Clinical trials, the fundamental tenet of clinical research, are crucial tools utilized by scientists, sponsors, and contract research organizations (CROs) to validate the safety and efficacy of drugs in humans. Large regulatory bodies like the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) typically divide the clinical testing stage of drug development into four phases of clinical research, each with its own unique characteristics, challenges, and considerations. New treatments, medications, or therapies must undergo rigorous testing, passing through the different clinical trial phases, before reaching the market. Each phase is crucial in ensuring the safety and effectiveness of the drug or device. Getting a new drug, device, or therapy approved for the market is significantly time-consuming, often taking nearly 10 years from initial discovery to full approval, of which six to seven years are dedicated to the various clinical trial phases.

In this article, we will provide a detailed breakdown of each of the four phases of clinical research, from Phase I to Phase IV clinical trials. Read on to learn more! 

 

Understanding the Purpose and Design of a Clinical Trial

Generally, clinical trials involve the study of an investigational drug or any other intervention within a defined population or participant. This usually involves a treatment group and a control group, which will typically involve administering a placebo, both of which are evaluated for the efficacy of the intervention. Randomized controlled trials (RCTs), in particular, are recognized as the most effective due to their unbiased design, which ensures that the results are reliable. Ultimately, clinical trials are designed to improve the understanding of the unknown, test a hypothesis, and perform public health-related research. This is primarily achieved by collecting and analyzing data to derive conclusions through a variety of types of clinical trials, primarily grouped as analytical, observational, and experimental research. Clinical trials may also be therapeutic or non-therapeutic, depending on the type of intervention. Whereas the former is used to test a drug that could directly benefit the patient, the latter type indirectly benefits them by providing additional knowledge about the drug’s safety and/or efficacy.

With that, let’s take a look at the four phases of clinical research! 

 

Phases of Clinical Research: Phase I

Purpose of Phase I 

A Phase I clinical trial, also known as a Phase I study, or an early-phase clinical trial, aims to evaluate whether the potential treatment is safe to administer to humans, understand potential side effects, and determine the safe dosage range. 

 

Clinical Research Process 

Although researchers may also look for evidence of a drug’s potential effectiveness against the disease of interest, the primary focus is on determining safety in humans. During this phase, this is done by initially administering a low dose of the investigational product and increasing the dosage in a controlled manner only if the previous dose was well-tolerated. Participants enrolled in Phase I studies are carefully observed and recorded, with particular attention given to any side effects, their severity, and dose dependence.

Specifically, Phase I, sometimes known as First-in-Human, studies are commonly classified as either a single ascending dose (SAD) trial or a multiple ascending dose (MAD) trial.  

• SAD study design: A small group of subjects or healthy volunteers receive a single dose of the study drug.  
• MAD study design: A group of healthy volunteers or patients receive multiple low doses of the drug. Following SAD studies, MAD studies are conducted to gradually narrow down the maximum tolerable dose (MTD) of a drug that will be applied in future phases.  

 

Phase I Key Characteristics 

Phase I clinical trials usually include six to eight groups of three to six participants and three groups of eight individuals each. Depending on the trial, the duration of this phase ranges from one week to several months. It’s worth noting that approximately 70% of drugs make it to the next phase of clinical testing. 

 

Phases of Clinical Research: Phase II

Purpose of Phase II

Phase II trials have several objectives and serve to further investigate the safety and effectiveness of the experimental treatment in a larger group:  

• Further monitoring of whether a drug is safe for use in humans.
• Understanding the side effects and how they can be managed. 
• Comparing the safety and effectiveness of the new treatment to existing treatments.  

 

Clinical Research Process 

Phase II clinical trials recruit a larger group of participants – often up to 100 to 300 patients – all of whom have the condition of interest. The dose administered in these trials is typically the MTD, or the highest dose with the most manageable safety profile, identified in Phase I, and patients are monitored for side effects and signs of effective treatment. This phase of clinical research is also unique in that it is divided into two sub-phases: 

• Phase IIa usually aims to decide the drug dosage and includes less than 100 patients, taking weeks or months. 

• Phase IIb studies the dose-response relationship, drug-drug interactions, and comparison with a placebo. 

 

Phase II Key Characteristics 

Phase II clinical trials often recruit a larger group of participants than seen in Phase I. They are also often multicenter studies to increase the diversity and reliability of the results. This phase also examines the most effective dosage in patients, as well as the therapeutic effects on the disease of interest, while also monitoring drug-drug interactions. Approximately 33% of drugs move on from this phase to the next stage of clinical testing. 

 

Phases of Clinical Research: Phase III

Purpose of Phase III

The main objective of Phase III clinical trials is to confirm the safety and efficacy of the investigational product. Specifically, it aims to demonstrate whether a drug has more significant benefits or fewer side effects than existing standard therapies on the market.  

 

Clinical Research Process 

Upon recruitment, patients during this phase of clinical research are randomized into different treatment arms to receive different doses and combinations of assigned treatments. This design enables researchers to investigate the effectiveness of a treatment compared to standard treatments, the efficacy of different doses, and the type, frequency, and severity of side effects associated with new versus existing treatments. These trials also initiate the process of New Drug Application (NDA) with regulatory agencies like the FDA. 

 

Phase III Key Characteristics 

One of the defining characteristics of Phase III trials is the large population sample involved. With patient numbers typically ranging from 300 to 3,000, these clinical trials are larger than both those conducted in earlier phases of clinical research. Another key characteristic is that they are pre-marketing phases that examine the safety and efficacy of the drug before it is made available to the general public. Approximately 25% to 30% of drugs at this phase of clinical research proceed to market approval and Phase IV clinical trials.  

 

Phases of Clinical Research: Phase IV

Purpose of Phase IV

The primary objective of Phase IV trials is to investigate rare but serious side effects that the new drug or therapy may cause. This phase of clinical research also serves to evaluate the long-term risks and benefits of the treatment and its efficacy across a larger population in real-world settings. 

 

Clinical Research Process 

Once a drug has successfully passed Phase III testing, it is common for the sponsor of the study to submit a New Drug Application (NDA) or a biologics license application (BLA) to the FDA. Following its regulatory approval, the drug in question typically proceeds to enter Phase IV of clinical research, also known as “Post-Approval Research and Monitoring.” The sponsor of the approved treatment continues to monitor patients who use the therapy to gain more insight into its long-term effects and efficacy compared to other options on the market.  

 

Phase IV Key Characteristics 

Unlike the earlier phases of clinical research, Phase IV clinical trials are performed on therapeutic interventions that have already been tested and approved. Instead, Phase IV studies focus on the frequency and severity of rare adverse events in the general population and the safety of the treatment for those who experience these events.  

 

Conclusion

In conclusion, understanding the purpose, process, and characteristics of the four drug development phases of clinical research is critical for sponsors, CROs, and researchers to ensure the safety and efficacy of new drugs. Each phase provides important information about the drug, from dose tolerability to effectiveness and potential side effects. Although the timeline between Phase I and Phase IV clinical trials is undoubtedly extensive and expensive, this structured approach to drug clinical testing helps ensure that any new medical intervention is both effective and well-tolerated by patients.  

 

TFS HealthScience CRO: Your Essential Partner From Phase I to Phase IV

TFS HealthScience is a global CRO that supports biotechnology and pharmaceutical companies throughout their entire clinical development journey. Our expert team of Clinical Operations professionals are well-versed in supporting our clients across the entire drug development pipeline, from Phase I-III clinical trials to Phase IV and real-world evidence (RWE) studies. Visit our website to learn more about the solutions TFS can offer for your next clinical trial, or connect with a TFS representative today!