of the individual * * * in serious jeopardy; (b) serious impairment to bodily functions; [or] (c) serious dysfunction of any bodily organ or part." He suggested that health care professionals will be confused by the different use of the term "emergency" in this regulation and under the Emergency Medical Treatment and Active Labor Act. The agency disagrees with these comments. Sufficient guidance is given in the regulation in §50.24, particularly in §50.24(a)(2)(iii), to ensure that there is a clear understanding of what constitutes a life-threatening situation that could invoke this rule and to ensure that it is not used routinely in all emergency research. In addition, each clinical investigation will be reviewed by FDA and the IRB to help ensure that this exception from informed consent is not used for research for which it was not intended. Further, emergency room personnel should not be confused because they should know when they are participating in FDA regulated research. The agency notes that the purpose of the Emergency Medical Treatment and Active Labor Act is different from this rule. This informed consent exception is intended to allow certain FDA-regulated research to proceed without informed consent provided specific conditions are met. Entities that deal with both regulations[*51507]will be able to understand whether one or the other regulation applies. *B. Exception Criteria* 1. Section 50.24(a) 27. One comment suggested that additional conditions be added to §50.24(a) to reinforce the statement in the preamble to the proposed rule that appropriate evidence is available to document clinical equipoise and to ensure that efforts are made to obtain consent from a legally authorized representative whenever possible. The two proposed additional sections would read: "[a]ppropriate animal and preclinical trial studies have been completed, and the information derived from those and related studies support the likelihood of providing a direct benefit to the individual subjects" and "[t]he IRB finds that the researcher defined the length of the therapeutic window based on scientific evidence, will try to contact the legally authorized representative within that window of time, and will ask each representative contacted for consent within that window rather than waive consent. The researcher will track the number of representatives contacted and provide that information to the IRB." The agency agrees that these are important concepts that should be contained explicitly in the regulation. It has incorporated these comments in the regulation, with slight modification to the language proposed in the comment. The agency has added a new paragraph to §50.24(a)(3) to read as follows: "(ii) Appropriate animal and other preclinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the intervention to provide a direct benefit to the individual subjects." The agency also has added a new paragraph §50.24(a)(5) and a new paragraph §50.24(a)(7)(v). The new paragraph §50.24(a)(5) reads as follows: "(5) The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legally authorized representative for each subject within that window of time and, if feasible, to asking the legally authorized representative contacted for consent within that window rather than proceeding without informed consent. The investigator will summarize efforts made to contact legally authorized representatives and make this information available to the IRB at the time of continuing review." The new paragraph §50.24(a)(7)(v) reads as follows: "(v) If obtaining informed consent is not feasible and a legally authorized representative is not reasonably available, the investigator has committed, if feasible, to attempting to contact within the therapeutic window the subject's family member who is not a legally authorized representative, and asking whether he or she objects to the subject's participation in the clinical investigation. The investigator will summarize efforts made to contact family members and make this information available to the IRB at the time of continuing review." The agency notes that if the window of time is narrow, it will be difficult or impossible to identify a legally authorized representative or family member, especially for potential subjects whose identities are unknown at the time of presentation. 28. One comment suggested that, in order to prevent abuses, the agency provide all IRB's with standardized forms that strictly define the circumstances and process for an IRB to invoke the waiver of informed consent. The agency does not think that standardized forms would be useful or practical. The regulation provides sufficient information and allows flexibility for each IRB to develop procedures and methods (and forms, if necessary) to fulfill its requirements. 29. Several wording changes were suggested to clarify §50.24(a). Two comments suggested that §50.24(a) be revised to add "prior to initiation of research" after the words "without requiring that informed consent be obtained" in order to stress that consent is being waived for the necessary immediate intervention. The agency thinks this change is unnecessary. This is clear from §50.24(a)(2) and new §50.24(a)(5). 30. One comment suggested the addition "of all research subjects" following the phrase "without requiring that informed consent" and modifying the parenthetical phrase in the next sentence to read: "(with the concurrence of a licensed physician voting member of the IRB or the concurrence of a licensed physician who serves as a consultant)." The agency has incorporated this language, with minor changes, to emphasize the need for concurrence by a licensed physician who is either an IRB member or consultant and who is not otherwise participating in the clinical investigation. The agency recognizes that in some instances it will be possible to obtain informed consent from some individuals or their legal representatives, or contact a family member when this exception is invoked for a clinical investigation. The agency has not included the term "voting" because it does not believe that it is necessary to explicitly require that this licensed physician who concurs be a voting member of the IRB because concurrence by this licensed physician is required by the regulation. Since 1981, FDA has stated its expectations that an IRB that reviews investigational new drug studies will include at least one physician. (See 46 FR 8942 at 8966, January 27, 1981.) This expectation is not changed by this rule. 31. Other comments were received on the "concurring licensed physician member or consultant." Three comments felt that this physician member or consultant would add nothing to the process because of pressure to endorse the study; one comment suggested that the interests of subjects would be better served if this physician or consultant were independent of the IRB; two comments suggested that the physician be independent of the investigator (i.e., have no ties to or be in the same department or supervised by, the investigator). The requirement for a concurring licensed physician is contained in the Medical Device Amendments of 1976 and, thus, it must be retained. The agency agrees with the need for this individual to be independent from the clinical investigation but disagrees with the suggestion that the physician be independent of the IRB. Thus, the agency has amended the language in §50.24(a) to make clear that the licensed physician must be one who is not otherwise participating in the clinical investigation. This language parallels the language contained in §50.23(a). 32. One of these comments suggested that an independent ombudsman who is aware of the acute risks of the specific research, the long term risks of the research for the individual, family, and society, based on the condition of the potential subject be appointed to oversee the study. The agency does not agree. There is no need for a special requirement for an ombudsman for these clinical investigations. Current §50.25(a)(7) requires the consent form to contain an "explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject." It may be the IRB or some other designated individual who performs these ombudsman-type functions for these investigations.[*51508] 2. Section 50.24(a)(1) 33. A few comments expressed concern about the phrase contained in §50.24(a)(1) that "available treatments are unproven or unsatisfactory." One comment suggested that "unproven" be changed to "ineffective." The agency disagrees with this suggestion because one may have insufficient data to know whether a treatment is ineffective. One may, however, know from the limited data available that it is "unproven." 34. Another comment suggested that the phrase "available treatments are unproven or unsatisfactory" be changed to read "the efficacy of available treatments has not been demonstrated, or is regarded as unsatisfactory." The agency does not believe this change is necessary or desirable. Available treatments need to be assessed in terms of both safety and effectiveness. The agency believes that the change proposed in the comment focuses solely on effectiveness. 35. Another comment expressed concern that nonscientific members of IRB's will have a particularly difficult time making determinations about whether available treatments are unproven or unsatisfactory. The agency disagrees. Current §56.107(a) requires the IRB membership to possess the professional competence necessary to review specific research activities. Further, current §56.107(f) permits an IRB to invite "* * * individuals with competence in special areas to assist in the review of complex issues which require expertise beyond or in addition to that available on the IRB." Thus, the IRB should have sufficient information from its own professional expertise, or from consultants, to make determinations about whether available treatments are unproven or unsatisfactory. 36. One comment suggested that guidance on the criteria for determining that current therapy is unsatisfactory should be provided or that the rule should explicitly recognize that IRB's have the discretion to make independent decisions on this point. One comment suggested that a study be allowed to proceed if there is an alternative therapy, provided that equipoise exists between the investigational product and current therapy. It is clear from the existing wording in §50.24(a) that it is the IRB's responsibility to make decisions as to whether the criteria in the rule are met. The agency notes that it will also be reviewing these clinical investigations and will evaluate whether these investigations meet the criteria in this regulation. There is nothing in this rule that would prohibit an investigation from proceeding if there is an alternative therapy where the alternative therapy is unproven or unsatisfactory. The agency expects that in most clinical investigations under this rule, the experimental intervention will be added to standard therapy. That is, subjects in the investigation would receive standard therapy, with a portion of the subjects receiving the investigational product in addition. In some clinical investigations, some subjects may receive standard therapy, while others may receive the investigational product instead of standard therapy because, for example, use of the investigational product precludes use of the standard treatment. In these latter investigations, the IRB may need to look more closely at why standard therapy is unproven or unsatisfactory, and may want to review additional preclinical data or results in less ill human subjects that the intervention is promising, because the standard care will not be provided to a portion of the subject population. 37. Other comments suggested that without clear definitions for "unsatisfactory" and other terms used in the proposal's preamble to describe clinical equipoise, i.e., unknown," "believe," and "reasonable minority," that abuse of the consent exception is likely. The agency disagrees with these comments. The agency has explained this provision in more detail in the preamble to the proposed rule and believes that such definitions are unnecessary. The agency also notes that the conduct of this research will be carefully monitored and will be subjected to public scrutiny through the requirements for community consultation and community disclosure. In the preamble to the proposed rule, the agency stated that "[w]hen the relative benefits and risks of the proposed intervention, as compared to standard therapy, are unknown, or thought to be equivalent or better, there is clinical equipoise between the historic intervention and the proposed test intervention. Clinical equipoise would exist * * * whenever at least a reasonable minority of medical professionals believe the experimental treatment would be as good as, or better than, the standard treatment." (60 FR 49086 at 49093, September 21, 1995.) The agency thinks that this description provides sufficient guidance to IRB's and that it is appropriate to allow IRB's to determine when clinical equipoise exists. 38. A number of comments suggested that the scope of the research covered by the proposed rule and contained in §50.24(a)(1) be extended to conditions beyond those that are immediately life-threatening so that conditions that result in permanent disabilities, such as a long-term or permanent coma, or conditions that would result in other serious irreversible injury are included under the rule. One example given was a near-drowning patient resuscitated in the prehospital setting who arrives at the Emergency Department comatose; the acute injury may no longer be immediately life-threatening, but the chances that the patient will regain consciousness again are highly unlikely. One comment noted that FDA has in the past interpreted "life-threatening" to include threats of serious disability and, if this is intended in the proposed rule, it would be helpful to add this interpretation to the supplementary information. Another comment suggested that both stroke and head injury do not necessarily immediately result in death and that potentially effective treatments are being developed for these conditions which may leave the patient with profound deficits. This comment proposed that such emergencies be covered under the final rule. Two comments suggested that "life-threatening" be defined and limited to include only those situations believed to be immediately life-threatening. Another comment suggested that "emergency privilege" is limited and should extend to care needed to stabilize or prevent further deterioration of the patient's condition as well as care necessary to prevent death or serious bodily injury or harm. Therefore, the care justified must be balanced with the emergent nature of the patient's condition, the patient's potentially transient incompetence to make decisions and give consent, and the time needed to make a reasonable effort to contact and involve the patient's family. The agency notes that the Medical Device Amendments limit this exception to life-threatening situations; the agency and the IRB will need to judge each clinical investigation to ensure that it meets the criteria of the statute and regulations. Specifically, the IRB must conclude that the intervention to treat a life-threatening condition must be administered before consent can be obtained. The criteria contained in the rule do not require the condition to be immediately life-threatening or to immediately result in death. Rather, the subjects must be in a life-threatening situation requiring intervention before[*51509]consent from a legally authorized representative is feasible. Life-threatening includes diseases or conditions where the likelihood of death is high unless the course of the disease or condition is interrupted. (See §312.81.) People with the conditions cited in the examples provided in the comments-e.g., long-term or permanent coma, stroke and head injury-may survive for long periods but the likelihood of survival is not known during the therapeutic window of treatment. People with these conditions are clearly at increased risk of death due to infection, pulmonary embolism, progression of disease, etc. The rule would apply in such situations if the intervention must be given before consent is feasible in order to be successful. The informed consent waiver provision is not intended to apply to persons who are not in an emergent situation, e.g., individuals who have been in a coma for a long period of time and for whom the research intervention should await the availability of a legally authorized representative of the subject. 39. The agency received a number of comments on the reference to placebo-controlled trials in §50.24(a)(1). One comment stated that it was vitally important to retain the reference. Other comments requested that the reference be removed. Reasons given for its removal included concern that placebo-controlled studies will not meet the requirement of clinical equipoise unless the placebo control is the standard of care for the situation or there is absolutely no standard therapy; that this conflicts with agency statements that the use of a placebo is not necessary when the end-point is clear and reasonably predictable; it is inappropriate for the agency to specify one study-design among many; and that unless the potential subject or legally authorized representative can consent, a placebo should not be an alternative. Some of the comments appear to presume that in a placebo-controlled trial, the placebo group would be untreated. In virtually all cases, when a placebo is used, standard care, if any, would be given to all subjects, with subjects randomized to receive, in addition, the test treatment or a placebo. An exception to this would be the situation in which the test is to determine whether standard treatment is in fact useful. In that case, there must be a group that does not receive it. The agency believes that it is important to recognize in the regulation that placebo-controlled trials may be conducted under this emergency research provision; thus, it is retaining the wording in this section. Different kinds of controls are described in FDA's regulations. For example, FDA regulations for drugs (§314.126) describe five kinds of study designs that can be used in carrying out the well-controlled investigations needed under law to provide the "substantial evidence of effectiveness" needed to market a drug. They are: Placebo concurrent control, dose-response concurrent control, no-treatment concurrent control, active treatment concurrent control, and historical control. In any given year, drug approvals will be based on clinical investigations using each of these designs. The study design used must, however, be adequate to the task of providing evidence that the drug or device will have the effect claimed. 40. Two comments suggested changing the wording of §50.24(a)(1) from "what particular intervention is most beneficial" to "the safety and efficacy of a particular intervention" in order to provide greater flexibility. Another comment suggested that "most beneficial" be followed by the clarifying phrase "to patients in the life-threatening situation." The agency agrees that it would be more precise to indicate that the clinical investigation is necessary to determine whether a particular intervention is safe and effective and it has modified the wording in the regulation accordingly. 3. Section 50.24(a)(2) 41. A number of comments on §50.24(a)(2)(ii) recommended that "or family members" be added to "legally authorized representatives" at each occurrence in the proposal and in its conforming amendments in order to ensure that the exception is used only in those cases where it is not feasible to contact the legally authorized representative or a family member. The agency generally agrees with these comments for the reasons previously stated and has modified the regulations accordingly. 42. Two comments requested that a definition of the term "legally authorized representative" be provided. One comment suggested that the language be clarified to read "* * * consent from the subjects' legally authorized representatives is feasible." "Legally authorized representative" is currently defined in §50.3(m) 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." This definition is being retained in the regulation. The agency has added the clarifying language that it is "the subject's" legally authorized representative. 43. One comment questioned whether one should seek oral consent/assent from a family member or other individual in those instances in which there may only be a few moments to convey the nature of the intervention, precluding full informed consent. If such assent is not given, the comment requested clarification on options available to the researcher. If it is feasible to obtain informed consent for some potential subjects, informed consent is required for those individuals. If there is insufficient time to obtain informed consent for some potential subjects, but there is sufficient time to convey some basic risk and benefit information about the clinical investigation, then that information should be provided to the subject, the subject's legally authorized representative, or the subject's family member. If the subject, legally authorized representative, or family member objects to the individual's inclusion in the investigation based upon the information provided, then that individual should be excluded from participation in the clinical investigation. If only partial information was conveyed, then the information described in §50.24(b) is to be provided at the earliest feasible opportunity. 44. Another comment suggested that there be a requirement that the determination that a subject cannot provide informed consent and efforts made to obtain informed consent from the subject's legally authorized representative be documented and notarized by an individual not directly involved in the research. This comment suggested that without such a requirement, investigators are likely to make little effort to obtain consent from subjects prior to enrollment. This concern was echoed by another comment, which suggested that the investigators' documentation of efforts to obtain informed consent would encourage researchers to expend greater efforts to obtain informed consent for these activities. Another comment suggested that this documentation be made by an individual not affiliated with the study team. The agency expects the IRB to determine, based on the specific details of the individual clinical investigation (including the window of opportunity for treatment), the procedures the investigator must follow to attempt to obtain informed consent before enrolling a subject in an investigation without such consent. The agency has added a new paragraph §50.24(a)(5) that requires the investigator to attempt to[*51510]contact a legally authorized representative for each subject within the therapeutic window and, if feasible, ask for consent within that window rather than proceeding without consent. The agency also has added a new paragraph §50.24(a)(7)(v) that requires the investigator to attempt to contact a family member within the therapeutic window and ask whether the family member objects to the subject's participation in the clinical investigation, if informed consent is not feasible and a legally authorized representative is not available. IRB's may create a hierarchy of family members or impose other conditions to increase the protections provided to research subjects. These paragraphs further require the investigator to summarize efforts made to contact representatives and family members and to make this information available to the IRB at the time of continuing review. The agency believes that these procedures will ensure that appropriate efforts are made by the investigator to obtain consent from subjects prior to enrollment. The agency expects these procedures to be documented in the protocol and/or by the IRB, and the efforts made by investigators to be documented in the material presented to the IRB for its continuing review. The agency believes that this documentation provides the necessary protections suggested by these comments. 45. One comment suggested that §50.24(a)(2)(iii) be modified to read "There is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the research study," omitting the remainder of the sentence. The agency agrees that the last phrase in the proposal that read "because the emergence of the condition to be studied cannot be predicted reliably in particular individuals" is not needed and it has therefore deleted this phrase from the final rule as suggested. 46. Although two comments stressed the importance of retaining the word "reasonable" in order to allow IRB's to exercise the judgment necessary to make satisfactory decisions about application of the exception in particular contexts, another comment suggested that the term "reasonable" may provide more flexibility than is desirable. The agency thinks that IRB's must be allowed to make responsible judgments when they review clinical investigations, and that it is important to retain the term "reasonable" in order to permit the IRB to judge the particular circumstances surrounding each investigation under review. 47. One comment asked how to document the case where prospective individuals have been notified and prior consent for participation has been sought in an institution with several co-investigators or where more than one institution in the area may be participating in the research. The comment asked further whether only those subjects with the condition who gave prior consent could be enrolled and whether those who did not render a decision would be excluded from participation in the study. Generally, the agency recommends that when prospective consent is being sought in an institution, the documentation that a potential subject consented or refused to consent be placed prominently in the subject's medical file. Consent will typically be documented through a signature on the consent form. It is the responsibility of the clinical investigator to determine how to identify prospective subjects who have agreed or refused to participate in a clinical investigation if they should become eligible in order to help ensure that their decisions are followed. When an IRB determines that it is not appropriate to waive the requirement of informed consent because there is a reasonable way to identify prospectively the individuals likely to become eligible for the clinical investigation, then only those subjects with the condition who gave prior consent may be enrolled in the investigation. Those individuals who either did not make a decision or who refused would be excluded from participation in the investigation. 48. Another comment noted that if a subset of the general population can be identified as potential subjects, anticipatory informed consent must be obtained, even if the subset is a very small percentage of a large patient population. For example, where a small percentage of patients undergoing a standard procedure may suffer a complication that would render them unconscious and make them potential subjects, informed consent should be obtained for that clinical investigation. The comment went on to note that if that procedure carries some known risk for a complication, the potential subjects would need to be informed of that risk in any event, and obtaining anticipatory consent for the investigation should therefore not be burdensome. The agency generally agrees with the concept that obtaining anticipatory consent from a target population where the complication rate is modest often would be feasible. As the complication rate grows small and the population hard to identify, this strategy becomes problematic. Each clinical investigation must be judged individually by FDA and the IRB. 49. Another comment suggested that the Coalition Conference Consensus Statement wrongly discounted the value of securing and the ability to secure prospective consent from identifiable individuals at high risk for study enrollment, particularly those in hospitals, and that neither the consensus statement nor the proposed rule mentioned the role of advance medical directives in guiding enrollment decisions. This comment, supported by others, suggested that a good faith effort should be mandated to locate advance directives and that the regulation should include a new paragraph, as follows: "Any individual likely to be eligible for a research protocol under this section may not be enrolled in the research if the investigators know, or reasonably should know, that the individual did not want to receive medical interventions of the type under study." Another comment suggested that, although advance directives have been addressed in clinical practice, their application to the conduct of clinical research has not received much scrutiny. This comment described the difficult task for potential subjects to imagine the kind of research they would want should they suffer a catastrophic illness; it went on to recommend that either FDA clarify how it intends clinical investigators to adopt the practice of advance consent, or this statement should be deleted. It further suggested that FDA consider requiring the use of consent auditors whose role would be to determine whether the subject truly understands the consent process. The agency does not believe that these comments require a change in this regulation. The agency recognizes that it may be possible in some situations to secure prospective consent from identifiable individuals at high risk for study enrollment, particularly if they are inpatients. It is for that reason that the agency has included §50.24(a)(2)(iii), which requires the IRB to determine that there is no reasonable way to identify prospectively the individuals likely to become eligible for the clinical investigation. Both the American Hospital Association's Patient Bill of Rights and section 4206 of the Omnibus Budget Reconciliation Act of 1990 recognize a patient's right to participate in and direct health care decisions affecting the patient. The agency agrees, particularly for clinical investigations involving inpatients, that[*51511]appropriate efforts be made to review the patient's medical file to determine whether there exists an advance medical directive or other indication of the patient's desires (e.g., do not resuscitate order). However, the agency also recognizes that, for at least some of the research that will be eligible for this exemption, there will be insufficient time to search for or locate such directives. The IRB should be knowledgeable about an institution's procedures regarding the use of advance medical directives and assess whether the proposed clinical investigation is consistent with those procedures. As discussed previously, if an IRB determines that it is not appropriate to waive the requirement of informed consent because there is a reasonable way to identify prospectively the individuals likely to become eligible for the clinical investigation, then only those subjects with the condition who gave prior consent may be enrolled in the investigation. Those individuals who either did not make a decision or who refused would be excluded from participation in the investigation. For research where individuals can give informed consent prospectively, the individual's consent or refusal should be documented in such a way to ensure that the individual's determinations are followed. As in other research that is reviewed by an IRB, it is up to the IRB to determine whether there is a need for a consent auditor. 50. Another comment recommended that the question of whether prior consent of subjects must be obtained should be resolved by considering the following questions: (1) From which populations will subjects be drawn; (2) what is the probability that any particular member of the at-risk population will become a potential subject; (3) where is the population from which subjects will be drawn; (4) how much effort is needed to inform the population of the study; and (5) what is the most effective communications media or mechanism to reach the population. Based on these questions, this comment recommended that a new section be added that would state: "When individuals likely to become eligible for the research are members of identifiable and accessible populations of the community at large, reasonable effort to target communications to those sub-populations should be made." This comment suggests what may be a reasonable thought process for an IRB to follow. However, it combines two different concepts: communication with the community and prior consent of individual subjects. As the agency has previously stated, if one can obtain prior consent of subjects, that should be done. Examples of situations where it may be feasible to obtain prior informed consent include: use of a surgical procedure with a known severe consequence; administration of a drug product with a known serious adverse reaction; identification of a population with a particular disease or condition who are at an extremely high risk for a serious event. In each of these instances, it may be feasible to identify in advance the specific patient population susceptible to the condition being studied and obtain consent. The agency believes that it would be inappropriate to add the suggested section to the regulation because it confuses efforts to inform the community with efforts to obtain prior consent of the individual. 51. Another comment recommended that the agency require preliminary studies of new products in patients admitted to intensive or critical care units who are able to consent or who have a legal representative who can consent on their behalf. This comment suggested that this would strengthen an inadequacy in the existing regulations that permits studies (with subjects unable to provide informed consent) to begin, without any knowledge regarding the clinical performance of the drug/device. Given the nature of the product and the medical condition, this suggestion may not be feasible for many of these clinical investigations. The agency, in its review of these investigations, will review the adequacy of the information about the proposed intervention to help ensure that there is sufficient knowledge, including clinical performance in other settings when possible, of the drug or device to justify its use in such investigations. In addition, the regulation has been modified to specify that evidence from appropriate animal and other preclinical studies support the potential for the intervention to provide a direct benefit to the individual subjects. 4. Section 50.24(a)(3) 52. A number of comments suggested deleting the phrase "is in the interests of the subjects" in §50.24(a)(3) in part because this phrase requires that a judgment be made about subjects whose interests may be largely, if not totally, unknown to the IRB and to the investigators. Some comments argued that there would be no possible benefit to the subject, but only to society at large if the experimental intervention were shown to be effective; the goal of the research is not to benefit subjects in the research, but rather to benefit science in the pursuit of knowledge. Others suggested that §50.24(a)(3) be modified to read: "The opportunity to participate in the research holds out the prospect of direct benefit to the subjects because * * *." Other comments objected to the word "opportunity" as being disingenuous and paternalistic and suggested that this section be modified to read: "Participation in the research * * *." The agency agrees that §50.24(a)(3) should be modified in response to some of these comments. The first comment points out that one cannot really know about all the interests of a person in these situations. The modification would make clear that the clinical investigation holds out the prospect of direct benefit to the subjects. The agency does not agree with the second comment that there would be no possible benefit to the subject, but only to society at large. To justify the use of this exception the IRB must believe that participation in the study holds out the prospect of direct benefit to the subjects. It is also true, but not the basis for the exception, that the interests of society will be served by the waiver because the research will produce valuable knowledge, applicable to future patients, that would otherwise never be obtained; an IRB should not approve a clinical investigation that is poorly designed and, thus, unable to answer the scientific question posed. In response to the third suggestion, the agency is clarifying any mis-impression that it would be the "opportunity" rather than the actual "participation" in the research that is beneficial. The agency intended that participation in the research should hold out the prospect of direct benefit to the subject and has revised the rule accordingly. 53. Another comment noted that if the null hypothesis is plausible, that is, if the effect of the investigational intervention is no different from that of the standard treatment, the subject has little to gain by being in a randomized trial rather than being treated by whichever arm of the study is standard. This comment recommended that historical controls be used when investigators or potential subjects are not "indifferent" to the treatment alternatives. If the use of a historical control is appropriate for the clinical situation being studied, that control may be used, but the difficulties of this design are well-known and it cannot reliably assess small, but potentially meaningful benefits and is frequently associated with false positive results. The comment related to the null hypothesis is not unique to emergency research. Rather, it reflects a fundamental ethical dilemma[*51512]in all clinical trials. This dilemma, however, has not been considered by most bioethicists as an impassable obstacle for the conduct of controlled trials. This is because continuing an intervention, even one thought to have promise, without determining that it does provide benefit, is not a responsible alternative. The investigational intervention in these clinical investigations must be promising, but one does not know that it is in fact safe and effective. Further, in these investigations, the standard treatment being compared to the investigational product or to which the investigational product is added will be of unproven benefit or unsatisfactory. 54. One comment suggested that an additional condition be added to 50.24(a)(3) which would require that the weight of scientific evidence be sufficient to support the likelihood that the individual subjects will receive a direct benefit. Another comment suggested that the rule require a progression of research from less severe medical cases to more severe and only permit the inclusion of patients unable to consent if there is an ombudsman independent from the research activity. As previously described, FDA has added a new §50.24(a)(3)(ii) which requires that "Appropriate animal and other preclinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the intervention to provide a direct benefit to the individual subjects." There is nothing in this rule that would preclude research from being conducted in subjects with less severe medical conditions (not in a life-threatening situation) before being conducted in subjects with more severe medical conditions provided that informed consent is obtained from the research subjects with the less severe conditions. When this exception is invoked for a particular clinical investigation, however, the FDA, sponsor, clinical investigator, and IRB will be responsible for ensuring that the subject population is appropriate; that is, that the subjects are in a life-threatening situation. 55. One comment recommended that §50.24(a)(3)(i) be reworded to clarify that "subjects are facing a life-threatening situation that necessitates intervention." The agency agrees with the comment and has modified this section accordingly. 56. One comment suggested that proposed §50.24(a)(3)(ii) be reworded to clarify that the rule is addressing the "prospective subjects' condition" and that "current therapy" equates to "standard therapy." This comment suggested that proposed §50.24(a)(3)(ii) be rewritten to state "risks associated with the intervention are reasonable in the light of what is known of the prospective subjects' medical condition, the risks and benefits of standard therapy * * *." The agency has renumbered proposed §50.24(a)(3)(ii) to be §50.24(a)(3)(iii) in the final rule. The agency agrees with the comment and has modified this section accordingly. The risk and benefit assessment that is required by §50.24(a)(3)(iii) will be conducted for future subjects meeting the entry criteria for the clinical investigation; therefore, it is appropriate to refer to these subjects as the "potential class of subjects." The agency intended that the risks and benefits of "standard" therapy be considered; it recognizes that "current" therapy may be too broad. 57. Several comments requested a definition of "reasonable." One comment noted that the rule requires a complex judgment about risks and benefits and yet lacks specificity as to how this judgment is to be made. This comment noted that in most research, an IRB can rely on the risks and benefits being explained to the subject and the subject judging whether they are reasonable. In the case of the research covered by this regulation, that recourse is not available. It is not possible to be specific about how to make the judgment about risks and benefits because, as the comment notes, the judgment to be made is complex, with different information and considerations determined by the particular clinical investigation. The agency thinks that sufficient clarity is contained in §50.24(a)(3)(iii) to allow an IRB to understand that it must consider: (1) What is known about the medical condition, (2) what is known about standard therapy, and (3) what is known about the proposed intervention or activity. The risks of the investigation must be considered reasonable in relationship to all of this information. The agency does not think that this requirement needs further explanation. 58. Two comments suggested that proposed §50.24(a)(3)(ii) be modified to incorporate the Coalition of Acute Resuscitation and Critical Care Researcher's concept of "appropriate incremental risk" stating that this would better protect the rights of subjects. One of these comments suggested that the 1981 FDA regulatory requirement that "there is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject" is the standard that should be used in this regulation. The agency disagrees with both suggestions. The protections provided by the rule are substantial and sufficient without these changes. The standard for risks, described in the regulation, are that they be "reasonable" in relationship to what is known of the medical condition of the potential class of subjects, the risks and benefits of standard therapy, if any; and what is known about the risks and benefits of the proposed intervention. The term "appropriate incremental risk" does not have a clearly different meaning, although it may imply greater precision than usually exists. In order to invoke this exception, the available treatments must be unproven or be regarded as unsatisfactory. 5. Section 50.24(a)(4) 59. Several comments suggested deleting or clarifying §50.24(a)(4) concerning the "practicability" of conducting the research without the waiver. One comment requested clarification as to whether "practicability" only referred to whether there is sufficient time to obtain consent from a subject's legally authorized representative; and recommended that if this is the sole basis for determining practicability, it should be added to the regulation. Another comment noted that "practicability" should not refer to convenience, cost, or speed. One other individual commented that although certain institutions may be unable to perform specific acute injury research because of logistical considerations, it is likely that most research projects could be designed such that performance under existing rules for nonconsenting subjects would be possible in other locations. This comment cited a multicenter trial where only one institution requested a waiver. One comment suggested that §50.24(a)(2)(ii) is sufficient for determining whether a study can be done; this comment stated that the primary reason that it would not be practical to carry out the research without the waiver would be because it is not feasible to contact the legally authorized representative or family member before the intervention must be administered. Another comment objected to §50.24(a)(4) and argued that the rule should state that if there are any potential subjects otherwise eligible for a trial for whom consent from a legally authorized representative cannot be obtained, the provisions of §50.24(a) may be utilized to include them, even if the trial could be carried out without[*51513]their participation, so long as all of the requirements for that section are met. This comment noted that if this section meant only that consent should be obtained wherever it can be, even when most subjects in a study do not have an available legally authorized representative, it would be unexceptionable, but the section goes beyond that to proscribe participation in a trial by patients without consent when the majority of eligible patients do have such consent available because in that case the study can be carried out "practicably" without those patients. This comment noted that it is the value of participation to the subject that permits an exception to the informed consent requirement; that implicit in the proposal is the view that most patients would choose a chance to receive promising rather than standard therapy that is known to have an often unsatisfactory outcome. Thus, to exclude patients unable to consent from this research is unethical, even if the study could be conducted with subjects for whom surrogate consent is possible. The agency has carefully considered these comments, particularly the latter comment that in effect contended that the "practicably" requirement is inconsistent with the ethical basis for the rule because it implies that the exception to consent is available to serve the community's needs rather than the individual's. The agency included this requirement not because it thought the research was not in individual patients' interests, but because research without informed consent represents a more difficult and complex situation than research with consent, in that it is a kind of research with greater than usual ethical issues that should be taken only when necessary. This is because the agency believes it is generally preferable to obtain case-by-case consent even from a representative of the individual. Just as consent by the subject is preferable to consent by their representative, consent by the subject's representative is preferable to the procedure in this regulation. This does not mean that these procedures are inadequate or unethical; rather, it recognizes within the realm of ethically proper actions a hierarchy of values and that we should seek the highest level of those values feasible in this situation. Similar considerations have arisen in the past. The National Commission for the Protection of Research Subjects of Biomedical and Behavioral Research argued that (wherever possible) clinical trials intended to benefit young children should first involve adult subjects, later older children as subjects, and finally trials in younger children (who cannot consent or assent). This is not because the trials in younger subjects are considered inappropriate or ethically doubtful. The agency understands the Commission to be saying that the principle of respect for persons of diminished autonomy applies in such a way that the less autonomy a subject possesses, the less suitable that subject is for research, even if the research shows promise. The Commission did not say to never involve persons with minimal or no capacity to exercise autonomy, but to do so only as a last resort. It is critical to recognize that an investigation of a promising (but unproven) intervention is not carried out universally, i.e., studies are conducted in particular places. Similarly, although a parent of a young child could argue that his or her child should not have to wait for the trial in adults and older children to be completed before having an opportunity to participate in research, the Commission was not persuaded by that argument (although, in some cases, early trials in young children might be carried out). The Commission did not recognize the right of a needy person to gain access to a research protocol. In choosing among sites for a clinical investigation, for example, it is usual to select those in which the skills of investigators and availability of subjects appear to predict an ability to carry out the investigation successfully. Similarly, it is reasonable to consider, in deciding where or in whom to conduct an investigation, the ability of subjects to consent (or have consent given for them). Widely accepted ethical principles indicate that a decision to participate or not to participate in an investigation should, if at all possible, be made by a competent subject who should (as stated in the Nuremberg Code) be free of all force, fraud, fear, or coercion. An exception from the requirement for informed consent should be rare and narrow, confined to cases where consenting subjects are not reasonably available. In addition, participation in the research must hold out the prospect of direct benefit to the subjects and the investigation must be one that is capable of providing useful scientific/medical information. If serving the interests of the subjects were considered sufficient alone, that would imply that potential subjects have a right to participate in the trial, an inappropriate consideration for an investigational use and unrealistic, because studies cannot in fact be carried out at all potential sites and in all patients. The agency thus agrees with the comment that it is necessary for there to be value to the subject from participating in the research; but, given the general principle of obtaining informed consent where possible, does not think that such potential benefit is sufficient justification to include nonconsenting patients when it is reasonably possible to conduct the clinical investigation in subjects who can consent. Therefore, if scientifically sound research can be practicably carried out using only consenting subjects (directly, or in most cases for the research contemplated in the rule, with legally authorized representatives), then the agency thinks it should be carried out without involving nonconsenting subjects. By practicable, the agency means, for example, (1) That recruitment of consenting subjects does not bias the science and the science is no less rigorous as a result of restricting it to consenting subjects; or (2) that the research is not unduly delayed by restricting it to consenting subjects. Continue to Part 2

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