Over the past decade, expectations of early-phase clinical development have changed significantly. Phase I studies are no longer seen as primarily tolerability or safety-driven. Instead, they are increasingly expected to inform clear development decisions, including whether to proceed, how to dose, and which patient populations to prioritise.
This shift is largely driven by growing clinical development costs, increasing portfolio pressure, and the continued risk of late-stage attrition. Advancing a compound through late-phase clinical trials without a robust understanding of its pharmacology in humans is no longer sustainable. As a result, there is a clear move toward early study designs that actively reduce uncertainty rather than defer it.
Defining the critical inflection points
In early clinical development, decision-making should be guided by the specific scientific and clinical questions relevant to the individual compound, rather than by adherence to a predefined development pathway. At each stage, the focus is on generating biologically meaningful evidence that informs progression.
Key questions typically centre around pharmacological activity and dose selection, although their relevance and timing depend on the compound and its mechanism of action.
One such question is whether the compound demonstrates pharmacological activity consistent with its intended mechanism. Safety and pharmacokinetics remain essential, but without early evidence of target engagement or a relevant downstream effect, further investment carries considerable risk.
Closely related is the question of dose selection. Advancing into patient studies without a well-characterised exposure–response relationship can lead to suboptimal dosing strategies that are difficult to correct later, increasing the risk of inconclusive or misleading efficacy outcomes in Phase II.
A further consideration before transitioning to larger and more costly trials is the extent to which the observed pharmacology supports a clinically meaningful effect. Establishing a well-founded expectation of clinical relevance reduces the risk of programmes progressing based on assumptions rather than evidence.
The cost of insufficient early insight
When these questions are not addressed early, uncertainty accumulates. This often becomes visible only in later stages, where studies are larger, more complex, and significantly more expensive. At that point, negative or inconclusive results do not only affect a single study, but also impact broader portfolio strategy and resource allocation.
In many cases, late-stage failure can be traced back to gaps in early understanding, such as inadequate target engagement, unclear dose rationale, or lack of translational alignment. Strengthening early decision-making is therefore not simply about efficiency, but about reducing structural risk across development programmes.
Enabling decisions through study design
To support better decisions, early-phase studies increasingly incorporate endpoints and methodologies that go beyond conventional safety and PK assessments. Functional endpoints, translational biomarkers, and mechanism-driven models play a central role in this evolution.
Functional endpoints allow researchers to observe pharmacodynamic effects that are directly relevant to the intended therapeutic outcome. Translational biomarkers help bridge preclinical findings with human biology, providing evidence that a compound behaves as expected in vivo. Mechanism-driven models, including integrated in vivo, ex vivo, and add-on in vitro approaches, can further contextualise clinical observations and strengthen the interpretation of results.
This approach can be extended by including selected patient populations in early-phase research. At this stage, the focus is typically on functional and objective endpoints rather than full clinical outcomes, allowing for an early assessment of pharmacological relevance in the target population.
When combined within a single study design, these elements create a more complete picture of a compound’s activity in humans. This enables sponsors to make informed decisions earlier, with a clearer understanding of both potential and limitations.
Moving from data generation to decision support
The role of early-phase clinical development is therefore shifting from generating regulatory-required data to enabling decisions. This requires a deliberate focus on study design and inclusion of relevant biomarkers, ensuring that every element contributes to answering the questions that matter most for progression.
By integrating scientific insight with clinical execution, early-phase studies can provide the level of understanding needed to reduce uncertainty at key decision points. This allows clinical development programmes to progress with greater confidence and a clear rationale for progression decisions.
