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ARCHIVED - NIH Regulatory Burden
V. Human Subjects Protection - Workgroups Report

Background

The Federal Government, through the Office of Protection from Research Risks (OPRR), within the National Institutes of Health (NIH) and the Department of Health and Human Services (DHHS), has promulgated regulations and policies which govern the protections for human subjects who participate in Federally-supported research. The DHHS regulations (45 CFR 46) flow from the Public Health Service Act as amended. Subpart A of these regulations governs the programs of 17 Federal agencies which support research using human subjects and is referred to as the "Common Rule" or "Federal Policy". Subparts B-D of the regulations apply only to research supported by DHHS. Further policy guidance is provided in Protecting Human Research Subjects, Institutional Review Board Guidebook (1993) and in periodic "Dear Colleague" letters issued by the OPRR, which administers these regulations on behalf of DHHS. OPRR also supports education programs on issues related to protecting human subjects participating in research.

The Federal government also has promulgated regulations on human subjects protections through the Food and Drug Administration (FDA). Unlike the DHHS regulations, Federal support is not necessary for the FDA regulations to be applicable as they apply to any FDA-regulated article. The FDA regulations, 21 CFR 50 and 56, apply to Informed Consent and Institutional Review Boards (IRB), respectively. In addition, FDA has promulgated regulations, 21 CFR 312 and 812, which govern research related to Investigational New Drug (IND) applications and Investigational Device Exemptions (IDE), respectively. These regulations flow from the Federal Food, Drug, and Cosmetic Act, as amended. Further policy guidance is provided through FDA Information Sheets. Education programs are also supported.

In order to identify the research community's view of streamlining opportunities, two workgroups of research institution officials were convened – one comprised of members of institutions performing a mid-to-large volume of human subjects research, and one of members of institutions performing a small-to-mid volume. At the low end, an institution may be performing relatively few protocols and at the high end, an institution may be performing over 3,000 protocols per year. Two workgroups were convened because there is some evidence to indicate that volume may influence how the IRB is administered. A further meeting was convened of a representative number of the members of each to discuss common themes across the two workgroups.

Each workgroup was diverse but each contained similar representation - one or more research investigators, chairs of IRBs, administrators of IRBs, and institutional officials responsible for compliance with these regulations. This diversity is necessary in order to capture the perspective of both those performing the research and those who are charged with developing, implementing and overseeing the program of protection at the institutional level. A listing of the individuals serving on each workgroup is included in Appendix 2.

The specific task assigned to the members was to develop proposals, and potential solutions, to reduce regulatory burden in the human subjects protection program. While the request came from the Appropriations Subcommittee that oversees the activities of the NIH and most of the Agencies of the DHHS, but not the FDA, it was not possible to assess the regulatory burden imposed on the research community without considering the impact of the FDA regulations because of the considerable overlap. Therefore, the workgroup considered specific aspects of this larger set of programs that could be made more efficient and to propose solutions for the issues that were identified.

This Congressional request to assess the potential for streamlining is only one of several studies of the human subjects program. The DHHS Office of the Inspector General (OIG) recently completed an evaluation of the program entitled Institutional Review Boards: A Time for Reform. A broad array of recommendations was made including some suggestions for streamlining, but within the context of a broader set of reforms. The OIG review followed a study by the General Accounting Office (GAO), performed at the request of the Senate Government Operations Committee, and entitled Scientific Research, Continued Vigilance Critical to Protecting Human Subjects. It concluded that time and resource pressures had the potential to reduce the effectiveness of the program and that human subjects protection should remain a priority. In a third review, James Bell Associates, under contract with NIH, undertook the Evaluation of NIH Implementation of Section 491 of the Public Health Service Act, Mandating a Program of Protection for Research Subjects. The central conclusion of this broad survey was that IRBs are providing an adequate level of protection at a reasonable cost. Finally, Executive Order 12975 created the National Bioethics Advisory Commission (NBAC) which is charged with reviewing the appropriateness of governmental policies and regulations as they relate to bioethical issues arising from research on human biology and behavior, and with developing broad principles governing the ethical conduct of research. NBAC will issue a report on IRBs. Each of these reports identifies certain aspects of the human subjects protection program that could be made more efficient although their assessment objectives were broader than the relatively narrower focus of this NIH initiative on regulatory burden.

Current Requirements

The PHS Act requires that DHHS issue regulations for the protection of human subjects in research and to implement a program of instruction and guidance in ethical issues related to research. The key provisions of Subpart A of these regulations are as follows:

  • "Research" is defined as a systematic investigation designed to develop or contribute to generalizable knowledge; "Human Subject" is defined as a living individual about whom the investigator conducting the research obtains either data through intervention or interaction with the individual, or identifiable private information.
  • Each institution engaged in the conduct of Federally-supported research involving human subjects must provide a written assurance that it will comply with the requirements of the regulations. This assurance document must be approved by the Agency Head or designee, and must contain the following information at a minimum:
    • A statement of principles governing how the institution will protect human subjects in research projects conducted or sponsored by that institution.
    • Designation of one or more IRBs meeting the requirements of the regulation, and for which sufficient meeting space and support staff are provided to support the required review and record-keeping functions.
    • A listing of IRB members by name, degree, representative capacity, experience, and institutional affiliation. Changes in IRB membership are to be reported to OPRR.
    • Written procedures for initial and continuing review; for determining when a review more frequently than yearly is required; and for assuring prompt reporting to the IRB of protocol changes by the investigator, and approval of those changes before implementation.
    • Written procedures for reporting any unanticipated problems with human subjects protections, and serious or continuing non-compliance with the policy or IRB decisions.

  • The IRB must review and approve all covered research and must require documentation of informed consent where appropriate.
  • The IRB must conduct continuing review of protocols at intervals appropriate to the degree of risk but no less than once a year.
  • The IRB may use expedited review procedures (review by the Chair or designee(s)) to approve items eligible for such review or minor changes to previously approved protocols.
  • In order to approve a research project, the IRB must be satisfied that:
    • Risks to the subjects are minimized.
    • Risks are reasonable in relation to the anticipated benefits.
    • Selection of the subjects is equitable.
    • Informed consent will be sought from the individual subject or the legal representative.
    • Informed consent will be appropriately documented.
    • When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
    • When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
    • Special protections are in place for populations that are vulnerable, e.g., children, prisoners, the mentally disabled, pregnant women, etc.

Additional protections apply to DHHS-supported programs pertaining to research, development, and related activities involving fetuses, pregnant women, and human in vitro fertilization (Subpart B); biomedical or behavioral research involving prisoners (Subpart C); and children (Subpart D).

As noted above, FDA has published its own regulations for IRBs and Informed Consent for evaluation of FDA-regulated test articles. In general, these regulations are consistent with the Common Rule but differences do exist beyond those dictated by the different missions of the agencies. Some of the significant differences are:

  • Rather than an assurance process, the FDA relies on on-site inspections of IRBs; the FDA goal is to inspect each IRB every five years.
  • Differences exist between the FDA regulations and, in turn, with DHHS regulations, with regard to the criteria for notifying IRBs of adverse events that occur during the course of the research study.
    • 21 CFR 312.32(c)(1)(i) requires that the sponsor notify FDA and participating investigators of any adverse event associated with the use of a test drug that is "both serious and unexpected."
    • 21 CFR 56.108(b) and 45 CFR 46.103(b)(5)(i) require that the IRB follow written procedures in ensuring prompt reporting to the IRB, institutional officials, and the Department or Agency Head of any "unanticipated problems" involving risks to human subjects.

  • Differences also exist with regard to the one time use of a test article in emergency situations.
    • The Common Rule, while stating explicitly that the rule does not limit the provision of emergency care, requires that there must be IRB approval and informed consent (with very limited exceptions, e.g., less than minimal risk) for data to be used as part of a research project.
    • The FDA, however, allows the waiving of informed consent and IRB approval in emergency situations under certain conditions, and also allows the data gathered from its use to be included as part of the research evaluation of the product's effectiveness.

  • DHHS regulations, through 45 CFR 46.103(b)(2), require that there are sufficient space and staff to support the IRB's review and record-keeping duties; FDA regulations contain no such provision.

Identification of Intent of Human Subjects Protections

In order to put potential issues and solutions into the appropriate context, workgroup members identified the intended level of protections, i.e., the objectives that must be achieved if a program of human subjects protection is to be considered effective. It is the members' view that the protections that should achieved by the federal regulations and the objectives of a credible program of human subjects protections are as follows:

  • At its core, a program must embody the basic ethical principles of the Belmont Report – respect for persons, i.e., that individuals should be treated as autonomous individuals and that persons with diminished capacity are entitled to additional protection; beneficence, i.e., do no harm, and maximize benefits and minimize possible harms; and justice, i.e., fairness in who is selected to participate in, and bear the burdens of, research.
  • The program must acknowledge that the central purpose of an IRB is to review research through a group process with balanced expertise to ensure adequate protection of the rights and welfare of the subjects, and to advise the scientist on the ethical conduct of research.
  • The program must ensure that research participants understand that, while risks have been minimized, research is not risk-free. As such, the program must ensure that these participants receive sufficient information upon which to make an informed decision regarding their participation.
  • For the program to operate efficiently and effectively, it should operate locally with sufficient flexibility to foster creative strategies to protect human subjects. To that end, Federal agencies have a responsibility to operate in the spirit of good will to assure that the regulations and policies are clear and flexible, consistent across the multiple agencies, and consistently applied and interpreted both within and across agencies.
  • The program must operate on the basis of trust and on the assumption that researchers and IRB members are ethical and guided by their professional codes of conduct.
  • The program of human subjects protection must have institutional support. The IRB's primary advocacy is for the research participants, not the institution or its investigators. Secondary protections are afforded to the institution and its investigators.
  • The program must have a comprehensive educational component reaching all who are involved – IRB chairs, members, administrators, investigators and research staff, institutional officials, students, and the community of research subjects.

In examining existing legislation, regulations, policies and practices, the members agreed that a credible policy of human subjects protection had to achieve these objectives. Any changes proposed to reduce regulatory burden should be consistent with, and foster, the achievement of these objectives.

Identification of Issues of Concern

Following the development of the objectives that a human subjects protection program must achieve, the members identified specific issues that were of concern. The following list includes issues related to the legislation, the regulations and the inconsistency between the agencies on some aspects of the regulations, the interpretation of the regulations, and policies and practices of the agencies. It should be noted that the purpose of the workgroup was not necessarily to come to consensus. While there was general agreement on the issues and the proposed solutions, there was not necessarily unanimity on each.

  • Off-site Adverse Events Reports – As noted above, the regulations require that IRBs be notified when adverse events occur. Several issues were identified by members:
    • The IRBs are being overwhelmed with off-site reports that are not presented in a useful format. Each IRB receives individual reports on every event from every site. Adding to the difficulty is that duplicate reports are received, sometimes months apart. Because many of these protocols are randomized, double blind studies, these reports cannot identify if the event occurred with a research participant receiving the study drug or the control treatment. In sum, the receipt of data that are neither aggregated nor interpreted does not provide useful information to the IRB to allow it to make an informed judgment on the appropriate action to be taken, if any.
    • The regulations may be confusing since they could be construed to establish different requirements for when an IRB should be provided with an adverse event report. As noted previously, 21 CFR 312.32(c)(1)(i) requires the sponsor to notify FDA and participating investigators of an adverse event that is "both serious and unexpected." However 21 CFR 56.108(b) and 45 CFR 46.103(b)(5)(i) contain a broader notification requirement defined as "unanticipated problems" involving risks to human subjects.
    • Although data safety monitoring boards (DSMBs) have existed for some time to oversee certain clinical trials for the purpose of data and safety monitoring, these reports are rarely received by IRBs. However, NIH issued a policy in June 1998 requiring the establishment of DSMBs for all NIH-funded multi-site clinical trials involving interventions that pose risks for research subjects. It further states that IRBs should be provided feedback on a regular basis, including findings from adverse-event reports, and recommendations derived from data and safety monitoring.

  • Overall coordination between and within FDA and NIH – The members recognized and expressed appreciation for the ongoing efforts to minimize differences between OPRR and FDA in the administration of their respective human subjects protection programs. However, throughout the discussion, items surfaced which highlighted differences that exist, and that result in regulatory burden.
    • Operational differences exist between FDA and OPRR. The most basic difference between FDA and OPRR, and which is likely reflective of different cultures of the two organizations, is that OPRR performs its oversight function primarily through the negotiation of assurances as described above. FDA does not pre-approve IRBs but, instead, relies on inspections of institutions.
    • Regulatory differences exist between FDA and OPRR. Although the language in the FDA regulations is nearly identical to that in the Common Rule, differences exist. The significant differences were noted earlier in this paper.
    • Policy differences exist between FDA and OPRR. An issue frequently identified by members is OPRR's refusal to allow the use of audio conference calls as part of full Board review. They insist on video-conferencing while FDA allows audio-conferencing.
    • Different interpretations of regulations and policies are made within and between agencies. Within NIH, members reported conflicting interpretations of regulations between OPRR and the various cooperative groups initiated under NIH auspices. Members also observed that Federal staff members often provided different interpretations of the same policy, e.g., approval periods, requirements for Single Project Assurances, etc.
    • Differences in sponsors' practices and their imposition of these practices on IRBs also adds to the burden. Members reported that different sponsors have slightly different practices, none which by themselves are major, but when taken together, result in significant burden. In these cases, sponsors insist on changes to the IRBs method of operation, even when their procedures are consistent with the regulations. Examples include special child assent and patient consent procedures, and paperwork requirements not mandated by regulation. In addition, the Contract Research Organizations (CRO), which may be used by pharmaceutical companies to manage various aspects of multi-site trials, are often cited as imposing conflicting requirements.

  • Timing of IRB review of new grant proposals – Under the current regulations (45 CFR 46.103(f)), when an investigator is submitting a research grant proposal to one of the 17 Federal agencies from an institution that has an approved assurance, the institution must certify at the time of submission of the application or a later date as prescribed by the department or agency, that the IRB has reviewed and approved the grant proposal with respect to human subjects protections. OPRR documents state the policy that certification for DHHS-supported projects in conjunction with an application is required of institutions only when the applicant possess a Multiple Project Assurance (MPA). When required, it is preferable that the certification be submitted with the application but in no event should it be received more than 60 days after the submission or less than three weeks before the scheduled scientific review. The net effect of this policy is that the IRB must undertake its review of the proposal before the funding agency makes a decision on funding. Since fewer than 1/3 of the grant applications submitted to NIH are actually funded by NIH, the members noted that a significant portion of the time spent by the IRB in reviewing new grant proposals is wasted and could be spent more productively.
  • Continuing Review of Protocols - Issues surfaced both with regard to the timing of the review and the type of review that is necessary.
    • Members thought the regulations governing the timing of continuing review to be too rigid. At the present time, the regulations require that the IRB review the project at intervals commensurate with the level of risk facing the research subject, but not less than once per year. OPRR policy has interpreted this to mean that the review must occur on or before the one-year anniversary date of the previous IRB review. Individual members observed that the rigid one-year requirement, particularly for the first continuing review, does not acknowledge the lag time that occurs in the initial subject accrual into protocols, requires review on a one-year anniversary date that may not be necessary based on the level of risk, and does not provide flexibility to accommodate unforeseen scheduling difficulties. While supporting the need for thorough continuing review, this rigidity, given the various complexities that exist and the workload faced by the IRBs, is considered to be unnecessarily burdensome by members. Increased flexibility has the potential to increase efficiency without compromising protections.
    • Under regulations current at the time of the workgroup meeting, continuing review normally requires the same level of IRB review that existed at the time of the initial review. OPRR's Dear Colleague letter of January 10, 1995, states that if a project did not qualify for expedited review for the initial review, it ordinarily would not qualify for expedited review for the continuing review. Members think this to be burdensome in situations where, for example, there is no change to the protocol, or there are no research subjects enrolled in the protocol, or there are no unanticipated adverse events. Expedited review could offer sufficient protections under such circumstances. Policy changes subsequently published in the Federal Register increase flexibility in this regard, however.

  • Assurance Process – The assurance document, which must be approved by OPRR, assures that an institution will comply with and implement the regulations designed to protect human subjects. Several issues emerged regarding the assurance documents and the approval process.
    • At the present time, the assurance process is exceedingly and needlessly legalistic and complex and includes unnecessary reporting requirements. There are a variety of specialized agreement documents, and the negotiation process often can be lengthy. Members particularly highlighted the MPA that is initially approved for three years and is then renegotiated every five years. Members believe that, while this process may have served an educational purpose at one time, it no longer accomplishes that objective, particularly as it is often written more as a legal document than as a tool for the scientific or administrative staff. OPRR leadership indicated substantial agreement with this position during the meetings.
    • The requirement that OPRR approve a variety of collaborative multi-institutional assurance documents significantly lengthens the time required to enter into these arrangements. Specifically identified by members were Cooperative Amendments (CA) between MPA institutions where one institution agrees to rely on the IRB's decisions of the other institution, and InterInstitutional Amendments (IIA) where members of MPA institutions routinely conduct DHHS research at another institution that does not have an IRB. Also of note is the potential to streamline the issuing of a Single Project Assurance (SPA) when its issuance is necessary for participation in multi-site research projects. An SPA is an institutional document submitted to OPRR to assure compliance that is limited in use and duration to an individual research activity. Members observed that opportunities exist to streamline the issuance of these documents and to facilitate institutional collaboration at the same time.
    • Other issues specific to the Single Project Assurance were also identified by members of institutions that perform a relatively lower volume of human subjects research. One issue is the lack of an assurance document for those institutions who undertake more than a single project, but less than the 8-10 DHHS-funded projects per year that are required by OPRR to be issued an MPA. It was also noted that the negotiation process for an SPA is complex and that it is difficult for those relatively inexperienced in the process.

  • Education programs are undervalued and underfunded – There was a general recognition by members for the need to improve education programs for all participating in the human subjects protection program. This includes IRB chairs, members, administrators, investigators and research staff, institutional officials, students and the community of research subjects. Besides inadequate funding for educational programs at both the national and institutional levels, a related issue noted by members is that minimum training needs, for each of the participants noted, have not been developed.
  • Ensuring adequate resources for IRBs – Members expressed strong concern that resources to support the IRBs are not growing at the same rate as workload. The fact that many IRBs are facing a significant workload has been well documented by the Report of the Office of the Inspector General. Members noted that a provision in the Common Rule (45 CFR 46.103(b)(2)), though vague, at least requires that adequate staff and meeting room resources be made available to support the IRB's review and record keeping duties; FDA, however, has no such provision. Members observed that workload is increasing not only because of increased numbers of protocols (and adverse event reports) but because the Federal government is increasing its responsibilities such as requiring the review of protocols for the inclusion of women, children, and minorities as subjects in clinical research. Members also expressed the concern that institutions may sometimes assign additional duties to IRBs without additional resources. While supportive of the policies themselves, the members were concerned that these new requirements are being imposed, without resources (i.e., unfunded mandates), on top of a system that is already overburdened. The resource issue is exacerbated by caps on the administrative portion of indirect cost reimbursement.
  • The resource issue, and a larger issue of establishing institutional credibility, legitimacy and importance, was a particular issue noted by the members from institutions performing a relatively lower volume of human subjects research. This manifests itself in the difficulty they experience in gaining institutional support for appropriate resource levels.

Proposed Solutions to Reduce Regulatory Burden

As noted above, in developing solutions, the workgroup emphasized the need to assure, at the outset, that these solutions must not compromise the objectives identified earlier as the intended levels human subjects protection. Many of these solutions are not new and have been recommended by others in various reviews. Recommendations from the members are as follows:

  1. Take actions to assure that IRBs receive useful off-site adverse event data. Several recommendations were offered by members to assure that IRBs receive useful data on off-site adverse events, upon which an informed judgment and reasoned action can be taken. Members noted that the recommendations proposed below will require coordinated action among institutions and their IRBs, FDA, NIH, the NIH-supported cancer and AIDS cooperative groups, and the DSMBs.
    1. Clarify the criteria for off-site reporting of adverse events. Members suggested that the definition be events that are "both serious and unexpected" and related to the research, the definition provided by the FDA in 21 CFR 312.32(c)(1)(i). As noted above, the reporting criteria may be clouded by the different definitions for reporting events to IRBs that are contained in 45 CFR 46.103(b)(5)(i) and 21 CFR 56.108(b), and in the NIH cooperative group policies, so that consistent, explicit clarification is needed.
    2. FDA should require the establishment of DSMBs and NIH should ensure adherence to its policy. NIH should ensure adherence to its June 10, 1998 policy requiring the establishment of a DSMB for multi-site clinical trials that entail a potential risk to participants. In addition, members recommend that FDA provide guidance to require sponsors to establish a DSMB for each IND application and IDE and develop methods to communicate the DSMB's deliberations to the IRBs.
    3. The DSMBs should provide aggregated and interpreted data to the IRBs at regular and defined times. Individual off-site adverse event reports should not be provided to IRBs. Instead, data from the off-site adverse events should be aggregated and interpreted by the DSMB or the FDA and provided to the IRB. These reports should be provided at regular and defined times. On-site reporting of adverse events should continue to be provided to the local IRB but be presented in a format that allows the individual report to be considered in the context of other previously reported events.
    4. Should the policy continue to be the submission of individual off-site reports, expedited review procedures or staff review should be permitted.

  2. NIH and FDA should both reconcile conflicting regulations and policies and better coordinate their programs for human subjects protections. As noted above, while FDA and NIH have achieved significant commonality in their regulations and policies, differences do exist in several areas beyond those resulting from their different missions. Both agencies should commit to a process to reconcile these differences.
  3. In addition, members recommend that each agency develop a mechanism to better coordinate and internally manage the various components of these complex programs within their own agency. During the workgroup meetings, NIH cooperative groups, Contract Research Organizations, and agency staff were cited as providing conflicting interpretations of regulations. Additional training by NIH and FDA was suggested as an approach although it would appear that more proactive management and coordination is also necessary to avoid the inefficiencies that result from reported disconnects. In addition, an external advisory board might be useful in this regard, and it could be useful also as a source of advice and counsel on a broader set of policy issues.

  4. Change regulations and/or policies on Continuing Review to provide flexibility to IRBs. The members made various proposals to allow the IRB more flexibility to set the timing and the method of continuing review of active projects. In suggesting this flexibility, the members contend that the IRBs will be better able to accommodate to local and unique situations, better able to respond to the level of risk of the research protocol, and better able to allocate scarce resources. The intent is to increase the effectiveness of this key component of the IRB function.
    1. Timing of review. The various suggestions made by members provide a menu of possibilities for providing this additional flexibility and are listed below in the descending order of the degree to which they would provide additional flexibility to the IRBs. They would, however, require changes to existing regulations and policies.
      1. Allow the IRBs the authority to set the period of approval (e.g., based on initial IRB review, the grant award date, the date at which research subjects begin being entered into the protocol, etc.) as well as the review date. This would allow the IRB the maximum flexibility to assign the start date and to determine when to conduct the continuing review. It would provide maximum flexibility to the IRB to use its judgment depending on individual circumstances and the level of associated risk.
      2. Eliminate mandatory annual review and allow the IRB to determine the appropriate time to undertake review based on the degree of risk that the study protocol presents to the research participants. This would allow the IRB the discretion to set the review date, allowing it to match the review date with its assessment of the level of risk.
      3. Allow a 30-day grace period beyond the anniversary date for the conduct of the review. This would retain the start date and anniversary date requirements currently in effect, but would recognize scheduling or other unanticipated difficulties that may preclude a review on or before the anniversary date, and would avoid the risk of an interruption to the protocol.

    2. Method of review. Members made various suggestions to increase the IRB's flexibility to determine the method of continuing review. These proposals require a change in regulation or policy. Again, as is the case with suggestions on timing, these are intended to assure satisfactory review while allowing a more efficient allocation of IRB resources.
      1. Use expedited review for studies where there have been no changes to the protocol and no additional risks have been identified, or a study in which no patients have been enrolled. This recommendation is partially accommodated by the subsequent publication of new guidelines on expedited review that occurred after the workgroup's meeting date. This new listing allows expedited review of research where no subjects have been enrolled and no additional risks were identified. The members acknowledged the considerable assistance to IRBs that this expanded set of expedited review categories will provide.
      2. Have the IRB determine the method of continuing review (full board or expedited review) at the time of initial review. This recommendation would be followed as long as no additional risks are identified and there are no significant changes to the protocol. Under the new expedited review policies cited above, expedited procedures may be used for continuing review when the research involves no greater than minimal risk and no additional risks have been identified.
      3. Eliminate the requirement for annual review and replace it with a system of random audits. While this would result in fewer reviews, it could allow more intensive reviews and would detect problematic issues that may be systemic.

  5. Change other policies to provide flexibility to IRBs. Members specifically cited changes to two other policies to provide additional flexibility to the IRBs, so as to allocate resources better and to respond to unique situations.
    1. Allow IRBs to determine the timing of initial review. As discussed above, initial review by the IRB must occur before scientific review and, therefore, before funding decisions are made by NIH. Members contend that the workload demands are such that the IRB's time not be wasted reviewing applications that ultimately will not be funded. Estimates vary on the workload that would be saved since some grant applications, if not funded by NIH, will be funded by other sources. The evaluation of IRBs by James Bell Associates reported that 85% of grants submitted to NIH are eventually funded by some source. However, while there was some skepticism expressed by members about the 85% figure, a savings of 15% on initial review for an overworked IRB is still substantial. Furthermore, it should be noted that grant applications initially rejected by NIH for funding may be re-written and eventually funded but this will entail still another IRB review. This proposal would give IRBs the option to conduct the review when they thought best – either at the time of submission or any time thereafter, but before the grant is awarded. This, however, will require that NIH notify the institution if a proposal has received a favorable review so that it can plan an IRB review.
    2. Members acknowledged the argument that IRBs that choose to perform initial review of the adequacy of human subjects protections after scientific review, potentially face increased pressure since the applications have already been approved based on scientific merit and IRB approval is the last remaining step prior to receipt of funding. However, members were confident in the IRB's ability to give first priority to the protection of human subjects, and that IRBs will only choose this option if they conclude that this more efficient process would ultimately result in better review. They also point out that non-NIH funded grants receive IRB approval after funding decisions are made with no apparent compromise to the human subjects protection program.

    3. Allow IRBs to utilize audio conference calls for full board reviews. Members suggested that OPRR change its policy to be consistent with FDA, and allow IRBs the option to utilize audio teleconferencing in the conduct of full board reviews. The intent is that it be an option available in limited circumstances.

  6. Reengineer the assurance process. The members concluded that substantial rethinking of the purpose of the assurance process and complete redesign was in order. While it may have served an educational purpose in earlier days, it is not serving that purpose now and there is little "value added" by the size and content of the document and the length of the negotiations.
    1. Simplify the document. Members generally favored a vastly simplified document, possibly one or two pages, which provides the basic information required by OPRR and which would be revised only as necessary. This new document would be the same regardless of the number of protocols performed by the institution.
    2. Eliminate multiple documents. Members would eliminate the various separate inter-institutional agreements that currently require OPRR approval. Members observed that these various agreements and the inherent time lags because of the need to secure OPRR approval slow, rather than facilitate, inter-institutional alliances. Therefore, members proposed that such alliances be administered at the institutional level; if OPRR has a need to be informed of such arrangements, an informational report could be provided.

    On a number of occasions, and at the meetings of these workgroups, OPRR has expressed its intent to streamline the assurance process but couple it with an enhanced education program. The members generally were very supportive of this approach.

  7. Develop an expanded and comprehensive training program. Members concurred with the proposal by OPRR that there needs to be an expanded program of education.
    1. Education program. Members saw the scope of this training program to be very broad. It should address the needs of all participants including IRB chairs, members, administrators, investigators and research staff, students, institutional officials and the community of research subjects. Specific suggestions were for NIH/FDA to sponsor educational conferences, to expand the current NIH-funded ethics training initiative into a broader program, to develop and implement educational strategies in association with professional organizations such as thePublic Responsibility in Medicine and Research (PRIM&R) Link to Non-U.S. Government Site - Click for Disclaimer , and for NIH/FDA to centrally design educational materials and utilize technologies to make these materials available to those at the local level, including research subjects.
    2. Technical assistance program. Closely related to this educational focus was the suggestion by members for OPRR to expand its technical assistance efforts to institutions. Of particular interest to the members is a significant role in identifying and disseminating "best practices" so that IRBs may draw on the successful experiences of others. This would also include technical assistance on interpretations or applications of the regulations that facilitate new approaches to achieving regulatory compliance by removing overly restrictive and/or unnecessarily complex procedures. Additional suggestions included its becoming a central data source for national data relevant to IRBs, and sponsoring regional workshops around specific issues.

    The net effect of the proposals recommended by members would significantly shift the focus and role of OPRR. Its role as a national focal point for leadership in education and technical assistance would be significantly expanded.

  8. Encourage additional resources for the IRBs. As noted above, members generally observed that resources available to the IRB are not expanding relative to the increased workload. Suggestions made by the members were:
    1. Provide additional Federal resources if mandating additional duties. While the mechanism for providing these resources was not defined, members observed that the Federal government should bear in mind that the role of the IRB is to ensure adequate protection of the rights and welfare of research subjects through the review of research protocols, assessment of informed consent, ongoing review and other activities. Assuming that any new requirement falls within this charter, additional resources should be provided, e.g., assuring the inclusion of women and minorities and the inclusion of children in research.
    2. Amend FDA regulations to include a provision similar to the requirement in the DHHS regulations for adequate staffing and space resources. 45 CFR 46.103(b)(2) recognizes the need for sufficient staff and space to carry out IRB functions; FDA regulations carry no such requirement. Congruence between the two agencies on this issue, at a minimum, would serve to highlight its importance and necessity.

  9. Pursue the development of longer-term paradigm shifts if they have the potential to reduce regulatory burden. The current assurance-based system is considered sufficiently onerous by some members that alternatives to the existing paradigm such as third-party accreditation of IRBs might be explored. While it merits long-term exploration, with a thorough evaluation of the pros and cons, it is considered a viable alternative only if it results in a net reduction in burden. Members see little advantage if it becomes an additional regulatory tool without a commensurate reduction in the current oversight activities. Some members observed that they would not proceed if the end result is similar to the outcome experienced by the Animal Care and Use community. The OPRR and the Department of Agriculture have not lessened their oversight of organizations that are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). Obviously, the other requirement is that such a system must provide at least an equal or better program of protections and should not be implemented unless this is assured.
  10. Similarly other results-based techniques such as performance measures were discussed as possible alternatives. Again, it was stressed that while there is merit in pursuing alternatives to the current process-based program, their development would require a considerable long-term effort and should only be considered if it will result in a net reduction in regulatory burden.

In conclusion, workgroup members are confident that with these changes, the objective of the NIH initiative would be achieved with respect to the regulations governing human subjects protections – the existing regulatory procedures would streamlined, i.e., made more efficient without reducing the intended levels of protections.


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