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Project Orbis was initiated in May 2019 by the Oncology Center of Excellence to facilitate faster patient access to innovative cancer therapies by providing a framework for concurrent submissions and review of oncology products among international partners. Since its inception, Australia's Therapeutic Goods Administration (TGA), Canada's Health Canada (HC), Singapore's Health Sciences Authority (HSA), Switzerland's Swissmedic (SMC), Brazil's National Health Surveillance Agency (ANVISA), United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), and most recently Israel's Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, have joined Project Orbis. While each country has its own expedited review pathways to bring promising therapies to patients, there are some similarities and differences in pathways and timelines. FDA's fast-track designation and MHRA's marketing authorization under exceptional circumstances (MAEC) allow non-clinical and limited clinical evidence to support approval under these programs. HC's Extraordinary Use New Drug (EUND) pathway allows granting exceptional use authorization with limited clinical evidence. ANVISA, HSA, MTIIR, and TGA do not have standard pathways that allow non-clinical evidence and limited clinical evidence. While there is no definite regulatory pathway for HSA, the current framework for approval does allow flexibility in the type of data (non-clinical or clinical) required to demonstrate the benefit-risk profile of a product. HSA may register a product if the agency is satisfied that the overall benefit outweighs the risk. All Project Orbis Partner (POP) countries have similar programs to the FDA accelerated approval program except ANVISA. Although HSA and MTIIR do not have defined pathways for accelerated approval programs, there are opportunities to request accelerated approval per these agencies. All POP countries have pathways like the FDA priority review except MHRA. Priority review timelines for new drugs range from 120 to 264 calendar days (cd). Standard review timelines for new drugs range from 180 to 365 cd., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined., Design: This is an observational retrospective comparative cohort study., Setting: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites., Results: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45)., Conclusions: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)