A substantial amendment is defined as change to the terms of the protocol or any other supporting documentation that is likely to affect to a significant degree:
- the safety or physical or mental integrity of participants
- the scientific value of the research
- the conduct or management of the research
- the quality or safety of any investigational medicinal product used
Addition of new sites, or appointment of a new principal investigator at an existing trial site (for CTIMPs only), are substantial amendments since they change the conduct or management of the research.