# 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

## TL;DR

This paper proposes a framework for designing early-phase clinical trials in Germany to streamline transitions between trial phases and reduce delays.

## Contribution

The paper introduces a multi-stakeholder consensus framework for integrated trial protocols in non-ATMP, non-oncology trials in Germany.

## Key findings

- A German guardrail concept clarifies when trial transitions don't require substantial modifications.
- EMA FIH guidelines support predefined transitions with clear safety thresholds and decision rules.
- Actionable recommendations improve protocol design and governance for early patient inclusion.

## 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.