The Journey of a New Drug: Beyond Preclinical Research
Before any new drug or medical treatment reaches human testing, it undergoes extensive preclinical research [1.4.7]. This essential stage involves laboratory (in vitro) and animal (in vivo) studies to gather initial data on safety, toxicity, and efficacy [1.4.1, 1.4.4]. These studies provide the foundational evidence required to justify moving forward to human trials. They help scientists understand how a compound interacts with biological systems, what its potential risks are, and how it is absorbed, distributed, metabolized, and excreted (ADME) [1.4.1, 1.4.3]. Only after a thorough review of this preclinical data can a drug sponsor apply to regulatory bodies like the FDA to begin testing in people [1.4.4].
Defining 'First-in-Human' (FIH) Trials
A "first-in-human" (FIH) or "first-in-man" study is precisely what the name implies: the very first time an investigational new drug is administered to human subjects [1.8.1, 1.8.3]. The primary goal of this initial step is to evaluate the treatment's safety, determine a safe dosage range, and identify potential side effects [1.8.2, 1.8.5]. For decades, this crucial milestone was synonymous with Phase 1 clinical trials [1.2.3]. However, the landscape of drug development has evolved.
The Rise of Phase 0: An Earlier First Step
The direct answer to the question, "is phase 1 always first in humans?" is no. An earlier, optional stage called Phase 0 now often represents the true first-in-human study [1.8.3]. Introduced by the FDA in 2006, Phase 0 trials are exploratory studies that involve administering a very small, sub-therapeutic dose of a drug, known as a microdose, to a small number of participants (typically 5-15) [1.3.1, 1.3.2, 1.7.3].
The key objectives of a Phase 0 study are:
- To study pharmacokinetics (PK): Researchers analyze how the human body processes the drug, providing real-world human data that is more predictive than animal models [1.3.2, 1.7.3].
- To gather biodistribution data: Using advanced imaging techniques, scientists can see where the drug accumulates in the body, confirming if it reaches its intended target [1.2.1, 1.3.2].
- To make early go/no-go decisions: The data from Phase 0 allows companies to eliminate unpromising drug candidates early, before investing significant time and resources in larger, more expensive Phase 1 trials [1.2.1]. This "kill-early-kill-cheap" strategy saves money and conserves patent life [1.7.5].
Phase 0 trials are not designed to assess safety at therapeutic doses or to measure efficacy; their purpose is to provide a preliminary look at the drug's behavior in humans to inform the design of subsequent Phase 1 trials [1.3.6]. A microdose is defined as less than 1/100th of the therapeutic dose, not to exceed 100 micrograms [1.7.1, 1.7.3]. Because of the low dose, the risk of adverse effects is minimized, and less extensive preclinical toxicity data is required to get started [1.7.3].
Understanding Phase 1 Trials
When a Phase 0 study is not conducted, or after a successful one is completed, the drug development process moves to a Phase 1 clinical trial. This is what many traditionally consider the first step in human testing. Unlike Phase 0, the primary goal of Phase 1 is to comprehensively assess the safety of the new drug at therapeutic doses [1.2.6, 1.5.1].
Key characteristics of Phase 1 trials include:
- Participants: They typically enroll a small group of healthy volunteers (around 20-100) [1.5.2, 1.5.6]. However, in fields like oncology, trials may recruit patients with the specific disease [1.2.7].
- Objectives: The main goals are to determine the drug's most frequent side effects, how it's metabolized and excreted, and to find the maximum tolerated dose (MTD) [1.2.7, 1.5.4].
- Dose Escalation: Studies often use a dose-escalation design, where small groups of participants receive increasing doses of the drug to find the highest dose that does not cause unacceptable side effects [1.8.5]. This process often involves "sentinel dosing," where one or two participants receive the drug first to monitor for immediate adverse effects before dosing the rest of the cohort [1.8.4].
Comparison of Clinical Trial Phases
To understand the full context, it's helpful to see how Phase 0 and 1 compare to the later stages of clinical research.
| Phase | Primary Purpose | Typical Number of Participants | Participant Type |
|---|---|---|---|
| Preclinical | Assess initial safety and efficacy | N/A (Lab & Animal Studies) | Cells and Animals [1.4.7] |
| Phase 0 | Exploratory Pharmacokinetics (PK) & Biodistribution | 5-15 [1.3.2] | Patients with target disease [1.2.1] |
| Phase 1 | Safety & Dosage | 20-100 [1.5.6] | Healthy Volunteers (usually) [1.5.2] |
| Phase 2 | Efficacy & Side Effects | Several Hundred [1.5.6] | Patients with the condition [1.5.2] |
| Phase 3 | Efficacy vs. Standard & Safety | 300 to 3,000+ [1.5.6] | Patients with the condition [1.5.2] |
| Phase 4 | Post-Marketing Safety & Efficacy | Several Thousand [1.5.6] | General population via prescription [1.5.1] |
Conclusion: A More Efficient Path to New Medications
While Phase 1 trials remain a cornerstone of drug development and are often the first time a drug is tested at therapeutic levels in humans, they are not always the first human exposure. The adoption of Phase 0 microdosing studies has created an earlier, exploratory first step. These trials provide invaluable human pharmacokinetic and biodistribution data, allowing for more informed decisions and a more efficient drug development pipeline [1.3.3]. By weeding out non-viable candidates before they enter costly and lengthy Phase 1 trials, Phase 0 studies help streamline the path from the laboratory to the pharmacy, ultimately accelerating the delivery of safe and effective new medications to patients.
For more information on clinical trial guidelines, you can visit the U.S. Food and Drug Administration (FDA) website.
