Writing and Amending the Clinical Protocol: IND and CTA Lifecycle Strategy for Oral GLP-1 Receptor Agonists in Type 2 Diabetes and Obesity

Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed the management of type 2 diabetes and obesity, but existing approved agents in this class are administered by subcutaneous injection, a barrier to initiation and adherence for a meaningful proportion of eligible patients (Davies et al., 2022). Oral GLP-1 receptor agonists, including both peptide formulations using absorption-enhancing excipients and non-peptide small molecules, aim to retain the metabolic benefit of this drug class while removing the injection barrier. This article is written from the perspective of a clinical trial manager carrying an oral GLP-1 receptor agonist program from its initial Investigational New Drug (IND) application or Clinical Trial Application (CTA) through subsequent protocol amendments. It reviews the pharmacological rationale, best practices for trial phase and population selection across the overlapping diabetes and obesity indications, anticipated risks and pharmacovigilance strategy with attention to gastrointestinal tolerability and dose titration, statistical sample-size rationale drawn from registered trials, the detailed regulatory requirements and timelines governing the initial submission and amendments across FDA, Health Canada, and EMA frameworks, a representative schedule of assessments spanning a twelve-month period, and the application of artificial intelligence tools to data capture and quality. The article closes with recommendations for regulatory affairs and clinical operations professionals managing this therapeutic category.Keywords: oral GLP-1 receptor agonist; type 2 diabetes; obesity; protocol amendment; Investigational New Drug application; Clinical Trial Application; gastrointestinal tolerability; regulatory artificial intelligence