Multicenter preclinical studies as an innovative method to enhance translation: a systematic review of published studies

Abstract

Multicenter preclinical studies have been suggested as a method to improve reproducibility, generalizability and potential clinical translation of preclinical work. In these studies, multiple independent laboratories collaboratively conduct a research experiment using a shared protocol. The use of a multicenter design in preclinical experimentation is a recent approach and only a handful of preclinical multicenter studies have been published. Here, we systematically identify, assess and synthesize published preclinical multicenter studies investigating interventions using in vivo models. Synthesized data included study methods/design, basic characteristics, outcomes, and barriers and facilitators. Study risk of bias, completeness of reporting and the degree of collaboration were evaluated using established methods. The database searches identified 3095 citations and 12 studies met inclusion criteria. The multicenter study design was applied across a diverse range of diseases including stroke, heart attack, traumatic brain injury, and diabetes. The median number of centers was 4 (range 2-6) and the median sample size was 135 (range 23-384). Most studies had lower risk of bias and higher completeness of reporting than typically seen in single-centered studies. Only four of the twelve studies produced results consistent with previous single-center studies, highlighting a central concern of preclinical research: irreproducibility and poor generalizability of findings from single laboratories. Our review suggests that multicenter preclinical studies may provide a method to robustly assess therapies prior to considering clinical translation. Registered with PROSPERO CRD42018093986.

The interpretation bias and trap of multicenter clinical research

“…It can offer a larger sample size, the ability to share resources across centers, and an opportunity for networking [ 1 ]. Multi-center research, compared to single-center studies, allows for enhancement of reproducibility, generalizability, as well as availability of clinical translation of clinical work [ 2 ].…”

“…None-the-less, the viability of multi-center research should be questioned. Although research shows that multi-center studies allow for better control of study quality than single-center studies [ 2 ], there is still a flaw in multi-center research.…”

Robust Preclinical Evidence in Somatic Cell Genome Editing: A Key Driver of Responsible and Efficient Therapeutic Innovations

“…The majority of articles does not report on well-established measures to reduce validity threats such as randomization, blinding, sample-size calculation, and data-handling. 17,27,28 None of these studies did report on additional, less established, but increasingly discussed and implemented measures, namely: pre-registration, 17,27,28 multi-centric experimental data collection 20,21 , independent validation. 22 Although the additional measures are still rare in the field of SCGE, some journals, e.g.…”

“…15,16 According to results of a multi-stakeholder workshop at the NIH in 2012 (so-called "Landis-4" criteria) 17 and the revised submission guidelines of Nature journals, 18 the measures to increase scientific validity include at minimum the use of (1) randomized group allocation, (2) blinded outcome assessment, (3) a sample-size calculation, and (4) the transparent explanation of exclusion of animals or data from analyses. 17 Further yet less established measures in preclinical research that would reduce risk of bias and increase reproducibility of published preclinical evidence are (5) the public pre-registration of study protocols, 19 (6) performing multi-centric studies involving primary data collection at two or more laboratory sites, 20,21 and an (7) independent validation to "confirm" promising preclinical results before translation. 22,23 The objective of this scoping review is to understand how well the field of preclinical genome-editing research is already meeting the well-established reporting standards for internal validity (1)(2)(3)(4).…”

Improving preclinical studies through replications

“…surgery). Moreover, if the centres are in different countries, ethics boards and local regulations will most likely differ, complicating and potentially delaying ethics approval ( Hunniford et al, 2019 ; Llovera et al, 2015 ; Maysami et al, 2016 ). For example, regulations for analgesic regimes differ between jurisdictions, so that it is difficult to follow the same protocol across sites.…”