Translational Research - Bench to Trial

Transcription

1 TRANSLATION BENCH TRIAL Translational Research - Bench to Trial Marc T. Avey Canadian Institutes of Health Research (Knowledge Translation) Post-doctoral Fellow Clinical Epidemiology Program Ottawa Hospital Research Institute Nature 2008 Outline Preclinical Reproducibility: A challenge for translation Preclinical Translation: New methods to reduce risk and increase success "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story (C. Glenn Begley, Reuters 2012) Reproducibility o Preclinical Cancer o 6/53 (11%) landmark studies were replicated (Begley & Ellis 2012) o ALS o 0/70 () of drugs reported to increase lifespan in ALS animal model held up when replicated (Scott et al. 2008) o Spinal Cord o 2/20 (1) of high profile studies were replicated (Steward et al 2012) o Method sections were often incomplete or misleading Adapted from Oswald 2016 SFN publications that do not report basic elements of experimental design include blinding, randomization, replication, sample-size calculation poor training of researchers in experimental design 6 1

2 Solutions? ARRIVE Guidelines Animal Research: Reporting In Vivo Experiments Published in 2010 Developed by the National Centre for the Three Rs (UK) Consultation with scientists, statisticians, journal editors, funders Endorsed by over 600 journals, funders, universities and learned societies 20 Items Covers title to discussion Evaluating Reporting in a Preclinical Systematic Review Clinical Acute Respiratory Distress Syndrome o 30 to 4 risk of death Preclinical Acute Lung Injury o Mesenchymal Stromal Cells (MSCs) Completeness of Reporting o Embedded in preclinical systematic review o ARRIVE & NIH Principles and Guidelines 8 Methods Operationalize ARRIVE o 17 of 20 Sub-sections o 109 discrete reporting items (yes/no) o 5123 data elements o Two independent reviewers collected data 47 English Language NIH Principles & Guidelines o Six core reporting items o Replicates, Randomization, Blinding, Sample Size Calculations, Inclusion/Exclusion Criteria, Statistics 9 10 ARRIVE Guidelines Sub-Section NIH Biological Materials (MSCs) Adverse Events Outcomes and Estimation Funding Title Abstract Objectives Ethical Statement Where (e.g. home cage) Rationale for Dose/Timing Species Source Species Source Sex Species Tissue Type Numbers Analysed 2 Study Design When (e.g. time postmodel) 2 Species Source Supplier Baseline Data Experimental Procedures Frequency of Administration MSC Vehicle Statistical Methods Experimental Animals MSC Site MSC Vehicle Volume Experimental Outcomes Allocating Animals Housing & Husbandry Sample Size 11 MSC Route MSC Dose 12 2

3 NIH Core Items Training in Experimental Design & Reporting Replicates 10 Made in Ottawa solution 8 Inclusion/Exclusion Criteria 6 4 Statistics Experimental design & reporting Two sides of the same coin 2 Practical training to solve challenges at the bench Sample Size Calculation Randomization Evidence-based development On going knowledge translation research to inform workshop content and delivery Blinding 13 Local and National Outline Preclinical Reproducibility: A challenge for translation Preclinical Translation: New methods to reduce risk and increase success Translation A Tale of Two Reviews: Horn et al Clinical Systematic Review (Human) Horn et al Preclinical Systematic Review (Animals) Effects of calcium antagonist (nimodipine) on stroke Effects of calcium antagonist (nimodipine) on stroke Kola & Landis 2004 No benefit of treatment There was no difference between the results of the animal experiments and clinical studies 3

4 Preclinical Clinical Clinical Systematic Review Preclinical Systematic Review No systematic synthesis of preclinical model No systematic synthesis of preclinical basis for clinical studies Find no benefit of treatment Find no benefit of treatment Horn et al., 2001 Preclinical Knowledge Translation Westfall et al 2007 Westfall et al 2007 Preclinical Blue Highway? Exploratory Bench Confirmatory T1 Case Series Phase 1 & 2 Clinical Trials One of the most expensive aspects of stroke drug development is the clinical trial stage: ~ $4 bn per successful compound Systematic Reviews & Meta-Analysis TRANSLATION TO HUMANS Clinical trial costs from failed compounds cannot be recouped Reducing cost (risk) by increasing confidence in preclinical efficacy 4

5 Magic Bullet? Cost of preclinical systematic review & meta-analysis ~100K (more for network meta-analysis etc.) Preclinical systematic reviews One piece of the puzzle Estimated attrition rate of compounds from preclinical systematic reviews = 25% Platform Approach Trial Package Take Home Message Preclinical Systematic reviews, evidence maps Multi-centre trial Clinical Systematic Review Safety Knowledge Translation Barriers and facilitators of patients & medical specialists Economic Assessment e.g. Headroom Bench to Trial failures Primary preclinical studies are designed and reported suboptimally Translation is not systematic, and siloed Solutions Improved training in experimental design & reporting Preclinical systematic reviews as part of integrated trial development platform Exemplar projects on going at OHRI Acknowledgements Ottawa Hospital Research Institute Lauralyn McIntyre David Moher Dean Fergusson Gilly Griffin Jeremy M Grimshaw Brian Hutton Carolina Ilkow Mazen Jazi Manoj M Lalu Shirley HJ Mei Michael Rudnicki Duncan J Stewart Katrina Sullivan BioCanRx Jovian Tsang University Edinburgh Malcolm Macleod Université Laval Alexis F Turgeon University of Toronto John Marshall 5