The Different Phases of Clinical Trials

The development of investigational new drugs (INDs) involves performing clinical trials (or studies) to assess the safety and efficacy of the IND in humans.  These trials are usually classified into 4 phases of development (Phase 1 to 4), with each potentially lasting for several years.  Successful completion of each phase and approval by the appropriate regulatory authority or authorities (the European Medicines Agency [EMA] in the European Union, Food and Drug Administration [FDA] in the United States, Health Canada in Canada, or the Ministry of Health, Labour and Welfare in Japan) is required for progression to the next phase.

Satisfactory completion and approval of Phases 1 to 3 is required for a drug to be approved for marketing.  Phase 4 studies are conducted after a compound has been approved, for the primary purpose of post marketing surveillance.

In an attempt to both speed up the drug development process and to quickly identify safety issues, Phase 0 studies, also referred to as ‘human microdosing studies’ were introduced. 

The different clinical trial phases are described in further detail below and summarised in the table below. 

* Not always performed

Phase 0

The official name of a Phase 0 study is an exploratory IND study, and the goal is to quickly establish whether an agent will work as desired in humans, based on in vivo safety pharmacology and toxicology preclinical studies. Unlike later phases, Phase 0 studies do not assess therapeutic efficacy; rather, they focus on gathering initial human data to inform whether further development is viable.

Study Design and Dosage:

In Phase 0 studies, a single subtherapeutic dose of the IND is administered to a small number of healthy subjects (c.10 to 15), over a short duration (7 days).  Since the dose administered is too low to result in a therapeutic effect (ensuring the absence of toxic effects), preliminary pharmacokinetic (PK) and, where possible, pharmacodynamic (PD) data are collected for evaluation. 

This approach helps answer basic questions that are crucial for determining if higher-dose testing is warranted.

Advantages:

Phase 0 studies enhance drug development by providing early human data, enabling faster decisions on compound viability, and reducing late-stage failures. This approach allows for “fast-fail” assessments, eliminating non-viable compounds with minimal resource investment, which can extend patent life for backup drugs and save millions in development costs. Key benefits include greater safety, reduced regulatory requirements, and faster trial timelines compared to Phase I. Unique methodologies—like cassette microdosing, which tests multiple compounds simultaneously, and intra-target microdosing, which achieves localised drug exposure—enable targeted data collection with minimal risk. Additionally, adaptive designs allow seamless transitions between Phase 0 and Phase I, further expediting viable drug candidates into development.

Limitations:

Despite their benefits, Phase 0 approaches in drug development face several limitations. Introducing an additional early stage may create delays if not strategically managed, and adoption remains limited due to industry resistance, concerns about extrapolating microdose results, and uncertain value across drug types. Methodological challenges, such as rapid radiolabeling and the lack of standardized analytical methods, further complicate implementation. Although Phase 0 studies enhance safety through subtherapeutic dosing, accurate extrapolation to therapeutic levels is complex and requires advanced modeling. Addressing these issues may require early regulatory consultations and flexible policies, while further research across various drug types is essential to validate the approach's overall utility. 

Phase 1

Phase 1 studies are designed to assess the safety of an IND, to understand its PK and PD properties, and to ideally identify a potential therapeutic dose. 

This phase is critical for determining whether the drug can safely proceed to broader testing and for identifying a potential therapeutic dose range. PK data provides insights into how the drug is absorbed, distributed, metabolised, and eliminated, while PD data explores its biochemical and physiological effects.

Study Design and Participant Profile:

Typically, Phase 1 trials involve a small group of 15 to 30 participants, often healthy volunteers. In cases of severe diseases, such as cancer, patients may participate instead. The phase 1 studies may be designed as single ascending dose (SAD) studies, where small groups receive increasing doses of the drug, or multiple ascending dose (MAD) studies if the drug is administered over multiple days. The primary purpose is to identify the maximum tolerated dose (MTD), or the highest dose with acceptable safety.

Methodology:

Phase 1 trials are generally open-label (not blinded), allowing researchers to observe any adverse effects in real time. As each cohort completes its dosing without serious side effects, the next group receives a higher dose until the MTD is reached. Throughout this process, frequent blood tests, imaging, and physical assessments are conducted to monitor the drug’s impact and gather essential PK/PD data. This phase enables researchers to determine dose-related safety thresholds and potential biomarkers for future studies.

Please note that recent advancements to phase I trial design have allowed researchers to target alternative endpoints that may be clinically preferential to the MTD. Instead, phase I trials may focus on endpoints such as the optimal biological dose (OBD) under the Project Optimus Initiative. In addition, recent extensions to the BOIN design methodology have allowed a Bayesian approach to be utilised in designing such trials.

Phase 2

These studies are typically conducted to test the IND in a larger group of patients who have the disease or illness for which the IND is being developed, to determine whether it is efficacious, at least in the short term. This phase builds on the safety profile established in Phase 1 and aims to determine if the drug has a measurable therapeutic effect in real-world patients. Researchers also continue monitoring for side effects and short-term safety, gathering data that supports progression to later-stage trials.

Study Design and Participant Profile:

Phase 2 trials are generally larger than Phase 1 studies, typically including up to 300 patients who have the specific disease or condition that the IND is intended to treat. This increased sample size enables a more accurate evaluation of the drug’s therapeutic potential and safety in the target population. Many Phase 2 trials are divided into Phase 2a, focusing on dose optimisation, and Phase 2b, which evaluates the drug’s efficacy more directly.

Methodology:

To improve reliability, Phase 2 trials often use a randomised, controlled design and may include a control group receiving a placebo or standard treatment, allowing for comparisons between the experimental and control groups. Many trials are double-blinded, ensuring that neither the researchers nor the participants know who receives the active treatment, thus reducing bias. Frequent monitoring of patient responses, adverse effects, and laboratory analyses are key aspects of this phase, helping to capture comprehensive data on the drug’s effectiveness and safety.

Phase 3

Phase 3 studies are designed and performed to assess the efficacy and effectiveness of an IND in a larger cohort of patients, all of whom have the disease that the treatment is intended to treat.  Such studies are typically conducted in several hundred patients, and are usually conducted at multiple sites in multiple countries.  Phase 3 studies often compare the new treatment versus the current ‘gold standard’ treatment for the condition for which the new treatment is being developed.

Study Design and Participant Profile:

Phase 3 trials typically involve several hundred to several thousand patients who all have the specific disease or condition for which the IND is being developed. The large sample size helps capture a broader range of patient responses and detect less common side effects that may not have been observed in smaller trials. These trials are usually multinational and multi-site, conducted in several locations worldwide to assess how the drug performs across diverse populations and healthcare settings. This helps confirm the drug's efficacy across different demographic and geographic backgrounds, which can be essential for regulatory approval in multiple regions.

Methodology:
Most Phase 3 studies are randomised, controlled trials (RCTs) and often double-blinded to reduce bias. Patients are usually assigned to either the experimental group receiving the IND or a control group receiving the standard treatment or placebo, allowing for a clear comparison between treatments. The use of blinding (where neither the participants nor the researchers know which group is receiving the IND) ensures that the results are objective. During the trial, patients undergo regular monitoring for efficacy markers and safety indicators, often including lab tests, imaging studies, and clinical assessments.

Phase 4

Post marketing surveillance involves monitoring for safety (pharmacovigilance) once a treatment has been approved by the appropriate regulatory authority or authorities.  Such surveillance is intended to identify any rare adverse effects that have not been observed previously or have only been observed infrequently, and to monitor the effects of long term administration in a wider population.

Study Design and Participant Profile:

Unlike earlier phases, Phase 4 trials often include a large and diverse population to better reflect the broader range of individuals who will use the drug in real-world settings. This stage may also involve patients with multiple health conditions, varying demographics, and those taking other medications, providing a realistic picture of the drug’s long-term impact and any potential drug-drug interactions. Data collection in Phase 4 may come from observational studies, patient registries, or cohort studies, where data on safety and effectiveness is gathered passively as patients use the drug.

Methodology:

Phase 4 trials frequently use observational study designs to monitor drug safety and effectiveness without the structured setup of earlier randomised trials. Many Phase 4 studies leverage real-world evidence (RWE), often incorporating data from healthcare databases, patient surveys, and electronic health records (EHRs). Monitoring in this phase focuses on identifying rare side effects, evaluating long-term outcomes, and assessing overall quality of life impacts associated with prolonged drug use. Regulatory authorities may also require additional controlled studies or registry-based studies to follow up on specific safety concerns.

References

 Phase 0/microdosing approaches: time for mainstream application in drug development? | Nature Reviews Drug Discovery