The opioid crisis has been hardest felt in British Columbia (BC), which declared a public health emergency in 2016. Last year, there were 1510 drug overdose deaths recorded in BC, which represented 4.5 times the deaths from motor vehicle accidents. The overdose crisis has been largely driven by increasing contamination of the illicit drug supply with powerful synthetic opioids (e.g., fentanyl). Despite efforts to expand harm reduction services and treatments for opioid use disorder, these have had limited success in curbing the current crisis. Innovative strategies to mitigate the crisis have become an urgent public health priority. This includes a critical need to evaluate the response to the overdose crisis to help develop and implement a comprehensive addiction treatment program across BC and ultimately prevent future drug-related fatalities. Vancouver Coastal Health (VCH) provides services to more than 1.25 million residents in BC (nearly 25% of the population), and has been a primary player at the heart of the overdose crisis response. As such, alongside the newly implemented VCH Regional Addiction Program, VCH has identified key policy-related challenges that the proposed work will seek to address: prevent fatal overdoses, reduce drug-related harms, increase access to low barrier services, and improve integration of harm reduction and treatment. The proposed work will consist of several overlapping components to achieve the overarching goal to establish comprehensive and integrated addiction care programs across the region. This will include evaluating the impacts of 'naturally occurring' interventions (e.g., supervised consumption sites) and efficacy of novel clinical therapies, conducting health system and program evaluation to identify gaps in care and healthcare provider capacity, and engaging in integrated knowledge translation to mobilize research into evidence-based policies and practices across the health system.