Background: The 2011 Canadian Cancer Research Alliance (CCRA) report on the State of Cancer Clinical Trials in Canada outlined in detail the threats to the conduct of academic oncology clinical trials caused by increasing complexity and workload resulting from a perceived onerous regulatory environment. The report recommended engaging Health Canada and key stakeholders to foster agreement in appropriate interpretations of the Canadian Food and Drug Regulations Part C Division 5 and ICH Good Clinical Practice (GCP) guidelines. Methods: The ISCT Working Group (ISCT WG) was formed in 2012 to address the CCRA recommendations for academic clinical trials and include experts from multiple therapeutic areas. The primary objective of the ISCT is to develop specific, practical interpretations of current regulations, laws and guidelines to facilitate Canadian clinical trials. Feedback was obtained from interested parties and ISCT members by means of surveys, face-to-face meetings and conference calls. Results: The major areas of concern identified include Health Canada Clinical Trial Applications, Investigational Product supply, monitoring, oversight of equipment and facilities, delegation of duties, validation of electronic systems, source documents and records retention, trial costs, the consistency of interpretation by different divisions of Health Canada, and access to related resources. A subcommittee was established for each area identified above and a series of recommendations to streamline processes with a focus to reduce regulatory burden for academic clinical trials. The ISCT WG used other relevant documents including the OECD framework and FDA Guidance on Risk Based Monitoring to inform its work. Conclusions: The final recommendations of the ISCT have been provided to all stakeholders, presented at international conferences and published on the N2 website. Canadian academic sites have used guidelines during Health Canada inspections with success. Future goals include an ISCT Workshop for academic site leaders to facilitate implementation of the ISCT guidelines, continue to address areas of concern, and track the success of the recommendations in ameliorating the conduct of academic trials.