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, vol. 16, pp. 1699906

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.

Authors 18

1. Robert Schultz-Heienbrok corresponding

   Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Charité Research Organisation GmbH

2. S. Baumann

   Clinical Research Services

   Affiliation as printed

   CRS Clinical Research Services Management

3. Ruwen Böhm

   SocraTec R&D (Germany) · University Hospital Schleswig-Holstein

   Affiliation as printed

   SocraTec R&D

   Universitätsklinikum Schleswig-Holstein

4. Andreas Bonertz

   Paul Ehrlich Institut

   Affiliation as printed

   Paul-Ehrlich-Institut

5. K. Breithaupt-Groegler
   Affiliation as printed

   Consultant Clinical Pharmacology

6. U. Buckpesch-Heberer

   Paul Ehrlich Institut

   Affiliation as printed

   Paul-Ehrlich-Institut

7. Martin Coenen

   University Hospital Bonn

   Affiliation as printed

   Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn

8. K. Erb-Zohar
   Affiliation as printed

   Clinphase

9. N. Faisst

   Dr Falk Pharma (Germany)

   Affiliation as printed

   Dr. Falk Pharma GmbH

10. G. Grass
    Affiliation as printed

    Spezialisierte Ethikkommission für besondere Verfahren

11. J. Höchel

    Bayer (Germany)

    Affiliation as printed

    Bayer AG

12. A. Kovar

    Sanofi (France)

    Affiliation as printed

    Sanofi

13. A. Muehlenbroich

    Novartis (Switzerland)

    Affiliation as printed

    Novartis

14. Jens Rengelshausen Aachen

    Universitätsklinikum Aachen

    Affiliation as printed

    Uniklinik RWTH Aachen

15. Barbara S. Schug

    SocraTec R&D (Germany)

    Affiliation as printed

    SocraTec R&D

16. Thomas Sudhop

    Federal Institute for Drugs and Medical Devices

    Affiliation as printed

    Bundesinstitut für Arzneimittel und Medizinprodukte

17. A. Warnke

    SocraTec R&D (Germany)

    Affiliation as printed

    SocraTec R&D

18. B. Ziegele

    University Hospital Bonn

    Affiliation as printed

    Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn