First-in-human (FIH) trials are the first time a new therapy is tested in people, designed to evaluate safety, dosing, and early pharmacology before larger studies. If you want the “how it works” and “is it safe?” answers, you’re in the right place.
FIH trials bridge the gap between preclinical research and patient care. They are small, tightly controlled studies—often involving only dozens of participants—run under rigorous oversight to understand how a drug behaves in the human body.
What Are First in Human Trials?
FIH trials (commonly Phase 1) follow extensive lab and animal testing. Their goals are to assess safety and tolerability, determine a safe starting dose and range, and characterize pharmacokinetics/pharmacodynamics. Designs can include single ascending dose, multiple ascending dose, food‑effect cohorts, or integrated protocols based on mechanism and risk.
For current risk-identification and mitigation principles, see the European Medicines Agency’s scientific guideline on strategies to identify and mitigate risks for FIH and early clinical trials and the EMA’s revised guideline explainer, both detailing integrated protocols and stopping rules.
“First-in-human (FIH) trials represent the first phase of clinical research, with novel drugs or therapeutic interventions being tested in humans for the first time to assess their safety and tolerability” — Lieke van Kempen, BMC Translational Medicine
The FIH Process: From Lab Bench to First Dose
Progressing to FIH requires a robust nonclinical package (toxicology, safety pharmacology, pharmacology), product quality/manufacturing data, and a risk‑based plan for first dose and escalation. Sponsors seek authorization (e.g., IND/CTA) and run the study at accredited units with emergency capability and continuous monitoring. These steps are codified in global guidelines and executed at specialized Phase I units.
Typical building blocks of an FIH program include:
- Preclinical evidence aligned to international standards like ICH M3(R2)
- Conservative starting dose, cautious escalation, and predefined stopping rules (see Simbec‑Orion’s FIH overview)
- Participant selection (healthy volunteers vs. patients) tailored to mechanism and ethics
- On‑site safety infrastructure and predefined response plans; UK context from the MHRA Inspectorate
For transparency and participant protection, review the World Health Organization’s clinical trials Q&A on registration.
Also Read: Clinical Trial Phases: Complete Guide to All 4 Stages (2025)
Who Should Be Enrolled? Ethics and Participant Selection
A central ethical question is whether to enroll healthy volunteers or patients (and which patients). A recent systematic review synthesizes reasons for and against inclusion across non‑maleficence, beneficence, scientific value, efficiency, respect for persons, and justice.
“This review provides the first comprehensive overview of the reasons for and against including potential participant groups in FIH trials. The results highlight considerations that are relevant to reflect upon when determining and justifying participant selection for FIH trials.” — Lieke van Kempen, BMC Translational Medicine
Healthy volunteer studies remain foundational when ethically appropriate and scientifically justified:
“With the exception of genotoxic oncology drugs, first-in-human (FIH), Phase 1 clinical studies for a wide range of investigational drugs have traditionally been conducted in healthy volunteers (HVs), defined by the National Institutes of Health as “someone with no known significant health problems who participates in research to test a new drug, device, or intervention”. The primary goal of HV studies is to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of a novel drug candidate, determine appropriate dosing, and document safety and tolerability.” — Joyson J. Karakunnel, BMC Translational Medicine
Also Read: Blinded Imaging Assessments in Multicenter Studies
Risk Mitigation: Design Choices That Protect Participants
Modern FIH programs use integrated protocols with guardrails such as sentinel dosing, staggered cohorts, conservative escalation, and rolling safety reviews. EMA guidance emphasizes identifying uncertainties and planning proportionate mitigation throughout early development. Design discipline is the backbone of participant protection.
Methodological cautions from preclinical translation remind us to be realistic about animal‑to‑human predictivity:
“Systematic reviews (SRs) are powerful tools with the potential to generate high quality evidence. Their application to animal studies has exposed the poor quality of the majority of these studies, highlighting that many essential procedures such as randomisation and blinding are frequently not performed or reported” — Pandora Pound, BMC Translational Medicine
What Do Outcomes Look Like? Early Evidence and Case Examples
FIH examples show the diversity of modalities and aims in early human testing. For instance, UW–Madison reported that a first clinical trial is showing promise in Parkinson’s disease, highlighting interest in autologous iPSC‑based approaches. In infectious disease, the U.S. Navy’s Naval Medical Research Command launched a first‑in‑human Staph vaccine study to address skin and soft tissue infections. For oncology, a Scientific Reports analysis describes outcomes across first‑in‑human programs in targeted and immuno‑oncology settings; see Outcomes of patients enrolled in first‑in‑human phase 1 clinical trials.
Also Read: Medical Imaging Workflow: Optimize Clinical Trial Success
Also Read: Imaging Endpoints for Medical Device Approvals: FDA Guidelines & Best Practices
Summary
First‑in‑human trials are where innovation meets people, prioritizing safety, dosing, and early PK/PD. Robust nonclinical packages such as ICH M3(R2) and regulator‑aligned strategies like the EMA FIH guideline guide design. Ethical participant selection and rigorous mitigation—sentinel dosing, staggered cohorts, predefined stopping rules—build trust and data quality. Case examples across neurology, oncology, and infectious disease show promise while underscoring disciplined, transparent practice.
Introduction to Collective Minds Research for MedTech, BioTech, CROs and Pharma
FAQ
- What’s the main goal of FIH trials? Safety and tolerability, alongside determining an initial dosing strategy and characterizing PK/PD.
- Who participates in FIH? Healthy volunteers for many modalities; patients where ethics or mechanism warrant it (e.g., oncology, higher‑risk mechanisms).
- How are risks managed? Conservative starting doses, sentinel dosing, staggered escalation, predefined stopping rules, and continuous safety oversight.
- Are FIH trials registered? Trials should be registered in a recognized registry before enrollment, per WHO expectations.
Reviewed by: Pilar Flores Gastellu on October 31, 2025
