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Increasing the Role of the Public in Research Oversight INTRODUCTION Recently, deaths resulting from research participation and federal shutdowns of prestigious institutions have elic- ited a great deal of media attention questioning the safety of participating in research. In response, the research commu- nity, regulators, and others have taken actions intended to ensure that research is conducted ethically and that partici- pants are adequately protected. Some efforts have focused on the protection system as a whole, while others have con- centrated on reforming Institutional Review Boards (IRBs), the bodies that have the primary responsibility for ensuring that research participants are protected. In either case, the ethical review of research is the linchpin of the system for protecting research participants; review by the IRB is re- quired for any federally funded research and for Food and Drug Administration (FDA) approval of products developed using human research.) Greater inclusion of the public on IRBs has been sug- gested as a way to reform the protection system. The Na- tional Bioethics Advisory Commission (NBAC) and the In- stitute of Medicine (IOM) both have recommended that public members constitute at least 25 percent of the board's membership (IOM, 2003; NBAC, 2001~. Currently, federal regulations require that unaffiliated and nonscientific mem- bers be included as part of the IRB.2 Inclusion of public members also referred to as independent, unaffiliated, and nonscientific members on the IRB is intended to further focus the board deliberations on participant issues such as 1 45 CFR 46 ("Common Rule"); 21 CFR 50, 56. 2 45CFR 46.107: " (c) Each IRB shall include at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution." 24 informed consent. In practice, however, recruiting and re- taining members, as well as ensuring that their voices are heard on boards dominated by scientific professionals, has been difficult. Both the Office for Human Research Protections (OHRP) and the FDA have compiled information about com- mon problems facing IRBs, including deficiencies related to noncompliance in the areas of IRB membership, research review, and oversight of informed consent (see Figures 3.1 and 3.2~. In the past two years, OHRP has become more active in enforcing federal regulations between 1990 and June 2000, the Office for Protection from Research Risks (OPRR, OHRP's predecessor) issued 40 Determination Let- ters (NBAC, 2001~; from July 2000 to November 2002, OHRP issued 335 such letters.3 During this session of the workshop, Daniel Federman described the recent IOM report about the system for pro- tecting research participants, and Nancy Dubler discussed a project to train public members of IRBs. Angela Bowen talked about recruiting and retaining independent members of IRBs, Marjorie Speers discussed the role of the public in formulating accreditation standards as well as the potential for accreditation to foster greater public input into the re- search process, and Greg Koski offered alternative models for the review of research. RESPONSIBLE RESEARCH: A SYSTEMS APPROACH TO PROTECTING RESEARCH PARTICIPANTS In the fall of 2002, IOM released Responsible Research: A Systems Approach to Protecting Research Participants (IOM, 2003~. During the Clinical Research Roundtable 3 OHRP maintains its Determination Letters from July 2000 onward at ohrp.osophs.dhhs.gov/detrm_letrs/lindex.htm. Multiple letters sent to a single institution are included in the count.

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INCREASING THE ROLE OF THE PUBLIC IN RESEARCH OVERSIGHT Deficiency in application of exemptions \ 2% \ Deficiency in reporting per 45 \ CFR 46.103(b)~5) 4% Deficiency in IRB records and written procedures 1 1 % Deficiency in IRB membership 3% Deficiency in i' 18% nformed consent 25 Other miscellaneous deficiencies 2% / / Research without IRB approval / / 1% Deficiency in IRB review 49% FIGURE 3.1 Distribution of Site Visit Noncompliance Findings, OHRP Compliance Data 10/98-12/2001 This graph was redrawn from OHRP Compliance Oversight Data by Institution, October 1998 to December 2001, a report produced by OHRP in January 2002. 25 20 15 10 o Failure to Falsification Informed Follow Consent Protocol Adverse Qualifications Records Event Reporting FIGURE 3.2 Formal Complaints to FDA Regarding IRB Deficiencies This chart was redrawn from a presentation given by Stan Woolen of the FDA Office of Medical Policy, Division of Scientific Investiga- tions, to the IOM Committee on Assessing the System for Protecting Human Research Participants in May 2001. workshop, Daniel Federman, M.D., Dean for Alumni Rela- tions and Clinical Teaching at Harvard University and Chair of the IOM committee that wrote the report, presented a se- lection of the committee's findings that were most relevant to the public's role in the ethical oversight of research. According to the committee, all research involving hu- man participants should take place in a framework known as a Human Research Participant Protection Program (HRPPP). These programs must have a culture of unequivocal commit- ment to the ethical conduct of research and the protection of

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26 participants that is supported by the highest authorities within organizations the CEO of a company or president of a uni- versity, for example said Dr. Federman. The necessary support includes fostering a culture of integrity as well as the allocation of appropriate resources for the HRPPP to func- tion optimally, including those for ongoing quality assur- ance and improvement. The IOM committee proposes that a three-pronged re- view of science, financial conflict of interest, and ethics should take place before research can proceed. Owing to the complexity and range of the science, the conflicts of interest issues, and the ethics of the review process, review of re- search is too burdensome for one group, said Dr. Federman. The scientific review utilizes scientific expertise within a field to ensure that the science is valid, "because if it is not good science, it cannot be ethical," Dr. Federman com- mented. The financial conflict of interest review mechanism would employ relevant expertise on that issue. "Participants and community representatives have a great Deal to contribute to the Design, review, and conduct of projects and should be energetically recruited." Daniel Federman These review bodies should inform the Research Ethics Review Board (Research ERB, the term the committee adopted to replace IRB in order to reflect the mission of the board) of their findings and recommendations prior to the Research ERB deliberation so that it can focus on the ethical issues of each proposed research project in an efficient and informed way. "Participants and community representatives have a great deal to contribute to the design, review, and conduct of projects and should be energetically recruited," commented Dr. Federman. To encourage the inclusion of public members on IRBs in practice, the committee recommends that "at least 25 per- cent of membership should be reserved for unaffiliated mem- bers" (IOM, 2003, p. 96~. Currently, regulations require only that the IRB have at least one member with a nonscientific perspective and one member who is unaffiliated with the institutions (see "Independent Research ERB Members" for further discussion). 4 45CFR 46.107: "(c) Each IRB shall include at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution." ENGAGING THE PUBLIC IN THE CLINICAL RESEARCH ENTERPRISE "Obtaining the informed consent of the participants should be an ongoing process rather than a Discrete moment." Daniel Federman Referring to the issue of informed consent, Dr. Federman noted, "Obtaining the informed consent of the par- ticipants should be an ongoing process rather than a discrete moment." This requires that the consent document be rede- signed to provide a clear picture of the research rather than providing information in legalistic and self-protective jar- gon that overwhelms the goal of informed participation, he commented. In addition, all studies that have more than minimal risk to participants should be monitored, with prompt reporting of adverse events to investigators and Research ERBs, as well as sponsors, according to the committee. The committee's feeling is that it should be an open process, that transparency in the whole sequence is crucial to restoring confidence and then making it possible for recruitment and community participation to be restored, commented Dr. Federman. The final recommendation that Dr. Federman discussed is that individuals non-negligently injured as a result of their participation in research should be compensated, at the least for their resulting medical care and rehabilitation expenses, without regard to fault. The committee also calls for "full recovery for economic loss, including work-related disabil- ity, and in appropriate cases, for lost earnings of a deceased participant" but acknowledges that there needs to be more research about the number and severity of research-related injuries before this is implemented (IOM, 2003, p. 193~. Comment on the IOM Report Myron Genel, M.D., Associate Dean at the Yale Uni- versity School of Medicine, supported Dr. Federman's as- sertion that buy-in from top leadership is very important for the protection of research participants but also expressed concern about the notion of separating scientific from ethi- cal review. Ken Getz, M.B.A., President of CenterWatch, also wondered about this type of review and the reaction to the report. Dr. Federman said that the response to the report has been very positive. Some of the concerns that have been ex- pressed are an increased role for government, the complex- ity of the three-prong review, the difficulty of balancing in- formed consent and reasonable disclosure, and implementation of compensation mechanisms for research . . . tunes.

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INCREASING THE ROLE OF THE PUBLIC IN RESEARCH OVERSIGHT The three-prong review has been the most controversial recommendation, because some fear that it will act as an impediment to review rather than as an aid. Dr. Federman countered that the scientific review could come from any number of sources, such as National Institutes of Health or National Science Foundation peer reviews of grants. Due to the complexity of science, the committee believed that an in- depth, prior review by a committee focused on science would allow the Research ERB to take the scientific aspects into consideration while focusing on the ethics of research pro- posals. Dr. Federman also explained that the committee envi- sions the reviews as being separated but integral components of a human research participant protection program. In other words, they have shared assumptions about ethics theY have shared assumptions about procedures, they have shared as- sumptions about where the process is heading. Good com- munication, including a liaison between the review mecha- nisms, and good staffing are crucial for this process to function properly, he said. Greg Koski of OHRP noted that according to the regula- tions, IRBs are responsible for ensuring that the science be- hind a protocol is good. He added that the complementary source of additional scientific information to inform the com- prehensive review recommended by the IOM is a positive development. "The emphasis on a comprehensive review was what was really important..., where they have smaller panels with the full ability to call for additional expert scien- tific input from consultants as appropriate," he said. He also commented that OHRP, which was a sponsor of the report, was hoping IOM would develop outcome mea- sures, because people are investing a large amount of time, effort, and money in the process of improving the research participant protection system without any way to concretely measure results. Dr. Federman responded, "No one currently knows those suffering harm from current investigation, [or] every- one currently a participant in a research protocol." Thus, one of the recommendations of the committee is that the govern- ment assume responsibility for collecting baseline data on the protection system. Dr. Speers added that the IOM and NBAC reports had similar findings and recommendations, indicating that the executive and legislative branches of government should take the reports into consideration. "No one currently knows those suffering harm from current inves- tigation, for] everyone currently a participant in a research proto- col." Daniel Federman 27 ISSUES REGARDING INDEPENDENT MEMBERS OF IRBS Meeting the Need for Inclepenclent Members of Research ERBs Nancy Neveloff Dubler, J.D., Director of the Division of Bioethics at Montefiore Medical Center and Professor of Epidemiology and Social Medicine at Albert Einstein Col- lege of Medicine, began the Certificate Program in Research Ethics intending to fill the need for training unaffiliated, non- scientist IRB members. However, she soon discovered that many IRB chairs had only one independent members on their boards of 20-25 and that while many chairs wanted more public members, they did not know how to recruit suitable individuals. Thus, she redesigned the project, gearing it to- ward recruiting and training unaffiliated Research ERB members. First, Ms. Dubler had to determine whom to train. She turned for assistance to New York City Health and Hospitals Corporation, which has 11 hospitals that each have a com- munity board. The community board members there are largely minorities, who often have been absent from the IRBs that Ms. Dubler has visited. She also is working with the United Hospital Fund, a corporate entity that gives and re- ceives grants; the Public Service Network, a group under the umbrella of the Bar of the City of New York; and soon, spe- cific disease groups who have participant involvement and a stake in particular types of research. She will gather resumes from members of these groups, interview them, and link them with IRB chairs, who will choose whether or not to have them sit on their particular committee. Some IRB chairs have welcomed the prospect of in- cluding more public members, but others have been more skeptical. Concerns about independent members voiced by IRB chairs include lack of quorum (fear that independent members would not attend meetings), compromise of confi- dentiality, the exposure of scientific secrets, a decrease in the quality of discourse at meetings due to the presence of unknowledgeable persons, and a slowing down of the pro- cess. Some chairs also worry that lawyers will try to impose their interpretation of regulatory language and that nonsci- entists have nothing to contribute. Independent IRB members have voiced their own con- cerns about their role on IRBs. They have said that they need more information; that they should not be specially educated, because they bring the "wisdom of everyman"; that board 5 The terms public, independent, nonscientist, and unaffiliated were used by workshop participants to describe similar members. In general, the terms independent or public are used to describe IRB members who are unaffili- ated and/or nonscientists.

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28 ENGAGING THE PUBLIC IN THE CLINICAL RESEARCH ENTERPRISE members do not listen to them; and that other members often do not understand how suspicious the community is of medi- cal research. Ms. Dubler noted that the IOM report recommends that "a Research Ethics Review Board's deliberative process should aim for consensus. If consensus cannot be achieved, approval of the protocol should require favorable votes by three-quarters of the voting members" (IOM, 2003, p. 98~. This further convinced her that there is a need for training and recruitment of public IRB members. During her visits to seven major IRBs in New York City, Ms. Dubler found that independent members were a small, largely nonvocal, com- ponent of the boards a circumstance that could lead to the marginalization of their perspectives. The certificate program, which aims to address this problem, will involve a two-day retreat for independent members, followed by monthly three-hour seminars to ad- dress issues raised in Research ERBs, and a one-day meet- ing at the end of the year. In addition, there will be required post-meeting emails pointing out interesting or troubling is- sues raised during the meetings. Unaffiliated, nonscientist Research ERB members will be trained about the back- ground of research and the context in which it takes place, scientific methodology and methodological issues, and dif- ficult study design questions such as use of placebos. They will learn about conflict of interest and the importance of cultural competency. The "intellectual calculus" of review- ing proposals weighing risks and benefits of specific pro- posals will be essential, as will be the ability to consider the importance of proposals within the current body of knowledge. The responsibilities of IRB members includ- ing ethics review, assessment, research participant advocacy, accountability, and community perspective also will be addressed.6 Ms. Dubler also is developing guidelines for participa- tion for independent Research ERB members, based on the principles that research is a collaborative enterprise that in- volves scientists, members of Research Ethics Review Boards, and research participants in a collaborative process and that the goal of therapeutic and non-therapeutic research is to develop new knowledge and protect participants (see Box 3.1~. Attracting and Retaining Unaffiliatecl Members- An Inclepenclent IRB Perspective Western IRB (WIRB) is an independent review board that has been in existence for 35 years and now has 10 func- tioning IRB panels that serve over 60 institutions. WIRB President Angela Bowen, M.D., shared the experience of WIRB to illuminate obstacles to and rewards of including unaffiliated members on IRBs. WIRB has 93 total board members, 80 of whom Dr. Bowen described as community members who are unaffili- ated with the organization of WIRB . Of these members, 27 are medical doctors, 20 are "other scientists," and 33 are non-scientists. The members serve for an average of 5 years. The panels are generally composed of three physicians, three other scientists, and three nonscientists, and use alternates and consultants as necessary. 6 For more detail, see page 100 of Responsible Research (TOM, 2003).

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INCREASING THE ROLE OF THE PUBLIC IN RESEARCH OVERSIGHT The initial membership of WIRB included Rotary Club members, who then recruited other community members. Since that time, WIRB has done little recruiting. Most of the members come to WIRB through word-of-mouth, network- ing, professional contacts, and community service affilia- tions. They are interviewed by the chairman of the entire board and two members, who make a recommendation to the board of directors, who then appoint new members. In 2002, 33 people applied to be board members; WIRB de- clined 19 of them. Members of WIRB are paid for their participation. Medical doctors receive $300 and other scientists and non- scientists are paid $225 per meeting. Board meetings last an average of four-and-a-half hours per week, and according to WIRB members, preparation for each meeting takes four to six hours. No more than six new protocols are discussed at any meeting, in addition to any continuing review that must take place. The benefits of participation in the process at WIRB, as cited by its members, include intellectual stimulation, ad- equate time for deliberation, an excellent training program, access to consultants, protection from sponsors and investiga- tors, indemnification, decision-making only responsibility, knowledgeable and respectful staff support (WIRB provides about two staff members for each board member 226 em- ployees that staff 10 panels), group camaraderie, and annual retreats. Dr. Bowen also noted the importance of seemingly minor conveniences such as free parking, free lunches, good snacks, and comfortable seating in a pleasant boardroom. Dr. Bowen commented that the training program, which is both initial and continuing, has been particularly well re- ceived. It consists of about three days of didactic work in the regulations and the documents that underpin ethical research. In addition, new members are assigned mentors who attend board meetings with them from four to six weeks, depending upon when the new members feel they are ready to perform in a voting capacity. WIRB also holds three major training exercises a year for all board members. To address the problem of intimidation of nonscientist IRB members that Dr. Bowen also has witnessed at some IRBs, WIRB screens members to ensure that they are strong, independent thinkers who can disagree with physicians and not feel marginalized. Retaining IRB Members E. Albert Reece, M.D., Ph.D., M.B.A., Vice Chancellor and Dean of the University of Arkansas College of Medi- cine, commented about the difficulty of retaining faculty members for IRBs, because of the time commitment and lack of recognition for these activities, particularly regarding ten- ure and promotion decisions. He asked the panel how IRBs can retain nonphysician, independent members and whether financial stipends are sufficiently attractive to recruit and retain members. 29 In WIRB's experience, recruiting has not been much of a challenge, according to Dr. Bowen. However, over the past couple years, WIRB has had to recruit African American members, because the board took on projects in an area where there is a higher percentage of African Americans than in Washington state, where WIRB is located. In that case, WIRB asked members and community groups if they knew anyone appropriate to fill the slots. Dr. Bowen noted that within universities, "there are people who are genuinely interested in the work. Raising the profile of the activity can help. Put the IRB office not in the basement but up by the Dean's of lice, make it more visible, and give participants a free parking place." Dr. Federman commented that the ethical conduct of research and the evaluation of research are professional re- sponsibilities that should be recompensed to compensate for time away from other duties. He also noted that the resources ``No recognition for the academic value of the work done by IRB members is an extreme injustice. . . we need to recognize that this is something that requires an enormous amount of knowledge and dedication and that it should be recognized... as part of the aca- demic promotion process." Greg Koski necessary for an optimally functioning HRPPP are part of the cost of doing research and should be recognized as such. Dr. Koski added, "No recognition for the academic value of the work done by IRB members is an extreme injus- tice... we need to recognize that this is something that re- quires an enormous amount of knowledge and dedication and that it should be recognized... as part of the academic promotion process." Dr. Bowen also noted that adequate staffing for the board is very important. Ms. Dubler com- mented that she has received about 60 resumes for IRB posi- tions over the past 3 years, even though the members would not be paid, except for expenses. PUBLIC INVOLVEMENT IN THE ACCREDITATION PROCESS The method of involving the public in oversight of re- search should be tailored to meet specific goals, commented Executive Director of the Association for the Accreditation of Human Research Protection Programs (AAHRPP) Marjorie Speers. If the purpose is to increase accountability of organizations for research conduct, the public could be involved in making policy decisions and sitting on policy boards or boards of directors. Educational activities or other types of community outreach could increase the public's support for research and the use of public funds for it. In-

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30 valving community coalitions or research participants in the design of research could serve to increase enrollment in re- search, improve the quality of research, and enhance the translation and dissemination of research findings. Dr. Speers focused her comments on the first goal- ~ncreasing accountability of research organizations and specifically on AAHRPP's process of involving the public in the accreditation process. AAHRPP' s Board of Directors made a decision early in the formation of the organization to incorporate the partici- pant perspective on site visit teams as well as on the Council on Accreditation, the body that makes the determinations regarding accreditation. Of the 21 board members, 5 repre- sent the public; they have either been research participants themselves or have had family members who participated in research. AAHRPP also considers the perspectives of the public and research participants in the development of its standards in two ways. First, a number of standards address participant concerns. Specifically, AAHRPP encourages establishing open channels between participants and investigators and the institutions that conduct research, and addressing outreach activities to increase the capacity of individuals to partici- pate in research. Second, there was an open comment period on the standards as they were developed, during which the organization heard from individuals representing participant perspectives. AAHRPP publishes the name and accreditation status (full or qualified) of accredited institutions,7 an additional form of accountability to the public. In addition, AAHRPP intends to have an outreach effort direct the public in order to raise awareness about accreditation and what it can and cannot accomplish. This outreach also will empower partici- pants to inquire about the accreditation status of a research organization before deciding whether to enroll in a research study. "When we involve the public or participants in research, we are not talking simply about having individuals sit on committees; what we want them to co is to really participate in the process, to be involved in decisions that are mace." Marjorie Speers ``When we involve the public or participants in research, we are not talking simply about having individuals sit on committees; what we want them to do is to really participate in the process, to be involved in decisions that are made," Dr. Speers commented. 7 See www.aahrpp.org for more information about AAHRPP, its pro- cess, its pnnciples, and its standards. ENGAGING THE PUBLIC IN THE CLINICAL RESEARCH ENTERPRISE She also noted that the criteria for choosing public mem- bers should be reasonable and cautioned against choosing members based on certain skills while ignoring the potential bias or agenda of a public member (or any other member). In addition, she called for special attention to involving groups that have experienced abuse or discrimination in research. NEW MODELS OF ETHICAL REVIEW Greg Koski, Ph.D., M.D., Director of OHRP,8 offered new models of review to improve the efficiency and effec- tiveness of the system for responsible conduct of human re- search. For the past 20 years, the twin pillars of informed consent and IRB review have formed the base of the protec- tion system. However, according to Dr. Koski, these pillars are often perceived as barriers to conducting research, and the model needs to be reconsidered. The reliance on IRBs for a variety of review functions may not be appropriate, and the discussions about improving research review and over- sight have therefore come to focus on programs to protect participants, noted Dr. Koski. He emphasized that the goal of the protection system should be prevention of harm and excellence in the conduct of research rather than simple com- pliance with the regulations. A complete program requires an effective administrative staff, an information system, and a communication system, as well as appropriate processes for quality assurance and management and compliance, he said. It also requires components to manage conflicts of in- terest, deal with adverse events, and conduct education. He noted these things are not direct responsibilities of the hu- man research review board; they are components of an over- all protection program. He commented that there has been a lack of account- ability within the system and the research community and that, consequently, mechanisms to ensure integrity and ac- countability must be part of the enterprise. Dr. Koski voiced his concern that some research is conducted without the pro- tections afforded by the Common Rule9 and that there is a need for a more uniform and consistent approach to the pro- cess of responsibly conducting human research. The IOM, NBAC, and others have expressed the same concern and leg- islators have included the extension of federal oversight to all research, regardless of funding source, in their proposed bills.l ~ Dr. Koski resigned from his position as OHRP director in December 2002. He is currently a cardiac anesthesiologist at Massachusetts General Hospital. 9 45 CFR 46, Subpart A, The Federal Policy for the Protection of Human Subjects. in Proposed bills from the House and from the Senate would require that all research conducted in the United States be carried out in accord with 45 CFR 46 [A Bill to Amend the Public Health Service Act with Respect to the Protection of Human Subjects in Research. H.R. 4697. 107th Congress, 2nd Sess. (2002); Research Revitalization Act. S. 3060. 107th Congress, 2nd Sess. (2002)].

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INCREASING THE ROLE OF THE PUBLIC IN RESEARCH OVERSIGHT Research Site B 31 | Research Site A | | Research Site C ( HRpp )~( HRPp ) I I ~ HRPP ~- HRPP , - HRPP , Research Site D FIGURE 3.3 Distributed Network Consortium For. Greg Ko ski presented Figures 3.3-3.6 at the workshop. Alternative Review Moclels Dr. Koski outlined multiple models for the ethical re- view of research involving human participants a distrib- uted network consortium, a centralized consortium, a tan- dem model, and a practice-based network model. The chosen approach must be appropriate to the venue and the type of research, the components of the system must be functionally organized, and there must be unequivocal delegation of re- sponsibilities and authority for any of these models to be effective, he noted. In a distributed network consortium model, each re- search site has its own human research protection program (HRPP) (Figure 3.3~. Rather than duplicating effort, the sites can distribute work and rely upon each other for different program functions. This could provide greater quality and more efficiency than the current system. A consortium such as MACRO (Multicenter Academic Clinical Research Orga- nization), in which the five member universities generally accept the conclusions of each other's IRBs, is one ex- ample.~i The centralized consortium is a second model (Figure 3.4~. In this model, a central HRPP is established by multiple entities that each contribute resources. Independent IRBs would fit this model, with one central IRE providing ser- vices to multiple sites. ii Participating members of MACRO are University of Pennsylvania School of Medicine, Baylor College of Medicine, University of Alabama at Birmingham, Vanderbilt University, and Washington University School of Medicine. For more information, see ccs.wustl.edu/macro/ aboutmacro.htm. Research Site B FIGURE 3.4 Centralized Consortium Research Site D The National Cancer Institute' s (NCI' s) central review pilot program is one example of the tandem model, in which an expert central board with public, ethics, and scientific and clinical representation carries out a high-level review and then, under a set of carefully-defined delegations of authori- ties and responsibilities, works with local boards that can address the issues at the local sites (Figure 3.5~. This model would avoid the redundancy of numerous reviews at mul- tiple sites while also allowing for local input. Finally, the practice-based network model is designed for research that takes place within physicians' practices (Figure 3.6~. Much research is done in this setting today, and practice-based research networks have been forming to meet the needs for research undertaken within physician practices (Genel and Dobs, 2003~. Privacy boards and ethics boards could be folded into the network and shared among partici- pating practices. ``ln making these models work, it is clear that institutions and their IRBs are only going to be willing to relinquish their own autonomy if they can be sure that they can trust the ones that they are going to partner with." Greg Koski Dr. Koski cautioned, ``In making these models work, it is clear that institutions and their IRBs are only going to be willing to relinquish their own autonomy if they can be sure that they can trust the ones that they are going to partner with." Accreditation could possibly encourage such trust among programs. In addition to its usual compliance functions, OHRP has been focusing on assessing and improving HRPP perfor-

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32 Practice HRPP Practice HRPP /\ ). 1> mance by providing quality improvement consultation and tools to measure performance. OHRP is developing its qual- ity improvement program in three phases quality assurance (a self-assurance tool), quality improvement, and continu- ous quality improvement to further its role in improving performance. The quality assurance phase has begun, and the tools for assessment are available from OHRP.~2 Dr. Koski noted that validation, which includes certification and accreditation, is also an important part of the performance domain. i2 See ohrp.osophs.&hs.gov/humansubjects/qip/qip.htm for more infor- mation about the quality improvement program. ENGAGING THE PUBLIC IN THE CLINICAL RESEARCH ENTERPRISE Central Review Board - Terms of Participation and Responsibilities ~~\ W;~K ~~d jV~.: ~ ~ ~ ~ Multicenter Clinical Trial FIGURE 3.5 Tandem Model Practice ~ ~ Practice HRPP ) ~ HRPP Ethics Review Privacy Board Practice HRPP \ i, \\ // Practice ~~ HRPP - 1 ( a/ FIGURE 3.6 Practice-Based Research Network Model \ Trust and Institutional Liability Practice ~ HRPP J Adrian Dobs, M.D., Professor at the Johns Hopkins University School of Medicine, commented, "Some institu- tions are very hesitant to trust other IRBs when, in the end, they are the ones who are going to be responsible and legally liable for any problems that develop." She and Bernard Schwetz, D.V.M., Ph.D., Senior Adviser at the FDA,13 asked how to engender trust among IRBs so that they are willing to cede some responsibilities to each other and overcome this impediment. 1 sin January of 2003, Dr. Schwetz was named Acting Director of OHRP.

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INCREASING THE ROLE OF THE PUBLIC IN RESEARCH OVERSIGHT "These things don't happen overnight. They take an enormous amount of commitment from people who really want to achieve the goal, and it is that shared goal that ultimately allows them to pro- ceec.... This is not a one-size-fits-all game, and we have to be sensitive to that." Greg Koski Dr. Koski responded that standards of excellence such as accreditation are essential to foster trust among different research institutions. He commented further that once a group of institutions are working together, they make a com- mitment to achieving common goals, and the liability issues tend to fall under a simple management strategy. Clearly defining who is responsible for what and making sure there are systems in place to see that those responsibilities are ful- filled is essential for this type of review to work. The NCI central review board is one example of this- it allows local boards to accept or reject a central assess- ment, preserving "an appropriate measure of autonomy," Dr. Koski noted, adding that clear lines of responsibility are es- sential for this to work. He cautioned, "These things don't happen overnight. They take an enormous amount of com- mitment from people who really want to achieve the goal, and it is that shared goal that ultimately allows them to pro- ceed... This is not a one-size-fits-all game, and we have to be sensitive to that." Dr. Federman commented that many faculty members at research institutions are reluctant to trust faculty from other institutions and that this reluctance "is legendary re- gardless of the suit implications." The IOM committee rec- ommends regional or central review as an option rather than a requirement, allowing institutions to undertake their own review if they choose to do so while also legitimizing other review mechanisms. Dr. Bowen noted that there currently is a willingness to try different models, partly because OHRP has encouraged such innovation during Dr. Koski's tenure. WIRE survives by establishing trust with the institutions for which it provides reviews. GUIDANCE ON INTERPRETATION OF THE REGULATIONS David Rimoin, M.D., Ph.D., Chairman of Pediatrics at Cedars-Sinai Medical Center commented that one of the problems with individual IRBs has been the tremendous vari- ability in their interpretation of what is regulation, what is guideline, and what is hearsay. He also noted that sometimes institutions focus on protecting themselves rather than pro- tecting research participants and that there should be some appeals process to address this issue. Centralizing the re- view process (i.e., taking the "I" out of "IRB") would ensure more uniform standards nationally, he said. 33 Dr. Koski pointed out that OHRP handles around 14,000 inquiries from the research community about interpretation of the regulations and has a compendium of nearly 20,000 entries to guide interpretation.~4 OHRP also is systemati- cally reviewing and revising as necessary the guidance is- sued by the Office for Protection from Research Risks (OHRP's predecessor) and OHRP to ensure that it is up-to- date and clear. The quality improvement program also will provide best practices and a "gold standard reference" to aid greater uniformity. He added, "I think that we are really suffering from such a lack of confidence and such a risk-averse environment within the research community that it has led to a phenomenon that I call 'reactive hyper-protectionism'... There is a reason why we have within the regulations categories for full review, ex- pedited review, exemptions, and even categories for research that is not human subject research. We need to get to the point where these programs and the institutions have sufficient con- fidence in what they are doing by having the expertise there, the training, and the feedback in order to exercise their re- sponsibilities in an efficient, effective fashion." "I think that we are really suffering from such a lack of confidence and such a risk-averse environment within the research commu- nity that it has lee to a phenomenon that I call 'reactive hyper- protectionism."' Greg Koski EVIDENCE OF MISCONDUCT IN CLINICAL RESEARCH Rick Martinez, M.D., Director of Medical Affairs for Community Relations at Johnson & Johnson, wanted to know how much actual fraud occurs in research and whether most misconduct is really technical noncompliance with con- fusing regulatory language. Dr. Koski responded that OHRP does not monitor re- search fraud and misconduct but that FDA suggested a few years ago that as much as 5 percent of clinical trials in- cluded fraudulent data. He added, "I don't think that most of the deficiencies that we see are willing deficiencies." In OHRP's 280 for-cause visits over the last two years, the office has found that by the time it responded, the original problems had been cleared up; the causes of the visits were almost never complete system deficiencies, but rather small, correctable aspects of compliance, according to Dr. Koski (see Figures 3.1 and 3.2 for common findings of non- compliance). i4 OHRP's policy guidance can be accessed at ohrp.osophs.&hs.gov/ polasur.htm.

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34 Sl MARY The review of research involving human participants is essential to the conduct of ethical research. Members of the public are not only affected by the results of such re- views; they also play an important role in the review pro- cess. Dr. Federman offered his IOM committee's sugges- ENGAGING THE PUBLIC IN THE CLINICAL RESEARCH ENTERPRISE lions to ensure that the system for protecting participants is functioning properly, Ms. Dubler described her pilot pro- gram to recruit and train public Research ERB members, Dr. Bowen shared the WIRE experience, Dr. Speers dis- cussed the role of the public in the accreditation process, and Dr. Koski focused primarily on new models for the ethical review of research.

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H[f[H[NC[S sUtu~ of acne. 2003. Re~e Re~; ~ ~~ -~6 fig froferh~@ Re~6 I. The Nadona1 Academies Press: Washington, DC. Genel ~ ad Dobs A. 2003. Trading cynics ~se~cb into pracUce: pracUce based ~se~b netwo~s as ~ pawing soluble. ^~' ~f~f~e ~~e 31(2~64~1. cNe111y PJ ad Cam a. 2001, July 19. Hum s~ects puns under ~lUple protect assurance (~PA) ~-1011. Lear to Edward D. >111er ad Cb1 Vat Dug, Jags Hopkins University Scboo1 of ~e~- cme. Nanny B1oe~cs Advisor Co~ss1on. 2001. ~~' ~~d fo Re~6 ~~ ~~ f~ ~~e ~ Bethesda ~D: ~AC.