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
• 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.
Authors
- Claudia A. Riedel (ORCID: https://orcid.org/0000-0001-6168-8601)
- Thomas Sudhop (ORCID: https://orcid.org/0000-0002-6780-587X)
- Jens Rengelshausen (ORCID: https://orcid.org/0000-0002-6344-1888)
- Barbara Schug (ORCID: https://orcid.org/0000-0001-8137-6509)
- Ruwen Böhm (ORCID: https://orcid.org/0000-0003-1007-3011)
- Andreas Bonertz (ORCID: https://orcid.org/0000-0002-6846-9265)
- Robert Schultz-Heienbrok
- N. Faisst
- U. Buckpesch-Heberer
- G. Grass
- K. Erb-Zohar
- J. Höchel
- K. Breithaupt-Groegler
- A. Warnke
- A. Muehlenbroich
- A. Kovar
- M. Coenen
- S. Baumann
- B. Ziegele
Institutions
- Federal Institute for Drugs and Medical Devices (DE)
- University Hospital Bonn (DE)
- Specim (Finland) (FI)
- Novartis (China) (CN)
- Clinical Research Services (DE)
- SocraTec R&D (Germany) (DE)
- Pharmacology Research Institute (US)
- University Hospital Schleswig-Holstein (DE)
- Clinique Saint-Joseph (BE)
- Universitätsklinikum Aachen (DE)
- Dr Falk Pharma (Germany) (DE)
- Bayer (Germany) (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Paul Ehrlich Institut (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Frontiers in Pharmacology
- Published
- 2026-01-26
- DOI
- https://doi.org/10.3389/fphar.2025.1699906
- Primary Topic
- Health Systems, Economic Evaluations, Quality of Life
- Type
- article
- Field-Weighted Citation Impact
- 0.00