Clinical phases (Phases I–IV) refer to the sequential stages of development in which a new medicinal product or therapeutic intervention is tested in humans. Each phase pursues specific objectives regarding safety, tolerability, dosage, and efficacy. The phase model is internationally binding—it forms the basis of clinical research according to Good Clinical Practice (GCP) and is regulated in EU Regulation 536/2014 on clinical trials.
Phase I – First-in-Human Application
In Phase I, an investigational product is tested in humans for the first time, typically in 20 to 80 healthy volunteers. The focus is on tolerability, safety, and pharmacokinetics (absorption, distribution, metabolism, and excretion of the active substance). Pharmacodynamic parameters—the effect of the drug on the organism—are also recorded. Phase I studies often utilize a dose-escalation design to determine the maximum tolerated dose.
For oncology investigational products, Phase I studies are often conducted directly in patients, as ethical considerations preclude testing in healthy individuals. For these studies, the sponsor compiles an Investigational Medicinal Product Dossier (IMPD) containing preclinical data and all available safety information.
Phase II – Feasibility and Dose-Finding
Phase II involves controlled studies in a limited patient group (100 to 300 individuals) with the target disease. Key focus areas include:
- Proof of Concept (PoC)
- Determination of the optimal therapeutic dose
- Further safety evaluation
- Identification of relevant endpoints for Phase III
Phase II studies are typically randomized and may be blinded. The study design can be adaptive, allowing dose-finding and efficacy phases to be combined in a so-called Phase II/III design (seamless design). The clinical study protocol must be submitted to the competent authority—in Germany, the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI)—as well as to the responsible ethics committee.
Phase III – Confirmatory Efficacy for Marketing Authorization
Phase III studies form the scientific core of the marketing authorization documentation. They are large-scale, randomized, controlled trials involving several hundred to thousands of participants, designed to provide evidence of efficacy compared to a placebo or a comparator product (active control). The benefit-risk ratio is comprehensively assessed.
Multicenter studies—trials conducted at several study sites simultaneously—are of particular importance in Phase III, as they strengthen the external validity of the results. Data from Phase III studies flow directly into the marketing authorization application, such as the Common Technical Document (CTD) for a Marketing Authorisation Application (MAA) submitted to the European Medicines Agency (EMA).
Key metrics in Phase III studies include endpoints such as overall survival, progression-free survival, and patient-reported outcomes. The Data Safety Monitoring Board (DSMB) continuously monitors the safety of study participants and can recommend early termination if significant harm or clear efficacy is established.
Phase IV – Post-Marketing Surveillance
Phase IV refers to studies and measures conducted after marketing authorization. The objectives are:
- Detection of rare or long-term adverse events (pharmacovigilance)
- Evaluation of efficacy under real-world conditions (real-world evidence)
- Investigation of new indications or patient populations
- Fulfillment of requirements from regulatory authorities (post-authorisation studies)
Non-interventional studies (NIS) are a typical instrument of Phase IV. They collect data from routine care without intervening in the treatment. The AMG (German Medicines Act) and the GCP Regulation also govern the requirements for documentation, safety reporting (SUSAR reports), and data protection for Phase IV studies.
Relevance for clinical trials
Understanding the phase model is indispensable for the planning and operational execution of clinical trials. Each phase places different demands on study design, site selection, protocol structure, and the resources to be deployed. Full-service CROs like mediconomics support sponsors across all four development phases—from Phase I planning and Phase III execution at multiple European sites to Phase IV post-marketing surveillance. The range of services includes project management, monitoring (risk-based monitoring), data management with electronic case report forms (eCRF), and medical writing for all study-relevant documents.
Frequently Asked Questions (FAQ)
What is the difference between Phase II and Phase III clinical trials?
Phase II primarily serves dose-finding and proof of concept in a small patient group (100–300 people). Phase III is the pivotal efficacy study conducted in several hundred to thousands of participants to comprehensively demonstrate the benefit-risk ratio. The results of Phase III form the primary basis for submitting a Marketing Authorisation Application (MAA) to the EMA or BfArM.
Do Phase I studies in the EU need to be registered with an authority?
Yes. Since EU Regulation 536/2014 (Clinical Trials Regulation, CTR) came into effect, all clinical trials—including Phase I studies—are registered via the EMA’s Clinical Trials Information System (CTIS). The sponsor must submit an approved study protocol, an IMPD, and a positive opinion from the ethics committee. In Germany, additional approval by the BfArM or PEI is required.
How long do the individual clinical phases typically last?
The duration varies greatly depending on the indication, design, and recruitment success. Phase I usually lasts 1 to 2 years, Phase II 2 to 3 years, and Phase III 3 to 6 years. Phase IV often runs for many years parallel to marketing. Overall, it frequently takes 8 to 12 years from the first clinical use to marketing authorization, which is why efficient study management and early feasibility assessments are key success factors.
Regulatory References
- EU Regulation 536/2014 (CTR): Regulation on clinical trials on medicinal products for human use; in effect since January 31, 2022, replacing Directive 2001/20/EC
- ICH E8(R1): General considerations for clinical studies – phase concept and study design principles
- ICH E6(R3): Guideline for Good Clinical Practice (GCP); authoritative for all clinical phases
- AMG (Arzneimittelgesetz, Germany): Sections 40–42a regulate requirements for clinical trials of all phases
- EMA/CHMP/ICH/291534/1995 (ICH E9): Statistical principles for clinical trials – relevant for Phase II/III
- EMA Guideline on clinical trials in small populations (CHMP/EWP/83561/2005): Special regulations for rare diseases (orphan drugs)