Randomized Controlled Trial in Sheep and Methodological Rigor in Preclinical Studies

Miller et al published a paper in blue journal (AJRCCM) "Combined Mesenchymal Stromal Cell Therapy and Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrom: A Randomized Controlled Trial in Sheep." At the first glance, I thought it was a randomized controlled clinical trial. Then I realized it was a randomized controlled trial in sheep and the word 'clinical' was not in the title. Whether or not the study is conducted in humans or in sheep, it can still be called 'randomized controlled trial' or RCT in short. 

It is great to see that the pre-clinical studies are conducted in a way with scientific rigor. The results from RCT in animals will be more reliable and provide more definitive evidence for us to decide if additional RCT in humans should be warranted. 

The presentation of the paper by Miller et al followed exactly the same way how a randomized controlled clinical trial will be presented. 

Study Design

Ethical approvals were obtained from University Animal Ethics Committees of Queensland University of Technology and the University of Queensland and authorization for in vivo use of hMSCs was granted by the Australian Department of Agriculture. The study was conducted in accordance with Australian Code for the Care and Use of Animals for Scientific Purposes and is reported in compliance with Animal Research: Reporting of In Vivo Experiments guidelines. ......

Statistical Analysis

An a prior sample size calculations, based on the primary outcome of PaO2/FiO2, ratio at 24 hours, is detailed in the online supplement. Data are expressed as mean (+/-SD) or median (interquartile range [IQR]) if nonnormally distributed. Analysis was undertaken in Graphpad Prism. Longitudinal data were analyzed by fitting a mixed model. This model uses a compound symmetry covariance matrix and is fit using restricted maximum likelihood. Where a significant interaction was observed, post hoc comparisons were undertaken. Correction for multiple comparisons was made using the Benjamini-Hochberg method (false discovery rate restricted to 5%). ......

Last July, I attended a symposium in Paris and Dr. Sébastien Bonnet from Université Laval in Canada from gave a presentation titled "Improving the rigour of preclinical studies to identify promising therapies". His presentation resonated with me.

Preclinical studies are usually small in sample size, conducted at a single institute, not randomized, and not reproducible. For years, there has been a push for improving the methodological rigor in preclinical studies. The methods used in the design and analysis of clinical trials can also be used in pre-clinical studies. We hope to see the terms (such as randomized, controlled, multi-center, meta-analysis) applied in more pre-clinical studies.   

• Methodological Rigor in Preclinical Cardiovascular Studies - Targets to Enhance Reproducibility and Promote Research Translation
• Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research
• Principles and Guidelines for Reporting Preclinical Research
• A call for transparent reporting to optimize the predictive value of preclinical research
• Limitations and Flaws of Preclinical Pulmonary Hypertension Studies

Flawed preclinical studies can produce misleading results that may be used as the basis for clinical trials. A lot of efforts and money be spent on clinical trials that are based on the results from shady preclinical studies.