Ethical considerations for quality assurance versus scientific research.

There is increasing evidence to support the contention that the boundaries between QA and scientific clinical research are blurred. This blurring is of particular concern in relation to the protection of human subjects rights (Brett & Grodin, 1991). The article thus concludes that it is essential that proposals for QA programs undergo periodic appraisal by an institutionally responsible, disinterested review panel. It further concludes that it is essential to submit proposals for all prospective QA projects, potentially scientifically meritorious QA projects, and all scientific clinical research projects to an institutional review board (IRB) to render decisions about the protection of human subject's rights before accessing data. Doing so protects the subject's rights, protects the investigator from unwittingly rendering harm rather than good, and enhances the ethical credibility of the projects. It also protects the investigator from embarrassing and potentially litigious situations. It is also incumbent on IRBs to develop efficient, effective, and expeditious review processes that encourage rather than discourage the a priori review process.     

Variability in Institutional Review Board Assessment of Minimal-risk Research

OBJECTIVES: To examine variability in responses from institutional review boards (IRBs) to submission of a proposed minimal-risk survey. METHODS: Identical research proposals to obtain information concerning beliefs about the needs of victims of intimate partner violence via surveys were submitted for IRB approval to three institutions in the Baltimore metropolitan area. One institution is an academic center, one is an inner-city hospital affiliated with the academic center, and the third is a suburban community hospital. The study population consisted of emergency department health care providers and individuals in emergency department waiting areas. RESULTS: Inconsistencies emerged among the three IRBs in the review process itself, the need for participant consent, and the need for revision of the consent form and study protocol. One institution approved the proposal in 15 business days after expedited review. The second institution approved the proposal in 12 business days and waived the requirement for informed consent. The third institution approved the research in 77 business days after three revisions. Questions raised included: methodology for selecting participants; appropriateness of surveying individuals in emergency department waiting areas; a request for background literature to assure that the research questions had not already been answered; and concerns about study methodology and sample size justification. CONCLUSIONS: In this sample, there is considerable variability in IRB processes even for minimal-risk studies.     

Computerized information management for institutional review boards

The use of human subjects for medical research in most industrialized nations requires the scientific and ethical scrutiny of research proposals by a governing institutional review board (IRB) or its equivalent. As part of their primary charge to protect human subjects, IRBs are responsible for the regulatory oversight of not only the research protocol itself but also the research conduct of the investigators and, if applicable, the funding sponsor. This article will discuss the regulatory requirements for an accurate account of IRB protocols and investigators and present an overview of the general flow of information for an IRB protocol. The current and potential uses of information management systems by IRBs will also be reviewed and accompanied by a discussion of the potential advantages and disadvantages of various computerized information systems for management of clinical research.     

Economies of scale in institutional review boards

BACKGROUND: Research with human subjects is essential for most clinical and social science research. As such, the ethical treatment of subjects, including the role of Institutional Review Boards (IRBs), is of paramount concern. The prevailing system of IRBs in the United States reflects an integrated approach in which research organizations have their own local IRB. Recent regulatory changes and a few high-profile problems have prompted proposals for greater investments in IRBs. OBJECTIVES: We conducted regression analyses, looking at how IRB size was associated with IRB costs (economies of scale). RESEARCH DESIGN: We studied data from a cross-sectional survey. SUBJECTS: We studied IRBs at Veterans Affairs (VA) and VA-affiliated medical centers (n = 109); 81 (73%) IRB administrators completed the survey. Fourteen of the administrators had missing data and were excluded from final analysis, leaving a sample of 67. MEASURES: The primary dependent variable was IRB costs in 2001, which we estimated from the survey. Independent variables included IRB size measured as the number of actions (ie, number of initial reviews, amendments, continuing/annual reviews, and harms/adverse event reports) reviewed by the IRB in the last year. RESULTS: The results indicate that very large economies of scale exist, especially for IRBs that handle fewer than 150 actions per year. CONCLUSIONS: A discussion of the costs of benefits of having 3000 to 5000 local IRBs in the United States is warranted because other organizational arrangements could be economically and socially advantageous.     

A study of warning letters issued to institutional review boards by the United States Food and Drug Administration

PURPOSE: This study explores the ethical issues contained in warning letters (WLs) issued to institutional review boards (IRBs) by the United States Food and Drug Administration (FDA). METHODS: The online FDA Warning Letter Index was reviewed for letters issued to IRBs in the United States under the violation categories "Institutional Review Board" and "IRB" for the period January 1997 through July 2004. The resultant letters were evaluated for violations in 4 regulatory themes: having and following written procedures for research review; documentation of research review; IRB membership and conflict of interest; and informed consent. RESULTS: Fifty-two (52) FDA WLs were issued to IRBs during this period. Hospital/medical centre IRBs received the most letters (n = 34), followed by university IRBs (n = 9) and private IRBs (n = 9). The most common regulatory violations were failure to have and follow adequate written procedures about how the review of research is conducted (50 WLs); failure to prepare and maintain adequate documentation of IRB activities (47 WLs); and failure to provide adequate continuing review of approved studies (36 WLs). Nineteen WLs were issued for consent form issues. CONCLUSIONS: Warning letters are informative with regard to clinical research regulations and research subject protection. The content of these letters consistently indicates weaknesses in review and documentation activities of audited IRBs, potentially signalling similar issues among IRBs across the United States. Our findings, in a setting of overburdened IRBs who, in general, passively monitor studies, raise concerns about study oversight and optimal protection of research subjects.     

Variation in Institutional Review Board Responses to a Standard Protocol for a Multicenter Clinical Trial

Multicenter clinical trials require approval by multiple local institutional review boards (IRBs). The Multicenter Airway Research Collaboration mailed a clinical trial protocol to its U.S. investigators and 44 IRBs ultimately reviewed it. OBJECTIVE: To describe IRB responses to one standard protocol and thereby gain insight into the advantages and disadvantages of local IRB review. METHODS: Two surveys were mailed to participants, with telephone follow-up of nonrespondents. Survey 1 was mailed to 82 investigators across North AMERICA: Survey 2 was mailed to investigators from 44 medical centers in 17 U.S. states. Survey 1 asked about each investigator's local IRB (e.g., frequency of meetings, membership), whereas survey 2 asked about IRB queries and concerns related to the submitted clinical trial. RESULTS: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40--83) after receipt of the protocol, and IRB approval took an additional 38 days (IQR, 26--62). Although eight applications were approved with little or no changes, IRBs requested an average of 3.5 changes per site. Changes involved study logistics and supervision for 45%, the research process for 43%, and the consent form for 91%. Despite these numerous requests, all eventually approved the basic protocol, including inclusion criteria, intervention, and data collection. CONCLUSIONS: The IRBs showed extreme variability in their initial responses to a standard protocol, but ultimately all gave approval. Almost all IRBs changed the consent form. A national, multicenter IRB process might streamline ethical review and warrants further consideration.     

Conducting research using the emergency exception from informed consent: the Public Access Defibrillation (PAD) Trial experience

BACKGROUND: The Public Access Defibrillation (PAD) Trial, a prospective, multicenter, randomized clinical trial comparing two prehospital resuscitation strategies, was conducted under the regulations for exception from informed consent (21CFR50.24) in 24 communities in North America. These regulations place additional requirements for human subject protection on investigators and Institutional Review Boards (IRBs), including conducting community consultation (CC) and public disclosure (PD). OBJECTIVE: To describe the IRB approval process at study sites and the number and types of community consultation and public disclosure activities conducted. METHODS: The 24 study sites in the United States and Canada submitted IRB applications, CC and PD plans, and a structured report on IRB process and investigator perceptions to the Clinical Trial Center at the University of Washington. RESULTS: The primary IRBs for all 24 trial sites and a total of 101 IRBs approved the study. The median interval from submission to approval was 108 days (IQR 43-196), and the mean number of revisions was two (range 0-7). Investigators conducted nearly 12,000 activities to achieve CC and PD; activities varied greatly from site to site in both type and quantity. CONCLUSION: The length of time to obtain IRB approval and the extent of community consultation and public disclosure varied greatly among trial sites in meeting the current regulations for conducting emergency research with exception from informed consent. This suggests that more specific guidance may be useful and that determination of effective strategies for community consultation and public disclosure is needed.     

Fraud, conflict of interest, and other enforcement issues in clinical research

Fraud in scientific research is a widespread problem. It can involve falsifying data or documents, or knowingly failing to comply with regulations protecting research participants. Fraud can be committed by individuals, institutions, or corporations; in the context of research, fraud often is motivated by considerations beyond financial gain. Institutional review boards (IRBs) are designed to ensure that researchers comply with human research subject protections, including conflict-of-interest controls, but IRBs may fail to do so if investigators avoid existing IRB processes or if IRB members do not take responsibility for addressting actual or potential conflicts of interest.     

The challenges of IRB review and human subjects protections in practice-based research

Practice-based research raises unique challenges with respect to human subjects protections and institutional review board (IRB) review. In this paper, three challenges posed by practice-based research are analyzed: (1) IRB review for clinician investigators who are not affiliated with an institution that has an IRB; (2) multiple IRB review; and (3) required human subjects protection training of key personnel. Investigators should be proactive in addressing required IRB review in practice-based research. In particular, they need to ensure that appropriate IRB review is obtained for all performance sites and plan for review for unaffiliated investigators. Practice-based research investigators and professional societies should educate IRB members and policy makers and publish articles regarding how IRBs might best address human subjects concerns in practice-based research. Furthermore, practice-based research investigators and professional societies should work with IRBs and the Office for Human Research Protections to facilitate centralized or cooperative review of practice-based research. Finally, practice-based research investigators need to ensure that their clinician investigators receive appropriate training in human subjects protection. Practice-based research investigators and professional societies can facilitate this process by helping to define and implement the appropriate training for busy practice-based research clinicians and office staff.     

A Survey of IRB Process in 68 U.S. Hospitals

PURPOSE: To compare IRB processes in 68 U.S. hospitals for the same multicenter study. DESIGN: Survey of IRB processes in 68 U.S. hospitals during 2001-2002. METHODS: Requirements of IRB submission including type and duration of review and qualifications of principal investigator were compared by hospital bed size, region, and academic affiliation. FINDINGS: The majority of hospitals (63.2%) were on the East coast, and mean bed size was 465 (range: 77-2,112). About one-third (33.8%) required that the principal investigator listed on the application be from within the institution, 26.5% required evidence of human subjects research training, 10.3% required a conflict of interest statement. Mean number of pages for the application was 5.24 (1-31) and up to eight copies were requested. Time from submission of the IRB application to approval averaged 45.4 days (range, 1-303 days), and the majority of reviews were "expedited" (61.8%). Expedited reviews required more time (mean, 54.8 days) than did either exempt (mean, 10.8 days) or full (mean, 47.1 days) reviews. CONCLUSIONS: Current IRB review processes are cumbersome and nonstandardized, and review time varies widely. The absence of efficient and streamlined review might unnecessarily impede national clinical research projects without improving participant safety.     

Ethical Attitudes of Nurse, Physician, and Unaffiliated Members of Institutional Review Boards

PURPOSE: To evaluate the recommendation for adding unaffiliated members to institutional review boards (IRB) by comparing the attitudes and influence of IRB members of different backgrounds, primarily nurses, physicians, and unaffiliated members. DESIGN: Survey. METHOD: A closed-ended self-administered questionnaire concerning ethical issues in human subjects research was completed by 284 IRB members in a nonprobability sample of 27 IRBs in 12 U.S. states. The attitudes and influence of IRB members with different backgrounds were compared. FINDINGS: Nurses rated most of the issues as more important than did all other members; physicians rated most of the issues as less important than did all other members; and unaffiliated IRB members rated the issues similar to the whole. Nurses and unaffiliated members were ranked the least influential IRB members, and IRB chairs and physicians were ranked the most influential. CONCLUSIONS: The responses of the IRB members in this study indicate that adding more unaffiliated members to IRBs is unlikely to increase IRB concerns with ethical issues. Adding more nurse members to IRBs might increase IRB concerns with ethical issues if the level of influence of the nurses is increased.     

Exception from Informed Consent: Viewpoint of Institutional Review Boards—Balancing Risks to Subjects, Community Consultation, and Future Directions

Differences in interpretation of the Final Rule for exception from informed consent (EFIC) requirements for emergency research result in inconsistencies in implementation and difficulties for some institutional review boards (IRBs) to approve such research. During a consensus workshop organized by the editorial board of Academic Emergency Medicine, participants discussed how IRBs balance the risks to human subjects in EFIC research, the conduct of community consultation and its role in IRB decision making, and future directions to improve and research EFIC effects. Areas of consensus and diversity of opinion were identified. During the workshop, the National Institutes of Health model of consensus building was used to develop statements pertaining to specific questions of the effects, directions, implementation, and ultimate goals for emergency research using EFIC. The program was composed of an overview of the history and issues related to EFIC or Final Rule research and presentations of viewpoints of experts in this area of research. A final consensus was developed regarding the major topics, including IRB perspective, effective community consultation (often considered the main difficulty in implementing EFIC research), and goals for future directions and research on the topic. Roundtable discussions and breakout sessions involving interested parties were used as a format. In regard to how IRBs balance risks, by consensus it was agreed the regulations stipulate that EFIC studies must involve treatment that is unproven or unsatisfactory. The committee agreed that resuscitation rates are currently unsatisfactory, and thus current treatments are unsatisfactory. Many treatments currently used as standard care have never been proven to be effective. IRBs and the public need education that resuscitation research is needed. The same can be said for other conditions to which this rule applies. Because IRB expertise differs across the country, a group of peer reviewers to act as consultants should be available to help IRBs determine if current treatment for a condition is unproven or unsatisfactory. In regard to community consultation, the experiences of others are important and helpful as guidance. The amount and formats of community consultation should correspond to the amount of risk involved in the study proposed. In regard to future directions, communities should be asked how they define “success” of community consultation and public disclosure. Research on community attitudes is critical. Ways to continue/add to research include the following: research including major National Institutes of Health/Centers for Disease Control and Prevention funding acquisition for evaluation of the clinical impact of EFIC research; education for research funding agencies about emergency research, including current outcomes (e.g., survival rates); participation of emergency medicine researchers in meetings of research ethicists/IRB members (Public Responsibility in Medicine and Research/Applied Research Ethics National Association); publication of experiences and of the effects of EFIC research; future update meetings such as this one at the Society for Academic Emergency Medicine meeting; and more membership on IRBs of emergency physicians. While IRBs must approve EFIC research based on their own local environment, additional guidelines from regulatory agencies may be helpful. In general, current treatments for EFIC conditions are unsatisfactory and many are unproven. A group of peer reviewers can act as consultants to IRBs that do not have this expertise.     

Global requirements for DNA sample collections: results of a survey of 204 ethics committees in 40 countries

The Industry Pharmacogenomics Working Group has an interest in attaining a better understanding of global requirements for sample collections intended for pharmacogenetics research. To have adequately powered pharmacogenetics studies representative of the clinical trial population, it is important to collect DNA samples from a majority of consenting study participants under many institutional review board/ethics committee (IRB/EC) jurisdictions. A survey was distributed to gather information from local and central IRBs/ECs. The survey included questions related to the approval of pharmacogenetics studies, collection and banking of samples, and return of data to subjects. A total of 204 responses were received from global IRBs/ECs with pharmacogenetic experience. The data show that requirements for approval of pharmacogenetic research differ between IRBs/ECs within and between countries but not between regions of the United States. A better understanding of differing requirements should facilitate global sample collection of DNA for pharmacogenetics research and may provide the basis for harmonized regulations for collection of genetic samples in the future.     

Maintaining Client Safety and Scientific Integrity in Research with Battered Women

Purpose: To increase awareness of considerations of privacy and safety as well as the potential for scientific misconduct in research with battered women and other groups especially vulnerable to these concerns. Research with such vulnerable populations demands consideration of privacy and safety of participants in order to limit any potentially negative consequences while also ensuring scientific integrity.
Organizing Framework: Maintaining scientific integrity and protecting vulnerable groups are important but potentially contradictory. Battered women are the examples to illustrate instances of conflict in which protecting participants may undermine scientific integrity.
Sources: Literature on scientific integrity and misconduct, battered women, and vulnerable populations, and socially sensitive topics from nursing, other biomedical and social sciences, and the U.S. Public Health Service, 1978–1998.
Method: Integrative literature review.
Findings: Conducting research with battered women in an ethically responsible manner that maintains scientific integrity without compromising advocacy or safety is possible when scientists are aware of potential conflicts and methods to ensure integrity.
Conclusions: Nurses frequently do research with vulnerable groups such as battered women. Being proactive can help promote scientific integrity, avoid scientific misconduct, and decrease negative outcomes.     

Exploring the institutional review board process

This article presents both the content required in preparing a proposal for review by an institutional review board (IRB) and the process involved in gaining approval. The six categories of a research proposal related to protection of human subjects are described, i.e., characteristics of the groups involved; special groups; type of consent; confidentiality of data; possible risks involved; and non-beneficial research. Federal requirements for ensuring informed consent are presented. The politics involved in winning approval for a nurse principal investigator are identified.     

Searching for an efficient institutional review board review model: Interrelationship of trainee-investigators, funding, and initial approval

In this study we sought to identify variables associated with institutional review board (IRB) decisions to develop an efficient "pre-IRB" review model. We explored several variables, including relationships among the identification of trainees as investigators, external sources of funding, and initial approval. The sample consisted of all new submissions reviewed by the 2 medical IRBs at the University of Miami (UM) during a 1-year period. Trainees included students, residents, and fellows. At least 1 trainee had to be identified for a proposal to be considered a trainee submission. The medical-science committees (MSCs) were similar with regard to the numbers of new submissions they reviewed during convened meetings (MSC-A 242, MSC-B 241) and the percentages of proposals that were initially approved (MSC-A 52.9%, MSC-B 53.1%). Approved submissions were defined as those initially approved or conditionally approved pending minor modifications. We noted a robust statistical difference between the percentages of trainee submissions initially approved (39.9%) and submissions that did not identify a trainee (59.4%) ( P <.0001). Of the proposals that were initially not approved (tabled [deferred] or rejected [not approved]), 28.9% of those including a trainee were rejected, compared with 11.0% without a trainee ( P <.001). Proposals in which the source of funding was identified were more likely to be approved (64.2%) than were those in which it was not (30.8%) ( P <.0001). Funding also seemed to influence the trainee and initial-approval interaction. Our results show that new submissions that identified trainee investigators were more likely to be deferred or not approved than those that did not. Nonapproved proposals that identified a trainee were 3.8 times more likely to be initially rejected than those that did not. A prereview model could target those submissions that list a trainee, lack funding, or both.     

Neuroscience nursing research: human subjects considerations.

Permission to conduct research must be obtained from all institutions which will be involved. The special nature of our target population may result in a particularly detailed review. Specific suggestions to facilitate approval to conduct research address utilization of institutional personnel, informed consent and concerns of the IRB. Seek guidance from knowledgeable employees. You can obtain a great deal of useful information from IRB secretaries and nurses who are engaged in research in the target institution. Informing potential subjects about the research is critical, and is best done using strategies such as assuring the language used enhances comprehension. Finally, be prepared to discuss concerns of the IRB. The ability of impaired subjects to communicate with you, the researcher, seems to be of particular concern to many IRBs.     

Informed Consent for Medical Research: Common Discrepancies and Readability

Objective: To identify common discrepancies and average reading grade levels for informed consent forms (ICFs) us submitted to institutional review boards (IRBs) by medical researchers.
Methods: A retrospective evaluation of ICFs as submitted to IRBs of 3 university-affiliated hospitals during a I-year period. ICF content was evaluated using a checklist of 23 requirements specified in the federal regulations governing human research. Documents then were computer-analyzed to determine the readability scores using 2 common indexes of comprehension. A discrepancy was defined as any instance in which an ICF did not address an applicable requirement in the Code of Federal Regulations.
Results: Eighty-two ICFs representing 16 medical specialties were evaluated; 8 (10%) were from emergency medicine. Eighteen ICFs (22%) were conspicuously incomplete, lacking 29 federal requirements. The mean number of discrepancies was 4.7 (95% CI, 3.9–5.5) Common omissions included: a statement about who is doing the research, number of subjects in the study, circumstances when a subject's participation may be terminated, disclosure of alternative procedures, and notice to subjects regarding new findings. The mean Flesch grade level required to read all ICFs was 13.8 (95% CI, 13.5–14.2), implying that the majority of the U.S. adult population would be unable to comprehend these forms.
Conclusion: Designing a consent form to meet all of the federal requirements while maintaining a level of reading comprehension suitable for the general population is a difficult task for investigators.