Improving the credibility and utility of in vitro research

Preclinical research (i.e. all stages of laboratory research prior to testing in humans) helps us understand diseases and informs the development of novel therapies. For this research to be of maximal value it needs to be robust. Many novel treatment strategies for human diseases show benefit in laboratory studies every year, but very few go on to show efficacy in patients. This failure in translation may be, in part, explained by substantial evidence showing that preclinical research is not sufficiently robust and that reported findings are often not reproducible.

All areas of the life sciences subjected to systematic scrutiny have shown to be at risk of bias; research at risk of bias is associated with unreliable research findings and contributes to research waste. There has been substantial activity in recent years to address the limitations in the robustness and reproducibility of preclinical research using animals. Informed by meta-research (research on research) studies highlighting the presence and impact of risks of bias, funders, institutions, publishers, regulators and learned societies have taken steps to implement tools and strategies to improve the rigour of animal studies.

Research using cells in an artificial environment, such as in a petri dish or test tube - in vitro research - is an integral component of preclinical laboratory research. Unfortunately, in vitro research has not yet been subjected to the same levels of systematic scrutiny as other biomedical research domains. Frameworks for the systematic review of animal and clinical research are well-established, and their use is associated with improvements in the quality of experimental design and reporting. No such framework exists for in vitro research and the tools and infrastructure to identify, synthesise and appraise in vitro research are not yet developed. Research is incremental, and if findings from in vitro studies are flawed this represents an important source of waste in basic biomedical research that can also lead to waste in later research stages.

We bring together a multi-disciplinary international collaboration that includes experts in primary in vitro research, meta-research (researchers that research research) and implementation science. We have a track record of effective and successful collaboration; and our research efforts in the meta-research of laboratory animal research have had substantial and direct impact on the policies and actions of a wide range of stakeholders.

We will define the characteristics of an in vitro experiment that determine its reliability. We will determine the most effective approach to identify all relevant in vitro studies and develop methods to assess their quality and reliability. We will implement automated methods to reduce the manual efforts to identify in vitro research. Finally, we will conduct an exemplar systematic review to pilot the framework and demonstrate the reporting and impact of key study design characteristics on outcomes. Although due to our expertise, we propose that this exemplar review uses neuronal injury research, this work will be relevant to conduct systematic reviews of in vitro studies across biomedicine.

We propose that by developing this infrastructure, we will provide the research community and associated stakeholders with the key tools to develop robust evidence to guide improvements in the design, conduct and reporting of in vitro research.

In vitro studies are integral to our basic understanding of human health, disease related pathophysiology and the drug development pipeline. We use them both to complement the understanding of mechanistic phenomena observed in in vivo and clinical studies and to inform the decision to advance to testing interventions in vivo. It is critically important that in vitro research be robust and reliable and that scientists are equipped to systematically identify, appraise and synthesise such evidence.

In vitro research has not yet been subjected to the same levels of systematic scrutiny as in vivo and clinical research, and pilot data suggest that it is at high risks of bias. Unlike in vivo and clinical research, the tools and infrastructure to identify, synthesise and appraise in vitro research do not yet exist. Our aim, with key stakeholder engagement, is to develop these tools and infrastructure.

We will identify and reach consensus of the critical facets that strengthen the experimental validity of in vitro studies using a systematic review of existing guidance, followed by a Delphi exercise. We will develop search strategies and compare the most effective methods to identify systematically primary in vitro studies for systematic review. We will develop the appropriate methodological framework and a protocol template for conducting systematic reviews of in vitro studies, using existing systematic review guidance and summaries of in vitro systematic reviews, followed by a Delphi exercise. Finally, we propose to test the feasibility of our tools and infrastructure and present the reporting and impact of key study design variables on outcome by conducting an exemplar in vitro systematic review.

High quality systematic reviews are an important and critical tool to generate empirical evidence to guide improvements in the design, conduct and reporting of research. The proposal meets an unmet need to improve the quality of in vitro systematic reviews.