GRADE for preclinical animal studies: translating evidence from bench to bedside

Oral
2016 Seoul
Hooijmans C1, de Vries R1, Ritskes-Hoitinga M1, Rovers M2, Leeflang M3, in 't Hout J2, Wever K1, Hooft L4, de Beer H5, Kuijpers T6, Macleod M7, Sena E7, ter Riet G8, Morgan R9, Thayer K10, Rooney A10, Schünemann H9, Langendam M3
1SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE), Radboud University Medical Center, Nijmegen, The Netherlands
2Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
4Cochrane Netherlands, University Medical Center, Utrecht, The Netherlands
5Guide2Guidance, The Netherlands
6Dutch College of General Practitioners, Utrecht, The Netherlands
7Center for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
8Department of General Practice, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
9Department of Clinical Epidemiology and Biostatistics, Department of Medicine, McMaster University, Hamilton, Canada
10Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, USA

Background:

Preclinical animal studies are used to develop new clinical treatments. The aim of animal studies (bench) ranges from unraveling pathophysiology and action mechanisms to investigating the clinical potential of selected interventions (bedside). Systematic reviews (SRs) can provide a reliable synthesis of the available evidence on the effect of interventions, but are relatively novel in laboratory animal research. SRs of animal studies can facilitate healthcare decisions, e.g. selection of interventions with therapeutic potential to be tested in clinical trials, regulatory decisions limiting human exposure (drugs or toxicants) or decisions on further animal studies. In addition, evidence from animal studies can inform clinical management decisions, if other evidence is lacking. Certainty in the evidence plays an essential role in these decisions, but guidance on the assessment is lacking.

Objectives:

To apply the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach to preclinical animal studies, to adapt if needed, and to identify methodological issues.

Methods:

A draft GRADE approach for animals studies was developed by a literature survey on how authors of SRs of animal studies address certainty in the evidence, and by applying the ‘human studies’ GRADE approach to three SRs of animal studies to flag challenges. The draft was discussed and improved in several rounds of expert meetings.

Results:

In general, the GRADE approach applied well. The evidence is based on animal studies (bench), but the clinical question (bedside) is central. No factors other than the current GRADE domains were identified. Identified methodological challenges were choice of baseline risk, dealing with inconsistency within and across species, upgrading for consistency across species and specification of translating animal models to humans as part of GRADE’s indirectness domain.

Conclusions:

GRADE can be applied to preclinical animal studies in the context of therapeutic interventions. Further work will concentrate on performing case studies, methodological issues and development of Evidence to Decision frameworks.