Designing integrated early-phase protocols to reduce substantial modifications, including considerations for patient...

• Frequent substantial modifications for initiating new trial parts slow down development and reduce transparency. • Combining healthy volunteers and patients in a single early-phase trial raises safety, feasibility, and regulatory concerns. • A multi-stakeholder consensus in Germany identified regulatory pathways to enable seamless transitions within integrated protocols for non-ATMP (advanced therapy medicinal product), non-oncology trials. • The EMA FIH (first-in-human) guideline supports predefined transitions if scope, safety thresholds, and decision rules are clearly described. • The German guardrail concept clarifies when transitions do not require a substantial modification, enhancing planning certainty. • Actionable recommendations are provided on protocol design, decision criteria, and governance structures to enable early inclusion of patients without compromising safety or compliance. • First positive experience has been gained with the presented framework in Germany.