IRB Review Research Articles

Maximizing Benefits and Minimizing Risks in Health Services Research Near the End of Life

This article explores the ethical issues specific to Health Services Research (HSR) in palliative care, with particular attention to similarities and differences between HSR and institutional quality improvement (QI) initiatives. We focus on the challenges of determining what level of protection is warranted by investigations of health services and programs of care, in contrast to the traditional randomized clinical trial design, and how best to assure subject protection. A decision algorithm regarding the requirements for full IRB review and informed consent is proposed as a mechanism to assure that the level of protection is commensurate with the level of risk.

Ethical regulations for innovative surgery: the last frontier?

There are no clear federal regulations governing innovative surgery, even though general guidelines regulating research with human subjects do exist. We hypothesized that US surgeons are unaware of Department of Health and Human Services regulations, rarely seek IRB review, generally oppose outside regulation of innovative surgery, and are uncertain what constitutes innovation and research. These circumstances, if true, would pose a significant ethical problem and present potential harm to patients as unwitting subjects of research. In a pilot study we reviewed 527 issues of US surgical and medical journals, selecting 59 articles published between 1992 and 2000, that described innovative surgery. Corresponding authors from university hospitals (71%) and other facilities (29%) were sent an anonymous questionnaire. The survey was conducted between November 2000 and May 2001. Twenty-one questionnaires were returned, completed with responses, constituting a 35% overall response rate. Fourteen authors confirmed their work was research, yet only six had sought prior IRB review. The majority of authors (15 of 21) did not submit their protocol to IRB. Only seven authors had mentioned the innovative nature of the procedure in the informed consent form. Seven authors claimed familiarity with Office for Human Research Protections definitions of research and human subject. Two-thirds of the respondents stated that government regulations for the protection of human subjects of innovative surgery would not be appropriate. The current system of definitions, ethical theories, and voluntary professional guidelines may be inadequate to meet the challenge of surgical innovation. Further research is proposed to examine the adequacy of the existing guidelines.

The IRB Is Not a Data and Safety Monitoring Board

At the November 1998 PRIM&R (Public Responsibility in Medicine and Research) and ARENA (Applied Research Ethics National Association) conferences a topic of interest in multiple sessions was the management of adverse event reports (AERs). Each year IRBs spend more time and energy reviewing AERs from multicenter trials. Many question the value of IRB review of AERs in this setting because the IRB does not have ac-

Demystifying Central Review Boards: Current Options and Future Directions: A Summary Report of Outcomes from "Central IRB Review of Multi-Site Trials," 27-28 October 1998

Demystifying Central Review Boards: Current Options and Future Directions: A Summary Report of Outcomes from "Central IRB Review of Multi-Site Trials," 27-28 October 1998

Testing drugs in pediatric populations: The FDA mandate

On November 27, 1998 the Food and Drug Administration (FDA) issued a new rule requiring that drugs and biological products be tested in pediatric populations. Since voluntary testing in pediatric populations had not resulted in a significant increase in pediatric labeling of drugs, stronger measures were needed to ensure that infants and children would receive the benefits of properly tested drugs and biologies. The mandate for pediatric testing raises a core ethical question: How should the need for validated treatments that benefit children as a group be weighed against the obligation to protect individual child subjects of research? The preamble to the new rule claims that adherence to Department of Health and Human Services (DHHS) and American Academy of Pediatrics (AAP) guidelines will provide adequate protection to individual subjects. Yet the special protections provided to children in these guidelines are not required by the new FDA rule, and have never been obligatory for research that is regulated by the FDA. While the new rule does not necessitate or encourage violation of these standards, the rule does not pay adequate attention to them nor clarify what role they should play in IRB review of protocols under FDA regulation.

At Law: Time for New Rules on Human Subjects Research?

An era of relative contentment with the federal rules on human subjects research appears to have ended. Beginning with the 1995 Final Report of the Advisory Committee on Human Radiation Experiments,[1] a growing array of federal officials and advisory groups have raised concerns about the state of human studies oversight. The latest assessment and the most detailed to date comes from the Department of Health and Human Services Inspector General, which in June 1998 presented four reports based primarily on a review of federal records and committee reports and on the literature on human subjects protection. The IG's overarching conclusion is that the long-established system for protecting human subjects has vulnerabilities that threaten its effectiveness.[2] To address those vulnerabilities, the IG proposed numerous revisions in the federal requirements governing human subjects research. According to the IG, the IRB system's effectiveness is jeopardized by a series of recent developments in the research environment. The reports emphasize six such developments. First, to recruit subjects, researchers rely more and more on advertising that stresses the financial and potential therapeutic benefits of participating in the research. Second, IRBs review a substantially increased volume of research proposals, some of which, such as those involving genetic testing, raise novel ethical questions. Third, IRBs fail to re-examine studies carefully after the initial approval process. A related problem is that IRBs are not getting the information they need from data safety and monitoring boards and from the existing method of adverse incident reporting. Fourth, greater reliance on commercially sponsored research in both academic and independent health centers can lead to pressure on IRBs to issue speedy and accommodating decisions. Although nonscientist and unaffiliated IRB members could in theory mitigate such pressure, most IRBs do not have enough such members to make a difference. The two remaining problems affecting the quality of IRB review concern the oversight of IRBs themselves. One is that research facilities and their IRBs fail to offer investigators and IRB members sufficient instruction on the ethics and regulations relevant to human subjects protection. Another is that there is no system for evaluating IRB performance. Because IRBs and federal agency officials neither observe the actual research process nor seek information from subjects during and after research, the adequacy of human subjects protection remains unclear. IG Recommendations The reports offer numerous recommendations to address these problems. Some of them will be welcomed by IRB members and administrators; others could be somewhat unsettling. Many would require changes in current federal regulations. For example, the IG says the National Institutes of Health and the FDA should hold IRBs more accountable for protecting human subjects but should at the same time give IRBs more freedom to determine how they carry out their mission. The reports suggest that current requirements for annual IRB review of all approved protocols impose significant administrative burdens on IRBs without necessarily advancing human subjects protection. Subjects would be better served if IRBs were able to devote less time to low-risk studies and more time to in-depth inquiries on projects that present the highest risk to subjects. Such inquiries could incorporate the use of consent observers or intermediaries, announced or unannounced site visits, and discussions with subjects. To reduce the burdens on IRBs, the IG also indicated that it might be appropriate to permit IRBs to review studies only after they have been funded. On a similar note, the IG recommended that the NIH abandon its requirement for lengthy and detailed institutional assurances in favor of an institutional attestation to conform to the IRB requirements set forth in Federal regulations. …

IRB Review of Adverse Events in Investigational Drug Studies

IRB Review of Adverse Events in Investigational Drug Studies

Structuring the Review of Human Genetics Protocols Part II: Diagnostic and Screening Studies

to many IRB members. As with other protocols, the IRB must evaluate the validity and value of the research, subject eligibility criteria and recruitment strategies, quantification or prediction of risks and benefits, disclosure of information to prospective subjects, privacy and confidentiality, and protocol monitoring. In reviewing genetics research, the challenge for IRBs is to recognize when new issues are presented, and to determine whether they are addressed appropriately by the investigators before recommending approval, amendment, or disapproval of protocols. In previous work, we addressed the review of gene localization and identification protocols.1 We have designed the present article to assist investigators and IRB members in their review of genetic dignostic and screening protocols. We provide a general description of diagnostic and screening studies, set out a checklist/critical path identifying issues for IRB review (table 1), and discuss in greater detail several points of controversy raised by this kind of research. A glossary is provided for terms that are not defined in the body of the text (table 2). Because gene localization and identification protocols and genetic diagnostic and screening studies frequently contain overlapping issues, we recommend that the two articles be read together.

Continuing IRB Review When Research Activity Is Limited to Routine Follow-up Evaluations

Continuing IRB Review When Research Activity Is Limited to Routine Follow-up Evaluations

A Survey of University Institutional Review Boards: Characteristics, Policies, and Procedures

review research proposals, 15-17 the reliability and variability of IRB reviews,18',19 the satisfaction of researchers with IRBs,13 and the politicization of the IRB review process.14,20 An excellent summary of the IRB literature can be found in Levine.21 Gregory J. Hayes, MD, MPH, is chairman and associate professor, Department of Health Sciences; Steven C. Hayes, PhD, is chairman and professor, Department of Psychology, University of Nevada, Reno; and Thane Dykstra, BA, is a psychology intern, Brown University, Providence, R.I. Federal regulations have attempted to set national standards for IRBs.22

Who Understands? A Survey of 25 Words or Phrases Commonly Used in Proposed Clinical Research Consent Forms

We all write excellent consent forms to be presented to prospective participants in clinical research studies. That is, we think that they are excellent. But many times consent forms are written from our jaded perspective and contain terms of clinical research jargon, common to us, but foreign to a participant. These terms slip through unnoticed because of their familiarity in our everyday language. In a recent study a computer analysis (Flesh-Fry scoring) of 71 consent forms at a midwest university showed that a mean U.S. school grade for 70 percent comprehension was about 15. In simple terms this means that you would have had to complete your junior year in college to understand 70 percent of the language in the consent forms, which implies about 37 percent of the U.S. adult population could read them. Similar analyses were done with columns of Ann Landers, articles from Reader's Digest, and columns from the New Yorker. Analysis of Ann Landers columns showed readability by a median seventh grader and by 75 percent of the U.S. adult population. Reader's Digest articles yielded data showing a readability by a 10th grader or about 60 percent. Lastly, analysis of the New Yorker columns revealed they were readable by only about 43 percent of the U.S. population. In short, these three widely published columns and articles all were more easily read than the analyzed consent forms. It was the authors' opinion that in their case IRB review did little to improve readability. In the above study 64 of the 71 consent forms received final IRB approval. Eighty percent of the forms were revised according to the IRBs’ wishes. No forms improved by more than a grade reading level and eight of the forms actually worsened. Prior studies have also shown that most consent forms are not readable by the general population. 5-9 In our IRB meetings we often question some of the terms that appear in the text. The clinical research jargon runs rampant in many cases and would appear to confuse the lay reader. In an effort to answer some of these questions we designed a questionnaire to quiz a cross-section of the population on their understanding of many of these terms. In the spring and summer of 1992 the survey was conducted in person by the interviewer on an individual basis. Many of the answers were predictable. Some were surprising! The questionnaire was on standard 81/2 x 11 plain bond with demographic information on top of the first page, such as gender, place of interview, occupation, and maximum educational level. This was followed by the paragraph below:

IRB Review of a Phase II Randomized Clinical Trial Involving Incompetent Patients Suffering from Severe Closed Head Injury

IRB Review of a Phase II Randomized Clinical Trial Involving Incompetent Patients Suffering from Severe Closed Head Injury

Transplantation through a Glass Darkly

Bioethical problems take many different forms, and fascinate many different kinds of people. Physicians and philosophers, lawyers and theologians, policy analysts and talk show hosts are all drawn by the blend of practical urgency and moral complexity that characterize these issues. But there seem to be only two kinds of bioethical problems that typically pull into their orbits not only theorists and practitioners, but pickets and protesters as well. When it comes to the treatment of fetuses and animals, people take to the streets. On the same day that demonstrators on both sides of the abortion issue lamented the Supreme Court's decision in Casey, representatives of PETA (People for the Ethical Treatment of Animals) gathered at the University of Pittsburgh to protest the implantation of a baboon's liver in a thirty-five-year-old man--the father of two children--whose own liver had been destroyed by hepatitis B virus. There is, of course, a big difference in the way the disputes are perceived: abortion's bona fides as a central ethical issue are well established, but despite an upsurge of interest among ethicists over the past decade and a half, concern about animals still seems a bit quirky, too exclusively the domain of zealots who maintain the moral equality of all species, and thereby mark themselves as fundamentally out of sympathy with our basic ethical traditions. Here I try to pull moral consideration of nonhumans closer to the ethical center, arguing that thinking about the fate of nonhumans at our hands shares with abortion--indeed, with many of our culture's most difficult moral issues--a fundamental problem: we don't really know what we are talking about. More concretely, we're at a loss to say what it is about baboons that makes their livers fair game, when we wouldn't dare take vital organs from those of our own species whose abilities to live rich, full lives are no greater than those of the nonhumans we seem so willing to prey upon. Unless we're able to isolate and defend the relevant moral distinction, we should reject the seductive image of solving the problem of organ shortage by maintaining colonies of animals at the ready for transplantation on demand. Moral Outliers Public protest about abortion is not galvanized by concern about the quality of informed consent, or its impact on the doctor-patient relationship. What does lie at the center of the dispute is an absolutely crucial kind of ignorance. As a society, we don't know what fetuses are, and, in an important sense, we don't know what pregnant women are either. Are fetuses babies or tissue? Are pregnant women mothers bound by special duties to their unborn children, or independent adults exercising their right to make important self-regarding decisions under the protection of a mantle of privacy? Because we don't know these things, and they matter so much, we have a hard time imagining what responsible compromise might really be like. And what gets people out into the streets in response to a daring attempt to rescue from certain death a young father of two? What, for that matter, causes medical research advocacy organizations to spend large amounts of money, not on research, but on fullpage ads in the New York Times defending what scientists do? Is it concerns about justice in the allocation of medical resources? Doubts about the courage to fail ethos? Misgivings centered around the independence of IRB review? Surely not. The ground of protest and counter-protest is a similar kind of ignorance about the fundamental terms of the relevant moral discourse: we don't know what animals are, either. We treat them as if they were morally protean; we mold them into anything from much-loved companions and symbols of virtue to mere machines for making food and instruments for scientific research. Our ignorance as a society about these dark corners of our moral commitments, our lack of consensus about where outliers really fit, is extremely divisive when coupled with individual assurance that there is in fact available knowledge about these matters, that the answers are of surpassing importance, and that there is something suspicious, if not downright evil, about the people who don't get it. …

Experiences with Contract Research Organizations

Over a period of 10 years, Schering has worked with at least 15 contract research organizations (CROs), including everything from IRB review to Phase III long-term safety studies. Perhaps 90% to 95 % of the studies have been “short-term” protocols, ie, Phase I, biopharmaceutical/bioequivalence, dermal irritation or sensitivity studies, etc. These have been the most successful. This article outlines some of the advantages-disadvantages of doing different types of studies and gives some recommendations for increasing the chances of a successful venture for both parties.

A Protocol Review Guide to Reduce IRB Inconsistency

The format employed for the review of research protocols by an IRB varies considerably across institutions. The basic principles underlying IRB review, however, should not. The National Commission for Protection of Subjects in Biomedical and Behavioral Research' and the federal regulations which govern human subject research2 require that IRB approval be based upon specified criteria: (a) the risks to subjects are minimized; (b) the risks to subjects are reasonable in relation to anticipated benefits; (c) the selection of subjects is equitable; and (d) informed consent is adequate. Thus, it is the charge of each IRB to apply these approval criteria during their review process fairly, equitably, and reliably. IRB members and investigators are generally aware that one of the most significant problems the IRB faces is inconsistency in the protocol review process. Although the literature contains few empirical studies, the data generated thus far indicate the existence of both internal IRB inconsistency and inconsistency among IRBs. 3-6 This inconsistency extends to all facets of the IRB review process including standards of review, decisions to approve or disapprove research protocols, required modification of the consent form, and/ or protocol and justification for IRB actions. Many factors influence an IRB's decision. IRB judgments may reflect institutional values, institutional pressures, committee composition, and prevailing community standards. Incidentals such as Board attendance, length of meetings, order of protocol review, and the number of ethically difficult protocols also affect IRB deliberations. Even the federal regulations contribute to inconsistency by virtue of their ambiguity. Since a number of sections of the regulations were written in purposefully vague terms in order to protect the autonomy of local IRBs it is not surprising that variation exists in their interpretation and application. The University of Nebraska IRB has experienced the same internal inconsistency of review that is common to other IRBs. In order, therefore, to reduce this inconsistency the Nebraska IRB developed and now operates according to a comprehensive set of guidelines and principles,7 which provides an interpretation and elaboration of the federal

IRB Review as a "Cooling out" Device

IRB Review as a "Cooling out" Device

Random-Sampling: A Modest Proposal for Reforming IRB Review

Random-Sampling: A Modest Proposal for Reforming IRB Review

Scientific Design, Ethics, and Monitoring: IRB Review of Randomized Clinical Trials

Scientific Design, Ethics, and Monitoring: IRB Review of Randomized Clinical Trials

IRB Review: A Moral Policy

IRB Review: A Moral Policy

'Conflicting Interests' in IRB Review

'Conflicting Interests' in IRB Review