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Exploring the Application of a Multicenter Study Design in the Preclinical Phase of Translational Research

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Exploring the Application of a Multicenter Study Design in the Preclinical Phase of Translational Research Exploring the Application of a Multicenter Study Design in the Preclinical Phase of Translational Research Victoria Hunniford Thesis submitted to the University of Ottawa in partial Fulfillment of the requirements for the Master of Science in Health Systems Telfer School of Management University of Ottawa © Victoria Hunniford, Ottawa, Canada, 2019 Abstract Multicenter preclinical studies have been suggested as a method to improve potential clinical translation of preclinical work by testing reproducibility and generalizability of findings. 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 these studies have been published. In this thesis, I aimed to provide insight into preclinical multicenter studies by 1) systematically synthesizing all published preclinical multicenter studies; and 2) exploring the experiences of, barriers and enablers to, and the extent of collaboration within preclinical multicenter studies. In Part One, I conducted a systematic review of preclinical multicenter studies. The database searches identified 3150 citations and 13 studies met inclusion criteria. The multicenter design was applied across a diverse range of diseases including stroke, heart attack, and traumatic brain injury. The median number of centers was 4 (range 2-6) and the median sample size was 133 (range 23-384). Most studies had lower risk of bias and higher completeness of reporting than typically seen in single-centered studies. Only five of the thirteen 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. In Part Two, I performed semi-structured interviews with researchers who have been involved in a preclinical multicenter study. Braun and Clarkes’ thematic analysis was used to identify emerging themes, and the extent of collaboration was evaluated using an established theory of collaboration developed by Wood and Gray. Twelve researchers from 6 studies were interviewed. Most participants indicated that funding and the culture of the scientific community were barriers, and that established relationships and transparency with collaborators were enablers to multicenter studies. Some participants felt that a harmonized protocol was optimal, while others stated that variability in the protocol across sites was more appropriate. Most participants indicated that multicenter studies had a purpose and place in preclinical research. My findings also suggest that multicenter preclinical studies may provide a method to robustly assess therapies prior to considering clinical translation. These insights will allow for more effective planning and execution of future preclinical multicenter projects and may support the development of best practices and guidelines. ii Acknowledgements Collaboration is a fundamental part of my thesis not only as it was a large focus of my research, but also because the work presented in this document was only achievable through a dedicated collaborative effort. This collaboration consisted of myself and my supervisors – Dr. Agnes Grudniewicz and Dr. Manoj Lalu, to whom I would like to express my deepest gratitude. Their mentorship, support, and motivation made the work presented in this thesis possible (more realistically: I would have been completely lost without them!). With their enthusiasm and immense knowledge, I could not have imagined two better people to guide me through this Master’s degree. I would also like to acknowledge all the past and current members of the Blueprint Translational Research Team for their indispensable help and feedback, and for being a fun group of people to work with. I would especially like to thank Dr. Dean Fergusson for his expertise and valuable input on my thesis. I am also grateful to my friends, for their genuine interest in what I’ve been doing over the past two years and their encouragement along the way. Whether they knew it or not, they provided me with the much-needed distraction from my research woes. After the countless explanations to their “what’s your thesis about, again?” I likely developed a better understanding of my research myself (though I suspect they still don’t know what my thesis is about). Last but by no means least; I wish to express my profound gratitude to my mom and dad. I would like to thank my parents for their unfailing support and continuous encouragement – not only in my academic career, but in all interests I choose to pursue. iii Table of Contents Abstract ......................................................................................................................................................... ii Acknowledgements ...................................................................................................................................... iii Chapter 1: Introduction ................................................................................................................................. 1 1.1 Background and rationale ................................................................................................................... 1 1.2 Objectives ........................................................................................................................................... 4 1.3 Theory and conceptual framework ..................................................................................................... 6 Theory of collaboration ......................................................................................................................... 6 Features of collaboration ....................................................................................................................... 8 Competing theories of collaboration ................................................................................................... 10 Chapter 2: Methods ..................................................................................................................................... 12 2.1: Systematic Review ........................................................................................................................... 12 Eligibility Criteria ............................................................................................................................... 12 Search strategy .................................................................................................................................... 13 Screening and data extraction ............................................................................................................. 14 Assessing completeness of reporting and risk of bias ......................................................................... 15 Assessing degree of collaboration ....................................................................................................... 16 Results and data synthesis ................................................................................................................... 17 Deviations from protocol .................................................................................................................... 17 2.2: Interview Study ................................................................................................................................ 18 Participants and recruitment ................................................................................................................ 18 Interview guide development .............................................................................................................. 19 Data analysis ....................................................................................................................................... 20 Chapter 3: Results ....................................................................................................................................... 23 3.1: Systematic Review ........................................................................................................................... 23 Search results and study characteristics .............................................................................................. 23 Reported outcomes .............................................................................................................................. 27 Risk of Bias ......................................................................................................................................... 28 Reporting quality ................................................................................................................................ 30 Reported barriers and facilitators ........................................................................................................ 32 Degree of collaboration ....................................................................................................................... 33 3.2: Interview Study ................................................................................................................................ 34 Objective 1: Experiences and perceptions of multicenter studies ....................................................... 36 Study logistics, structures, and processes ......................................................................................
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