A drug can be safe, tolerable, and well-characterized pharmacokinetically. And still enter Phase II without clear evidence that it is doing anything meaningful in the brain.
This is where a gap lives. Not a scientific gap. A business one.
Neuroimaging biomarkers in CNS clinical trials are usually framed as a scientific or technical problem: which modality to use, which signal to measure, whether to prioritize target engagement, pharmacodynamic response, patient stratification, or disease progression. Which population to study — healthy volunteers, early-stage patients, prodromal groups, treatment-resistant subgroups, or broader diagnostic populations. These questions matter. But they may be secondary to a more structural problem.
Phase I has a specific role in drug development, and early human studies must prioritize safety. That logic is sound. But Phase I is also rewarded for being fast, lean, and PK-oriented. Including neuroimaging beyond PET to characterize pharmacodynamic activity might increase costs and delay decisions. It appears as an optional scientific burden, not a development requirement.
The contradiction is this: if Phase II later depends on neuroimaging to support mechanism, stratification, or treatment-response interpretation, the absence of an early pharmacodynamic mindset drives costs far higher than the early investment would have been.
This is not primarily a neuroimaging problem. It is an incentive problem.
Etkin, Powell, and Savitz (2025) argue that neuroimaging can help de-risk CNS drug development, particularly in psychiatry, through pharmacodynamic measures, target engagement, and patient stratification. They also emphasize that this requires a deeper commitment to a precision-oriented development model, rather than treating neuroimaging as a marginal or occasional add-on. But neuroimaging cannot de-risk Phase II if the evidence needed to guide its use has not been generated earlier. An imaging endpoint may be scientifically attractive and still not be aligned with the drug's mechanism of action.
The better question is: what evidence do we need before Phase II to know whether neuroimaging will be decision-useful?
A stronger development strategy would not mean adding expensive neuroimaging to every Phase I study. It would mean creating a structured bridge between early pharmacology and the later adoption of biomarkers, so that Phase II begins with assumptions that have been tested, not inherited.
Neuroimaging should not be included because it is technologically impressive. It should be included because it answers a specific development question and improves a decision. If the early evidence is weak, a larger Phase II will not become more informative. It will only become more expensive.
Garbage in, garbage out.