Alignment of registered cell therapy trial protocols with regulatory guidance on preclinical evidence: a systematic,...

Cell therapies often advance into clinical trials based on supportive preclinical evidence, yet it remains unclear whether such evidence is presented in trial protocols in ways that explicitly justify translation to humans. We assessed whether preclinical efficacy evidence in cell therapy trial protocols aligns with regulatory guidance principles (e.g., mechanism of action, evidence of disease modification, clinically relevant model selection).

We systematically searched ClinicalTrials.gov for cell therapy trials with available protocols. The primary outcomes were the proportions of protocols explicitly reporting 20 predefined preclinical evidence elements corresponding to regulator-derived translational principles. Secondary outcomes included the types and sources of evidence used to justify trial initiation and differences in reporting across trial contexts.

We identified 305 eligible trials with protocols, of which 209 (68·5%) incorporated preclinical evidence. Reporting was uneven across domains of translational principles: at least one therapeutic mechanism of action element was explicitly reported in 95% of trials (95% confidence interval [CI], 91-97, n = 198/209), preclinical evidence of disease modification in 70% (95% CI, 63-76, n = 146/209), evidence informing trial intervention parameters in 69% (95% CI, 62-75, n = 144/209), and explicit justification of model relevance in 24% (95% CI, 19-31, n = 51/209). Protocol-level reporting of translational principles was generally higher in trials incorporating large-animal or original preclinical data, and lower in trials citing prior human data or sponsored by industry. Preclinical evidence was more often used to demonstrate biological plausibility than to justify key aspects of trial design.

Although key translational principles are partially reflected in current practice, domains central to translational validity remain underrepresented. While additional preclinical evidence may be available in investigator brochures or regulatory submissions, publicly available protocols are important documents through which investigators formalise and communicate the rationale for trial initiation. Strengthening how preclinical evidence is structured in protocols may improve trial justification, regulatory evaluation, and support more reliable clinical translation.

Canadian Stem Cell Network Impact Awards: Ethical, Legal, and Social Impact Stream.