First-in-man trials
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First-in-man trials
A First-in-Man (FIM) trial—also known as a First-in-Human (FIH) trial—is the first clinical study in which a new investigational drug, biologic, or medical device is administered to human participants. These trials follow extensive preclinical testing and are typically classified as Phase 1 trials. The primary focus of FIM trials is to assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) before proceeding to larger, more definitive studies.
Key Objectives
The primary goal of a First-in-Man trial is to evaluate the safety profile of a novel intervention. Researchers aim to identify any dose-limiting toxicities and determine the maximum tolerated dose (MTD). Close monitoring of adverse events is essential at this stage.
Another key objective is to characterize the drug’s pharmacokinetics—how it is absorbed, distributed, metabolized, and excreted. This is typically assessed through blood samples, urine collection, and other biomarker studies.
Pharmacodynamic assessments measure the biological effect of the drug on the body. These may include evaluating target engagement, biomarker changes, and physiological responses.
A critical part of FIM trial planning involves defining a safe starting dose, often based on preclinical toxicology data. Regulatory guidance (e.g., from the FDA or EMA) recommends deriving the starting dose from the no observed adverse effect level (NOAEL) in animals—usually beginning at one-tenth of the NOAEL.
Trial Design
First-in-Man trials are commonly structured as randomized, placebo-controlled, dose-escalation studies. The two main formats are:
- Single Ascending Dose (SAD): Participants receive a single dose of the investigational product, with subsequent groups receiving increasing doses.
- Multiple Ascending Dose (MAD): Participants receive multiple doses over time to assess accumulation and repeated exposure effects.
The trials typically begin with healthy volunteers, especially for low-risk drugs. However, when safety risks are high—such as in oncology or gene therapy—patients with the target condition may be enrolled directly.
The intended clinical route of administration (oral, intravenous, subcutaneous) is usually used from the outset. Participants are closely monitored, and trial conduct is overseen by a Data Safety Monitoring Board (DSMB). Predefined stopping rules are implemented to mitigate risk.
Regulatory and Ethical Considerations
Before initiating a FIM trial, extensive preclinical safety assessments are required. These include toxicology studies in at least two animal species, as well as evaluations for genotoxicity, reproductive toxicity, and carcinogenicity (when applicable).
Regulatory submissions must be approved before human enrollment. In the U.S., an Investigational New Drug (IND) application must be submitted to the FDA. In Europe, a Clinical Trial Authorization (CTA) is required under EMA guidelines.
Ethical oversight is critical. Participants must provide informed consent, with a clear understanding of the risks involved. Risk minimization strategies—such as dose staggering and intensive monitoring—are essential. Independent review by Institutional Review Boards (IRBs) or Research Ethics Committees (RECs) ensures that trials meet ethical standards.
Challenges and Risks
One of the greatest challenges in FIM trials is the unpredictability of human responses. Despite extensive preclinical testing, a drug may behave differently in humans. A well-known example is the TGN1412 trial in 2006, where healthy volunteers experienced life-threatening immune reactions after receiving a monoclonal antibody.
Another challenge is dose selection. Choosing a dose that is too high may cause toxicity, while starting too low may delay development due to a lack of observable effects.
There are also ethical concerns, particularly when enrolling healthy volunteers. Ensuring informed consent, fair compensation, and adequate risk disclosure are all essential components of ethical trial conduct.
Examples of First-in-Man Trials
- mRNA COVID-19 Vaccine Trials: The first human trials of the Pfizer-BioNTech and Moderna vaccines began in 2020 and provided critical safety and dosing information.
- CAR-T Cell Therapy Trials: First-in-human studies evaluated genetically engineered T-cells in patients with leukemia and lymphoma.
- CRISPR Gene Editing Trials: Early FIM trials explored genome editing for conditions such as sickle cell disease and inherited blindness.
Conclusion
First-in-Man trials are a cornerstone of medical innovation. They represent the first step in translating scientific discovery into clinical application. Due to the high level of uncertainty and potential risk, FIM trials require robust design, regulatory compliance, and a strong commitment to participant safety. With careful planning and ethical oversight, these trials can pave the way for transformative advances in health care.
See also:
- Phase 1 Trials
- Investigational New Drug (IND) Application
- Data Safety and Monitoring Board (DSMB)
- Informed Consent
- Clinical Trial Ethics
Bibliography
- Kimmelman J, London AJ. Predicting harms and benefits in translational trials: ethics, evidence, and uncertainty. PLoS Medicine. 2011;8(3):e1001010.
- EMA. Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. European Medicines Agency; 2017. EMA/CHMP/SWP/28367/07 Rev. 1.
- FDA. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Food and Drug Administration; 2005. Available from: https://www.fda.gov
- Doshi P, Hur P, Kesselheim AS. Characteristics of first-in-human trials for high-risk medical devices approved by the FDA, 2006–2020. JAMA Internal Medicine. 2022;182(7):768–775.
- van Gerven JM, Cohen AF. Integrating PK and PD in early clinical drug development: principles and practice. British Journal of Clinical Pharmacology. 2018;84(7):1405–1414.
Adapted for educational use. Please cite relevant trial methodology sources when using this material in research or teaching.