13 years and 900 applications: perspectives and advice from the NC3Rs peer review service

The NC3Rs has provided a peer review and advice service to the major UK funders of animal research for over a decade. Having recently completed our 900th review, it seems a fitting time to discuss how the service fits into the overall peer review processes of the funding bodies and consider the ways in which applicants might best prepare for the NC3Rs review.

The purpose

NC3Rs staff members review certain types of research proposals submitted to UK public funders of bioscience research, as part of our peer review and advice service. Our role as reviewers is to advise both applicants and funders on opportunities to implement the 3Rs, raise specific animal welfare concerns, highlight where good practice is and is not being adopted, and monitor implementation of specific policies and guidance. The advice we provide is taken into account during funding decisions and when drafting the terms and conditions of grant awards. In this way, we help to ensure that the 3Rs are implemented in the science that is supported.

We currently assess all proposals involving the use of non-human primates, cats, dogs and equines – these species receive special protection under the Animals (Scientific Procedures) Act 1986 due to the level of societal concern about their use. Such applications can be submitted to any funding scheme (e.g. research grants, studentships, fellowships) and the research based in any part of the world, though the standards of animal use and care in funded work must be equivalent to those provided in the UK. Since 2015 we have also reviewed proposals involving pigs submitted to the BBSRC, in line with growing demand for their use in agricultural research and as a model for human physiology. Under special circumstances, such as when use of a very large number of animals or severe procedures is proposed, we are asked to review applications involving smaller species, such as mice and rats.

The focus of our review can be as varied as the applications we are asked to assess. However, there are three broad areas of consideration:

  1. The need for animal use. It is important for the applicant to justify why the animal species/model is necessary to achieve the research aims, including why other approaches (non-animal or animal) are not feasible for the project. Generally the need for animal use is well justified by applicants. However, in some cases the species used has been changed, or certain studies removed, as a consequence of our review.
     
  2. The design of the experiments and the number of animals requested. We look for evidence that the proposed experimental design is robust and efficient in terms of animal use, and that the experiment is adequately powered to detect an effect of importance. Such considerations are often as likely to result in a recommended increase in the number of animals required as they are a recommended reduction in animal numbers.
     
  3. The provisions in place to optimise animal welfare. We review the animal supply, housing, husbandry, handling and procedures, aiming to establish that defined efforts have been made to refine each of these factors as much as possible. In many cases, our service has led to the implementation of provisions such as group housing, larger enclosures, additional enrichment, training for voluntary cooperation with procedures, better welfare monitoring and use of humane endpoints. Even research plans that have previously been considered by the AWERB/IACUC can lack these important refinements.

The process

Our review takes place concurrently with that performed by the scientific referees chosen by the funding body. To streamline this process, we have worked with funders to develop harmonised questions about animal use that are embedded within their respective application forms. Often after reviewing the application we will pose additional questions for the applicants to address, but much of the key information should already be captured in the main form. The goal of this iterative process (see diagram, right) is for the panel and funding body to be able to make decisions with confidence knowing the 3Rs have been given due attention.

The number of proposals we review per year has grown as additional funders, schemes and species have been added to the remit (see graph below). Over 20 funding bodies now use the service, spanning the breadth of UK biological and medical research.

Tips for applicants

Drawing on our experience of the past 13 years of reviews, we have put together the following ten tips to help any applicant prepare and respond to the questions we may pose during our review of their application.

  1. Be open and honest. The goal of our review is not to catch applicants out, or to prevent the appropriate use of animals in research. Our reviewers all have doctoral degrees and practical experience of working in animal research, as well as 3Rs expertise. They appreciate the challenges such work can present. Honesty about the potential welfare issues involved in a study protocol and its severity classification will always be received better than will obfuscation.
     
  2. Demonstrate that you’ve considered the 3Rs in your research plan. Implementation of the 3Rs is a condition of securing research funds. Therefore, demonstrate how you’ve taken these principles into account, with direct reference to your experimental design and the procedures you will use. Non-specific statements such as “We will endeavour to use the minimum number of animals at all stages of our research” are not sufficient.
     
  3. Treat the questions seriously. Pithy, dismissive answers rarely go down well in any review process. Demonstrate that you take the 3Rs and your responsibilities as an animal researcher seriously. If appropriate detail is not provided, it will mean further work for you later as the NC3Rs seeks the required information.
     
  4. Answer the questions fully, with reference to the entire application. As part of their assessment, NC3Rs reviewers will read your entire application, not just the answers to the standard questions about animal use. Answers that are inconsistent with the rest of the application, or irrelevant to the question, will be followed up. Cutting and pasting text from elsewhere in the application doesn’t usually work well.
     
  5. Be consistent. Conflicting information across sections of an application on factors such as number of animals required, procedures they will be subject to, and the institutions that will be utilised at, appear quite regularly in applications we review. Resolving these inconsistencies before submission will save time for everybody.
     
  6. Consider your justification for the choice of species fully and logically. “Special protection” means you cannot utilize these higher mammal species if another would be suitable to answer your research question. Explain in your justification for the choice of species why no other species would be suitable. Try to avoid broad generalisations such as “Non-human primates are more similar to man” and instead focus on providing a scientific rationale (e.g. lack of the anatomical structures, pathways, targets or behaviours of interest in other species).
     
  7. Always back up your animal numbers. Incomplete or indiscernible justifications for the number of animals required in an application will always result in further questions from our reviewers. This can be avoided by providing the workings of your sample size calculation (where one is appropriate), stating each of the variables and the software used to perform the calculation. Be sure to justify your chosen effect size (i.e. the magnitude of response which would be of scientific or clinical interest and worthy of further investigation) and variability (e.g. based on your previous experiments or the published literature).
     
  8. Consider submitting an EDA diagram or report as part of your application. By providing tailored feedback on the design of your experiment and supporting power calculations, randomisation and blinding, use of the Experimental Design Assistant (EDA) sends a strong signal to reviewers (both scientific and 3Rs) that your experimental design has been optimised to yield the best possible data from the lowest number of animals. Many funding bodies (e.g. NC3Rs, BBSRC, MRC) recommend use of this free online tool and we already see EDA diagrams included within applications. Applicants will soon be able to upload an EDA PDF report as part of their application, summarising the essential information the panel want to see on experimental design.
     
  9. Pick your CRO wisely. If requesting funds for drug safety and efficacy studies, choose an appropriate contract research organisation (CRO). The cheapest option will likely fall below the animal welfare standards required in the UK and expected by the funders. If you haven’t yet chosen a CRO, let us know and don't give speculative answers. If funded, it is likely that your award will be ‘milestoned’ with release of funds for studies with higher species made conditional on a satisfactory NC3Rs review once the contractor has been chosen.
     
  10. Use the guidelines and 3Rs resources available from the NC3Rs. There is a wealth of information available on the NC3Rs to website to support you in applying the 3Rs and meeting funders’ expectations in this regard. Some key resources are given below.

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