Summary: The translation of preclinical research into first-in-human (FIH) studies is one of the most demanding and decisive stages in biomedical innovation. It marks the point at which laboratory discoveries are tested in humans for the first time, carrying both significant promise and considerable risk. This article examines the scientific, regulatory, ethical, and operational processes that underpin successful translation from preclinical models to early clinical investigation. It discusses the role of robust experimental design, predictive validity of models, regulatory expectations, safety assessment, and multidisciplinary collaboration. By focusing on best practice and common challenges, the article highlights how translational rigour can improve patient safety, reduce attrition, and accelerate clinical impact.
Keywords: Clinical translation; First-in-human studies; Preclinical models; Early-phase trials; Translational medicine; Drug development
Introduction
Translating preclinical research into first-in-human studies is a critical step in developing new medicines, diagnostics, and medical technologies. At this stage, years of laboratory work converge into a carefully designed clinical investigation intended to evaluate safety, tolerability, and early biological activity in humans. The success or failure of this step often determines whether an innovation progresses further or is abandoned altogether.
Preclinical research aims to establish a scientific and biological rationale for human testing. However, many promising interventions fail during early clinical development due to limitations in model predictivity, insufficient understanding of the mechanism, or gaps in safety evaluation. As a result, the translational interface between laboratory and clinic has become a major focus for regulators, funders, and researchers alike.
This article explores the pathway from preclinical discovery to first-in-human studies, highlighting the scientific foundations, regulatory frameworks, and practical considerations required to enter clinical evaluation safely and effectively.
The Purpose of Preclinical Research in Translation
Preclinical research serves several essential functions in the translational pathway. It provides evidence that a candidate intervention interacts with a biological target in a meaningful way, produces a measurable effect, and can be administered within an acceptable safety margin. These objectives are typically addressed through a combination of in vitro experiments, animal studies, and increasingly, computational modelling.
A central goal of preclinical work is to generate data that support a clear hypothesis for human testing. This includes defining the mechanism of action, identifying relevant biomarkers, and establishing dose–response relationships. Without this foundation, first-in-human studies risk becoming exploratory exercises with limited interpretability.
Equally important is the identification of potential hazards. Preclinical toxicology, pharmacokinetics, and pharmacodynamics are designed to anticipate adverse effects and inform starting dose selection. The quality and relevance of these studies directly influence regulatory confidence and ethical approval for human exposure.
Selection and Limitations of Preclinical Models
The choice of preclinical models plays a decisive role in translational success. Animal models, cell-based systems, and ex vivo human tissues each offer specific advantages and constraints. No single model can fully replicate human physiology, which means translational decisions rely on the convergence of evidence rather than absolute prediction.
Animal models remain central to safety and efficacy assessment, yet their relevance varies depending on disease context and biological pathway. Species differences in metabolism, immune response, and target expression can lead to misleading results if not carefully considered. For this reason, model selection should be driven by biological relevance rather than convenience or tradition.
Advances in human-derived systems, such as organoids and microphysiological platforms, are helping to bridge translational gaps. While these technologies cannot fully replace animal studies, they can provide valuable insight into human-specific responses and reduce uncertainty before clinical entry.
Dose Selection and Starting Dose Justification
Determining a safe and rational starting dose is one of the most critical decisions in first-in-human study design. This process integrates data from toxicology studies, pharmacokinetic modelling, and mechanistic understanding to estimate an exposure level that minimises risk while allowing meaningful observation.
Traditional approaches have relied on no-observed-adverse-effect levels derived from animal studies, adjusted using safety factors. More recent strategies incorporate minimal anticipated biological effect levels, particularly for biologics and highly potent agents. These approaches aim to align dosing more closely with biological activity rather than toxicity alone.
Transparent justification of dose selection is essential for regulatory review and ethical approval. Investigators must clearly explain the assumptions, uncertainties, and safeguards embedded in their calculations, recognising that first-in-human dosing carries inherent unpredictability.
Regulatory Frameworks and Expectations
Regulatory oversight is central to the transition from preclinical research to human studies. Authorities require comprehensive documentation demonstrating that potential risks have been identified, evaluated, and mitigated as far as reasonably possible. This includes detailed reports of pharmacology, toxicology, manufacturing quality, and study design.
Regulatory expectations emphasise scientific coherence across the development programme. Preclinical findings should align with the proposed clinical protocol, including population selection, dosing schedule, and endpoints. Inconsistencies or gaps can lead to delays or rejection of clinical trial applications.
Early engagement with regulators is increasingly encouraged. Scientific advice meetings allow developers to discuss translational strategies, clarify data requirements, and address concerns before formal submission. Such interactions can reduce uncertainty and improve the likelihood of approval for first-in-human studies.
Ethical Considerations in First-in-Human Studies
Ethical responsibility is heightened at the first-in-human stage, as participants are exposed to interventions with limited human safety data. The primary ethical obligation is to minimise harm while ensuring that the potential knowledge gained justifies the risks involved.
Informed consent must be particularly robust. Participants should receive clear explanations of uncertainty, potential risks, and the exploratory nature of the study. Avoiding therapeutic misconception is essential, especially when studies involve patients with serious or life-limiting conditions.
Ethics committees play a key role in evaluating whether preclinical evidence adequately supports human exposure. Their assessment considers not only scientific merit but also study design, participant selection, and risk mitigation strategies. Strong ethical review contributes to public trust in translational research.
Designing First-in-Human Studies
First-in-human studies are typically conducted as early-phase clinical trials with a primary focus on safety and tolerability. However, modern designs increasingly incorporate pharmacodynamic and biomarker endpoints to generate early signals of biological activity.
Adaptive designs, sentinel dosing, and staggered enrolment are commonly used to manage risk. These approaches allow investigators to review emerging safety data before escalating the dose or enrolling additional participants. Careful monitoring and predefined stopping criteria are essential components of this process.
The choice between healthy volunteers and patient populations depends on the nature of the intervention and its risk profile. While healthy volunteer studies offer greater control, certain therapies may only be appropriate for patients due to safety or ethical considerations.
Multidisciplinary Collaboration in Translation
Successful translation from preclinical research to first-in-human studies requires close collaboration across disciplines. Scientists, clinicians, toxicologists, statisticians, regulatory specialists, and manufacturing experts all contribute to the translational pathway.
Communication between laboratory and clinical teams is particularly important. Preclinical researchers must understand how their data will inform clinical decisions, while clinicians need insight into experimental limitations and assumptions. This mutual understanding supports a more realistic study design and interpretation.
Institutional structures that encourage cross-disciplinary engagement, such as translational research centres, can strengthen this interface. By aligning incentives and expertise, such environments improve the efficiency and quality of early clinical development.
Common Challenges and Causes of Failure
Many translational programmes encounter difficulties at the first-in-human stage. Common challenges include overinterpretation of preclinical efficacy data, insufficient safety margins, and the lack of validated biomarkers. These issues often reflect systemic pressures to advance candidates rapidly rather than methodological shortcomings alone.
Another frequent problem is inadequate consideration of clinical context. A therapy may show promise in controlled laboratory settings yet prove impractical or ineffective in real clinical scenarios. Early input from clinicians can help address these issues before human testing begins.
Learning from translational failures is essential. Transparent reporting of negative outcomes and unexpected toxicities can inform future programmes and reduce repetition of avoidable mistakes.
Future Directions in Translational Science
The translation of preclinical research into first-in-human studies is evolving alongside advances in science and technology. Improved modelling, human-relevant systems, and data integration tools are enhancing predictive accuracy and decision-making.
Greater emphasis is also being placed on translational quality rather than speed. Funders and regulators increasingly recognise that robust preclinical evidence and thoughtful study design are more likely to yield meaningful clinical outcomes.
As expectations rise, translational science will continue to demand rigorous methodology, ethical sensitivity, and collaborative practice. Strengthening this transition point remains essential for turning scientific discovery into tangible benefit for patients.
Conclusion
First-in-human studies represent a defining moment in the journey from laboratory discovery to clinical application. The translation of preclinical research into these early trials requires careful integration of scientific evidence, regulatory standards, and ethical responsibility. By prioritising model relevance, transparent decision-making, and multidisciplinary collaboration, researchers can improve the safety and effectiveness of this transition. Ultimately, strong translational practice not only protects participants but also increases the likelihood that innovative ideas will deliver real clinical value.
Preclinical to First-in-Human: Q&A
The primary goal is to determine whether an intervention that has shown promise in laboratory and animal studies can be administered safely to humans. This stage focuses on establishing initial safety, tolerability, and biological behaviour in the human body, while also generating early evidence that the intervention interacts with its intended target in a meaningful way.
Q2: Why do many promising preclinical discoveries fail at the first-in-human stage?
Failures often stem from limitations in the predictive power of preclinical models. Differences in physiology, metabolism, and disease biology between models and humans can lead to unexpected safety issues or a lack of effectiveness. In some cases, preclinical efficacy is overinterpreted, or safety margins are not sufficiently robust to support human exposure.
Q3: How is the starting dose for a first-in-human study determined?
Starting dose selection is based on integrating toxicology, pharmacokinetic, and pharmacodynamic data from preclinical studies. Investigators estimate a safe dose that allows biological effects to be observed. Conservative safety factors, modelling approaches, and clear assumptions are used to reduce risk at this early stage.
Q4: What ethical considerations are unique to first-in-human studies?
First-in-human studies involve heightened ethical responsibility because human safety data are limited or absent. Researchers must minimise risk, ensure fully informed consent, and clearly communicate uncertainty to participants. Ethics committees assess whether the potential knowledge gained justifies the risks involved and whether safeguards are adequate.
Q5: Why is multidisciplinary collaboration important in first-in-human translation?
Translational success depends on coordinated input from preclinical scientists, clinicians, regulators, and other specialists. Effective collaboration ensures that laboratory findings are interpreted realistically, study designs are clinically relevant, and regulatory and ethical requirements are met. This integrated approach reduces avoidable errors and improves the quality of early clinical research.
Disclaimer
This article is intended for informational and educational purposes only. It does not constitute medical, clinical, regulatory, or legal advice, nor should it be relied upon as a substitute for professional judgement. The views expressed reflect general principles of translational research and early clinical development and may not apply to specific investigational products, study designs, or regulatory jurisdictions. Readers involved in preclinical or first-in-human studies should seek appropriate expert guidance and comply with all relevant ethical, institutional, and regulatory requirements before undertaking or interpreting clinical research activities.
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