The role of the IACUC in ensuring research reproducibility

Abstract There is a “village” of people impacting research reproducibility, such as funding panels, the IACUC and its support staff, institutional leaders, investigators, veterinarians, animal facilities, and professional journals. IACUCs can contribute to research reproducibility by ensuring that reviews of animal use requests, program self-assessments and post-approval monitoring programs are sufficiently thorough, the animal model is appropriate for testing the hypothesis, animal care and use is conducted in a manner that is compliant with external and institutional requirements, and extraneous variables are minimized. The persons comprising the village also must have a shared vision that guards against reproducibility problems while simultaneously avoids being viewed as a burden to research. This review analyzes and discusses aspects of the IACUC's “must do” and “can do” activities that impact the ability of a study to be reproduced. We believe that the IACUC, with support from and when working synergistically with other entities in the village, can contribute to minimizing unintended research variables and strengthen research reproducibility. Main In recent years there has been increasing awareness and concern about the difficulty in obtaining reproducible data when the same experiment is repeated in a laboratory other than the laboratory where it was originally conducted. The extent of this problem is underscored by publications, surveys, and workshops devoted to the topic1,2,3,4. The problem extends beyond biomedical experimentation as similar concerns have been raised for research conducted in psychology5,6, ecology7, nutrition8, bioinformatics9, human clinical medicine10 and homeopathic disciplines11. Improving reproducibility success takes the effort of an entire “village” that includes entities such as funding review panels, investigators, research institution leadership, laboratory animal facilities, IACUCs, and journals. Using an example emanating from an institution's animal program, the inability to reproduce experimental results may be due to nothing more than one unintentional experimental variable that might seem innocuous at first glance, such as temperature variations, exposure to different microbiomes, or surgical technique variations. Fortunately, safety nets already exist to help guard against such seemingly innocuous variables, and when properly employed they can individually and collectively enhance the likelihood of a study's reproducibility. For instance, a) an organization's leadership can set an example for, and insist upon, the highest level of research integrity, including institutional expectations for regulatory compliance and principled support for compliance committees, b) principal investigators can provide more detailed and coherent animal procedure protocols and provide adequate oversight of laboratory operations that can include assuring that reagents or diets are in date and properly stored, animals are correctly identified, study endpoints are clearly understood and applied, all needed records are retained, and staff members are appropriately and adequately trained, c) animal facilities can ensure a consistently high level of animal husbandry, veterinary care and recordkeeping practices, including records of the vendors used to purchase commodities as well as records of the food, bedding, room environmental conditions and other variables that have the potential to impact the reproducibility of a study, d) IACUCs can ensure that reviews of animal use requests, program self-assessments and post-approval monitoring programs are sufficiently thorough to reasonably ensure that the animal model is appropriate for testing the hypothesis and that animal use is conducted in a manner that is compliant with external and internal requirements. Thus, IACUC responsibilities must synergize with the rest of the institutional animal program to minimize unintended variables that can impact reproducibility. Outside of an institution's animal program, a) federal study sections or other review panels should require a thorough description and evaluation of the chosen model, proposed study design, and specific procedures involved and b) professional journals should establish and enforce criteria for manuscript acceptance, including those suggested in the ARRIVE12 and CONSORT13 guidelines. The difference between what the IACUC can do from what it must do should be recognized. Whether it is referred to as the “high road” versus the “low road”, the spirit versus the “letter of the law” or, most likely, some combination thereof, each institution has a culture that influences its approach to regulatory oversight and research integrity. However, it is the IACUC that has the latitude to set performance standards and, therefore, set the stringency with which it performs its mandated duties. Clearly, as investigators have increasing pressures on their time, their concerns about regulatory burden and creep must be acknowledged and managed when establishing the level of checks-and-balances applied and safety nets implemented in the oversight of animal-based research. Thus, the IACUC's role in reproducibility can be broad, but ultimately boils down to the institution's philosophical approach to addressing regulations and research integrity. The remainder of this article will focus on what IACUCs can do to promote experimental reproducibility within the context of its mandated responsibilities. However, as alluded to above, the IACUCs' efforts are only one of the safety nets needed to maximize the chance that an experimental finding can be reproduced. Indeed, the committee's efforts will be greatly diminished or even negated if the other entities supporting, reviewing, approving, disseminating and otherwise contributing to animal-based research do not ensure that their own safeguards are in place and free from ambiguity. The IACUC's role in the choice of an animal model One of the first decisions an investigator has to make when designing an experiment using animals is to select the appropriate model. The public has a right to expect that the model will advance knowledge and have societal value. If the proposed work has not undergone peer review, IACUCs are obligated to confirm that the model choice is supported by sound, objective and logical reasoning14. Animal models can be used to study normative biology or behavior or a pathological process having one or more attributes resembling the condition in humans or other animals. Realistically, most animal models have limitations and the validity and applicability of a model to predict responses in another species may or may not be consistent or reproducible. In other words, model reproducibility may arise independently or concurrently with model validity. Model reproducibility can also be dependent on the natural biological variability of the animal population, which is an intrinsic characteristi (...truncated)