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U.S. Department of Health and Human Services

Science & Research

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Protection of Human Subjects; Informed Consent 61 FR 51498 (continued)

21 CFR Parts 50, 56, 312, 314, 601, 812, and 814

[Docket No. 95N-0158]

RIN 0910-AA60

 
6. Section 50.24(a)(5)(i)-(a)(5)(iii)-Community Consultation and Public Disclosure

The greatest number of comments were received on §50.24(a)(5)(i) through (a)(5)(iii), which have been renumbered §50.24(a)(7)(i) through (a)(7)(iii) in this final rule in order to have a more logical presentation of information. To assist readers, these sections will be referred to as §50.24(a)(7)(i) through (iii) in the discussion that follows. While most comments supported the requirement for community consultation and public disclosure, many requested clarification, offered suggestions, or concluded that fulfilling these requirements would be impossible. Other comments questioned whose responsibility it would be to disclose-the clinical investigator, sponsor, or IRB. These comments are discussed in more detail below.

60. A number of comments suggested alternatives to the requirement for §50.24(a)(7)(i) for consultation with representatives of the communities from which the subjects will be drawn. These included limiting this provision to only those diseases for which a patient advocacy organization exists; relying on the existing IRB mechanism that already requires inclusion of an individual not otherwise affiliated with the institution; requiring that IRB's have a community member or an ad hoc community consultant who is intimately involved with the projected research population; permitting an IRB to determine that balanced community consultation is not feasible and documenting and reporting[*51514]this determination to the sponsor and to FDA; increasing public participation in the IRB process by specifying acceptable kinds of individuals (e.g., clergy, local commissioners, police, paramedics) who should be added to the IRB (limited to two); having the IRB membership include individuals from the community groups from which subjects would come and ensuring that the preferences of those members were followed; establishing a standing community advisory board that would reflect the diverse values and beliefs of the community. This board could serve several IRB's within the same community. Another comment stressed that the IRB must take into account the diverse religious and community beliefs and attitudes about treatment of the dying and of research.

None of the suggested alternatives to §50.24(a)(7)(i) would by themselves provide the protections of broad community consultation of this section. While an IRB may appropriately decide to supplement its members with consultants from the community, broader consultation with the community is needed for this type of research. The agency expects the IRB to provide an opportunity for the community from which research subjects may be drawn to understand the proposed clinical investigation and its risks and benefits and to discuss the investigation. The IRB should consider this community discussion in reviewing the investigation. Based on this community consultation, the IRB may decide, among other things, that it is appropriate to attempt to exclude certain groups from participation in the investigation; or that wider community consultation and discussion is needed. As described in the preamble to the proposed rule (60 FR 49086, September 21, 1995), IRB's should consider, for example, having a public meeting in the community to discuss the protocol; establishing a separate panel of members of the community from which the subjects will be drawn; including consultants to the IRB from the community from which the subjects will be drawn; enhancing the membership of the IRB by adding members who are not affiliated with the institution and are representative of the community; or developing other mechanisms to ensure community involvement and input into the IRB's decisionmaking process. It is likely that multiple methods may be needed in order to provide the supplemental information that the IRB will need from the community to review this research.

61. Another comment noted that tribal approval and not just consultation should be required and suggested that for American Indian/Alaska Native tribal governments, the regulation require approval by the tribal government for all research done within its jurisdiction. This comment suggested that the regulation permit a recognized government of the political community to disapprove research.

This regulation does not restrict or have an impact on any existing authority of tribal governments to review and approve or disapprove research that would otherwise be conducted on persons residing in tribal jurisdictional boundaries. If existing tribal authorities require tribal government approval of such research before it proceeds, then the tribal governments continue to have that authority. Thus, the agency thinks that adopting this suggestion is unnecessary.

62. Comments opposed to the community consultation required in §50.24(a)(7)(i) suggested that the current requirement for a community representative on the IRB (56.107(a)) was adequate; that this would be burdensome for noncommercially sponsored studies; that it was an insurmountable goal and that there is no guarantee that an IRB could reach all impacted individuals. Other comments suggested that only a central agency such as FDA or the Public Health Service should decide because the clinical investigator will bias the outreach meetings to a disinterested community that would be unable to make knowledgeable decisions, and the community will be biased because the research would bring funding support to the community, and because it is difficult to define the community, especially for those institutions that receive patients from a large region or State. A number of comments suggested that community consultation could lead to IRB liability on the basis of failure to solicit adequate community participation in the decision process. Other comments noted that disclosure to the community does not substitute for consent and that unless one included information about the subject's right to refuse and how to exercise that right, community consultation would be inadequate.

As discussed previously, the agency does not think that the current IRB membership requirements adequately substitute for the community consultation called for in this rule. The agency thinks that community consultation provides a very important protection for research subjects and, therefore, every effort should be made by the IRB to involve, and consult with, the community from which research subjects may be drawn.

63. Other comments stated that without clear definition of terms, the vagueness of the requirement would lead to inadequate consultation and disclosure. Another comment noted that if minority or lower income populations were unlikely to agree to the research and they represented a large proportion of the potential research population, then the conduct of the research would violate the principle of justice because these populations would not share in its benefits or burdens.

The agency thinks that IRB's will ensure, through their review and oversight activities, adequate consultation and disclosure. It is impossible, without conscription, to ensure that each subpopulation shares both the benefits or burdens of all research. Achieving the principle of justice is a goal that must be balanced by other principles. In the case of a population that is unwilling to agree to participation in a research activity, honoring this population's unwillingness is, in effect, permitting the community to express its views.

64. A number of comments requested clarification of this requirement. These comments asked how the consultation should take place (newspaper, institutional newsletter, advertisement, local radio stations, meeting); who in the community needs to be informed and who may be legitimate representatives of the community; what the IRB does with the community response (e.g., can a community veto research, what if a small or a large number oppose the research, what is the sponsor or IRB's responsibility to respond to questions or requested changes in the research); how is an IRB to assess the effectiveness of the consultation (e.g., if there is a poor turnout at an adequately publicized meeting, is the IRB obliged to do more)? Another comment requested clarification of what the public representatives and representatives of the population at risk would be asked to do. One comment urged the agency to refrain from providing precise definitions for the various terms in §50.24(a)(7)(i) through (a)(7)(iii) in order to permit IRB's adequate flexibility in making judgments.

Community consultation is likely to be multifaceted and to use a number of the mechanisms suggested by the comments. As described earlier, the IRB needs to provide an opportunity for broad community discussion. If, for example, there is poor turn-out at a meeting to discuss the research, an IRB may consider targeting specific[*51515]community representatives for inclusion in an additional meeting, or it may decide that the research was not found by the community to be objectionable. The IRB is responsible for listening and considering the community's support, concerns, etc., and then ultimately deciding whether the investigation should be modified, approved, or disapproved. The community is expected to provide input to the IRB on its support for or concerns about the research activity.

65. A number of comments requested clarification on who is responsible for the community consultation and disclosure requirements contained in §50.24(a)(7)(i) through (a)(7)(iii). Most comments suggested that the IRB should be responsible for reviewing and approving the content and method of consultation and disclosure; the sponsor should be responsible for developing the plan for consultation with the community and for disclosure and provide this information to the IRB to review for adequacy.

Although a sponsor may provide to an IRB model information for use in consultation with the community and for disclosure, just as it may now provide a model consent form for a clinical investigation, it is the responsibility of the IRB to ensure the adequacy of the community consultation and disclosure requirements contained in §50.24(a)(7)(i) and (a)(7)(ii).

66. Another comment recommended that the sponsor and clinical investigator should pay for the costs associated with the disclosure requirements.

The agency does not dictate the entity responsible for the costs related to research. However, the agency anticipates that the sponsor would normally incur the costs associated with disclosure to and consultation with the community.

67. Several comments on §50.24(a)(7)(ii) suggested that for multicenter trials, disclosure be required once for each metropolitan area and that the disclosure be made by the sponsor or a designated institution in a notice that would list all institutions, investigators, and IRB contacts.

The agency would not object to such centralized disclosure if all of the responsible IRB's agreed that this is appropriate and acceptable.

68. Another comment suggested that instead of requiring disclosure prior to the commencement of the study, disclosure occur at periodic time intervals (e.g., every 2 years) and include a public notice of general issues, specific projects, results of the research, and permit public input.

It is the responsibility of the IRB to consider how to maintain the flow of information to the community. In addition to requiring disclosure to the community prior to the initiation of the clinical investigation, the IRB may determine that it is appropriate to require further disclosure at periodic intervals of time.

69. Another comment requested that the regulation specifically ban "general disinformation campaigns" by sponsors performing the research.

The agency thinks that such a ban is unnecessary and that IRB involvement in the disclosure process helps to eliminate the possibility that biased or misleading information will be disseminated. The information disseminated will be reviewed by the IRB to ensure its adequacy and balance.

70. A number of comments were opposed to the requirements for disclosure contained in §50.24(a)(7)(ii). The comments suggested that they would take an exhaustive amount of time; could prevent valuable research because the investigator and institution could be targets of a poorly informed community; the investigator may not be the best individual to discuss the study; they could cause persons to not seek care; they would be burdensome for noncommercially sponsored studies; for parties with an interest in the research, a requirement for disclosure could lead to either a dishonest or incomplete disclosure of information; the regulation requires disclosure of less information than that which would be given to a research subject; that it is essential to include information about financial and economic incentives for the research; and that it is essential to permit public participation in the disclosure sessions.

As discussed previously, it is the IRB's responsibility to determine the information to be disclosed. As described in the preamble to the proposed rule, the IRB should consider how best to publicly disclose, prior to the commencement of the clinical investigation, sufficient information to describe the investigation's risks and benefits, e.g., relevant information from the investigator's brochure, the informed consent document, and investigational protocol. Initial disclosure of information will occur during the community consultation process. Disclosure of this information to the community will inform individuals within the community about the clinical investigation and permit them to raise concerns and objections.

71. Another comment suggested that the release of confidential information required by this section could serve as a disincentive for sponsors to conduct the research and that it would create a precedent that could affect companies not otherwise affected by the regulation.

The agency disagrees with this comment. While it is true that much information relating to clinical investigations is normally treated as confidential by sponsors, the agency believes that when a sponsor chooses to invoke the exception from informed consent contained in this rule that it is essential that reasonable disclosure occur to the community. The agency believes that the benefit to a sponsor of invoking the rule will outweigh concerns that a sponsor will have about disclosing information about the investigation. Because this disclosure is made only when the exception from informed consent is invoked, it will not create any precedent for companies not invoking the exception.

The agency notes that sponsors release research information to investigators and IRB's (for example, through the protocol and investigators brochure) and to potential subjects in the research through the informed consent process and informed consent form; this rule states that the same information should be released to the community so it can be informed as it considers the research.

FDA believes that American Indian and Alaska Native Tribal governments and communities currently require both presentation of the research protocol and reporting results to the community before they permit any research to occur on their reservation. Recent Phase 2 and Phase 3 trials of several vaccines (e.g., Haemophilus B, Hepatitis A, and rotavirus vaccines) have been done on reservations under those rules by the pharmaceutical companies sponsoring the research. Under this rule, no company is required to release additional information to a community if it does not want to have a waiver of consent for its emergency research.

72. One of these comments stated that information is a property right and to require that it be surrendered without compensation may violate the Fifth Amendment of the Constitution.

The agency disagrees with this comment. The Fifth Amendment requires that no private property be taken for a public purpose without just compensation. (U.S. Constitution, Amendment V.) One factor used to determine whether there has been a taking is whether the action interferes with the reasonable investment backed expectations of the owner of the alleged[*51516]property right. (Kaiser Aetna v. United States, 444 U.S. 164, 175 (1979).) Where a voluntary submitter of information is aware of the conditions under which the information must be disclosed, the submitter gains an economic advantage related to the submission (such as registration), and the disclosure is rationally related to a legitimate government interest, there is no taking. (Ruckelshaus v. Monsanto Co., 467 U.S. 986, 1007-8 (1984).) Under this rule, the disclosure is directly related to protecting the individual members of a community that may be involved in the clinical investigation without informed consent by providing the community with advance notice of the nature of the investigation and the possibility that they may be involved in the clinical investigation without their informed consent. Furthermore, the regulation provides a mechanism under which the sponsor may perform the clinical investigations and sets the conditions under which the disclosure will occur. Therefore, the regulation serves as advance notice that prevents a sponsor from having any reasonable investment-backed expectation concerning the information and, thus, there is no unconstitutional taking.

73. A number of comments raised questions about §50.24(a)(7)(ii) including: what criteria would be used to determine that disclosure was adequate; when is the disclosed information to be provided to FDA; what is meant by "sufficient" and "relevant"; whether it is sufficient prior to the study to simply post a notice on the bulletin board; who determines the adequacy of the disclosure; whether this places an obligation to "disclose" or to "disseminate" information to the community; what this disclosure is supposed to accomplish. Clarification was requested as to the method and scope of disclosure.

It is the responsibility of the IRB to determine the "sufficiency" of the information to be disclosed. The agency advises that this information could include, but may not necessarily be limited to, the information that is found in the informed consent document, the investigator's brochure, and the research protocol. The obligation to disclose information includes an obligation to disseminate information to the community. The purposes of disclosure are to provide community confidence in the role of the IRB and in its decisionmaking capability, to permit the community to express its concerns and possible objections to the research, and to inform the community so that it is aware that the research is to be conducted involving individuals from the community.

74. Another comment suggested that FDA and DHHS should provide IRB's with copies of disclosure forms.

The agency disagrees. It is the IRB's responsibility to determine the method for disclosure and information to be disclosed. A "form" would stifle IRB creativity and flexibility.

75. Comments on §50.24(a)(7)(iii) suggested that the regulation specifically include the requirement that the underlying data be disclosed following the end of the study; another suggested that product approval decisions should be based on compliance with this requirement as well as the timeliness of disclosure.

The agency does not think that these comments require a change in the regulation. The agency thinks that it is necessary to provide comprehensive summary data from the completed trial to the research community in order to permit other researchers to assess the results of the clinical investigation. The agency thinks that there must be a scientific need to conduct clinical investigations involving subjects who are unable to consent; if previous investigations have already provided the scientific answer, this should be shared broadly with the research community. Sufficient information may be contained in a scientific publication of the results of the completed investigation; in other instances, it may need to be supplemented by additional information. The agency has modified §50.24(a)(7)(iii) to clarify that the information to be disclosed is to include the demographic characteristics (age, gender, and race) of the research population.

In response to the suggestion that product approval decisions should be based on compliance with this requirement, the agency notes that it has a variety of compliance procedures that it may use to enforce this disclosure requirement.

76. Comments opposed to this disclosure requirement suggested that it would jeopardize the ability to publish the results of the research in peer review journals; it would foster unscientific conclusions without peer review; an investigator cannot control the peer review process to ensure publication; it could negatively influence future trial recruitment and force a sponsor to disclose proprietary information. Several comments suggested that in multicenter studies, one institution may get a negative result, while another may get a positive result; thus, disclosure could be misleading. Comments suggested that updating the disclosure could be burdensome and that the disclosure itself could be considered dissemination of off-label use information and advertising. Another comment questioned the need for such disclosure because the community would have no opportunity to modify the research; another commented that the disclosure would be so delayed and the community to which the disclosure would occur has such insufficient knowledge to understand the disclosure, that the disclosure would be meaningless.

Some comments requested that the agency define what and how disclosure is to be accomplished; what is "sufficient" and what would constitute the "scientific community." One comment questioned whether the information that would be disclosed to the community and researchers would differ.

The comments opposed to this disclosure requirement illustrate a need for the agency to clarify what is intended by this section. For a multicenter investigation, the agency anticipates that the sponsor and/or lead investigators will be responsible for analyzing the results of the overall investigation, including the demographic characteristics of the research population, and that these results will be published (or reported in the lay press) within a reasonable period of time following completion of the investigation. Publication in a scientific journal or reports of the results by lay press, that would be supplemented upon request by comprehensive summary data, will enable the research community, e.g., researchers not connected to the clinical investigation, to learn of the research's results. Following publication, the IRB will be responsible for determining appropriate mechanisms for providing this information, possibly supplemented by a lay description, to the community from which research subjects were drawn. The usual rules of marketing and promotion apply to the disclosure of this information. The agency notes that it is common for the results of research to be reported in the lay press and published in peer reviewed journals.

77. One comment noted that the comment in the preamble that there would be a need for fewer subjects if disclosure took place did not recognize the possible need for replication of the research-a sound scientific principle.

In the preamble to the proposed rule, the agency stated that: "[b]y broadly sharing the results of the research with the scientific community, there may be less need to replicate the research; therefore, fewer subjects may be needed[*51517]to obtain the same level of scientific knowledge and to advance emergency medicine." The agency recognizes that there is frequently a need to replicate research in order to verify its findings. The agency thinks, however, that broadly sharing both positive and negative results of research with the scientific community may reduce or eliminate unnecessary duplication of research that has been conducted and verified by others.

7. Section 50.24(a)(5)(iv)-Data Monitoring Committees

A number of comments on proposed §50.24(a)(5)(iv), which has been renumbered §50.24(a)(7)(iv) in this final rule, supported the requirement for the establishment of an independent data monitoring committee. These comments also requested clarification of the requirement and offered various suggestions. A discussion of these comments and the agency's response follows.

78. Editorial changes were suggested to this section to clarify the function of the data monitoring committee.

The regulation has been changed to clarify that the purpose of the data monitoring committee is to exercise oversight of the clinical investigation. In addition, on the agency's own initiative, the agency has changed "data and safety monitoring board" to "independent data monitoring committee" to conform to wording used in the international community.

79. Clarification was requested on the function, nature, authority, and responsibility of the committee. One comment requested citations to reference materials on data monitoring committees; another suggested that the regulation reference FDA's "Guideline for the Monitoring of Clinical Investigations" (53 FR 4723). One comment questioned whether the committee was simply advisory or whether it would have authority to halt a study. Other comments requested advice on the appropriate composition of the committee and another requested that FDA define its minimum size and expertise.

A number of comments requested clarification as to who is responsible for establishing and operating the data monitoring committee. One comment suggested that if it is the responsibility of the sponsor to establish the committee, then the term "independent" needs to be defined. Several comments noted that if the responsibility for establishing the committee changes, depending upon whether the study is multicenter with a commercial sponsor or a single center, noncommercially sponsored study, the circumstances for this shift in responsibility must be clearly described. Another comment asked for clarification as to who is responsible for establishing "the preestablished stopping rules" and how these rules are defined. Several comments suggested that it should be the responsibility of the principal investigator and/or the sponsor of the research to convene the committee. Another comment suggested that if it is the responsibility of the sponsor to convene the committee for multicenter studies, it should be explicitly stated in the regulations.

A number of suggestions were given for how the committee should be composed and its functions. The agency also received suggestions for alternatives to the establishment of such a committee. Several comments suggested that the IRB be responsible for approving the composition of the committee based on the complexity, size, and risks associated with the study. Others suggested that the committee should be composed of specific types of individuals, including scientists, community members, IRB representatives without a conflict of interest, data management representatives, biostatisticians, and noninvestigator clinicians. Others suggested that a link be created between the committee and the IRB and that specific reporting requirements between the two entities be established so that the IRB can have the necessary information to terminate or modify the study.

The agency recognizes that there is no clear consensus within the scientific community regarding the optimal model for data monitoring committees. It is not the intention of the agency to settle the debates that are ongoing in the scientific community at this time. Rather, the agency recognizes that there is diversity in this area; the role, functions, and responsibilities of data monitoring committees are evolving, and it may be the case that there is no single model that is optimal in all circumstances. The data monitoring committee is established by the sponsor of the research, as an advisory body to the sponsor. An independent committee is constituted of individuals not otherwise connected with the particular clinical investigation. A variety of expertise is required for an effective data monitoring committee. Typically included are clinicians specializing in the relevant medical field(s), biostatisticians, and bioethicists. The data monitoring committee receives study data on an ongoing basis on a schedule generally defined in the investigational protocol; based on its review of the data it may recommend to the sponsor that the clinical investigation be modified or stopped. In effect, it is responsible for making sure that continuing the investigation in its current format remains appropriate, on both safety and scientific grounds. A number of reasonable models for establishment and function of these committees are described and discussed in S. Ellenberg, N. Geller, R. Simon, S. Yusuf (editors), Practical issues in data monitoring of clinical trials (Proceeding of an International Workshop) Statistics in Medicine, vol. 12; 1993. If a sponsor accepts a data monitoring committee's recommendation to stop the investigation or to institute a major modification of the trial, the sponsor is required to notify FDA and all participating investigators and IRB's in a written IND or IDE safety report within 10 working days after the sponsor's initial receipt of the information. (See § §312.32, 312.56(d), and 812.150(b)(1)).

Protocols frequently contain statistical guidelines for permitting trials to stop prior to completing the protocol-specified accrual and followup, on the basis of definitive efficacy or safety differences between the treatments being compared.

80. Comments opposed to this requirement mainly cited concern that for single project/single institutional studies without a commercial sponsor, the cost and resources required for establishing such a body would be prohibitive and, therefore, important research would not be done. Another comment suggested that for noncommercially funded studies, the agency permit the investigator/sponsor to request a waiver of the requirement to FDA. If such a waiver were granted, timely data summaries could be submitted to FDA for review.

The agency disagrees with these comments. Trials of life-threatening conditions may discover favorable or adverse effects on survival during the trial. Requiring a data monitoring committee will help ensure that if it becomes clear that the benefits of the investigational intervention are established, or that risks are greater than anticipated, or that the benefits do not justify the risks of the research, the investigation can be modified to minimize those risks or the clinical investigation can be halted. The data monitoring committee is established by the sponsor of the research, as an advisory body to the sponsor. It is the appropriate role of the sponsor, not FDA, to receive and evaluate a data monitoring committee's[*51518]recommendation. The agency thinks that a data monitoring committee is a very necessary protection for the human subjects participating in this research. The agency thinks that the cost of operating such committees does not need to be prohibitive and that the cost is justified by the protections provided by having such a committee.

81. Others commented that the requirement for a data monitoring committee is unnecessary given that these studies already will have oversight by FDA and the IRB, both of which are independent of the research, as well as by the sponsor and the clinical investigator.

The agency disagrees. The FDA, IRB, and research sponsor, unlike the data monitoring committee, do not receive outcome data from the clinical investigation on an ongoing basis. Thus, oversight by these entities does not substitute for the requirement for a data monitoring committee.

82. Another comment pointed out that there was no need for such a committee for nondrug and nondevice studies if these involved no more than minimal risk.

This regulation is applicable only to clinical investigations involving products regulated by FDA.

83. One other comment suggested that this requirement would be unduly burdensome unless the sponsor paid for the cost of establishing and operating the committee (including paying for the salaries of members on the committee).

As discussed previously, FDA does not prescribe what entity pays for particular aspects of clinical research and review. However, if, as previously described, the data monitoring committee is established by the sponsor of the research as an advisory body to the sponsor, the agency believes that it is likely that the sponsor will pay the cost of establishing and operating the committee.

84. Another comment suggested that the make-up of the data monitoring committee should not be left to the sponsor or clinical investigator to decide and that "independent" should be defined as "separate" from the research team and sponsor. Another comment noted that financial interest is only one aspect of what constitutes a conflict of interest and that the preamble to the final rule should clarify both terms when describing what constitutes an "independent" committee.

The agency believes that the 1993 Statistics in Medicine publication of the proceedings of an international workshop (previously referenced) will assist sponsors in establishing appropriate data monitoring committees. As previously discussed, a variety of expertise is required for an effective data monitoring committee; the agency believes that it would be inappropriate for it to dictate the specific make-up of each such committee. In the preamble to the proposed rule, the agency defined "independent" to mean that the committee would be composed solely of individuals who have no financial interest in the outcome of the clinical investigation, and who have not been involved in the design or conduct of the investigation. The agency does not think that further clarification of "independent" is needed, but other factors can certainly be taken into consideration in individual cases.

85. One comment stated that the data monitoring committee should be charged with monitoring the makeup of the study population to ensure that it does not disproportionately consist of disadvantaged groups.

There is nothing to prevent a data monitoring committee from performing this type of monitoring. It is the responsibility of the sponsor to determine the scope of the data monitoring committee's responsibilities.

86. Some comments suggested alternatives to requiring the creation of a data monitoring committee, including requiring more frequent continuing review by the IRB or permitting a sponsor's monitor to perform the function. For noncommercially funded studies, it was suggested that the agency permit the IRB, with scientific and statistical consultants if needed, to perform the function.

An IRB, as well as a sponsor's monitor, may not have access to study data on an ongoing basis and may not have the variety of expertise required for an effective data monitoring committee. If an IRB, a subcommittee of the IRB, or some other preexisting institutional committee were to serve as a data monitoring committee, it would need to be constituted as a data monitoring committee when it functions in that capacity. The agency thinks that the duties and scope of activities of an IRB and a data monitoring committee are quite different and that it is important for separate entities to be established. The agency would not object, however, to an already established committee, such as an IRB, serving as a data monitoring committee as long as that committee was constituted to perform the duties of a data monitoring committee and operated as such separately and distinctly from its IRB activities.

87. As described previously, the agency has added a new section, §50.24(a)(7)(v), to provide an additional protection to research subjects. This new section clarifies that if obtaining informed consent is not feasible and if a legally authorized representative is not available, the investigator will attempt to contact a family member of the subject to determine whether the family member objects to the subject's participation in the clinical investigation.

8. Section 50.24(a)(6)

88. Several comments were received on §50.24(a)(6). One comment questioned whether the statement "obtaining such consent may be feasible for some subjects" referred to a circumstance in which obtaining consent may become feasible.

This comment did not take into account §50.24(b). Section 50.24(b) concerns providing information to the subject, representative, or family member at the earliest feasible opportunity. Section 50.24(a)(6) is included to cover those instances where it may be feasible to obtain informed consent from the individual subject or subject's representative or contact a family member prior to entry into the clinical investigation.

89. Two comments suggested specific wording changes to acknowledge the IRB's responsibility to review informed consent procedures. One suggested that this section be reworded to state:

The IRB has reviewed and approved informed consent procedures and an informed consent document for subjects or their legal representatives in situations where use of such procedures and documents is feasible.

The agency has incorporated wording similar to that suggested into the regulation. It is appropriate to recognize the informed consent process, and not just the document, as requiring IRB review and approval. In addition, in order to help ensure that the family member has sufficient information to make a decision about a subject's participation in a trial, the agency has added a sentence to the end of §50.24(a)(6) that states "[t]he IRB has reviewed and approved procedures and information to be used when providing an opportunity for a family member to object to a subject's participation in the clinical investigation consistent with paragraph (a)(7)(v) of this section." The agency anticipates that these procedures and information will likely parallel those approved by the IRB for use in obtaining informed consent from subjects or their legally authorized representatives.[*51519]

90. A second comment suggested that this section be replaced with the following:

The IRB has reviewed and approved: (i) the informed consent document and procedures to ask for informed consent by subjects or legally authorized representatives when obtaining such consent may be feasible for some subjects, (ii) the information provided and process to ask for a decision by subject or legally authorized representative to continue or discontinue participation after the research has begun, (iii) the information provided and procedures for consultation with representatives of the community, (iv) the information provided and procedures for public disclosure before the research, and (v) the information provided and procedures for public disclosure of the results of the research. All documents and procedures should also be submitted to the FDA for review.

This modification would require both the IRB and FDA to review and approve all documents or procedures that give information to the public, subjects, or representatives. The comment suggesting this modification notes that this is currently required for all nonemergency IND and IDE research.

The language suggested in this comment appears to duplicate requirements already contained in the regulation, that is: the requirement for review of informed consent documents is already contained in §50.24(a)(6); the requirement for review of information concerning the subject's ability to discontinue participation in the research is contained in §50.24(b); and the requirements for review of information used during consultation with or disclosure to the community are contained in §50.24(a)(7)(i) to (a)(7)(iii). FDA has confidence in the IRB review process and does not think that it is necessary for all of these documents and procedures to be submitted to FDA for its review. The agency notes that conforming amendments to this regulation require that a copy of the information publicly disclosed under §50.24(a)(7)(ii) and (a)(7)(iii) be submitted to the IND or IDE file and to Dockets Management Branch. The agency further notes that the statement that FDA currently requires all of these documents and procedures to be submitted for its review for all nonemergency IND and IDE research is incorrect. Rather, it is the IRB that traditionally reviews information that is to be provided to the research subject; the requirements for consultation with and disclosure to the community have not been previously required.

9. Section 50.24(b)

91. A number of comments were received on §50.24(b) that suggested clarifying or tightening the requirement for informing subjects or their legal representatives. One comment recommended that the agency change the wording from "at the earliest possible opportunity" to the "earliest feasible opportunity." Another comment suggested that the timeframe for notification was too open-ended and that there should be a specific time limit.

The agency agrees with the wording change and has incorporated it into the regulations. The term "feasible" incorporates the idea of "practicability" and recognizes that in some instances it may not be feasible to provide information to the subject (e.g., if the individual does not survive or is mentally incompetent), and to the subject's legal representative or family member (if the identity of the subject is never determined). The agency also thinks that the phrase "at the earliest feasible opportunity" establishes a reasonable time limit.

92. Another comment suggested deleting the initial phrase "when possible and," noting that if the subject does not survive and no representative is found, then there will be no "opportunity" for a debriefing-thus, the initial phrase is not needed.

The agency agrees with this comment and for the reasons addressed in the previous response, has deleted this initial phrase from the regulation.

93. One comment suggested that the regulation require that if a representative is told and the subject's condition improves, the subject must also be informed as soon as possible. Two comments stated that if the subject dies, the subject's legal representative or family member must be provided with this information.

The agency agrees with these comments and has modified §50.24(b) to state:

If a legally authorized representative or family member is told about the clinical investigation and the subject's condition improves, the subject is also to be informed as soon as feasible. If a subject is entered into a clinical investigation with waived consent and the subject dies before a legally authorized representative or family member can be contacted, information about the clinical investigation is to be provided to the subject's legally authorized representative or family member, if feasible.

94. A few comments suggested that §50.24(b) be revised to require documentation that the subject, authorized representative, or family member, were informed of the research. Another comment suggested that the agency require a signed consent document for continued participation in the research.

The agency thinks that it may not always be possible to develop a meaningful informed consent document for continued participation in the research, because the relevant information may vary significantly depending upon when it becomes feasible to provide the information to the subject or legally authorized representative. The agency is, therefore, not requiring that such a form be developed. The agency notes, however, that §50.24(a)(6) places the responsibility on the IRB to review and approve "informed consent procedures and an informed consent document" for use with subjects or their legal representatives, and procedures and information to be used in consultations with family members, in situations where use of such procedure is feasible. Thus, a consent form will have been reviewed and approved for use in the clinical investigation. The agency has modified the wording in §50.24(b) to specify that the "information contained in the informed consent document" is to be provided to the subject, legal representative, or family member. This will help to ensure that adequate information is provided to the subject, legal representative, or family member upon which a judgment can be made as to whether to continue or discontinue the subject's participation in the investigation.

It is up to the IRB to determine whether it is possible or desirable, given the nature of the clinical investigation, to have an actual document that could be signed for continued participation in the investigation. The agency notes that such a document, that would be signed after entry into an investigation, would not constitute consent for what had already occurred; it could, however, serve to document that the subject consented to continued participation in the investigation. The agency notes that § §312.60 and 812.140 require the clinical investigator to document data pertinent to each individual in the investigation. This documentation should include information that the subject, legally authorized representative, or family member was informed of the subject's inclusion in the clinical investigation, the details of the investigation, and other information contained in the informed consent document.

95. One comment on the subject's ability to discontinue participation in the research suggested that §50.24(b) be reworded to state:[*51520]

The subject or legally authorized representative should be presented with three options: continue fully, continue the intervention (if it is still taking place) but do not include the subject's data in the research database or results, or discontinue both the intervention and the use of the subject's data. The researcher will track the percentage of subjects or representatives choosing each option.

FDA regulations (see, for example, §312.62 and §812.140(a)(3)) require investigators to prepare and maintain adequate case histories recording all observations and other data pertinent to the investigation on each individual treated with the drug or exposed to the device. The agency needs all such data in order to be able to determine the safety and effectiveness of the drug or device. The fact of having been in an investigation cannot be taken back. Also, if a subject were able to control the use (inclusion and exclusion) of his or her data, and particularly if the clinical investigation were not blinded, the bias potential would be immense. Thus, the agency rejects this comment because it could prevent FDA from learning of an important effect of the product and significantly bias the results of the investigation.

96. One comment noted that in cases where withdrawal from a study would be life-threatening, FDA might consider additional guidance on counseling of subjects who have regained competence regarding their remaining in the study. Another comment noted that in some cases, a subject cannot be withdrawn from the study, particularly in the case of an implanted device, without some degree of medical harm-that is, the possibility of additional risk for the subject due to its removal. In this case there is a "penalty" for withdrawal from the research.

In all clinical investigations, when appropriate, it is the responsibility of an investigator to advise the subject of the consequences of a subject's decision to withdraw from the investigation and explain procedures for orderly termination of participation by the subject. (See §50.25(b)(4)). If withdrawal from an investigation would or could be life-threatening, this consequence would need to be conveyed to the subject. The agency acknowledges that for certain interventions, such as implantation of an investigational device, there may be a serious consequence following a subject's decision to discontinue participation in the research. Similarly, for an investigational drug that cannot be halted immediately without medical consequences, the subject will need to be advised of the consequences of a decision to withdraw and procedures for withdrawal that would minimize risks to the subject.

10. Section 50.24(d)

A number of comments expressed concern about §50.24(d) requiring a separate IND or IDE for studies conducted under §50.24 if an IND or IDE already exists. Others expressed concern about requiring an IND or an IDE for products that have received FDA approval for other uses.

97. One comment suggested a modification to the wording of §50.24(d) to state that: "[s]uch IND or IDE should only include enough detail to satisfy the administrative oversight responsibilities of appropriate FDA officials."

The agency disagrees with this suggestion. The information that is required to be in an IND or IDE is the information that is needed by the agency to conduct an adequate review of the application. As described in more detail below, if an IND or IDE exists, the separate application does not need to duplicate, and the sponsor does not need to resubmit, information that is contained in the existing IND or IDE; the separate application will need to reference the existing IND or IDE, contain a protocol for the clinical investigation that includes a description of how the investigation proposes to meet the conditions of this regulation, and contain only the study-specific information required by § §312.23, 812.20, and 812.25, as appropriate.

98. A number of comments suggested alternative approaches to the requirement contained in §50.24(d) for products that have received marketing approval or for which there already exists an IND or IDE, noting that for these studies this requirement would be unduly burdensome, would create the need for unnecessary paperwork, and could effectively prohibit much needed research. One comment suggested that the agency limit the scope of this requirement or consider an alternative for single-center studies under which an IRB can waive consent if the investigator has informed the appropriate branch of FDA of the proposed study at least 30 days before submission to the IRB to allow FDA time to submit its views on the study for consideration by the IRB. This comment argued that such a requirement would provide sufficient opportunity for FDA involvement, while at the same time permit a focused FDA review, consuming fewer resources than would the review of an IND or IDE for each study. Other comments suggested that the agency has ample authority under existing IND and IDE regulations to require strict adherence to the 30-day review period and that the agency should simply require that emergency research protocols be clearly identified as such, submitted to the agency under an existing IND or IDE, and be unable to commence until 30 days after submission. These comments argued that this would meet the objective of the regulation without adding additional administrative burdens to the sponsor or investigator.

These comments may not appreciate why the agency is requiring the submission of an IND or IDE for each clinical investigation and the information that must be contained in such an IND or IDE. The submission of a separate IND or IDE will ensure that FDA reviews the application before the study may proceed. FDA review of the application will enable the agency to assess whether the available treatments for the condition are unproven or unsatisfactory, whether the intervention is reasonable, whether the study design will provide the information sought, and whether other conditions of the regulations are met. The amount of information needed in the application will differ depending upon the particular intervention. If an IND or IDE exists, the separate application does not need to duplicate, and the sponsor does not need to resubmit, information that is contained in the existing IND or IDE; the separate application will need to reference the existing IND or IDE, contain a protocol for the clinical investigation that includes a description of how the investigation proposes to meet the conditions of this regulation, and contain only the study-specific information required by § §312.23, 812.20, and 812.25, as appropriate.

If the investigation involves a product that has received marketing approval and the use is within the product's approved labeling, and without dosage or schedule change if for a drug product, the protocol may simply need to be accompanied by the product's approved labeling and a description of how the investigation proposes to meet the conditions of this regulation; no toxicology or manufacturing controls or chemistry information may need to be submitted. By submitting this information to the agency for review, the dual review by both FDA and an IRB will provide additional protections to the subjects of this research. The agency does not think that this requirement is unduly burdensome, creates unnecessary paperwork, or would prohibit needed research.

If the clinical investigation involves a product that has received marketing[*51521]approval, but involves a route of administration or dosage level or use in a subject population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the product, or if the investigation involves an investigational product for which an IND or IDE does not exist, then the IND or IDE would need to include information to support the altered conditions of use, including toxicology, chemistry, and clinical information, as appropriate.

99. Another comment suggested that the agency should: (1) Include a mandatory internal "ethics consult" of the protocol and informed consent (this would necessitate requiring the submission of proposed informed consent documents with the IND/IDE application); (2) ensure that data on these submissions are captured in a readily retrievable form for future analysis and reporting so that information on the types and numbers of such submissions will be available; (3) be able to provide names and contact information for IRB's reviewing these protocols to ensure communication among these IRB's; and (4) respond actively in writing to any submission under these regulations either placing the study on "clinical hold" or indicating that the agency's review has been completed. This would ensure that the agency has completed its review before the study is permitted to proceed.

The agency's response to each of these suggestions follows: (1) The agency believes that it would be inappropriate to mandate an internal agency "ethics" consultation on each protocol proposing to invoke this exception from informed consent. It is within the province of the IRB to determine the ethical acceptability of a proposed clinical investigation. The agency does intend, however, to periodically review actions on these protocols to help ensure that the rule is implemented consistently and appropriately throughout the agency. The agency notes that under the IDE regulations the agency requires the submission of the proposed informed consent documents with the IDE application. (2) FDA thinks that it can best monitor the implementation of this rule by requiring the submission of a separate IND or IDE for these clinical investigations. By requiring the submission of a separate IND or IDE for these investigations, FDA expects to be able to provide information on their type and number. (3) The agency believes that it would be more appropriate for the sponsor of the research to facilitate communication among reviewing IRB's, instead of FDA performing this function. (4) FDA agrees that it should provide a written response to the sponsor following the agency's review of these protocols. FDA currently sends written responses following review of IDE's and treatment IND's and believes that sending letters here will serve as an additional protection for subjects. The response will serve to document that FDA has reviewed the clinical investigation and agreed that it may proceed, and the letters will result in the ability of sponsors to begin these investigations as expeditiously as possible. The agency has added language to § §312.20(c) and 812.20(a)(4)(i) to clarify that a clinical investigation involving an exception from informed consent under §50.24 is not permitted to proceed without the prior written authorization from FDA. FDA will provide such notification 30 days after FDA receives the application, or earlier.

100. Section 50.24(d) raised a number of questions and caused confusion concerning its applicability to: Studies designed to compare the efficacy of two already marketed agents; the study of systems, processes, and procedures that are not designed to assess the efficacy of a test agent, but rather to determine the best process or technique for its use; a study comparing the effect of a standard of care with the use of no agent at all; and FDA exercising jurisdiction over studies that do not involve evaluating the safety or efficacy of a product subject to FDA regulation. One comment recommended that the regulations be expanded to apply to not only new devices or drugs, but also to new uses for existing devices and drugs, as well as to new therapeutic techniques and that researchers be permitted to seek FDA approval for research on drugs or devices already in use through alternate forms and/or procedures developed by FDA for this purpose.

This comment incorrectly interpreted the wording in §50.24(d) to apply only to unapproved new devices or unapproved new drugs. As discussed earlier, §50.24(d) also applies to clinical investigations involving already marketed products that are regulated by FDA. This regulation does not apply to research that is outside of FDA's regulatory jurisdiction-that is, studies involving no product subject to FDA regulation.

101. A number of examples were provided of studies that purportedly would have been prevented if an IND or IDE had been required: (1) High versus low dose epinephrine; (2) interposed abdominal counterpulsation CPR; (3) saline infusion during trauma; (4) effect of high pressure ventilation during CPR; (5) studies on sodium bicarbonate during CPR; (6) studies on MAST trousers during CPR; and (7) comparison of various intravenous crystalloid solutions in shock-trauma. The application of this requirement to these types of studies was described, by at least one comment, as the "fatal flaw" in the regulation. Other comments suggested that the broad scope of this requirement would be wasteful of sponsor resources in terms of filing the IND and IND annual reports, wasteful of FDA resources in terms of reviewing such studies, cause unnecessary paperwork, and would suppress necessary studies.

As discussed previously, the agency believes that it is necessary to require an IND or IDE for these types of clinical investigations and it does not believe that this requirement is unduly burdensome or that it will prevent needed research. The information required in a sponsor's annual report would not increase because of the requirement for a separate IND or IDE. The sponsor would simply need to prepare a separate cover letter and excerpt the information from the other IND's or IDE's annual report, and file it in the separate IND or IDE.

102. Several comments suggested that the IND/IDE regulations could be revised to allow for a 30-day review period for those studies that qualify for this exemption; that sponsors would voluntarily agree to wait 30 days for agency review of such studies; or that the agency could place "on hold" for 30 days such studies in order to allow for agency review.

FDA thinks that the most efficient way for the agency to ensure that these clinical investigations are reviewed by the agency before they commence is to require the submission of a separate IND or IDE for that investigation. FDA is concerned that to allow these investigations to be submitted as amendments to existing IND's or IDE's could be confusing to sponsors and might lead to these investigations beginning before FDA review. This is because the agency's current regulations do not require a 30-day wait for amendments; they can begin immediately following submission to the agency and receipt of IRB approval. The agency thinks that this is a simple and nonburdensome mechanism that achieves an important protection for subjects in this research in which subjects may be enrolled without informed consent.

11. Section 50.24(e)

103. Most of the comments on §50.24(e) objected to FDA modifying[*51522]the traditional reporting/information flow from IRB to clinical investigator to sponsor and the reverse. These comments requested that the agency retain this flow of communication in the rule.

The agency disagrees with these comments. Although FDA recognizes that the sponsor's interaction with the IRB should primarily occur through the investigator who conducts the clinical investigation, FDA has never prohibited direct communication between the sponsor and the IRB when doing so would result in a more efficient flow of information. For clinical investigations involving medical devices, FDA requires direct communication between the sponsors and the IRB's in a number of instances. (See, for example, multiple paragraphs in §812.150(b).) The agency thinks that it is appropriate for the IRB to communicate directly with the sponsor and for the sponsor to communicate directly with the IRB when this improves efficiency and/or safety, as it does in this regulation. The agency has amended this section and its related conforming amendments to specify that the IRB shall document its findings and provide them promptly in writing to the investigator and the sponsor of the clinical investigation when an IRB determines that it cannot approve the investigation because the investigation does not meet the criteria in the exception or because of other relevant ethical concerns. The agency thinks that this is the most efficient mechanism to ensure that both the investigator and sponsor are advised of the IRB's findings in a timely manner.

104. In a related comment, clarification was requested for studies in which there is no commercial sponsor and whether it is then the responsibility of the institution or the individual investigator to carry out the requirements specified in this section (as well as in the conforming amendments of § §56.109(g), 312.30, and 312.54).

Whether or not there is a commercial sponsor, each clinical investigation has a sponsor and it remains the sponsor's responsibility to carry out the requirements assigned to the sponsor in this section. (I.e., if the investigation is investigator-sponsored, the investigator is the sponsor of the research and, therefore, the investigator assumes all the responsibilities of the "sponsor.")

105. Another comment suggested that when an investigator is proposing a previously IRB-rejected protocol, the investigator is ethically obligated to disclose the rationale of the earlier rejecting IRB.

The agency agrees with this comment, but it believes that no change is needed in the regulations. The requirements in §50.24(e) will compel a sponsor to disclose to IRB's that have reviewed or are asked to review a clinical investigation the findings of an IRB that could not approve the investigation because the investigation does not meet the criteria in this exception provided under paragraph (a) of §50.24 or because of other relevant ethical concerns.

106. Another comment suggested that in order to avoid delay or failure to convey information about previously disapproved protocols, the IRB should submit information directly to FDA.

The agency disagrees with this comment. The conforming amendments (§312.54(b) and §812.47(b)) require a sponsor to monitor these studies to identify when an IRB determines that it cannot approve the research because it does not meet the criteria in §50.24(a) or because of other relevant ethical concerns, and to promptly provide this information in writing to FDA. The sponsor is, therefore, obligated to submit this information promptly to the agency.

107. Another comment suggested that sharing IRB research rejection information compromises the autonomy of the IRB and that it will make impartial decision making more difficult.

The agency disagrees and believes that human subject protections will be enhanced by sharing of this information.

108. A number of comments and questions addressed the phrase "substantially equivalent clinical trials." Several comments noted that a given sponsor may not be aware of a substantially equivalent clinical trial proposed by another sponsor; thus, FDA and/or OPRR should be responsible for ensuring that communication about such trials takes place. One suggestion was for FDA to establish an on-line registry at FDA of studies that have applied for waiver of consent; this registry could be searched by IRB's and investigators to determine which other IRB's have reviewed the same or substantially equivalent trials.

The agency intended this requirement to refer to clinical trials with the same sponsor. The regulation has been modified to clarify this issue.

109. One comment suggested that the extent of this reporting (of "disapproval" information) should be defined in the preamble, with the minimum content of such a report contained in the regulation.

Existing §56.109(d), redesignated as §56.109(e) requires an IRB to "notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity." It states that "[i]f the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision.* * *" The new sentences to §56.109(e) requires the IRB to notify the investigator and sponsor in writing when an IRB determines that it cannot approve the research because it does not meet the requirements of §50.24(a) or because of other ethical concerns. FDA has revised the wording of §56.109(e) to make it explicit that this written notification must include a statement of the reasons for the IRB's determination. The correspondence from the IRB should contain sufficient information for a receiving IRB to understand the concerns of the initial IRB.

110. One comment noted that if it is the agency's concern that a sponsor may minimally modify the rejected proposal (i.e., a substantially equivalent trial) and submit it to another IRB, that should be clarified and prohibited. Another questioned whether "equivalent" referred to medical conditions, treatments compared, subject populations, or something else. Another comment questioned whether "substantially equivalent" only applies to other trials with the same drug/device; if the sponsor subsequently requests an exemption for a similar trial with another drug in the same class must the sponsor disclose the IRB findings about the first drug.

By "substantially equivalent" the agency means other clinical investigations that propose to invoke this exception from informed consent and that involve basically the same medical conditions and investigational treatments. As noted previously, the agency intends this requirement to refer to clinical investigations conducted by the same sponsor.

111. Another comment questioned who is expected to make the determination that a study is "substantially equivalent." This comment described a potential situation whereby an IRB rejected a protocol as written and the sponsor then modified the protocol according to the IRB's recommendations. This comment, as well as others, questioned whether, in a multicenter study, the other centers that approved and initiated the initial protocol would have to review this trial again.

It is the sponsor's responsibility to determine that a study is "substantially[*51523]equivalent." If, in the scenario described, a protocol invoking this exception is modified by the sponsor in order to respond to IRB concerns that it does not meet the criteria in §50.24(a) of the exception or because of other relevant ethical concerns, and it is a multicenter study, then the IRB's written findings are to be disclosed to other centers that either are, or may be, participating in the study. If there is a change in a protocol in a multicenter trial, there is re-review of the protocol by all the IRB's of the institutions participating in the multicenter trial. If the change is minor, it may be eligible for expedited review under §56.110, which permits the IRB to use an expedited review procedure to review minor changes in previously approved research during the period for which approval is authorized. If the change is significant, it would need to be reviewed by the full committee. It is the sponsor's responsibility to determine if it has a substantially similar protocol necessitating information dissemination.

112. One comment noted that the current wording of §50.24(e) appeared to require disclosure of IRB disapprovals only to future IRB's and investigators. This comment suggested that the regulation should specify that investigators already participating and IRB's that have already approved the study be notified of an IRB disapproval.

The agency agrees with this comment and has modified §50.24(e) accordingly. The agency thinks that this information is relevant to IRB's that have reviewed and approved the study and that will be responsible for conducting continuing review of the research as well as to IRB's that will be asked to review the study. Although this information may not change an IRB's final determination on the approvability of a particular protocol, it will allow access to, and the ability to consider, information that negatively influenced another IRB.

113. Several comments questioned the timing of IRB review and submission of the IND. One comment suggested that IRB review precede the submission of the IND to prevent agency review of studies that would eventually be found to be unacceptable to the reviewing IRB's. This comment suggested that the regulations be modified to indicate that if an IRB refuses to approve the study, the sponsor could request a pre-IND meeting with FDA to discuss the reasons for the disapproval. Another comment suggested the opposite, noting that many IRB's will not consider a protocol under an IND or IDE until after FDA approval because FDA review includes aspects that are not within the scope of IRB review. Thus, FDA should agree to review and approve IND's and IDE's that contain a firm and binding sponsor commitment to local IRB review. This comment noted that implementation of the §50.24(a) provisions will be policed by OPRR and, thus, both FDA and the public can be ensured that the sponsor's advance commitment will be met. This comment suggested the following language:

§312.40(b)(3) For a separate IND submitted under §312.20(c), if a sponsor provides a commitment to local IRB establishment and approval of procedures for compliance with §50.24(a).

§812.30(a)(3) For a separate IDE submitted under §812.20(a)(4), if a sponsor provides a commitment to local IRB establishment and approval of procedures for compliance with §50.24(a).

§50.24(c) [Add the following sentences] The IRB must document the additional protections provided under subsection (a)(5) in writing to the sponsor of the research. The sponsor of the research must share this information with FDA.

The agency does not agree that it should mandate the timing of IRB and FDA review. As evidenced by the comments, sponsors currently differ in whether they request FDA or IRB review first. FDA does not believe it should reduce the sponsor's flexibility to determine the sequence of IRB and FDA review. The agency notes that FDA may find a clinical investigation unacceptable or require modifications in an investigation which, if it had been reviewed by an IRB, would require re-review by the IRB.

The comment concerning an IRB refusal to approve a study and the need for a pre-IND meeting does not explain the reason such a meeting should occur. As described in 312.47(a): "[m]eetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA's resources permit." Thus, while there is nothing to prevent a sponsor from requesting a meeting with FDA, it is not clear that a sponsor would want to meet with the agency to discuss why an IRB did not approve its investigation.

In response to the comment that FDA should agree to review and approve IND's and IDE's that contain a firm and binding sponsor commitment to obtain local IRB review, FDA agrees. FDA will accept a sponsor's commitment in an IND or IDE application to obtain IRB review in this situation as it does in others. The agency understands that IRB review may follow submission and review of the investigation by FDA. Thus, where an IRB has not yet reviewed and approved the protocol that the agency has reviewed and allowed to proceed, an IRB's review and approval, as well as community consultation and disclosure, are then required prior to subjects entering the investigation.

The agency notes that OPRR does not enforce the provisions in §50.24(a) for clinical investigations that are regulated by FDA. Instead, FDA oversees the quality and integrity of the research that is conducted under the agency's jurisdiction through its Bioresearch Monitoring Program. FDA's Bioresearch Monitoring Program includes inspections of clinical investigators, sponsors, and IRB's to evaluate whether each entity's obligations are met.

Finally, the agency does not believe there is a need to adopt the additional language suggested regarding IRB review because the language is redundant with existing regulations, i.e., the regulations already require sponsors to obtain the investigator's commitment to obtain IRB review (see, for example, 312.53(c)(1)(vii)); IRB's are required to "find and document" each item under (a), including (a)(6)) (see § 50.24(a)); and IRB's are required to provide information that has been publicly disclosed under §50.24(a)(7)(ii) and (a)(7)(iii) to the sponsor and the sponsor is required to provide this information to FDA (see, for example, §56.109(g), §312.54(a), §601.51(d), and §812.38(b)(2)). In addition, as previously described, FDA expects the protocol for the investigation to include a description of how the investigation proposes to meet the conditions of this regulation.

114. A number of comments questioned the value of §50.24(e) and suggested that it be deleted. The reasons given in these comments included: its impracticality, its irrelevance to local decision making, the inappropriate line of communication (previously discussed), and the precedent that it establishes for requiring public disclosure of IRB decision-making (potentially leading to extra liability from disclosure for the IRB). Comments also questioned whether the requirement would apply to unsponsored research (discussed above), noted that if FDA needs this information it can request it from the IRB, and asserted that it is inappropriate for the IRB to apparently review a study and give feedback to FDA when IRB's depend on FDA to conduct an adequate preliminary review of such studies. Comments also noted the paperwork[*51524]burden on IRB's (which may need to write a very different type of document than the one that it would typically write in rejecting a study), and that this requirement could undermine the authority of the IRB if it were obliged to report each rejection to FDA. One other comment questioned the value of this requirement noting that one IRB's decision to reject a study would have no impact on the substantive, factual medical and other information available to all IRB's. This comment noted that the relevance of this evaluation for an IRB that has already approved a study would be even more untenable and burdensome and could potentially be disruptive to the sponsor and ongoing studies. Another comment noted that this requirement is ambiguous and questioned whether the sponsor would need to provide the report exactly as provided by the IRB or whether the sponsor could summarize the IRB's findings. This comment also questioned how FDA would use this information.

The agency disagrees with these comments. The agency does not think that this will create an additional recordkeeping burden on IRB's because these findings are already required to be documented by the IRB under §56.109(e) and §56.115(a)(2). As noted earlier, the agency has modified this section to require the IRB to provide these findings to the clinical investigator and to the sponsor of the research. The agency has a great deal of respect for the IRB system and for decision-making that occurs by IRB's. Given the nature of this research, the agency thinks that it is important for entities with responsibility for allowing these investigations to proceed to consider IRB concerns related to these investigations. The agency will expect the sponsor to forward the report exactly as it was provided by the IRB; however, the sponsor may choose to provide additional relevant information to the agency along with the IRB's findings. Similarly, if an IRB chooses to prepare more extensive documentation of its findings than that which is required by §56.109(e), §56.115(a)(2), and §56.115(a)(4), there is nothing in this regulation that would prevent the IRB from so doing.

115. One comment noted that an IRB may reject a study based on the ethical criticism of a single member. This comment argued that if an IRB raised a relevant ethical issue, the sponsor, which is the entity with the greatest legal liability, should evaluate the issue and if the concern is found to be valid, it should be up to the sponsor to decide to communicate the issue to other IRB's. This comment suggested that abridging the sponsor's responsibility will lead to less independent thinking by IRB's, slower progress in expanding clinical trials, and a "mass" of less than well-considered ethical comments being presented to FDA for its consideration.

The agency intends to monitor and evaluate the implementation of this regulation on an ongoing basis. While the agency doubts that such effects will be caused by this requirement, the agency will evaluate the impact of this requirement on IRB's and the conduct of clinical investigations. The agency notes that if an IRB "rejected" an investigation on the basis of an argument put forth by a single IRB member, it would appear likely that member's arguments were persuasive to the whole IRB.

116. The agency received a number of comments that suggested editorial or technical changes to clarify the language contained in the regulations.

The agency has incorporated editorial and technical changes where the agency thinks that they add clarification to the language in the regulation. In certain cases, the agency disagreed that the editorial or technical changes would clarify the language in the regulation.

C. Conforming Amendments

A variety of comments were received on the conforming amendments. Some of these have been previously discussed. Others, that relate solely to the conforming amendments, are discussed below.

117. One comment objected to §56.109(c)(1) which allows an IRB to waive the requirement that the subject sign a written consent form if it finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. This comment noted that one cannot ensure that informed consent is obtained, if a written consent form is not signed.

The language contained in §56.109(c)(1) has been in effect since 1981 and applies to research that involves no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. This section does not apply to research conducted under the provisions of this rule.

118. One comment suggested that §56.109(c)(2) be modified to include the suggestion that the IRB should seek additional input, as necessary, from sponsors or other experts to aid them in their decision making.

The IRB currently is free to consult with anyone that it wants; no change in the regulation is needed.

119. One comment on §56.109(d) suggested that the discretion suggested by the use of the term "may" was inappropriate and that this term should be changed to "must" in order to require the investigator to provide subjects with a written statement. Another comment questioned whether the proposed §56.109(d) replaced the current (d) or extended it.

Proposed §56.109(d) was taken from the existing IRB regulation; it was the last sentence in §56.109(c). Section 56.109(d) became proposed §56.109(e) with an additional sentence added at the end. In writing this conforming amendment, the agency intended new §56.109(d) to apply only to §56.109(c)(1)-that is, to studies that involve no more than minimal risk and involve no procedures for which written consent is normally required outside the research context. The agency has modified §56.109(d) to make this clear; on its own initiative, the agency has also corrected a typographical error in this paragraph. The agency notes that §50.24(b) describes the requirements for emergency research.

120. One comment suggested that §56.109(e) does not match the intent of §50.24(e), in that not only the notice of disapproval, but also the reason and/or concern needs to be provided. This comment suggested that §56.109(e) be modified to include the following sentence: "The written notification shall include a statement of the reasons for the disapproval."

The agency agrees with this comment and had intended that the reasoning behind the IRB's determination be provided. The agency notes that it is not only IRB disapprovals, but also an IRB's determination that it cannot approve an investigation, that triggers this requirement.

121. Another comment suggested that elsewhere in the regulations, there is allowance given for discussion between an investigator whose study has been disapproved and the reviewing IRB. This comment suggested that similar wording, or clarification, should allow for sponsor and IRB negotiation.

The agency disagrees with this comment. The purpose of this requirement is to enhance, not limit, communication of information between IRB's, investigators, sponsors, and FDA. §56.109(d), renumbered as §56.109(e), continues to state that "[i]f the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing." There is nothing in this regulation that prevents this[*51525]opportunity for discussion from occurring. It is up to the IRB, however, to determine when a final determination has been made on a study.

122. One comment questioned whether §56.109(e) should be paragraph (f) (a new paragraph), referring only to documentation of refusals to approve.

Old 56.109(d) which concerns decisions to approve, disapprove, or modify research, was renumbered in the proposal as new section 56.109(e). Thus, this paragraph does address documentation of disapprovals.

123. One comment recommended that the responsibility for determining when disclosure has occurred be assigned to the IRB's and that IRB's should be required to notify the sponsor so that the sponsor could notify FDA. This comment would affect § §56.109(g), 314.430(d), 812.38(b)(2) and 812.47(a).

The responsibility for determining when information has been publicly disclosed is a dual responsibility of the IRB and sponsor. Section 56.109(g) requires the IRB to provide a copy of information that has been publicly disclosed to the sponsor of the research; the sponsor is responsible for notifying FDA. Sections 312.54(a) and 812.47(a) require the sponsor to monitor the progress of all research invoking §50.24 to determine when the public disclosures occur and to promptly submit copies of the information that has been publicly disclosed to the IND or IDE file and also to the Dockets Management Branch.

124. One comment recommended that proposed section 56.111(c) be deleted, noting that this section is a documentation statement, rather than an approval criterion. This comment notes that proposed §50.24(a) contains similar language requiring such documentation and, therefore, no benefit is evident in the proposed modification to §56.111.

The agency agrees that there is no need for proposed section 56.111(c). Under §50.24(a), the IRB is responsible for finding and documenting that each of the safeguards are met; this is also covered broadly by §56.111(a)(4).

125. Several comments suggested that §312.54(a) be modified to state that the "sponsor shall document" rather than "determine" when public disclosure has occurred. These comments suggested that "determine" could be misconstrued to mean that the sponsor shall "decide" what constitutes adequate public disclosure, and that it is the responsibility of the IRB to make that determination.

The agency agrees that it is the responsibility of the IRB to determine what constitutes adequate disclosure to the community; however, it is the responsibility of the sponsor to provide copies of the information disclosed to the agency. The language in §312.54(a) has been modified to clarify that when the sponsor receives from the IRB information concerning the public disclosures required by §50.24(a)(7)(ii) and (a)(7)(iii), the sponsor is required to submit the information that was disclosed to FDA.

126. One comment recommended that the reference to §50.23 be removed from §312.60 but provided no explanation.

FDA rejects this comment and believes that the reference to §50.23 in §312.60 is needed to identify the various provisions in the regulations permitting an exception to informed consent. Because §50.23 provides different criteria for permitting an exception to the informed consent requirement, the agency is retaining reference to this section in §312.60.

127. One comment questioned the meaning of the modification to §314.430 and whether it means that Freedom of Information (FOI) requests for this information will not be processed, or that requests for information publicly disclosed under §50.24(a)(7)(ii) and (iii) must be submitted to the Dockets Management Branch.

Requests for copies of this public disclosure information are to be submitted as Freedom of Information Act requests. FDA has amended §312.130(d), 314.430(d)(2), 601.51(d)(2), 812.38(b)(4), and 814.9 to clarify that persons wishing to request the publicly disclosed information in the IND or IDE that was required to be filed with the Dockets Management Branch shall submit a request under the Freedom of Information Act. Alternatively, persons wishing to view this information may visit FDA's Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. A special docket, Docket Number 95S-0158, has been established for this purpose. To facilitate retrieval of information that may pertain to a single clinical investigation, FDA is specifying that information submitted to the docket must be identified by the IND or IDE number.

128. This comment also suggested that §312.130 be modified by the addition of

312.130(d) For investigational new drug applications involving an exception from informed consent under §50.24 of this chapter, sponsors are required to submit copies of information that has been publicly disclosed under §50.24(a)(5)(ii) and (a)(5)(iii) [renumbered §50.24(a)(7)(ii) and (a)(7)(iii)] to the IND file and to Dockets Management Branch. Copies of this information will be available to the public from the Dockets Management Branch.

The agency agrees with this comment that it would be clearer if §312.130(d) were modified. Consistent with the discussion above, the agency has amended §312.130 to add a new paragraph (d) which contains similar language to that suggested in the comment.

129. On the agency's own initiative, FDA is amending the clinical hold regulation at § 312.42 to explicitly include a failure to comply with the requirements in §50.24 as a reason for clinical hold. The agency believes this revision will remove any confusion that may exist regarding the authority to stop, where warranted, an investigation invoking this rule. The agency does not believe a change is needed to the device regulation at §812.30 on disapproving or withdrawing approval of an IDE because that regulation currently expressly authorizes FDA to take such action for failure to comply with "any other applicable regulation or statute, or any condition of approval imposed by an IRB or FDA."

D. Preemptive Effect

In developing these rules, FDA considered whether there were existing State or local legal requirements governing informed consent that might limit or preclude participation in research in circumstances that otherwise could be authorized by IRB's acting in accord with these proposed rules. FDA recognizes that nationally uniform informed consent requirements governing this type of research could serve to lessen the current confusion created in the research community by differing Federal regulations. FDA also recognizes that the existing Federal Policy for the Protection of Human Subjects, which governs much of this type of research, currently provides that it does not affect any State or local laws or regulations that may otherwise be applicable and that provide additional protections for human subjects. Accordingly, FDA specifically invited comment on whether there are existing State or local legal requirements that might limit or preclude participation in research in circumstances that otherwise could be authorized by IRB's acting in accord with these proposed rules and whether any such requirements should be preempted by Federal requirements. As discussed previously, FDA received limited information on existing State or local legal requirements that might limit or preclude participation in research covered by this rule. The agency also[*51526]received a number of comments in favor of the status quo. The information submitted on existing State or local legal requirements was insufficient for the agency to justify changing the existing Federal policy for the protection of human subjects, which governs much of this type of research, and which currently provides that it does not affect any State or local laws or regulations which may otherwise be applicable and which provide additional protections for human subjects. Thus, the agency does not intend to preempt existing State or local requirements that provide additional protections for human subjects.

IV. Effective Date

These regulations are effective November 1, 1996. IND's and IDE's that intend to invoke this rule may be submitted to the agency on or after the publication date of this rule and must 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.

V. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.

VI. Executive Orders

A. Executive Order 12606: The Family

Executive Order 12606 directs Federal agencies to determine whether policies and regulations may have a significant impact on family formation, maintenance, and general well-being. FDA has analyzed this rule in accordance with Executive Order 12606, and has determined that it has no potential negative impact on family formation, maintenance, and general well-being.

FDA has determined that this rule will not affect the stability of the family, and particularly, the marital commitment. It will not have any significant impact on family earnings. The rule would not erode the parental authority and rights in the education, nurture, and supervision of children.

B. Executive Order 12612: Federalism

Executive Order 12612 requires Federal agencies to carefully examine regulatory actions to determine if they would have a significant effect on Federalism. Using the criteria and principles set forth in the order, FDA has considered the rule's impact on the States, on their relationship with the Federal Government, and on the distribution of power and responsibilities among the various levels of government. FDA concludes that this rule is consistent with the principles set forth in Executive Order 12612.

Executive Order 12612 states that agencies formulating and implementing policies are to be guided by certain Federalism principles. Section 2 of Executive Order 12612 enumerates fundamental federalism principles. Section 3 states that, in addition to these fundamental principles, executive departments and agencies shall adhere, to the extent permitted by law, to certain listed criteria when formulating and implementing policies that have federalism implications. Section 4 lists special requirements for preemption.

Section 4 of Executive Order 12612 states that an executive department or agency foreseeing the possibility of a conflict between State law and federally protected interests within its area of regulatory responsibility is to consult with States in an effort to avoid such conflict. Section 4 of the Executive Order also states that an executive department or agency proposing to act through rulemaking to preempt State law is to provide all affected States notice and opportunity for appropriate participation in the proceedings. As required by the Executive Order, States have had, through this rule's notice of proposed rulemaking, an opportunity to raise the possibility of conflicts and to participate in the proceedings (section 4(d) and (e)). Consistent with Executive Order 12612, FDA requested information and comments from interested parties, including but not limited to State and local authorities, on these issues of federalism. FDA is not preempting State law through this rulemaking.

VII. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). Executive Order 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). The agency believes that this rule is consistent with the regulatory philosophy and principles identified in the Executive Order. The agency has determined that this rule is a "significant regulatory action" as defined in section 3(f)(4) of the Executive Order because it raises novel policy issues.

If a rule has a significant economic impact on a substantial number of small entities, the Regulatory Flexibility Act requires agencies to analyze regulatory options that would minimize any significant impact of a rule on small entities. This rule is a deregulatory action insofar as it will permit research to proceed that could not proceed under existing regulations, and because relatively few research projects will need to meet the requirements of this rule. Therefore, under the Regulatory Flexibility Act 5 U.C.C. 605(b), the Commissioner certifies that the rule will not have a significant economic impact on a substantial number of small entities. Therefore, under the Regulatory Flexibility Act, no further analysis is required.

VIII. Paperwork Reduction Act of 1995

This rule contains information collection requirements that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (Pub. L. 104-13, May 22, 1995), and that are already approved under Protection of Human Subjects-Recordkeeping Requirements for Institutional Review Boards, part 56 (21 CFR part 56) under OMB Control No. 0910-0130; Investigational New Drug Application under OMB Control No. 0910-0014; and Investigational Devices Exemption Reports and Records, part 812 (21 CFR 812) under OMB Control No. 0910-0078. Modifications to these approved information collection requirements are underway or will be made at the time that each information collection is renewed. The agency believes that this is appropriate because this rule has only a minor impact on these existing information collection packages.

One comment was received on the agency's estimate of paperwork burden. That comment noted that the estimate of 20 sponsored investigational drug and 10 sponsored device studies that will require waiver of consent may be correct for multicenter studies sponsored by manufacturers. However, based on results from an informal survey of[*51527]Emergency Medicine Research Directors conducted in May 1994 and again in December 1994, there may be a substantial number of single investigator/single institution studies that will also involve waiver of consent. The comment, thus, concluded that the agency had underestimated the total number of studies that will be advanced for consideration of a waiver of consent.

This comment is correct; the agency did not consider single-investigator/single-institution studies. In response to this comment, the agency has estimated that there will be approximately 25 single-institution studies requiring an IDE and 50 single-institution studies requiring an IND annually. This paperwork section has been revised accordingly.

For Protection of Human Subjects-Recordkeeping Requirements for IRB's under OMB Control No. 0910-0130, FDA has calculated the existing recordkeeping burden on IRB's required by §56.115 based on the estimated number of IRB's and the estimated annual number of hours each IRB spends in recordkeeping activities. FDA does not believe that this rule will increase the number of IRB's. However, the agency estimates that the number of hours for recordkeeping related to studies that propose to invoke this exception from informed consent will increase for an estimated 275 IRB's by 5 annual hours per record-keeper. This will change the estimated recordkeeper burden from 65 to 70 hours annually for these estimated 275 IRB's.

The newly redesignated and revised §56.109(e) proposes to require that an IRB notify in writing the sponsor of the research when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception provided under §50.24(a) of this chapter or because of other relevant ethical concerns. In accord with the Paperwork Reduction Act of 1995, the agency discloses that this rule requires this third party notification.

For Investigational New Drug Application under OMB Control No. 0910-0014, the agency estimates that sponsors will submit an average of 20 studies a year, with an average of 20 clinical investigators each, that propose to invoke this exception from informed consent and that sponsor-investigators will submit an average of 50 studies a year. Currently, the agency estimates the reporting requirements contained in part 312 (21 CFR 312) to average 123.34 hours per respondent annually. Reporting requirements are contained in the following sections of part 312: 312.7, 312.10, 312.23, 312.30, 312.31, 312.32, 312.33, 312.35, 312.36, 312.38, 312.41, 312.44(c)(d), 312.45, 312.47, 312.53, 312.55, 312.56, 312.58, 312.64, 312.66, 312.70, 312.83, 312.85, 312.110, 312.120(b), 312.120(c)(3), 312.140, and 312.145. FDA estimates that respondents will increase by 450 annually, resulting in an increase of 55,503 hours over that currently estimated. The reporting burden for respondents will, as a result, increase from an estimated 3,926,308 hours annually to 3,971,811 hours annually.

New §312.54(b) proposes to require the sponsor to provide information when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in §50.24(a) or because of other relevant ethical concerns. This information is to be provided promptly in writing to FDA, investigators who are asked to participate in the clinical investigation or a substantially equivalent investigation, and other IRB's that are asked to review the investigation or a substantially equivalent investigation. In accord with the Paperwork Reduction Act of 1995, the agency discloses that this rule requires this third party notification.

For recordkeeping, under §312.52, 312.57, 312.59, 312.62(a), 312.62(b), 312.62(c), 312.160(a) and (c), the agency estimated that an average of 165.13 hours were spent per respondent. For the estimated additional 450 recordkeeping respondents invoking this rule, this would result in approximately 74,309 hours annually. The recordkeeping burden for respondents will, as a result, increase from an estimated 2,244,090 hours annually to 2,318,399 hours annually.

For Investigational Devices Exemption Reports and Records under OMB Control No. 0910-0078, the agency estimates that 35 studies proposing to invoke this exception will be submitted to the agency annually. The number of studies upon which the current paperwork reporting burden is estimated (§812.20, 812.25, 812.27, 812.35, and 812.150) may, therefore, increase from 244 original submissions to 279 original submissions, increasing the number of hours by 2,800 for respondents (estimated at 80 hours per submission), from a total of 19,520 to 22,320 hours annually.

New §812.47(b) proposes to require the sponsor to provide information when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in §50.24(a) of this chapter or because of other relevant ethical concerns. This information is to be provided promptly in writing to FDA, investigators who are asked to participate in the clinical investigation or a substantially equivalent investigation, and other IRB's that are asked to review the investigation or a substantially equivalent investigation. In accord with the Paperwork Reduction Act of 1995, the agency discloses that this rule requires this third party notification.

The number of recordkeepers, under § §812.43 and 812.140, is currently estimated at 700; this number is not expected to change. The estimated number of annual hours for recordkeeping requirements is expected to increase by 350 hours. The agency had estimated that original submissions require 10 hours annually of recordkeeping per submission; recordkeeping related to studies invoking this rule are expected to increase the submissions from 244 to a total of 279.

As required by section 3507(d) of the Paperwork Reduction Act of 1995, FDA has submitted a copy of this rule to OMB for its review of these previously approved information collection requirements. The agency solicited comments on the information collection requirements in order to: (1) Evaluate whether the collection of information is necessary for the proper performance of the functions of the agency, including whether the information will have practical utility; (2) evaluate the accuracy of the agency's estimate of the burden of the collection of information, including the validity of the methodology and assumptions used; (3) enhance the quality, utility, and clarity of the information to be collected; and (4) minimize the burden of the collection of information on those who are to respond, including through the use of appropriate automated, electronic, mechanical, or other technological collection techniques or other forms of information technology, e.g., permitting electronic submission of responses.

List of Subjects

21 CFR Part 50

Human research subjects, Prisoners, Reporting and recordkeeping requirements, Safety.

21 CFR Part 56

Human research subjects, Reporting and recordkeeping requirements, Safety.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical research, Reporting and recordkeeping requirements, Safety.[*51528]

21 CFR Part 314

Administrative practice and procedure, Confidential business information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential business information.

21 CFR Part 812

Health records, Medical devices, Medical research, Reporting and recordkeeping requirements.

21 CFR Part 814

Administrative practice and procedure, Confidential business information, Medical devices, Medical research, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 50, 56, 312, 314, 601, 812, and 814 are amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

1. The authority citation for 21 CFR part 50 continues to read as follows:

Authority: Secs. 201, 406, 408, 409, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371, 379e, 381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 262, 263b-263n).

2. Section 50.3 is amended by adding a new paragraph (n) to read as follows:

§50.3 -- Definitions.

* * * * *

(n) Family member means any one of the following legally competent persons: Spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship.

3. Section 50.24 is added to subpart B to read as follows:

§50.24 -- Exception from informed consent requirements for emergency research.

(a) The IRB responsible for the review, approval, and continuing review of the clinical investigation described in this section may approve that investigation without requiring that informed consent of all research subjects be obtained if the IRB (with the concurrence of a licensed physician who is a member of or consultant to the IRB and who is not otherwise participating in the clinical investigation) finds and documents each of the following:

(1) The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions.

(2) Obtaining informed consent is not feasible because:

(i) The subjects will not be able to give their informed consent as a result of their medical condition;

(ii) The intervention under investigation must be administered before consent from the subjects' legally authorized representatives is feasible; and

(iii) There is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation.

(3) Participation in the research holds out the prospect of direct benefit to the subjects because:

(i) Subjects are facing a life-threatening situation that necessitates intervention;

(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; and

(iii) Risks associated with the investigation are reasonable in relation to what is known about 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 or activity.

(4) The clinical investigation could not practicably be carried out without the waiver.

(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 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.

(6) The IRB has reviewed and approved informed consent procedures and an informed consent document consistent with §50.25. These procedures and the informed consent document are to be used with subjects or their legally authorized representatives in situations where use of such procedures and documents is feasible. The IRB has reviewed and approved procedures and information to be used when providing an opportunity for a family member to object to a subject's participation in the clinical investigation consistent with paragraph (a)(7)(v) of this section.

(7) Additional protections of the rights and welfare of the subjects will be provided, including, at least:

(i) Consultation (including, where appropriate, consultation carried out by the IRB) with representatives of the communities in which the clinical investigation will be conducted and from which the subjects will be drawn;

(ii) Public disclosure to the communities in which the clinical investigation will be conducted and from which the subjects will be drawn, prior to initiation of the clinical investigation, of plans for the investigation and its risks and expected benefits;

(iii) Public disclosure of sufficient information following completion of the clinical investigation to apprise the community and researchers of the study, including the demographic characteristics of the research population, and its results;

(iv) Establishment of an independent data monitoring committee to exercise oversight of the clinical investigation; and

(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.

(b) The IRB is responsible for ensuring that procedures are in place to inform, at the earliest feasible opportunity, each subject, or if the subject remains incapacitated, a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member, of the subject's inclusion in the clinical investigation, the details of the[*51529]investigation and other information contained in the informed consent document. The IRB shall also ensure that there is a procedure to inform the subject, or if the subject remains incapacitated, a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member, that he or she may discontinue the subject's participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. If a legally authorized representative or family member is told about the clinical investigation and the subject's condition improves, the subject is also to be informed as soon as feasible. If a subject is entered into a clinical investigation with waived consent and the subject dies before a legally authorized representative or family member can be contacted, information about the clinical investigation is to be provided to the subject's legally authorized representative or family member, if feasible.

(c) The IRB determinations required by paragraph (a) of this section and the documentation required by paragraph (e) of this section are to be retained by the IRB for at least 3 years after completion of the clinical investigation, and the records shall be accessible for inspection and copying by FDA in accordance with §56.115(b) of this chapter.

(d) Protocols involving an exception to the informed consent requirement under this section must be performed under a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly identifies such protocols as protocols that may include subjects who are unable to consent. The submission of those protocols in a separate IND/IDE is required even if an IND for the same drug product or an IDE for the same device already exists. Applications for investigations under this section may not be submitted as amendments under § §312.30 or 812.35 of this chapter.

(e) If an IRB determines that it cannot approve a clinical investigation because the investigation does not meet the criteria in the exception provided under paragraph (a) of this section or because of other relevant ethical concerns, the IRB must document its findings and provide these findings promptly in writing to the clinical investigator and to the sponsor of the clinical investigation. The sponsor of the clinical investigation must promptly disclose this information to FDA and to the sponsor's clinical investigators who are participating or are asked to participate in this or a substantially equivalent clinical investigation of the sponsor, and to other IRB's that have been, or are, asked to review this or a substantially equivalent investigation by that sponsor.

PART 56--INSTITUTIONAL REVIEW BOARDS

4. The authority citation for 21 CFR part 56 continues to read as follows:

Authority: Secs. 201, 406, 408, 409, 501, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 351, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371, 379e, 381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C 216, 241, 262, 263b-263n).

5. Section 56.109 is amended by revising paragraph (c), by redesignating paragraphs (d) and (e) as paragraphs (e) and (f), by adding two new sentences to the end of newly redesignated paragraph (e), and by adding new paragraphs (d) and (g) to read as follows:

§56.109 -- IRB review of research.

* * * * *

(c) An IRB shall require documentation of informed consent in accordance with §50.27 of this chapter, except as follows:

(1) The IRB may, for some or all subjects, waive the requirement that the subject, or the subject's legally authorized representative, sign a written consent form if it finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context; or

(2) The IRB may, for some or all subjects, find that the requirements in §50.24 of this chapter for an exception from informed consent for emergency research are met.

(d) In cases where the documentation requirement is waived under paragraph (c)(1) of this section, the IRB may require the investigator to provide subjects with a written statement regarding the research.

(e)* * * For investigations involving an exception to informed consent under §50.24 of this chapter, an IRB shall promptly notify in writing the investigator and the sponsor of the research when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception provided under §50.24(a) of this chapter or because of other relevant ethical concerns. The written notification shall include a statement of the reasons for the IRB's determination.

* * * * *

(g) An IRB shall provide in writing to the sponsor of research involving an exception to informed consent under §50.24 of this chapter a copy of information that has been publicly disclosed under §50.24(a)(7)(ii) and (a)(7)(iii) of this chapter. The IRB shall provide this information to the sponsor promptly so that the sponsor is aware that such disclosure has occurred. Upon receipt, the sponsor shall provide copies of the information disclosed to FDA.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

6. The authority citation for 21 CFR part 312 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C 321, 331, 351, 352, 353, 355, 356, 357, 371); sec 351 of the Public Health Service Act (42 U.S.C. 262).

7. Section 312.2 is amended by adding paragraph (b)(6) to read as follows:

§312.2 -- Applicability.

* * * * *

(b) * * *

(6) A clinical investigation involving an exception from informed consent under §50.24 of this chapter is not exempt from the requirements of this part.

* * * * *

8. Section 312.20 is amended by adding new paragraph (c) to read as follows:

§312.20 -- Requirement for an IND.

* * * * *

(c) A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent under §50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide such written authorization 30 days after FDA receives the IND or earlier.

9. Section 312.23 is amended by adding new paragraph (f) to read as follows:

§312.23 -- IND content and format.

* * * * *

(f) Identification of exception from informed consent. If the investigation involves an exception from informed consent under §50.24 of this chapter, the sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements in §50.24 of this chapter.

10. Section 312.30 is amended by adding a new sentence to the end of the introductory text to read as follows:[*51530]

§312.30 -- Protocol amendments.

* * * Whenever a sponsor intends to conduct a clinical investigation with an exception from informed consent for emergency research as set forth in §50.24 of this chapter, the sponsor shall submit a separate IND for such investigation.

* * * * *

11. Section 312.42 is amended by adding new paragraph (b)(5) to read as follows:

§312.42 -- Clinical holds and requests for modification.

* * * * *

(b) * * *

(5) Clinical hold of any investigation involving an exception from informed consent under §50.24 of this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed consent under §50.24 of this chapter on clinical hold if it is determined that:

(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or

(ii) The pertinent criteria in §50.24 of this chapter for such an investigation to begin or continue are not submitted or not satisfied.

* * * * *

12. New section 312.54 is added to subpart D to read as follows:

§312.54 -- Emergency research under §50.24 of this chapter.

(a) The sponsor shall monitor the progress of all investigations involving an exception from informed consent under §50.24 of this chapter. When the sponsor receives from the IRB information concerning the public disclosures required by §50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor promptly shall submit to the IND file and to Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, copies of the information that was disclosed, identified by the IND number.

(b) The sponsor also shall monitor such investigations to identify when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in §50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall provide this information in writing to FDA, investigators who are asked to participate in this or a substantially equivalent clinical investigation, and other IRB's that are asked to review this or a substantially equivalent investigation.

13. Section 312.60 is amended by revising the second and third sentences in the text as follows:

§312.60 -- General responsibilities of investigators.

* * * An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in § §50.23 or 50.24 of this chapter. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.

14. Section 312.130 is amended by adding a new paragraph (d) to read as follows:

§312.130 -- Availability for public disclosure of data and information in an IND.

* * * * *

(d) The availability of information required to be publicly disclosed for investigations involving an exception from informed consent under §50.24 of this chapter will be handled as follows: Persons wishing to request the publicly disclosable information in the IND that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, shall submit a request under the Freedom of Information Act.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN ANTIBIOTIC DRUG

15. The authority citation for 21 CFR part 314 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

16. Section 314.430 is amended by redesignating paragraph (d) as paragraph (d)(1) and by adding new paragraph (d)(2) to read as follows:

§314.430 -- Availability for public disclosure of data and information in an application or abbreviated application.

* * * * *

(d)(1) * * *

(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the investigational new drug application that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under §50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

* * * * *

PART 601--LICENSING

17. The authority citation for 21 CFR part 601 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520, 701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381); secs. 215, 301, 351, 352 of the Public Health Service Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging and Labeling Act (15 U.S.C. 1451-1461).

18. Section 601.51 is amended by redesignating paragraph (d) as paragraph (d)(1) and by adding new paragraph (d)(2) to read as follows:

§601.51 -- Confidentiality of data and information in applications for establishment and product licenses.

* * * * *

(d)(1) * * *

(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the IND that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under §50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

19. The authority citation for 21 CFR part 812 continues to read as follows:

Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371, 372, 374, 379e, 381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C 216, 241, 262, 263b-263n).

20. Section 812.20 is amended by revising paragraph (a)(1) and adding new paragraph (a)(4) to read as follows:

§812.20 -- Application.

(a) Submission. (1) A sponsor shall submit an application to FDA if the sponsor intends to use a significant risk device in an investigation, intends to conduct an investigation that involves an exception from informed consent under §50.24 of this chapter, or if FDA[*51531]notifies the sponsor that an application is required for an investigation.

* * * * *

(4)(i) A sponsor shall submit a separate IDE for any clinical investigation involving an exception from informed consent under §50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization of FDA. FDA shall provide such written authorization 30 days after FDA receives the IDE or earlier.

(ii) If the investigation involves an exception from informed consent under §50.24 of this chapter, the sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements in §50.24 of this chapter.

* * * * *

20. Section 812.35 is amended by adding a new sentence to the end of paragraph (a) to read as follows:

§812.35 -- Supplemental applications.

(a) * * * Whenever a sponsor intends to conduct a clinical investigation with an exception from informed consent for emergency research as set forth in §50.24 of this chapter, the sponsor shall submit a separate IDE for such investigation.

* * * * *

21. Section 812.38 is amended by adding a new paragraph (b)(4) to read as follows:

§812.38 -- Confidentiality of data and information.

* * * * *

(b) * * *

(4) Notwithstanding paragraph (b)(2) of this section, FDA will make available to the public, upon request, the information in the IDE that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under §50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

* * * * *

22. New section 812.47 is added to subpart C to read as follows:

§812.47 -- Emergency research under §50.24 of this chapter.

(a) The sponsor shall monitor the progress of all investigations involving an exception from informed consent under §50.24 of this chapter. When the sponsor receives from the IRB information concerning the public disclosures under §50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor shall promptly submit to the IDE file and to Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, copies of the information that was disclosed, identified by the IDE number.

(b) The sponsor also shall monitor such investigations to determine when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in §50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall provide this information in writing to FDA investigators who are asked to participate in this or a substantially equivalent clinical investigation and other IRB's that are asked to review this or a substantially equivalent investigation.

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

23. The authority citation for 21 CFR part 814 is revised to read as follows:

Authority: Secs. 501, 502, 503, 510, 513-520, 701, 702, 703, 704, 705, 708, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372, 373, 374, 375, 379, 379e, 381).

24. Section 814.9 is amended by redesignating paragraph (d) as paragraph (d)(1) and by adding new paragraph (d)(2) to read as follows

§814.9 -- Confidentiality of data and information in a premarket application (PMA) file.

* * * * *

(d)(1) * * *

(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the IDE that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under §50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

* * * * *

Dated: July 17, 1996.

David A. Kessler,
Commissioner of Food and Drugs.

Donna E. Shalala,
Secretary of Health and Human Services.

[FR Doc. 96-24967 Filed 9-26-96; 8:59 am]

BILLING CODE 4160-01-F

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