Phase I trials are the first stage of clinical trials designed to assess the safety and tolerability of new drugs or treatments in humans. These trials involve a small number of healthy volunteers or patients, and are usually conducted in a controlled setting, such as a hospital or research facility. The main objective of phase I trials is to determine the maximum tolerated dose (MTD) of a drug, as well as to evaluate its pharmacokinetics and pharmacodynamics. In this article, we will explore the main features of phase I trials, including their patient selection, study design, endpoints, and ethical considerations.
Patient Selection
The selection of participants for phase I trials is critical, as it determines the safety and tolerability of the drug in the first human subjects. Healthy volunteers are typically used in the initial stages of phase I trials to establish a baseline for safety and tolerability. Later stages of phase I trials may involve patients with the target disease or condition to evaluate the drug’s efficacy and safety in a clinical population.
Design of Phase I Trials
Phase I trials are typically conducted after preclinical studies have shown promising results in animal models, and after the drug has undergone extensive safety testing in vitro. These trials are usually conducted in three stages, each involving a different group of participants.
The first stage involves a small number of healthy volunteers, usually between 10 and 20, who receive the lowest possible dose of the drug. This is done to establish a baseline for safety and tolerability, as well as to evaluate the pharmacokinetics of the drug. Pharmacokinetics refers to how the drug is absorbed, distributed, metabolized, and excreted by the body.
The second stage involves a slightly larger group of volunteers, usually between 20 and 50, who receive increasing doses of the drug to determine its MTD. The MTD is the highest dose of the drug that can be administered without causing unacceptable toxicity or side effects. Once the MTD has been established, the third stage of the trial can begin.
The third stage involves testing the drug at the MTD in patients with the target disease or condition. This is done to evaluate the drug’s efficacy and safety in a clinical population. Phase I trials may also include a dose-escalation phase, where the drug is gradually increased in dose until the MTD is reached.
Endpoints of Phase I Trials
The primary endpoints of phase I trials are safety and tolerability. Safety is typically evaluated by monitoring adverse events, such as nausea, vomiting, or changes in blood pressure or heart rate. Tolerability refers to the ability of the participant to tolerate the drug, and is often assessed using various questionnaires and scales.
Secondary endpoints of phase I trials include pharmacokinetics and pharmacodynamics. Pharmacokinetic endpoints include measurements of drug concentration in the blood or other tissues, as well as how long the drug remains in the body. Pharmacodynamic endpoints include measurements of the drug’s effect on the body, such as changes in biomarkers or disease symptoms.
Ethical Considerations
Like all clinical trials, phase I trials are subject to strict ethical guidelines and regulations. The main ethical considerations in phase I trials include the risks and benefits of participation, informed consent, and protection of vulnerable populations.
Participants in phase I trials must be fully informed of the risks and potential benefits of participation, and must provide their informed consent before participating. Vulnerable populations, such as children or the elderly, may require additional safeguards to protect their rights and interests.
Phase I trials are an essential component of the drug development process, and provide valuable information on the safety, tolerability, pharmacokinetics, and pharmacodynamics of new drugs. By establishing the MTD and evaluating the drug’s safety in a controlled setting, phase I trials provide a foundation for subsequent clinical trials and regulatory approval. However, it is important to balance the potential benefits of new drugs with the ethical considerations and protection of human subjects in these trials.
References
- Clinical Trials: What You Need to Know. National Institutes of Health. https://www.nih.gov/health-information/nih-clinical-research-trials-you/clinical-trials-what-you-need-know.
- Guidance for Industry: Estimating the Maximum Safe Starting Dose. U.S. Food and Drug Administration. https://www.fda.gov/media/72309/download.
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. https://www.ich.org/home.html.
- Good Clinical Practice. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. https://www.ich.org/page/good-clinical-practice.