Phases of clinical trials

A phase of a clinical trial is a defined stage in the evaluation of a drug or biological product. The phase is determined by the study’s objectives, the number and type of participants, and specific design characteristics.

The concept of phases is increasingly considered outdated and gradually being replaced by the concept of clinical study type, as modern drug development often uses adaptive, overlapping, or multi-objective study designs.

Definitions

21 CFR § 312.21 

Phase 1

(1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.

(2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.

Phase 2

Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.

Phase 3

Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects .

Overview of clinical trial phases

Each clinical trial phase contributes distinct evidence that supports the safe and effective development of new medical interventions.

Phase	Characteristics
Phase I	First use of a new drug or intervention in humans, typically in a small number of healthy volunteers. The focus is on safety, tolerability, dose range, and basic pharmacokinetics, including how the drug is administered.
Phase II	Studies in patients with the target condition, usually using doses identified in Phase I. The aim is to explore preliminary efficacy while continuing safety evaluation and further characterizing side effects.
Phase III	Large, often multinational trials designed to confirm efficacy, compare the new intervention with standard treatments, and establish an overall benefit–risk profile to support regulatory approval.
Phase IV	Post-authorization studies conducted after market approval to collect additional information on long-term safety, effectiveness, risks, and optimal use in real-world settings.

The clinical trial phase concept is a description and not a requirement, and the phases of drug development may overlap or be combined (ICH E8 4.3 ).

Phase I clinical trials

Phase I clinical trials are the first studies of an investigational drug or treatment in humans. Their primary purpose is to evaluate safety, tolerability, and dose limits, not therapeutic efficacy. These trials usually enroll a small number of participants, most often healthy volunteers, though patients with the target disease may be included in areas such as oncology. The key outcomes are identification of dose-limiting toxicities, the maximum tolerated dose, and basic pharmacokinetic characteristics.

Dose escalation is a common, but not universal, feature of Phase I trials . In many first-in-human and oncology studies, participants are treated in cohorts and doses are adjusted based on emerging safety data. Rule-based designs such as the 3 + 3 approach and model-based methods like the continual reassessment method are frequently used for this purpose. Other Phase I studies use fixed-dose or adaptive designs without formal cohort-based escalation, depending on the objectives and nature of the intervention.

Phase I trials require a predefined protocol, ethical review, and regulatory authorization before initiation. Throughout the study, intensive safety oversight is maintained, including real-time adverse event reporting and predefined stopping rules. The resulting data provide the foundation for dose selection and risk assessment in later-phase clinical development.

Phase II clinical trials

Phase II clinical trials evaluate an investigational intervention in a defined patient population to explore preliminary efficacy while continuing safety assessment. Building on Phase I findings, these studies aim to determine whether the intervention shows sufficient biological or clinical activity to justify further development, while refining the understanding of its safety profile.

Phase II designs vary and may include randomization, control groups, and different dosing regimens, depending on the research question. Endpoints commonly focus on measures of treatment effect such as response rates, biomarkers, or disease-related outcomes. Safety monitoring remains continuous, and dose adjustments or optimization may be incorporated to identify a suitable regimen for later-phase trials.

See also

Another relevant pages

• Clinical research

External links

• US FDA web site, "Step 3: Clinical Research", 04 Jan 2018, https://www.fda.gov/patients/drug-development-process/step-3-clinical-research