Fit for Purpose Assessment: A New Direction for IACUCs.

The organization and function of the institutional animal care and use committee (IACUC) is the key component of government regulation and oversight of necessary scientific research using live animals and of AAALAC - International accreditation of animal care and use programs in the United States. The regulations, roles, and responsibilities of IACUCs have evolved since their inception 35 years ago from a limited focus on animal welfare and specific animal procedures to embracing scientific quality, data reproducibility and translation, and animal welfare as inextricably interdependent and critical components of generation of new scientific knowledge and medical treatments. A current challenge for IACUCs is in evaluating whether benefits to be derived (eg, new knowledge or treatments) justify any unavoidable pain, stress, or injury associated with proposed research protocols, because the former are long-term and at best speculative outcomes, whereas the latter are immediate and tangible for the study animals. Scientific consensus is that research most likely to generate significant new knowledge and medical treatments is that conducted to high scientific, technical, and quality standards and reported with full transparency to facilitate reproducibility. As an alternative to current benefits evaluations included in risk benefit and harm benefit constructs, the authors propose that IACUCs assess the proposed research for scientific quality and alignment of study elements with the study purpose (e.g., Fit for Purpose [FfP]), including justifications for study design components, selection of primary endpoints and technologies, rationale for data and statistical analyses, and research communication plans. Fit for Purpose endpoints are objective, immediate, and impactful as are the potential risks for study animals, and at the same time they are the best predictors for achievement of longer-term benefits. We propose that IACUCs and any revision of The ILAR Guide consider FfP concepts in place of traditional benefits assessment to accelerate the generation of new knowledge and treatments benefiting medical and veterinary patients and the environment through better science and animal welfare rather than to continue to rely on speculative future outcomes.

Patients beware: commercialized stem cell treatments on the web.

A report by the International Society for Stem Cell Research (ISSCR)'s Task Force on Unproven Stem Cell Treatments outlines development of resources for patients, their families, and physicians seeking information on stem cell treatments.

Research knowledge among the participants in the Treatment for Adolescents With Depression Study (TADS).

OBJECTIVE: We examined the extent to which parents and adolescents participating in the Treatment for Adolescents With Depression Study (TADS) understood key aspects of the study. METHOD: TADS was a clinical trial comparing the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), their combination, and placebo in 439 adolescents (12-17 years old) with major depressive disorder. Six weeks after starting treatment, adolescents and their parents were asked to complete a questionnaire about critical elements of the trial. RESULTS: Completion rate was 67.2% for adolescents (N = 295) and 73.6% for parents (N = 323). More than 90% of the completers knew of the main purpose of the trial, possible assignment to placebo, and their right to withdraw participation at any time. However, about one third overall (and 49% in the CBT group) described TADS as "education" rather than "research." Of 12 questions, the mean number of correct answers was 10.3 (SD 1.7) among adolescents and 11.2 (SD 1.2) among parents (p <.0001). The most frequently stated reason for TADS participation was the pursuit of high-quality care. CONCLUSIONS: Most parents and adolescents were well-informed research participants. Difficulties in appreciating the research nature of the trial, however, emerged, especially among participants assigned to psychotherapy. Parents were overall better informed than adolescents.

Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations.

United States federal regulations for pediatric research with no prospect of direct benefit restrict institutional review board (IRB) approval to procedures presenting: 1) no more than "minimal risk" ( section sign 45CFR46.404); or 2) no more than a "minor increase over minimal risk" if the research is commensurate with the subjects' previous or expected experiences and intended to gain vitally important information about the child's disorder or condition ( section sign 45CFR46.406) (DHHS 2001). During the 25 years since their adoption, these regulations have helped IRBs balance subject protections with the pursuit of scientific knowledge to advance children's welfare. At the same time, inconsistency in IRB application of these regulations to pediatric protocols has been widespread, in part because of the ambiguity of the regulatory language. During the past decade, three federally-charged committees have addressed these ambiguities: 1) the National Human Research Protections Advisory Committee (NHRPAC) (Washington, DC), 2) the Institute of Medicine (IOM) Committee on the Ethical Conduct of Clinical Research Involving Children (Washington, DC); and 3) the United States Department of Health and Human Services Secretary's Advisory Committee for Human Research Protections (SACHRP) (Washington, DC). The committees have reached similar conclusions on interpretation of language within regulations section sign section sign 45CFR46.404 and 406; these conclusions are remarkably consistent with recent international recommendations and those of the original National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) report from which current regulations are based. Drawing on the committees' public reports, this article identifies the ethical issues posed by ambiguities in regulatory language, summarizes the committees' deliberations, and calls for a national consensus on recommended criteria.

Verification of IACUC approval and the just-in-time PHS grant process.

Public Health Service Policy requires institutional animal care and use committees (IACUCs) to review and approve the animal care and use aspects of grant proposals submitted for funding. Initially, submission of verification of approval was required with submission of the proposal; however, in 2002, a ''just-in-time'' (JIT) process was begun to allow submission when it appeared that the proposal would be in the fundable range. After 3 yr, no evaluation of JIT and its impact on the IACUC has been published. An online survey designed by the authors to determine this impact is described. Invitations to participate in the survey were sent to 1002 IACUC chairs and administrators, and responses were received from 168. Surprisingly, 30% of respondents indicated that they did not review grant proposals at all. The majority of those respondents reported that they rely on principal investigator assurance that approved IACUC protocols match grant proposals. In the authors' experience, this procedure is not safe 23% of the time, and several respondents described the same experience. Most respondents indicated that they use JIT whenever possible for all investigators. Of those who reviewed grant proposals, most indicated that each review consumes 20 to 29 min, and most respondents indicated that the granting agency does not allow enough time for a JIT verification to complete a de novo submission and review of a protocol. Instead, the protocol must have been submitted and reviewed prior to the JIT request. Respondents indicated that there is considerable uncertainty about what the granting agency would do when an IACUC requires changes in a protocol during the JIT process.

Should IACUCs review scientific merit of animal research projects?

Whether IACUCs should review animal research protocols for scientific merit is not addressed in the federal regulations, resulting in ongoing confusion on the subject. The authors examine this issue, discuss the pros and cons, suggest how IACUCs can go about reviewing protocols for scientific merit, and question what effect recent changes in regulations will have on this issue.