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Secretary’s Advisory Committee on Human Research Protections March 13 and 14, 2006 Alexandria, VA Minutes MONDAY, MARCH 13 Welcome and Opening Remarks Ernest Prentice, Ph.D. The Chairman welcomed everyone to the meeting and introduced a new member of the Secretary's Advisory Committee on Human Research Protections (SACHRP), Dr. Neil Powe. He reminded attendees of SACHRP's Charter, issued on September 8 of 2004, which comprises protection of human research populations, especially vulnerable populations such as children and prisoners. SACHRP works closely with staff members of the Office of Human Resource Protections (OHRP), who act as liaisons on SACHRP subcommittees. Dr. Prentice thanked ex-officio members of SACHRP. He also expressed appreciation to all OHRP staff who work in partnership with SACHRP. The Chairman provided an overview of charges to existing SACHRP committees. He noted that the subcommittee on Subpart D has been very active and observed that the new subcommittee on Subpart A is likely to have a long tenure. Minutes for the previous meeting (November 1-2, 2005) were approved unanimously. Dr. Prentice then reviewed the agenda for the day. Report on Issues Bernard Schwetz, D.V.M., Ph.D., Director, Office of Human Resource Protections (OHRP) Status of SACHRP Recommendations. Dr. Schwetz summarized the status of SACHRP's recommendations to the Secretary of the Department of Health and Human Services (HHS) as well as the status of activities of concern to SACHRP. He reminded SACHRP that three sets of recommendations have gone to the Secretary (Secretary Thompson, then Secretary Levitt). The first set of recommendations went to Secretary Thompson in July of 2004. These related to research involving children, the §407 process, accreditation, and the recommendation for an Institute of Medicine (IOM) panel in regard to Subpart C. Dr. Schwetz reported that a new §407 process is in place, with new guidelines. There is a good working relationship between OHRP and FDA when a joint process is required. In regard to accreditation, SACHRP suggested a conference to address key issues such as self-regulation. Dr. Schwetz noted that accreditation has been a dynamic and rapidly evolving process, and it did not seem to be the right time for a conference; the idea is therefore on hold. The Subpart C committee reported that Subpart C might be “broken” and in need of major changes that could not be accomplished through guidance alone. OHRP is therefore funding a committee through the Institute of Medicine to review the ethics of conducting research in prisoners. A report is expected later this year. The second set of SACHRP recommendations related to the need to harmonize the Common Rule with the Health Insurance Portability and Accountability Act (HIPAA) in regard to research. This recommendation has been sent to the Office of Civil Rights, which is still working on the issue. The third set of recommendations, which originated in July of 2005, has just been returned to OHRP for action by the Office of the Secretary. A number of issues were to be addressed, including the wider range of jurisdiction within Subpart C and the consideration of the standard of care for protocols involving prisoners. The recommendations also included a number of recommendations related to research involving children and the recommendation to form a Subpart A Subcommittee (now at work.). OHRP has also acted on SACHRP's recommendation that a workshop be held on IRB review strategies. Also, the FDA has been working on draft guidance relative to central IRBs and on the use of central IRBs relative to FDA regulator products. FDA has finalized the document and it will soon be printed in the Federal Register. On international issues, OHRP has arranged two sessions for SACHRP to air and explore related issues. OHRP has also followed through on SACHRP's recommendation to issue guidance on adverse events. Draft guidance was issued, and the agency is currently assessing the comments received. FDA is at work on its guidance on the same subject and has held a Part 15 hearing to get advice from the community on this key topic. In addition, Amy Patterson of the National Institute of Health (NIH) and others have formed a Federal Adverse Events Task Force to try to coordinate the handling of adverse event reports and related activities among agencies. The group is finalizing a document for discussion and the activity continues to move forward. OHRP also coordinated presentations for SACHRP on patient advocacy and litigation, which were informative but did not result in any specific, defined action. Status of SACHRP Nominees. Five new members will be invited to replace SACHRP members who are now leaving. OHRP expects these members to be confirmed by the mid-year meeting of SACHRP in August. Four additional new members will be needed in 2007, which means that there will be considerable turnover on a committee that has been working well. A Federal Register notice will be issued this month inviting either self-nominations or nominations of others. Recommendations from SACHRP and audience members are welcome and can be accepted either through or independent of the Federal Register process. Status of the SACHRP Charter. The charter for SACHRP is set to expire on October 2nd of this coming fall. OHRP is awaiting action by the Department on its recommendations for revisions to the charter. Dr. Schwetz has heard nothing to indicate that SACHRP would not be reauthorized. Subpart A Subcommittee Report Felix Gyi, Pharm.D., M.B.A., CIP, Co-Chair; Gary Chadwick Pharm.D., M.P.H., CIP; Daniel Nelson, M.S., CIP, Co-Chair Mr. Nelson reviewed the charges of the subcommittee, which included to review and assess all provisions of Subpart A of 45 CFR 46 and relevant OHRP guidance documents, then, based on this review and assessment, to develop recommendations for consideration by SACHRP. Specific goals of the subcommittee are to
Subcommittee meetings to date have included a January 18, 2005 teleconference; a meeting February 14, 2005 in Alexandria, VA; a May 20, 2005 teleconference; a meeting July 20-21 in Alexandria, VA; and a teleconference on October 4, 2005. Working groups have been established for continuing review and for expedited review. At its second on-site meeting, the subcommittee reviewed draft reports from each subcommittee, considered issues related to minimal risk, and heard input from Federal agency representatives. Showing a picture of an angel crouched uneasily on a bowling pin, Ms. Nelson observed that IRBs are spending less time protecting human subjects and more time trying, in effect, to balance on the head of a pin. He also commented that while IRB audiences generally appreciate SACHRP's work, he finds glazed eyes among investigators and academicians when he addresses the same subjects. He stressed the importance of keeping the “big picture” in focus as SACHRP proceeds with its deliberations. Continuing Review (CR) Mr. Nelson reminded SACHRP that of the 16 recommendations brought forward by the subcommittee at the meeting in November of 2005, 9 have been approved and 7 tabled. Only items that have not been approved were presented for further consideration in this presentation. He also reminded SACHRP that the requirement for CR is a legacy of the infamous Syphilis Study; lack of CR allowed it to go on for decades, long after effective treatment for the disease was available. The provision for CR was intended to prevent research continuing in the face of unacceptable harm, futility, or scientific or ethical obsolescence. The Co-Chair observed that CR plays a central but often undervalued role in the IRB process. Regulations related to how CR should be conducted are “rather sparse,” and there is considerable uncertainty and variability in how IRBs should interpret and apply them. The only section of the Common Rule that addresses the continuing review process with any detail says in its entirety: “An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research” (§46.109[e]). The most recent guidance on CR from HHS was issued in July 11, 2002 and includes no specific instructions to IRBs on how to establish rules and policies to address the CR requirement. In comparison to HHS guidance, FDA guidance is relatively permissive. Mr. Nelson found considerable uncertainty and variability in how IRBs interpret and apply the “rather sparse” regulations pertaining to CR. When can Continuing Review Stop? The Co-Chair posed the question of whether CR must continue as long as identifying data exist or whether there is a prior point at which the IRB and investigator can close the study file. He observed that HHS regulations do not address this issue and that HHS and FDA have different operational definitions for what constitutes human subjects research – a difference that complicates not only CR, but the oversight of research in general. Several examples of instances in which “interminable” CR is not valuable include minimal risk social science surveys; individual sites in multicenter trials after activity ceases at the site, though it continues elsewhere; and cooperative group studies that remain open solely to collect survival data. In fact, he held that every study reaches a point at which CR ceases to add value and contribute to the protection of human subjects. Mr. Nelson observed that many investigators remain in possession of identifiable data long after the study is closed. IRBs currently follow different practices on when to declare a study complete. The subcommittee brought forward the following recommendation:
DISCUSSION SACHRP members discussed the recommendation and raised the following questions. The Chairman asked why the IRB should continue to be in the loop when a study has been closed for a decade, given that the IRB may in fact have destroyed relevant records. Dr. Gyi responded that the subcommittee did not consider logistics, but asserted that it would still be incumbent on the IRB to determine how an issue that arises after records have been destroyed should be addressed. Dr. Fisher understood that as long as the researcher has the records of individuals' identities, the research would remain under the IRB's review. She asked for clarification of what is actually required and to what extent the regulations create an obstacle to stopping CR. Mr. Nelson explained that a person becomes a human subject whenever data is collected, regardless of whether the individual knows that data are being collected. This triggers the need for protection. At some point, however, he suggested that active oversight ceases to add value. Dr. Prentice further explained that even though data may be retained, when analysis described in the protocol stops, research may also be considered to have stopped. Dr. Fisher agreed but asked whether the recommendation is really different from existing guidance. Dr. Carome affirmed that the guidance would be a new direction, since OHRP has long stated that the use and analysis of identifiable private information from living subjects constitutes research. Mr. Nelson clarified that the intent of the recommendation is that data analysis might in fact continue for years, and CR would not be triggered unless subjects are re-engaged in the process. Balancing the concern about protection of human subjects when identifiable information is used and the desire to reduce the administrative burden, Dr. Fisher asked whether there might be a way to streamline CR. Ms. Selwitz said that in fact IRBs do expedite review under such circumstances, but a substantive review is still required, albeit by fewer people. She also pointed out that most IRBs have an electronic record that is maintained for a long time; therefore, it would be possible to manage issues that arise after CR has ceased. Dr. Fisher expressed concern that the recommendation does not allow for oversight of a sloppy investigator who may fail to report an emerging problem. Dr. Gyi observed that oversight of an investigator-initiated study might be different than oversight of a multi-center study in which the investigator holds data, but may not play a part in data analysis. Mr. Nelson added that the qualitative assessment that an ethnographer performs might also go on for years. Dr. Powe asked what would happen if a colleague wishes to use identifiable data that have already been collected. Dr. Prentice responded that such use would require a new proposal that would have to be reviewed by the IRB. Dr. Powe wondered whether the recommendation might have the unintended consequence of increasing burden on IRBs if there were new investigators. Ms. Kornestsky said she felt comfortable with the recommendation, since identifiers would typically be removed from the primary data. However, if the investigator forgot a data point, the IRB would need to become involved. Dr. Fisher agreed with Ms. Kornetsky and wanted to see more explicit language specifying this assumption. She said it was important that the situation covered be one in which, while the link might exist between the data being used and a code book, the current researcher does not use that link. Dr. Prentice suggested amending the recommendation to encompass situations when “data collection and analysis for research purposes are complete as described in the approved protocol.” Dr. Gyi said such an amendment would mean that IRBs overseeing FDA-regulated products would have to continue to provide oversight until the sponsors have completed that analysis. Dr. Prentice held that such analysis would not be described in the protocol since the site investigator is not doing it, but Dr. Gyi said data analysis in commercially sponsored protocols often would be described in the protocol and might take years to accomplish. Dr. Prentice asked how OHRP guidance justified the apparent inconsistency of saying that research is continuing when the IRB is out of the loop but that it is not continuing when “because of a technicality” the investigator does not have the data for analysis. Dr. Carome said he saw no inconsistency; sites that are not engaged in analysis of identifiable information would not be considered to be engaged in research. However, he said OHRP was not a priori rejecting the recommendation. Dr. Powell asked how the recommendation would apply to an industry trial in which samples are being collected periodically for biomarker analysis. Dr. Prentice said this would constitute further collection of research data, so the recommendation would not apply. However, routine follow-up with patients that does not involve the collection of data for research purposes could continue. Dr. Fisher suggested adding a provision that analyses for research purposes must also be complete. Ms. Selwitz said that would mean that the status quo would continue and the recommendation would be unnecessary. ACTION Recommendation 1.1 was approved without changes. Circumstances when CR can be Conducted less often than Once per Year. Mr. Nelson raised the question of whether circumstances exist under which continuing review could appropriately be conducted less often than once per year. He commented that the preamble to the original regulations stated that “the precise procedure adopted by the IRB for continuing review without unnecessarily hindering research should be left to the discretion of the IRB.” The preamble also stated that appropriate reporting would vary depending on risk from a “simple annual notification” to “more frequent reporting” or, for clinical trials, a “special mechanism to carry out data and safety monitoring functions.” Regulations require that continuing review should occur “not less than once per year,” but the content of the process is not specified. The subcommittee felt that the requirement for an annual review limits IRB flexibility to employ appropriate procedures and criteria. It therefore proposed the following recommendation:
Mr. Nelson explained that this recommendation is the only one that would require a regulatory change. He suggested that OHRP issue an advanced notice of proposed rule making to seek comments on the issue. The same notice would also seek comments on the following:
DISCUSSION Dr. Prentice pointed to an apparent contradiction between the subcommittee's recommendation that OHRP seek comments on the issue and the recommendation that, in the interim, IRBs be permitted to develop their own procedures. Mr. Nelson and Dr. Gyi explained that it was the committee's wish to do something in the interim to provide flexibility. Dr. Prentice questioned the need for OHRP to go through the advanced notice of proposed rule in regard to Recommendations 2.2 and 2.3; instead, he suggested, the recommendations could focus exclusively on the need for guidance that is relevant to the nature and risk level of the project. Ms. Kornetsy agreed with the Chairman's suggestion. However, she was concerned that if IRBs were given the latitude to begin developing their own procedures and then comments result in tightening, it would appear that OHRP is being restrictive and over-regulating. She felt that OHRP probably has the authority to issue guidance about what elements should be applied. Ms. Selwitz agreed. ACTION SACHRP approved Recommendation 2.1 without changes. Recommendation 2.2 and 2.3 were approved, with the understanding that they would be rewritten to eliminate the need for an advanced notice of rulemaking and proceed directly to the development of recommended guidance based on the nature of the research, risk level, and other considerations. An approximate rewording follows:
Can Existing Guidance be Consolidated? The subcommittee addressed the question, “can existing guidance on continuing review be consolidated and integrated?” While OHRP has come a long way in this regard, the subcommittee feels that the absence of consolidated guidance makes regulatory compliance more difficult than necessary, sometimes requiring IRBs to explore extensive case law. When the recommendation was previously presented to SACHRP, the subcommittee was asked to consider removing any reference to common practice or best practice. This has been done, yielding the following recommendation:
Mr. Nelson stressed the need for “simplified, unified, and practical guidance for CR.” DISCUSSION Dr. Prentice clarified that the recommendation means that current OHRP guidance should incorporate guidance that has been issued in the form of OHRP determination letters. He asked the Co-Chair to clarify whether Recommendation 2.2 and 6.1 are viewed as distinct or as two related points that should be integrated. Mr. Nelson saw the two as separate; Dr. Gyi indicated that the two could be blended, but felt there was merit in separating them. Dr. Prentice also asked for the subcommittee's perception of the difficulty of accomplishing this goal. The Chairman observed that he did not know the status of the revisions to FDA's information sheets. Mr. Nelson replied that the recommendation as it stands is focused only on OHRP guidance. Dr. Fisher understood the advantage of consolidating available guidance but was not sure whether the distinction between “case law” and actual guidance could be made. Mr. Nelson stressed that the elevation of single cases to “de facto guidance” is a difficulty; what was intended as example sometimes becomes a requirement, whether or not this was intended. Ms. Kornetsky suggested that this concern would seem to apply to all guidance rather than the specific issue of continuing review. Dr. Prentice concurred and saw this as a potential problem. Ms. Selwitz also saw this as a universally applicable concern. Dr. Gyi and Mr. Nelson conferred and removed the recommendation from consideration. Flexibility in the Timing of CR. Mr. Nelson addressed two questions:
Under guidance issued in 2002, "OHRP recognizes the logistical advantages of keeping the IRB approval period constant from year to year throughout the life of each project when continual review occurs annually and the IRB performs continual review. Within 30 days before the IRB approval period expires, the IRB may retain the anniversary date as the date by which the continuing review must occur.” In practice, he argued, the so-called “30-day rule” has proved logistically problematic. A substantive and meaningful review requires time for the IRB to ask questions, for investigators to respond, and for the IRB to seek further clarification if need be. The 30-day window may result in lapsed approval. Also, many IRBs send reminder notices before approval period expires; if an investigator responds promptly, information may become stale. The subcommittee felt that a 60-day rule would be more likely to avoid automatic lapses and enable IRBs to be more responsive to prompt submissions by investigators. Accordingly, the following recommendation was brought forward:
DISCUSSION Dr. Prentice observed that the 30-day rule appears inconsistent with the regulatory language; if the period is extended to 60 days, then the next year might conceivably have a 14-month approval period. The Chair asked OHRP to clarify how the 30-day rule fits in with regulatory requirements in scenarios in which an investigator submits early in one year but not the next. Dr. Carome responded that the 30-day rule goes back at least 10 years. OHRP staff felt that over the life of a multi-year project, on average the protocol would be reviewed at least annually. Dr. Carome believed the same rationale would likely apply for a 60-day period. The Chairman also questioned how many IRBs actually use the 30-day rule; his, he said, does not. Ms. Selwitz believed that most high-volume IRBs do not use the rule, and even moderate-volume IRBs may not do so. It is an important rule for low-volume IRBs that are not likely to meet every month. Ms. Kornetsky added that when a substantial review is done and concerns are raised, 30 days is not a long period of time to address issues that may arise thoughtfully. It takes time to generate letters and assess the response. She felt the 60-day period would be more reasonable. Dr. Gyi commented that larger-volume IRBs that get information ahead of time simply recalibrate the approval date to the date of the meeting. He added that although research must be suspended when time frames are violated, guidance does not require a report to OHRP; the matter is handled locally. The Chair suggested that when a CR process is already in place and the application for CR is under review, requests for clarifications or modifications should not result in a suspension. He said it should not be necessary to suspend a project simply because it is “two days out of sync.” Mr. Nelson responded that Recommendation 10.3, which stated that automatic study suspension was not required when the process was underway, had been withdrawn by the committee as “effectively obsolete” in view of other recommendations; however, it could be reintroduced if it appeared necessary. While the subcommittee felt the 60-day period would supply the leeway necessary to avoid lapses, the Chair felt that the withdrawn recommendation was important for the institutions that do not follow the 30-day rule at present. Recommendation 10.3 was therefore reintroduced. ACTION Recommendation 10.2 was approved.
DISCUSSION Dr. Prentice placed on the table an additional concept called the “post-30 day rule” which would allow an extension of IRB approval before mandatory expiration, providing that the IRB is already engaged in a substantive process of continuing review. This would apply if the application is legitimate but there are a few questions or issues to address. Mr. Kornetsky was in favor of the concept, but felt the meaning of continuing review being “underway” should be pinned down. Does it mean, for example, that the investigator got the documents to the office but too late for the next agenda? Dr. Prentice said he believed the review process should have begun so the application is actually under review, whether by the full committee or select reviewers for expedited review. Dr. Fisher stressed the importance of articulating the reason for the recommendation, particularly in regard to the potential benefits to human subjects. She would be concerned to see the recommendation used to benefit an investigator who simply did not respond on time, but she saw the benefit of avoiding a study suspension that might harm participants. Dr. Prentice responded that whenever the IRB reviews an application and finds significant problems, it is obligated to suspend approval until problems are corrected. He added that the current position of OHRP is that all activities must cease when IRB approval expires. However, the IRB can approve the continuing participation of human subjects if it is in their best interest. The Chair felt the leeway offered by a 30-day extension might especially be helpful for behavioral science studies where it is not possible to prove that participation is clinically in the subjects' best interest, but the risk-benefit ratio would be affected negatively. Ms. Selwitz observed, however, that even low-risk research may still have potential benefits. Sometimes delays occur because of very minor changes, and the leeway would help. It would still be up to the IRB to act in the best interest of the subjects. Dr. Jones added the subcommittee believed a benefit of the recommendation would be that it would allow time for “substantive reflection” when needed. Dr. Fisher agreed that the recommendation might improve human subject protections by allowing time for a more informed dialogue between the investigator and the IRB. However, she wanted to be sure that investigators who simply get their material in too late are not rewarded, and she felt existing language was too open-ended. Members felt the recommendation was not ready for a vote and should be reconsidered by the subcommittee. It was therefore tabled. If need be, previously approved recommendations might be reconsidered. Expedited Review Mr. Nelson reminded members that HHS and FDA regulations provide for an expedited review procedure under which the IRB Chairperson (or one or more experienced IRB members designated by the Chairperson) may approve research in categories appearing on a list published in the Federal Register and found by the reviewer to involve no more than minimal risk. The same process may be used for minor changes in previously approved research that arise during the period for which approval is authorized (one year or less). Expedited review should be as rigorous as full review, but with fewer reviewers; it is not “review lite.” Reviewers may exercise all the authorities of the IRB except disapproval, which requires action by the full IRB. All of the applicable requirements for approval must still be met. The subcommittee felt that expedited review is a valuable mechanism; using this process for minimal risk research frees the time and resources of IRBs and allows them to be concentrated on protecting subjects facing the greatest levels of risk. However, sometimes changes are received that are purely administrative, such as correction of typographical errors or updated contact information for investigators. Currently, low-impact changes in previously approved research must be handled by expedited review or full convened review, which does not contribute meaningfully to the protection of human subjects and may actually reduce such protections by diverting IRB time and effort from more substantive considerations. Accordingly, the following recommendations were presented.
DISCUSSION: Both recommendations were readily approved with the following “friendly amendment”: Recommendation 2 will be reworded to state that “IRBs may give…” rather than “should be encouraged to give…”. Dr. Fisher felt that IRBs should be able to make a decision about whether or not they want their own members to carry out such functions. New Term for Expedited Review. The subcommittee explored the question of whether the term “Expedited Review” should be revised to better reflect intent and process. The term “expedited review” is widely misunderstood to imply increased speed and decreased thoroughness of review. Nevertheless, the spirit and letter of the regulations requires that expedited review be as substantive and meaningful as convened meeting review. Criteria for approval and the requirements for informed consent are identical. The only difference is that one or more experienced IRB members are delegated to perform the review on behalf of the entire membership. Analogous oversight bodies for animal research (Institutional Animal Care and Use Committees [IACUCs]) use the term “designated review” instead. Mr. Nelson argued that a term other than “expedited review” would remove misconceptions about the supposed expedience if this type of review, while emphasizing that it is based on the delegation of authority by the full IRB to the chairperson or other member.
DISCUSSION The Chair questioned whether the second recommendation's reference to “other changes” was appropriate in this context because of its broad scope. Dr. Fisher saw the recommendation to change the term as a “trivial” one that does not increase human subject protections. Dr. Prentice, however, commented that investigators often do have the misapprehension that an “expedited” review must be briefer, simpler, or less detailed. It therefore may give them the wrong impression about human subject protection and their obligations. Ms. Kornetsky pointed out, however, that numerous documents would have to be changed at considerable cost. The Chair directed, however, that SACHRP should make the recommendations it believes make sense without considering the regulatory impediments. Dr. Gyi added that this recommendation would be packaged with others; it would be up to OHRP to react to the recommendations, including deciding on the most efficient and best use of its own resources. The recommendation regarding the new term was approved with four persons in favor and three abstentions. The recommendation regarding harmonization was approved with rewording similar to the following: SACHRP encourages all agencies under the Common Rule to harmonize with the new terminology (i.e., delegated rather than expedited review). “Not Exactly” Expedited Review: The subcommittee explored the following questions:
Mr. Nelson explained that a common outcome of convened IRB review is a list of minor stipulations or contingencies that must be resolved before the IRB grants final approval. Guidance on how to handle such issues with confidence is difficult to find and appears to exist only in determination letters where it is not readily accessible. An OHRP determination letter stipulates that “only when the convened IRB stipulates specific revisions requiring simple concurrence by the investigator may the IRB chair or another IRB member designated by the chair subsequently approve the revised research protocol on behalf of the IRB under an expedited review procedure.” OHRP has also cautioned against approving research contingent upon “substantive modifications or clarifications” that are directly relevant to the determinations required by the IRB without requiring additional review by the convened IRB. It remains unclear, however, what qualifies as “simple concurrence” as opposed to a “substantive” modification or clarification. Another source of potential confusion is the use of the term “expedited review” to refer to “contingent approval.” The subcommittee concluded that current OHRP policy is overly restrictive; the IRB should have the discretion to rely on qualified staff under appropriate circumstances rather than require full board review. The subcommittee therefore recommended the following:
ACTION The motion was unanimously approved without discussion. Subcommittee Considerations on Investigator Responsibilities The Co-Chairs then turned to additional issues under concern by the Subpart A Subcommittee (SAS), the first of which is investigator responsibilities. The subcommittee endorsed the principle that investigators have the primary responsibility for protecting the rights and welfare of their subjects, but there was no consensus on a proposal that would define areas of specific responsibility and insert them in the regulations. Some members felt that while investigators are key protectors in the protection of human subjects, the regulations may send a message that primary responsibility for protecting subjects lies with institutions and IRBs. While HHS regulations implicitly refer to investigators throughout, they explicitly identify them only in the section that deals with informed consent. FDA regulations, on the other hand, include sections that address investigator conduct and responsibility. SAS considered a proposal that would insert new regulations aimed specifically at investigators into 45 CFR 46. The proposal would state that they have specific areas of responsibility, including qualifications and resources, medical care of subjects, communication with the IRB, compliance with applicable regulations, research products and procedures, assuring informed consent, and reporting. However, after considerable discussion and debate, SAS found no consensus on the need for or advisability of additional regulations. The principle that investigators do have primary responsibility for protecting the rights and welfare of their subjects was endorsed, but many subcommittee members felt that investigator training was a sufficient alternative to new regulations. Dr. Jones added that the subcommittee agreed that investigators need to be at the table and offer their viewpoint. She did not feel that training in itself was likely to have a strong impact on the culture, but she was also concerned that regulations would be seen as externally imposed. She felt the question should be recast to encompass a variety of possible ways of achieving the goal of increased social responsibility on the part of investigators. The Co-Chairs explained that it was their intent to continue to discuss the issue and to engage in conversations with investigators, as with other stakeholders, as recommendations are developed. Subcommittee Considerations on Minimal Risk Mr. Nelson reported that the subcommittee continues to address the complex topic of minimal risk. . In order to address a wide range of key concerns, the subcommittee plans to prepare a short guidance document that will set forth for SACHRP consideration the most problematic elements in the regulatory definition and the most difficult elements for IRBs and investigators to handle. This will include such issues as whose daily life is referenced as a standard in the definition, the choice of an absolute or uniform vs. relative standard for assessing risks, and the concept of risk equivalence. The document will include examples of common research scenarios. The subcommittee does not envision rewriting the current definition but does see a need to clarify how it should be applied. Expedited Review of Social and Behavioral Research Activities The subcommittee endorsed a recent report, “Expedited Review of Social and Behavioral Research Activities,” which was prepared by the Social and Behavioral Working Group of the Human Subjects Research Subcommittee and approved in November 2005. The subcommittee is impressed with the report and grateful for its contribution. Dr. Barratt and Dr. Schwetz are co-chairs of the Human Subjects Research Subcommittee. Dr. Barratt noted that the document will need a further review by the Committee on Science before it becomes a public document. The document will be made available for review by SACHRP members for the next meeting with a view to possible endorsement by the committee as a whole. Harmonization of Guidance Mr. Nelson highlighted the fact that harmonization of regulations, interpretations, and guidance across agencies is critical to the success of SACHRP efforts. He also noted that participation by agencies in addition to OHRP has been extremely helpful to subcommittee deliberations. However, members feel the subcommittee would benefit from more active participation. The subcommittee therefore brought forward this recommendation:
The Chair suggested that Dr. Schwetz encourage ex officio members to attend SAS meetings. Recognition of Departing Members/Swearing in of New Member Ernest Prentice, Ph.D.; Bernard Schwetz, D.V.M., Ph.D.; Admiral John O. Agwunobi, M.D., M.B.A, M.P.H. Dr. Schwetz introduced Admiral Agwunobi, Assistant Secretary for Health of HHS, noting that the protection of human subjects of research is a high priority for him. Dr. Prentice welcomed the Secretary and invited him to make comments. Assistant Secretary Agunobi thanked SACHRP for the invitation and briefly reviewed some of the experiences in his career that increased his awareness of the importance of human subject protection. He explained that as a pediatrician, he served in a small hospital that treated children who had special health care needs, many of whom orphan diseases or particularly complex clinical situations. Through the course of their lives, they often were exposed to the benefits of research, and he would advocate in their behalf as their clinician. He later served as the chair of a hospital ethics committee, where he learned that no two situations were ever going to be the same and that the whole field of ethics was a moving concept that “rolls over time across changes in community values and principles,” as well as across changes in science. In Florida, he joined an entity that was in effect an IRB for the State; it reviewed research protocols for both adult and children who were under the care of the State government. He was called to serve as Chair during a period when “clean up” was needed and was struck by the dedication and professionalism of the OHRP staff who were involved. As a “perpetual student of this process,” he is interested in learning how it works, how things are deliberated, what the issues really are, what the priorities are, and future directions. He recognized the dedicated community of advocates and experts who serve on SACHRP and others present in the room and assured them that the subject is one of importance to the Secretary of HHS. The Assistant Secretary told SACHRP that the Department is engaged in a number of “transforming initiatives.” These include the American Health Information Community (AHIC), which seeks to transform the health system through a dramatic increase in the use of health information technology and the development of countermeasures to ensure pandemic influenza preparedness. He stressed that rapid change is occurring and SACHRP plays an important role in “making sure that we do it right the first time.” Dr. Prentice responded with the observation that while the regulations have remained largely unchanged since 1981, their interpretation has been continually evolving, making everyone a “perpetual student” of human subject protection. Dr. Prentice recognized departing members Felix Gyi, Susan Kornetsky, and Ada Sue Selwitz. He acknowledged Dr. Gyi as an analytical, thoughtful individual who helped resolve many difficult issues; Ms. Kornetsky as a well-recognized IRB administrator and expert on IRB review of pediatric research; and Ms. Selwitz as a “star” in the IRB world who is both intuitive and committed. He thanked each of them for contributing to SACHRP. Secretary Agwunobi presented plaques of appreciation to each of the departing members and expressed the Department's gratitude for their service. Dr. Mary Lake Polan, who was unable to attend, was also thanked for her contribution. A new SACHRP member, Dr. Neil Powe, was sworn in by Admiral Agwunobi. DISCUSSION SACHRP members were given an opportunity to make comments or ask questions. Ms. Selwitz said she was reassured by the Assistant Secretary's comments on HHS's commitment to human research protections. She explained that the Subpart A Committee is struggling to balance the need for protection of human subjects against the potential for unnecessary regulatory burden and invited the Admiral's perspective. He shared his reflections, based on his experience as the Chair of a Florida group seeking to improve access to research for minorities, that the system for regulatory oversight appeared complex, with multiple layers. He has seen the need for balance first-hand and recognizes the need to reduce complexity where it is possible. In this effort, it is important to have feedback from those “downstream” of the regulations – the IRBs, the PIs, and the research subjects. He suggested that the Department will have the best chance of finding the right balance when engaged in appropriate dialogue. Ms. Kornetsky thanked Admiral Agunobi for attending the meeting and highlighted the need for harmonization among the different sets of regulations promulgated by regulatory agencies. She said anything top-level administrators could do to help harmonize these regulations would be deeply appreciated. He responded that he was committed to working in that direction. Dr. Prentice commented that the constructive relationship SACHRP has with OHRP also helps in finding the best balance. The Assistant Secretary thanked all SACHRP members for their work and hoped they would find their reward in a strengthened system. Mr. Nelson then presented highlights of the work of the Subpart A Subcommittee over the past several months. He stressed that the Subcommittee is addressing some fairly major issues and he believes the recommendations will have a positive effect on the field. Dr. Prentice continued by highlighting the work of each of the other subcommittees and naming several of the panels that have addressed SACHRP and shared their expertise. Discussion of IRB Workshop Ernest Prentice, Ph.D.; Bernard Schwetz, D.V.M., Ph.D. Dr. Schwetz began by informing SACHRP that Dr. Agwunobi was impressed by the committee's work and indicated a desire to attend one or two SACHRP meetings per year. Dr. Schwetz thanked the committee that helped plan the IRB workshop recommended by SACHRP, which was held on November 17-18, 2005. Members of the planning committee included Amy Patterson and Alan Shipp from NIH, Lynn Cates and Genevieve Nowolinski from the U.S. Veterans Administration, Susan Ehringhaus of the Association of American Medical Colleges (AAMC), and Lowell Schnipper from the American Society of Clinical Oncology (ASCO). About 50 people attended the conference, representing academia, business, government, independent IRBs, and subject advocates. The Planning Committee made a major effort to ensure all these groups were represented. Workshop time was allocated primarily to discussion, with both plenary and breakout groups used to elicit feedback. Attendees were charged with discussing the pros and cons of alternatives to local IRBs and addressing the need to encourage the use of the IRB model best suited for specific protocols and programs. Factors that influence the choice of model were identified. The Director's observations included the following:
Dr. Schwetz highlighted the barriers to the use of alternative models identified by participants. He noted that fears about liability were voiced the loudest, but in fact every model has some liability associated with it. Institutions are responsible for what happens at their institution, whether a nonlocal IRB is used or not. The need to address the local context appears to be a real concern; although some IRB mechanisms have worked hard at being able to address local context, others have further to go. Participants also voiced the concern that the use of an alternative mechanism might result in a net loss of resources; rather than freeing up time to do a better job on what remains, IRBs feared losing staff and funding. Attendees were concerned to ensure the quality of alternative mechanisms. Finally, they wanted more information on costs and the time required for review when alternative models are used. Dr. Schwetz closed with several points for further discussion that arose from the workshop:
If more information is needed to convince people to use alternative mechanisms, then further questions arise: who could sponsor, collect, analyze, and publish these data so they are available? DISCUSSION The Chair invited sponsors of the workshop to add their comments. Dr.Ehringhaus said Dr. Schwetz had summarized the workshop well and that it was a privilege for AAMC to participate. Dr. Patterson agreed that the summary was on target, but added that she had been surprised at how little of the discussion was spent on the pros and cons of different types of review models for different research contexts. The conclusion seemed to be that almost any model might fit, given the right expertise. Dr. Cates added that the VA found the workshop useful and educational. Ms. Kornetsky found the summary document useful. She wondered if the discussion addressed how to handle noncompliance and unanticipated problems, since her impression is that division of responsibility is a major concern. Dr. Schwetz said it did come up, and unfortunately many people wanted to believe that their institution is free of responsibility if another institution approved the protocol. Dr. Cates responded that many attendees stressed the importance of “crisp” agreements that delineate roles and responsibilities. Dr. Gyi, who was a public attendee at the workshop, said that those present had distinguished between the type of liability associated with financial litigation and the liability that is tied to public relations or to regulatory compliance. In the latter case, there is concern about which entity or entities might be subject to sanction. While FDA has a system capable of teasing out different components, HHS has an approach that holds the institution responsible regardless. Dr. Ehringhaus added that she was surprised at the extent of misinformation about liability and responsibility and by the persistent myths about what might happen. She suggested that the workshop had illuminated a number of areas, all of which could be considered as aspects of liability or accountability, that “cried out” for information and education. These could be addressed through a national workshop or through focus groups. Dr. Fisher said that the models described in the summary were exciting, and she wanted to see the dialogue continue. She suggested it might be helpful to create models for shared liability with legal advice, since the fear of liability seems to be fueling resistance to the use of alternative models. It is possible that liability issues would differ on a multi-site project as opposed to the use of a centralized IRB for other circumstances. Ms. Selwitz also found the summary document useful and congratulated the sponsors on their work. She observed, however, that developing guidance may be premature. She felt more solutions were needed first, including clarifying responsibilities and related ethical and regulatory issues. There are clearly major public relations concerns. She noted that the reality that centralized review is acceptable has not filtered down to many IRBs, and education is apparently needed. Dr. Jones saw the concern that IRB resources would be jeopardized as a significant one. In regard to the need for data on the performance of various models, she wondered whether evaluation funds might be used to glean this information. Dr. Schwetz responded that there is money set aside each year to evaluate program performance, which is available on a competitive basis. However, evaluation is complicated by the lack of criteria to measure the performance of the IRB system. Dr. Jones responded that it might be possible to devise an evaluation tool that would help develop and test performance measures. The Chair then introduced the question of next steps, highlighting major issues:
He added that there is no obvious way to get data on the performance of various models, particularly in regard to quality of performance. However, he felt there were enough issues explored that warrant further consideration to move to the next step. Dr. Prentice said his bias was toward having a national conference to give another airing of issues, followed by targeted workshops, including one on liability. Ms. Selwitz raised the issue of whether people would come. She also suggested that education could occur through channels other than workshops. Members articulated a variety of suggestions relative to next steps:
Dr. Jones observed that a conference could still have breakout groups on interest topics. Dr. Prentice agreed, noting that didactic presentations or panels could be followed by breakout sessions. A Senior Policy Analyst from ASCO thanked the entire planning committee and reiterated the organization's “profound” continued interest in the subject. Members agreed that an appropriate next step would be a national conference along the lines discussed, followed by targeted workshops. Institutional Officials (IOs). Dr. Schwetz said that one of his priorities is reaching out to signatory officials and other IOs. Dr. Schwetz recently had an opportunity to talk to 40 IOs at a meeting of the Association for the Accreditation of Human Research Protection Programs (AAHRPP) about their concerns. He said they were interested in talking to each other, which should be encouraged. He also highlighted the importance of the Signatory Official (the person who signs the Federal-Wide Assurance), who provides OHRP with its primary leverage over institutions. Dr. Schwetz said he believed more focus should be placed on the SOs because they are responsible for oversight of investigators. Dr. Prentice added that there is interest in developing an organization for IOs. Ms. Selwitz was enthusiastic about the approach and characterized it as overdue. Dr. Powe was also positive, but thought the impetus for IOs getting together should come from professional groups rather than the government. Dr. Gyi agreed on the importance of leveraging the role of the SO, but reminded SACHRP that many research sites receive Federal funds that are not under an institutional umbrella. PUBLIC COMMENT The Chairman invited public comment. Linda Ehler offered her personal observations as a staff member for the Regulatory Affairs Branch of the Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health. She was interested in alternative IRB review models because the Division sponsors multi-site trials all over the world and hears complaints from investigators on related issues. She urged that members of the international IRB community be invited to participate in the forthcoming conference. National IRBs, industry representatives, and the Medical Control Councils in South Africa might have useful input. Cheryl Ann Mathias also works for the Division of AIDS at NIH. She applauded SACHRP for considering the issue of a “60-day rule.” She said the additional time provided would be extremely helpful in many international settings in which IRBs meet less frequently and barriers to communication lengthen the time required to work through issues. John Mather of Chesapeake Research encouraged SACHRP to make full use of the interest shown by the Assistant Secretary of Health in its deliberations. He suggested asking for the Admiral's help in moving recommendations forward and also in addressing the staff shortage OHRP is experiencing. It might also be helpful to discuss with him the significance of accreditation and the need to promote the accreditation process. Dr. Prentice thanked Dr. Mather for his comments. He also encouraged OHRP to make the Assistant Secretary aware of their staff limitations. He noted that SACHRP's recommendations regarding the §407 process have been implemented in a timely way and hoped the others would be implemented as soon as possible. TUESDAY, MARCH 14 Welcome and Opening Remarks Ernest D. Prentice, Ph.D. The Chairman provided an overview of events for the day. He also reminded attendees of future meeting dates: July 31-August 1, 2006 and November 2-3, 2006. Report of the Subcommittee on Research Involving Children Celia B. Fisher, Ph.D., Co-Chair; Susan Kornetsky, M.P.H., Co-Chair At the last meetings, there were many recommendations on parental permission and child assent that were approved. Dr. Fisher reviewed recommendations that were modified in response to feedback from SACHRP at its last meeting (see minutes of November, 2005). Parental Permission and Child Assent Dr. Fisher reminded attendees that Subpart A §46.116(d) regulations require the informed consent of all human subjects, with some exceptions for research involving no more than minimal risk. Subpart D §46.408(c) provides additional protections for children by requiring parent/guardian permission and participant assent, with some exceptions for research involving all levels of risk. The subcommittee found the Subpart A language in need of clarification and sought to offer a decision-making tree that would assist IRBs in determining that an exception could be granted. Subpart A indicates that an IRB may “waive the requirements to obtain informed consent” if several conditions are met. One of these is a determination that the waiver or alteration “will not adversely affect the rights and welfare of the subjects.” The subcommittee’s first recommendation speaks to the factors that should be taken into account to make this determination. The third bullet in Recommendation 1 was altered based on feedback from SACHRP at the last meeting (November 2005). Changes made in the recommendations that follow to address SACHRP concerns are underlined.
Consideration of local norms might be assured, for example, by having an unaffiliated nonscientific IRB member who knows the community speak to the issue or by engaging a consultant. An example of an approvable request for a waiver would be a survey on soft drink and fast food intake in which the investigator has worked with the local PTA to develop procedures, the middle school children who will participate are old enough to understand assent information, and arrangements have been made with school personnel to ensure that participation is voluntary. There are no laws that would be violated. On the other hand, a waiver could not be granted if the investigator also wanted to correlate eating patterns with student grade point averages, since the Family Educational Rights and Privacy Act (FERPA) does not permit access to school records without parental consent. Another example of a reason not to grant the waiver would be concern from an Orthodox Jewish community about questions related to pork. Another finding that must be made to grant a waiver is that the research “could not practicably be carried out without the waiver or alteration.” The subcommittee's second recommendation speaks to this requirement. The subcommittee worked to make the recommendation more understandable and cohesive
An example in which the permission of a parent or guardian could be waived under this recommendation would be an instance in which the PI proposes to waive parental permission for a national study of diet and after-school activities to predict census tract concentrations of middle school children's respiratory disease. To meet the requirement for scientific validity, a large random sample of children is necessary for statistical power. In regard to alternative methods, Census tract neighborhoods vary with respect to ability to contact parents through telephone directory or other measures; therefore, data would not be evenly spread out across the census tracks. All census tracts must be included for data to be meaningful. The subcommittee sought to clarify the circumstances under which parental permission can be waived as “not a reasonable requirement” (other than instances of abuse or neglect). At the last meeting, SACHRP asked the subcommittee to craft a recommendation that makes it clear that the proposed guidance refers specifically to situations in which there is a conflict in the interests of the role of the parent or guardian as compared to that of the potential subject.
The subcommittee then attempted to define instances in which this would be the case.
An example of the application of criterion 1 would be an instance in which the PI seeks to identity patterns of psychological risk and resilience in high school students who consider themselves gay or lesbian, but who have not made this identity public. The PI might present literature on the social stigmatization of gay or lesbian youth, their potential confusion, and whether or not there is evidence of abusive reactions in particular populations. An example of the application of the second requirement would be an instance in which a Principal Investigator (PI) seeks to study coping behaviors of adolescents who have joined an Al-Anon Group. If there were only one parent and that parent were an alcoholic, there might be a conflict that would render the parent unable to make a decision in the child's best interest. A third example presented by Dr. Fisher is one in which a PI applies for a parental waiver to study adolescent girls' attitudes toward and use of different forms of birth control. Participants will be recruited from a clinic serving teenage girls 14 years and older who are permitted by state law to receive gynecology services and birth control without parental permission. To satisfy the third requirement, the PI would have to show that the research is important to the health and well-being of adolescent females who are sexually active and provide empirical evidence demonstrating adolescents of this age are capable of understanding informed consent at adult levels. The PI must also have assured during recruitment that it is clear to the teenagers that participation in the study is not related to their treatment and that a decision not to participate will not jeopardize their ability to get services. Finally, the PI might show that asking subjects about their sexual practices and use of birth control is reasonably commensurate with questions asked during gynecology services they are permitted by law to receive without parental permission. The subcommittee withdrew previous Recommendation 7, which requested OHRP guidance to clarify that IRBs may apply the Emergency Waiver to research involving children when parents/guardians are either present or not present DISCUSSION Recommendation 1. “Adversely Affect,” as Modified. Dr. Powell questioned whether there is a requirement that the understanding of the norms of the community reflect its cultural and ethnic diversity. Dr. Prentice responded that this would depend on the study, noting that in some instances actual community consultation might be needed, and one representative on the IRB would not suffice. The IRB would have the responsibility of determining the acceptability of the information. ACTION Recommendation 1 was approved unanimously. DISCUSSION Recommendation 2. “Cannot be Practicably Carried Out,” as Modified. The Chair pointed out that the recommendation would not support waivers driven solely by cost and convenience but would not exclude them from consideration. Ms. Selwitz was concerned that the recommendation might be read as a requirement. Dr. Fisher said it was difficult to write any guidance that does not sound like a requirement. The following revised wording was proposed by the Chair:
Dr. Fisher agreed with the wording, but added that she did not see the criteria as reducing flexibility or interfering with IRB judgment. Ms. Selwitz was not convinced that each of the criteria spelled out in Recommendation 2 needed to be addressed in every circumstance. She gave the example of students getting Master's degrees and Ph.Ds; they might be working with records and have no way to reach parents. Dr. Fisher said there is flexibility to address this example. At the same time, students should be trained to do valid research and not to sacrifice the rights of children. Dr. Gyi, however, was concerned that the recommendation would place the IRB in the position of mentoring investigators in appropriate design instead of placing the responsibility on the investigator. Agreeing, Ms. Kornetsky said she was uncomfortable with the word “require”; she felt the criteria should simply be presented as things to take into account. Dr. Powe agreed with the new wording. He noted, however, that other considerations not listed could also be taken into account. Dr. Fisher was concerned that the new language did not make it clear the burden was on the investigator to provide this information. Ms. Kornetsky, however, emphasized that the burden is always on the investigator, but the intent was to give the IRB flexibility in how the information was provided. Dr. Jones suggested that guidance for investigators might also be needed in order to help them fulfill this requirement. The Chair observed, however, that a paper could easily be written on the first criterion alone. He observed that education and training will be needed to help investigators interpret this guidance, as on any aspect of the Common Rule. However, some flexibility must be left to investigators and IRBs. Dr. Gyi asked whether any of the ex officios wished to comment. Dr. Bartlett noted that “such as,” included in original wording, would be “softer,” and the new wording was finalized as follows:
ACTION: Recommendation 2 was unanimously approved. Recommendation 3. “Not a Reasonable Requirement and Recommendation 4. Criteria for Waiver under §408(c), as Modified. Both recommendations were discussed together because of their close relationship. Dr. Powe asked whether there was still flexibility for the IRB to use its best judgment. Ms. Kornetsky responded that this would always be the case. Dr. Powe questioned whether item 3(d) of Recommendation 4 would be equally applicable to all research that falls under these recommendations, in that it appears to assume a study that involves treatment. Dr. Fisher agreed and suggested substituting the word “services” for “treatment.” Ms. Selwitz was not sure that the provision would apply equally to social science research. On the same criterion, Dr. Flanzer raised the question of what would happen if State laws were silent on the issue. While Dr. Flanzer was concerned about a “checkbox approach,” Ms. Kornetsky explained that the intent was to be restrictive, because all the considerations listed are important, and some limits are appropriate. Dr. Fisher added that the intent was to provide the flexibility to do important research on adolescents that could not be done if parental permission is required and to allow decisions to be informed by the mature minor laws. Dr. Lepay added that investigational products are precluded by the current wording because the state law could not permit the use of an investigational product. Dr. Prentice suggested that there were actually two situations that needed to be spelled out separately rather than blended into one criterion. A State law might exist that would prohibit a waiver of parental permission, or a State law might exist that permits a mature minor to consent to the type of services included in the protocol. Dr. Fisher said the situation in which State laws are silent must also be addressed. The following language was proposed:
Dr. Jones strongly encouraged the use of examples to clarify the intent of the guidance. ACTION Recommendations 3 and 4 were approved unanimously. Initial Presentation of Proposals on Key Issues Related to §46.405 Dr. Fisher presented proposals to address some of the key concerns identified by subcommittee members. She reminded committee members that this section of the regulations is related to research that may be greater than minimal risk but that provides the possibility of direct benefit for the child. Acceptable Risk. The first question addressed by the subcommittee is what level of risk is acceptable under this regulation. The subcommittee proposed to underscore the risk benefit decision with the following guidance:
Available Alternatives. The subcommittee sought to provide IRBs with language that would help them weigh risks and benefits within the framework of the regulations.
Evidentiary Base for Available Alternatives. The subcommittee felt that guidance was also needed to help IRBs identify the type of evidence that would prove an alternative is effective or appropriate. They proposed the following, which is in keeping with the thinking of the National Commission on the need for scientifically sound expectation of success to justify risk.
Monitoring Procedures as Benefit. Dr. Fisher reminded members that the regulations state that “direct benefit” can be shown if the intervention itself, the monitoring procedures, or both will have a direct benefit. Subcommittee members felt that the monitoring procedures should not count as having a direct benefit if they are simply “add-ons”; the procedure's efficacy should be a focus of the research and the benefit should be intended, not incidental.
Phase 1 Studies. The subcommittee considered whether Phase I studies, in which drugs are introduced in humans for the first time, can be approved for pediatric patients under section 405. Such studies are designed to determine the absolute level of acceptable toxicity, not to test direct benefit. However, there is sometimes a benefit that occurs for a small percentage of subjects. The subcommittee recommends a conservative approach that places the burden on the PI to demonstrate that a Phase I trial qualifies under 405, using evidence and relevant prior studies:
The subcommittee was concerned to make sure that participation in Phase I is voluntary and that both risks and benefits are made clear. They proposed the following:
Phase 1 Vaccine Studies. Dr. Fisher stressed that vaccine trials are research with the potential to save the lives of large numbers of children. In the past, such trials have saved more lives and benefited more children than many other types of studies.
Applying Component Analysis under §46.405 Dr. Fisher suggested that while SACHRP has already recommended component analysis – specifically, it recommended that each research procedure in a study must be evaluated independently in terms of its potential benefits and risks to subjects – it may wish to clarify how component analysis applies to pre-randomization and post-randomization, the risks of research procedures used in the intervention as well as control groups, the ability to receive the intervention at end of the trial, and symptom management. Specific proposals brought forward include the following:
These proposals were not discussed further at this meeting. Rather, the subcommittee chose to focus its remaining time on recommendations related to wards of the State. Wards of the State Ms. Kornetsky discussed issues related to wards of the State as subjects, noting that the issue is a timely one. A recent compliance investigation focused specifically on the issue of wards, and the OHRP Web site posts 15 to 17 letters to institutions throughout the United States about wards and pertinent regulations. OHRP has found that in particular studies, IRBs failed to obtain sufficient information regarding the selection of wards and foster children as research subjects, failed to obtain sufficient information regarding the process for obtaining permission from parents or guardians, and failed to consider safeguards related to their enrollment. The subcommittee has considered how to assist IRBs in ensuring adequate protection for these subjects under the regulations. Under §46.409, regulations require the following: If the research is approved under paragraph (a) of this section, (§46.406 or §46.407) the IRB shall require
More generally, Section §46.111 (b) requires IRBs to consider extra protections for vulnerable populations, which might include wards. Ms. Kornetsky highlighted a number of practical issues that affect the involvement of wards in research. These include the following:
The subcommittee considered how best to avoid exploitation of wards as a vulnerable population, while assuring that wards are not excluded as beneficiaries of research that offers direct benefit. Members also sought to assure continuity of care, safety, and oversight of research for wards who are involved in research, despite the challenges cited above. Their deliberations also addressed key questions:
Definition of a Ward. The following recommendation is designed to synchronize FDA and HHS regulations regarding wards; it proposes that HHS adopt the same definition of a ward already in use by FDA.
Appointing an Advocate. The subcommittee sought to give guidance to IRBs on the selection of an appropriate person to assume an advocacy role for wards of the State, though the guidance is not intended to be prescriptive.
Appointing an advocate. Ms. Kornesky commented that a subcommittee involved in some of the early HIV trials appointed an advocate for wards in the study even though it was not required because it seemed the right thing to do. The subcommittee recommends this step be considered, regardless of whether the research is beneficial or nonbeneficial, since wards are vulnerable by nature of their status regardless of the research category.
Becoming a Ward. When a child already engaged in research becoming a ward of the state, decisionmaking authority may change and the implications of participation in the research might change as well.
Anticipating Subjects Becoming Wards. In order to avoid disruptions to research, the subcommittee suggested giving a "heads-up" to encourage investigators to think about this possibility at the outset.
Guidance to the Research Team on Wards. The subcommittee felt that IRBs should be sure that investigators and research personnel are aware that they should let the IRB know when wards of the State will be involved, or may become involved, in research.
Component Analysis. The rationale for this recommendation is that component analysis applies to all pediatric research; therefore if any part of the protocol fits the criteria of 406 or 407, the special protections for wards must be applied. Recommendation 7. If component analysis of a study finds that one arm or procedure is approvable under 404 or 405 and another is approvable under 406 or 407, the most restrictive component will govern. Therefore any ward participating in that research will need to included in accordance with the provisions of §46.409, which include the appointment of an advocate. DISCUSSION Recommendation 1. Definition of a Ward. Dr. Jones wondered how the term would apply internationally. Dr. Fisher was uncertain, but suggested that this should not stop the effort to harmonize the definition with FDA. Dr. Prentice saw flexibility in the definition and saw nothing to preclude its application. ACTION Recommendation 1 was approved unanimously. Recommendation 2. Appointing an Advocate. The SACHRP discussion focused primarily on conflict of interest. Dr. Powe suggested broadening the concept to encompass other areas in which a conflict of interest might occur. The Chair suggested the following rewording for the third bullet of the definition: Have the ability to make a decision regarding each ward's participation in research that is autonomous and independent of any employment, professional relationship, or contractual requirements, financial gains, or other conflicts of interests concerning the number or types of subjects required for recruitment, enrollment, and ongoing participation. Members were concerned that nothing in the recommendation be read to imply that paying advocates is a bad idea or constitutes a conflict of interest. Rather, the intent is to ensure that advocates are not "paid by the head." Another concern was whether the reference to financial gain would encompass a situation in which the advocate is the spouse of the investigator. The Chair suggested the following wording, which would leave the IRB free to determine what does and does not create a conflict of interest. Have the ability to make a decision regarding each ward's participation in research that is autonomous and free of any conflicts of interest. Dr. Powe also raised the question of what is meant by "appropriate qualifications" in the first bullet. However, Co-Chairs responded that they have seen many people fill the role successfully and did not want to be overly prescriptive or shut doors. Dr. Jones asked for clarification of what was meant by "appropriate time to commit..." Dr. Fisher explained that the advocate needed to be able to meet with each child and understand that child's specific situation. Co-Chairs considered the possibility of combining the second and last bullet to make it clear that the point is to enable the advocate to "become familiar with the child's health, behavior, and social and physical environment." The subcommittee determined to table the recommendation to consider the committee's input. Recommendation 3. Appointing an Advocate. Dr. Jones was concerned that the guidance might amount to an "unfunded mandate" by raising the bar of expectations for advocates. Dr. Prentice rejoined, however, that if wards are a vulnerable population, extra protection for them is already required. Dr. Schwetz questioned whether the recommendation was one that was aimed at OHRP. He felt the remaining recommendations did not appear to constitute subjects for guidance, but rather more general suggestions for the IRB community. OHRP is not specifically asked to take a position. Also, he did not want to be perceived as increasing regulatory burden. The recommendation was tabled to allow further consideration by the subcommittee. Recommendation 4. Becoming a Ward in the Course of Research and Recommendation 5. Anticipating Subjects Becoming Wards. Dr. Fisher suggested that this issue is similar to issues related to persons who become prisoners during the course of a study. She said it would helpful for OHRP to clarify whether an IRB or investigator could be considered to be in violation of the regulations if this occurred and they were unaware the child had become a ward. Dr. Carome said OHRP had not issued formal guidance on this point. Ms. Kornetsky reminded SACHRP that "case law" is not the best way to communicate OHRP expectations on such issues. Dr. Prentice asked whether the subcommittee felt the issue was an important one that needed to be addressed. Ms. Kornetsky responded that something has changed in the child's status, and something is needed in response. Depending on the type of study, the change in the child's status could effect the child's participation in significant ways. The recommendation was tabled to allow further consideration by the subcommittee. Recommendation 6. Guidance to the Research Team on Wards. Dr. Prentice was uncertain of the meaning of the second bullet. He also wanted it made clear who is responsible for notifying the IRB (the investigator). Dr. Flanzer added that a subject becoming a ward may be analogous to an adverse event; in each case, the PI has certain reporting responsibilities. Dr. Powe saw the third bullet as putting the burden on the investigator to know this information, and it is not clear how the investigator would make sure he or she did know about this type of change. Ms. Kornetsky responded that she would need to talk with legal counsel and some investigators to get a sense of the practical issues and processes involved. In light of Dr. Schwetz's earlier comments, Dr. Fisher pointed out that this recommendation may be an insight rather than a recommendation that should go to the Secretary. The recommendation was tabled to allow further consideration by the subcommittee. Recommendation 7. Component Analysis. There was no discussion of this recommendation. PUBLIC COMMENT Cami Gearheart with Quorum Review, an independent IRB located in Seattle, Washington, observed that SACHRP is airing issues of importance that are creating difficulties and issues for the IRB's Board. The solutions are appreciated. Ms. Gearheart had the opportunity to observe the workshop held last fall on alternative modes of IRB review and found it helped her understand the pressures and concerns of institutions that are looking at the centralization process. She was pleasantly surprised by the level of acceptance and encouragement for the centralization process in some quarters but taken aback by the level of hostility in others. She came away with the understanding that as academic medical centers move toward centralization, independent IRBs may or may not be part of the solution, since the centers have issues of financial support and liability to work through. It may be that collaborations within and among institutions will help address those concerns. She expressed willingness to share lessons learned with academic colleagues as the process moves forward. Dr. Prentice assured her that independent IRBs would be represented at the upcoming conference on the topic. Linda Ehler identified herself as a nurse consultant in the Regulatory Affairs Branch of the Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health. She asked SACHRP to broaden references to State laws in guidance to encompass Federal, State, and local laws. She noted that this change was made in the new section 3(d) of "Recommendation 4: Criteria for Waiver under §408(c), as Modified" but not in (e). Consistency in this regard would be helpful to the international community. Ms. Ehler also offered comments in regard to wards. She noted that in some international settings, when children become wards, physical custody may be different from legal custody. Also, while the committee has considered the implications of a child becoming a ward during the course of research, it has not considered what happens when research is suspended (again, with an international setting in mind). This should be addressed. It is possible that the IRB would then need to reconvene and reconsider the research with an advocate in place. When children are receiving benefits as a result of participating in a trial, this situation can be problematic. Ms. Ehler also observed that the Division has found that in some of its pediatric trials, IRBs are not properly documenting their determination of pediatric risks. The Division has responded with training. She emphasized the need to train IRBs and investigators about the needs to document their pediatric risk determinations. Dr. Prentice thanked the speaker for her comments and assured her that her input would be considered by the subcommittee. Ed Bartlett of OHRP commended the children's subcommittee for its work. However, he pointed out an inconsistency related to recommendations passed by SACHRP earlier in the day. He noted that the regulatory language related to the waiver of parent or guardian permission under §46.116(d) says the waiver or alteration will not adversely affect the rights and welfare of the subjects. Recommendation 4, however, says that the IRB may waive permission under 408(c) if “the investigator has provided a reasonable argument that informing parents may result in harm to the child. Mr. Bartlett argued that this is a very important discrepancy because the regulatory language sets quite a rigorous standard to meet and the recommendation appears to weaken it. DISCUSSION Ms. Selwitz thanked the Chair for his "excellent job" and thanked the OHRP Director and staff for "how you consistently listen to what we're trying to do." Finally, she thanked her colleagues on SACHRP and expressed the opinion that "what this committee has done and will continue to do is of significant importance for human subjects' protection." Ms. Kornetsky agreed. The Chair thanked them for their comments and added that subcommittee members are dedicated people who work hard, noting that the enthusiasm they bring to the committee's deliberations is infectious. He was grateful that the members leaving SACHRP will continue to be active on subcommittees. Dr. Schwetz also thanked each of the three departing members and said he had learned from each of them. Dr. Prentice commented that in the months between this meeting and the next (in July) subcommittees will meet to consider issues raised by SACHRP so they can bring modified recommendations back to the committee. Also, OHRP will be planning to implement the latest recommendations sent to the Secretary, which have just been accepted. A progress report is expected in July. Also by the July meeting, it is hoped that progress will have been made in the development of a national conference on alternative models of IRBs. A report is also expected on issues related to adverse event reporting, as well as a status report on the IO initiative. Dr. Schwetz reported that there have already been several planning meetings for the national conference. Based on the current status of planning and recent input from SACHRP, he said the conference would probably be open to everyone and use breakout groups to reach specific audiences, such as signatory officials, institutional attorneys, IRB members, and investigators. Since the conference sponsors provide links to key audiences, OHRP will seek to ensure wide enough representation on the planning committee to move the agenda forward. Panel on Status of Research Ethics/Training Internationally Moderator: Robert Levine, M.D. Panelists: Melody Lynn, Ph.D.; David Lepay, M.D., Ph.D.; Jean-Louis Saillot; Maureen Power, R.N., M.P.H.; Barbara Sina, Ph.D. Dr. Schwetz commented on the expectations for the panel. He recalled that SACHRP has benefited from two previous panels on international research. As the subject is large and complex, it was decided to focus this panel on a topic that was narrow enough that a handful of people could address it from their experience. This smaller slice of the topic is training in the area of ethics. The subject encompasses ethical issues relative to the investigator, the institution that is supporting the research, the IRB, the review process, and the Ethics Review Board. Voices represented on the panel nclude not only U.S. regulators, but also those in the medical product industry, funding agencies, and those already involved in training related to research that occurs in the international setting. These speakers were asked to address several key questions:
The Chair introduced Dr. Levine, who served as moderator for the panel. Remarks by Robert Levine, M.D. Dr. Levine began by stressing that the "worst thing we can do is dictate ethics." Guidelines set forth by the Council for International Organizations of Medical Sciences (CIOMS) are intended to guide sponsors and investigators from wealthy countries as they carry out their work in developing countries, not to dictate to collaborators in those countries how they "ought to behave." Rather, it is important to learn from them about what works in their cultural context. CIOMS Guideline 11 has proved the most controversial. This requires that each subject be provided with an "established effective intervention" (EET) – not necessarily the best intervention. Placebos may be used only under the following circumstances:
Dr. Levine said many people saw the fourth bullet, in particular, as representing a double standard. He felt, however, that the results of the research should be responsive to the health needs and priorities of the community of subjects, and the products developed should be reasonably available. He agreed that this provision violates the fiduciary standard, under which physicians must have no interest of equal or higher priority than the patient's wellbeing; however, he felt the guidelines put strict limits on the degree of violation tolerated. Dr. Levine highlighted several other key guidelines: Guideline 3: Ethical review of externally sponsored research. An external sponsor…should submit the research protocol for ethical and scientific review in the country of the sponsor… and the ethical standards applied should be no less stringent than they would be for research carried out in that country. The health authorities of the host country, as well as a national or local ERC, should ensure that the proposed research is responsive to the health needs and priorities of the host country and meets the requisite ethical standards. Division of labor is permissible. Dr. Levine added that "stringency" is interpreted in the context of the country where the research is carried out. Division of labor may allow the ethical review committee or IRB in the host country to see that certain universal standards are applied appropriately in the context of the local culture. For example, the local IRB will know what constitutes undue inducement in the light of local traditions. Guideline 6: Informed consent. Sponsors and investigators have a duty to...seek consent only after ascertaining that the prospective subject has adequate understanding of the relevant facts and of the consequences of participation and has had sufficient opportunity to consider whether to participate. In regard to Guideline 6, however, Dr. Levine observed that in some tribal villages it is almost unthinkable that an individual will refuse to participate in an activity to which their governing body has agreed. Dr. Levine also briefly reviewed Guideline 10: Research in populations and communities with limited resources; Guideline 12: Equitable distribution of burdens and benefits in the selection of groups of subjects; Guideline 16: Women as research participants; Guideline 20: Strengthening capacity for ethical and scientific review and biomedical research; and Guideline 21: Ethical obligation of external sponsors to provide health-care services. Dr. Levine closed by reflecting that while the distribution of wealth among the nations of the world is inequitable, "research did not cause this and research cannot fix this." While it is tempting to use international research documents as a means of correcting these inequities, he said, it is important to avoid developing guidelines that would impede the efforts of sponsors and investigators in industrialized countries to help countries with less resources develop treatments and preventions that they can afford. Remarks by Melody Lin, Ph.D. Dr. Lin addressed each of the questions posed to panel members in turn:
Remarks by David A. Lepay, M.D., Ph.D. Dr. Lepay began by explaining that FDA is essentially a regulatory agency. It funds very little clinical research, with the exception of some domestic research in the areas of orphan products, women's health, and epidemiologic surveillance. In connection with this research, FDA has sponsored training for program coordinators, investigators, and its own IRB. FDA has no legal authority or jurisdiction outside the U.S. However, it does have authority to set conditions for accepting non-U.S. data that will be used in support of research or marketing permits in the U.S. for the U.S. population, which gives the agency some significant leverage. FDA can accept this non-U.S. data in two ways: the non-U.S. studies may voluntarily operate under a U.S. Investigational New Drug application (IND), in which case all U.S. regulations apply, or the data may be submitted under separate FDA regulations that apply to non-U.S., non-IND studies. FDA can reject studies that do not meet applicable requirements. In regard to IND studies, FDA has general regulations that require "qualified investigators"; however they do not specify a single core curriculum or a set of core competencies. There is no regulatory requirement from either FDA or OHRP that anyone serving on this committee have any basic ethics training. In regard to non-IND studies done outside the U.S., the Declaration of Helsinki currently serves as a minimum standard. FDA has a proposal out for public comment that would instead reference internationally recognized standards for good clinical practice similar to those in place in the U.S. However, there would still be no specific requirements for curricula. Instead, FDA requires documentation showing how standards have been met, including a description of how investigators were trained. FDA's ability to conduct international inspections is a criterion for accepting non-U.S. non-IND studies. This authority is embedded in IND regulations. Since 1980, FDA has conducted over 600 non-U.S. inspections in nearly 60 countries. These international inspections encompass investigator qualifications as well as training. Dr. Lepay added that as broad international standards have been articulated, differences in GCP between domestic and international locations have become increasingly small. A forthcoming handbook from the World Health Organization (WHO), built on CIOMS guidelines, will further advance education related to ethics and GCP. FDA leverages and promotes ethical conduct and ethics training through partnership with other regulatory authorities. Information sharing helps to identify ethical issues and provide a basis for targeted education and outreach. Dr. Lepay highlighted four international strategies as particularly helpful in promoting ethical practices internationally. These include:
Discussion. The Chairman asked whether it was FDA's intention to eliminate any reference to any version of the Declaration of Helsinki in its revised guidance. Dr. Lepay explained that this would be true of the regulation itself, but in practice the principles of the document that are also common to good clinical practice will be promoted. Remarks by Jean-Louis Saillot, M.D. In regard to industry-sponsored trials, Dr. Saillot stressed the need for global approaches based on standards that ensure that the dossier that presents the scientific evidence is acceptable by all relevant health authorities, including by the FDA. At this point, however, the vast majority of clinical research is still conducted within the U.S. and the European Union; only about a third of such activity is outside these countries. In practice, all global clinical development programs are based on full compliance with International Conference on Harmonization (ICH) guidelines. Sponsors fulfill their obligations under the guidelines not only through training, but also through monitoring, quality assurance, and selection of investigators with the appropriate credentials and experience. In general, the same global standards are applied whether the project is an IND or non-IND effort, though there are some procedural differences between the two. In such studies, both the sponsor's personnel and investigators are targets for training. Sponsor personnel such as monitors visit sites regularly, as do investigators. Important ethical principles are communicated through publications and training. For example, the Pharmaceutical Research and Manufacturers of America (PhRMA) has put together a document called "Principles of Conduct of Research Study." Many companies have internal codes of ethics or credos that are communicated through training to monitors and to the people in charge of the programs. Sponsors typically have a curriculum and Standard Operating Procedures (SOPs) that proceduralize the requirements of GCP and the ethical principles behind the protection of patients in clinical trials. All the monitors of any company would receive significant training to be sure they understand these requirements. Dr. Saillot referred to this training as encompassing "applied ethics" rather than abstract principles. Sponsors have a large impact on investigators. A typical study would have what is called an investigator meeting, which is to go over the protocol for all the investigators included in the sites. Frequently, a significant proportion of this time is spent on GCP and specific ethical expectations applicable to the study, including training on the reporting of adverse events and safety issues. In addition, monitors visit to examine the way the study is conducted. These visits are considered a training fun |