Current On-site Monitoring practices are frequency-based, conform to a prescribed monitoring visit schedule, and provide generalized quality control at investigational sites. Although this practice does provide a level of control, advances in risk-based approaches and technology provide an opportunity for a more holistic and proactive approach through Off-site and Central Monitoring and a targeted approach to On-site Monitoring. By building quality and risk management approaches into the scientific design and operational conduct of clinical trials, risks can be mitigated and issues can be detected early or prevented entirely. TransCelerate BioPharma Inc. (TransCelerate) developed a methodology that shifts monitoring processes from an excessive concentration on Source Data Verification to comprehensive risk-driven monitoring. This philosophical shift in monitoring processes employs Centralized and Off-site mechanisms to monitor important study parameters holistically and uses adaptive On-site Monitoring to further support site processes, subject safety, and data quality.