Phase I clinical trials

Phase I clinical trials – initial step in testing a new drugs or treatments in humans with focus on safety and dosage. They are designed to assess the safety, dosage, and potential side effects of the treatment in a small group of healthy volunteers or patients. These trials are typically conducted in specialized research centers or hospitals. The primary goal is to determine:

• the maximum tolerated dose (MTD) and
• the pharmacokinetics (how the drug is absorbed, distributed, metabolized, and excreted by the body).

Planning, ethical review, regulatory approval, and stringent safety monitoring are key components of the Phase I trial process to ensure the well-being of participants and the generation of valuable safety data.

Design

The design of Phase I clinical trials can vary depending on the nature of the treatment being tested. They can be single-center or multicenter studies, randomized or non-randomized, open-label or blinded. The choice of design depends on various factors, including the research question, the number of participants available, and the resources and expertise of the research team.

Key aspects of the design of Phase I trials:

• Participants: Phase I trials typically involve a small number of healthy volunteers or, in some cases, individuals with the medical condition the intervention is intended to treat.
• Objective: The primary goal is to determine the maximum tolerated dose (MTD) and the safety profile of the intervention. Researchers also gather initial data on how the drug is metabolized and its pharmacokinetics.
• Dosing: Participants are often divided into cohorts, each receiving different doses of the experimental treatment. Dosing usually starts at a low level and is gradually escalated as the trial progresses.
• Duration: Phase I trials are relatively short in duration, lasting several months. The focus is on early safety assessment.
• Endpoints: The main endpoints are safety and tolerability. Researchers also collect preliminary data on the intervention's efficacy, although this is not the primary focus.

3 + 3 design

Under the 3 + 3 design, cohorts of three patients are assigned to increasing dose levels until one or more dose-limiting toxicities (DLTs) is observed. If one out of three patients has a DLT, a further three patients are assigned to the current dose. If two or more patients out of three or six patients at the current dose experience a DLT, the trial is terminated and the dose below this level is declared the MTD .

Planning of Phase I trials

• Protocol development: Researchers create a detailed protocol outlining the trial's objectives, design, inclusion and exclusion criteria, dosing strategy, and safety monitoring procedures.
• Investigator selection: Qualified medical professionals, such as clinical pharmacologists, oncologists, or other specialists, are chosen to conduct the trial.
• Study site selection: Phase I trials are often conducted in specialized research centers or academic medical institutions with the necessary infrastructure and expertise.
• Recruitment: Participants are recruited, and informed consent is obtained. Participants are provided with detailed information about the trial, its risks, and potential benefits.
• Regulatory submissions: The trial protocol, along with informed consent documents, is submitted to regulatory authorities, such as the FDA in the United States, for approval.

Approval of Phase I trials

Before a Phase I trial can begin, it must receive approval from regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). The trial protocol, which outlines the study objectives, design, and methodology, must be submitted for review. The approval process ensures that the trial is scientifically sound, ethically conducted, and that the potential benefits outweigh the risks for participants.

• Ethical review: The trial protocol is reviewed by an independent ethics committee or institutional review board (IRB) to ensure that the study is conducted ethically and that participants' rights and safety are protected.
• Regulatory approval: In many countries, the trial must be approved by a regulatory agency, such as the FDA in the United States. Regulatory agencies evaluate the protocol's scientific validity and safety measures.

Safety Monitoring

During the trial, safety monitoring is of utmost importance. Participants are closely monitored for any adverse events or side effects. The research team follows predefined safety protocols and conducts regular safety assessments to ensure participant well-being. If any safety concerns arise, the trial may be modified or terminated to protect the participants.

• Adverse event reporting: Participants are closely monitored for adverse events, and any unexpected or serious adverse events are promptly reported to the regulatory agency and the ethics committee.
• Dose escalation: The dosing strategy is carefully designed to minimize risks. Dose escalation may be halted or adjusted if adverse events occur.
• Pharmacovigilance: Researchers collect data on how the drug is metabolized, its pharmacokinetics, and its potential interactions with other drugs.
• Safety committees: Some trials may have independent data safety monitoring boards (DSMBs) that assess safety data and can recommend modifications or early trial termination.

See also

• Phases of Clinical Trials