Muehlenbroich, Angela, Schultz-Heienbrok, R, Baumann, S, Böhm, R, Bonertz, A, Breithaupt-Groegler, K, Buckpesch-Heberer, U, Coenen, M, Erb-Zohar, K, Faisst, N, Grass, G, Höchel, J, Kovar, A, Rengelhausen, J, Riedel, C, Schug, B, Sudhop, T, Warnke, A and Ziegele, B (2026) Designing integrated early-phase protocols to reduce substantial modifications, including considerations for patient cohorts – a multi-stakeholder consensus view for a practical approach in Germany. Frontiers in pharmacology, 16. ISSN 1663-9812

Abstract

• 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.

Item Type:	Article
Keywords:	First-in-human, clinical trials, integrated protocols, complex trial design, substantial modification
Date Deposited:	10 Feb 2026 00:45
Last Modified:	10 Feb 2026 00:45
URI:	https://oak.novartis.com/id/eprint/58314