What You Need to Know About Phase I Trials

Overview

Phase I trials are a critical first step in testing new investigational treatments or drugs in humans¹. These trials mainly focus on determining the safety and appropriate dosage for further testing¹. In this article, we provide a comprehensive and easily understandable guide to Phase I trials, including their purpose, the informed consent process², potential risks and benefits, patient eligibility criteria, and common questions and concerns that may arise³.

```

Understanding Phase I Trials

Phase I trials, also known as first-in-human (FIH) trials, are the initial step in clinical research for testing new investigational treatments or drugs in humans<sup>1</sup>. Before a Phase I trial begins, the experimental treatment has generally undergone extensive laboratory and animal testing to evaluate its potential effects and safety<sup>1</sup>.

During a Phase I trial, a small group of participants, typically between 10 and 80 healthy volunteers, are enrolled to evaluate the drug's safety, tolerability, and pharmacokinetics - how the drug is absorbed, distributed, metabolized, and eliminated by the body<sup>1</sup>. The study may involve participants with specific medical conditions if the drug under investigation is intended to treat serious or life-threatening illness<sup>1</sup>.

The trial usually follows a dose-escalation approach, which means that the participants are divided into small groups (called cohorts), and each cohort receives a different dose of the investigational treatment<sup>1</sup>. The lowest dose group starts first, and depending on the tolerability and safety findings, the dose is increased for subsequent cohorts<sup>1</sup>. Dose levels are carefully monitored and adjusted to ensure participants' safety<sup>1</sup>.

Data Monitoring Committees (DMCs) are often involved in overseeing the trial's progress and ensuring that any safety concerns are promptly addressed<sup>1</sup>. DMCs can recommend adjustments to the dosing schedule, changes in participant eligibility criteria, or early termination of the trial based on emerging safety data<sup>1</sup>.

Completing a Phase I trial is essential as it lays the foundation for further clinical research<sup>1</sup>. If the trial demonstrates acceptable safety and tolerability, the investigational treatment can progress to Phase II trials, where its clinical effectiveness will be evaluated in a larger group of participants with specific medical conditions<sup>1</sup>.

Purpose of Phase I Trials

The primary objective of Phase I trials is to determine the safety and maximum tolerated dose (MTD) of a new investigational treatment or drug in humans<sup>1</sup>. This is important because it helps researchers to:

• Assess safety and tolerability: Phase I trials focus on identifying any potential side effects associated with the investigational treatment and determining the highest dose levels that can be administered without causing unacceptable side effects<sup>1</sup>.
• Understand pharmacokinetics: These trials provide essential information about how the drug is processed in the body, such as absorption, distribution, metabolism, and elimination<sup>1</sup>. This information helps researchers design more effective Phase II and III trials by informing dose levels and frequency.
• Systematically increase the dose: Phase I trials follow a dose-escalation approach, which allows researchers to gradually increase the drug's dose to find the optimal therapeutic range that balances potential benefits and risks<sup>1</sup>. This process also helps minimize the risk of exposing participants to unnecessarily high levels of the drug.
• Gather preliminary information on efficacy: While Phase I trials are not primarily designed to evaluate the clinical effectiveness of the investigational treatment, they can provide early indications of whether the drug has a potential therapeutic effect on specific diseases or medical conditions<sup>1</sup>.
• Refine patient populations: Researchers may use the findings from Phase I trials to further define the patient populations that are most likely to benefit from the investigational treatment in later-stage trials<sup>1</sup>.

In summary, Phase I trials are crucial in the drug development process, as they provide the initial safety and pharmacokinetic data necessary to move forward with subsequent phases of clinical research<sup>1</sup>. By carefully evaluating the safety, tolerability, and MTD of new treatments in small groups of participants, researchers can make informed decisions about whether to advance the investigational drug to Phase II trials, where the focus shifts to evaluating its clinical effectiveness in larger, more specific patient populations<sup>1</sup>.

Informed Consent Process

Before participating in a Phase I trial, it is essential for potential participants to be fully informed about the study and its risks and benefits. This is achieved through the informed consent process, which is designed to protect patients and ensure they understand the trial's purpose, procedures, potential risks, and potential benefits<sup>1</sup>.

Informed consent is an ongoing communication process between the research team and the participant, which involves:

• Clear explanation of the study: The research team discusses the study with the potential participant, including its purpose, details of the treatment, study duration, and any procedures involved. They also provide a written informed consent document containing all essential information<sup>2</sup>.
• Discussion of potential risks and benefits: The research team clearly explains the possible side effects, risks, and potential benefits of participating in the study. It is emphasized that the primary purpose of a Phase I trial is to understand the safety of the investigational treatment, and its effectiveness might not be fully determined at this stage<sup>1</sup>.
• Opportunity to ask questions: Potential participants are encouraged to ask questions at any time during the informed consent process. This helps ensure they have a complete understanding of the study and their potential involvement in it<sup>2</sup>.
• Time to consider participation: Once all questions are addressed, potential participants are given sufficient time to carefully consider their decision, discuss it with family and friends, or seek a second opinion before deciding to join the study<sup>2</sup>.
• Voluntary agreement to participate: If a potential participant decides to join the study, they will sign the informed consent document as an acknowledgment that they fully understand the study and voluntarily agree to participate. This consent can be withdrawn at any time during the study without any negative consequences<sup>2</sup>.

The informed consent process is an essential aspect of clinical research, designed to support patients in making thoughtful, well-informed decisions about their involvement in a study<sup>3</sup>. By ensuring transparency and open communication between researchers and participants, this process helps uphold ethical standards and protects the rights, safety, and well-being of those who join clinical trials<sup>3</sup>.

Potential Risks and Benefits

It is important for potential Phase I trial participants to understand the potential risks and benefits associated with their participation. Phase I trials are primarily focused on evaluating the safety, dosage, and side effects of an investigational treatment<sup>1</sup>. While efficacy may also be assessed, it is not the primary goal at this stage. While participating in a Phase I trial, participants may encounter different risks and benefits:

• Potential Risks: As investigational treatments have not been fully tested for safety, there is a possibility of experiencing side effects that can range from mild to severe. Some side effects may be temporary or reversible, while others may become permanent or may not manifest until later in the study or after completion. Participants may also receive a placebo, depending on the design of the trial, and may not receive any direct medical benefit from participating<sup>1</sup>.
• Monitoring and Support: Throughout the trial, participants will be closely monitored to ensure their safety and well-being. This close observation by a team of professionals can lead to early detection and management of side effects, helping to mitigate potential risks. In some cases, participants in Phase I trials may receive additional supportive care and medical attention beyond what they might get with standard treatment alone<sup>1</sup>.
• Potential Benefits: Although it's important to remember that the primary purpose of a Phase I trial is to assess safety, there is still a possibility that participants may experience some therapeutic benefit from the investigational treatment. For some individuals, this benefit may offer a potential alternative when standard treatments have not been effective or are not available. Additionally, by participating in a Phase I trial, patients contribute to the progress of medical research, which may benefit others in the future<sup>1</sup>.
• Access to Novel Treatments: Participating in a clinical trial can provide access to new and innovative therapies that may not be available outside of the trial context. This could potentially benefit patients who have exhausted other treatment options, who are seeking alternatives, or who want to be involved in cutting-edge research<sup>3</sup>.

Participating in a Phase I trial is a personal decision that should be made after carefully considering the potential risks and benefits, as well as discussing the trial with the research team, healthcare providers, and loved ones. Informed consent is an essential component of this process, ensuring that potential participants have the necessary information to make informed decisions about their involvement in a clinical trial<sup>2</sup>.

Patient Eligibility Criteria

Each Phase I trial has a specific set of eligibility criteria that must be met for a patient to participate in the study<sup>1</sup>. These criteria help ensure that the patients enrolled have similar characteristics, which can make interpreting the results of the trial more reliable. Eligibility criteria for Phase I trials may vary depending on the investigational treatment and the purpose of the study. However, some common eligibility criteria may include:

• Age and Gender: Participants must meet the age and gender requirements specified by the trial. Some trials may be open to adults only, while others may include pediatric populations. Furthermore, certain trials may focus on one gender or have specific enrollment targets for each gender.
• Diagnosis: To be eligible for a Phase I trial, patients must have a particular disease or condition, as specified in the trial's eligibility criteria<sup>1</sup>. The disease or condition may be confirmed by specific diagnostic tests, medical history, or other methods.
• Medical History: Prior treatments, surgeries, or other medical events can affect a patient's eligibility for a Phase I trial<sup>1</sup>. This can include the type and timing of previous treatments or the presence of certain pre-existing medical conditions.
• Physical or Laboratory Tests: Physical exams, blood tests, or other laboratory or imaging tests might be performed to determine a patient's eligibility<sup>1</sup>. These tests may assess organ function, blood counts, or other aspects related to the potential risks and benefits of the trial.
• Performance Status: An individual's ability to carry out daily activities and care for themselves is often considered when evaluating eligibility<sup>1</sup>. Performance status measures can help determine whether patients can safely participate in a Phase I trial and provide information about their general health status.

It is crucial for potential participants to discuss their eligibility with the research team and provide accurate and complete information about their medical history, previous treatments, and present health status<sup>2</sup>. Before enrolling in any clinical trial, including Phase I studies, patients should carefully review the informed consent document, ask questions, and consult with their healthcare providers and loved ones<sup>3</sup>.

Common Questions and Concerns

It's natural to have questions and concerns about participating in a Phase I trial. To help you better understand what Phase I trials entail, we've addressed some frequently asked questions and concerns below:

• How is my safety ensured during a Phase I trial?Participant safety is a top priority in all clinical trials, including Phase I trials<sup>1</sup>. Researchers and the study team monitor patients closely and implement stringent safety protocols to minimize risk. Should any adverse effects occur, the research team will address them promptly and may adjust treatment or study protocol, if necessary.
• Will I receive any benefit from participating in a Phase I trial?The primary purpose of a Phase I trial is to determine the safety and dosing of a new therapy<sup>1</sup>. While patients may still receive potential benefits from the investigational treatment, this is not the primary focus of Phase I trials. Nonetheless, some individuals may experience symptom relief or stabilization of their disease, and participating in a trial may offer access to a novel therapy that may not be available otherwise.
• What are the chances of receiving a placebo?Phase I trials usually do not involve placebos, as their primary focus is evaluating the safety and dosage of a new treatment<sup>1</sup>. All participants typically receive the investigational therapy at varying dosages or in combinations with other treatments. However, each trial's design is unique, so potential participants should ask about the specific trial's use of placebos, if any, before joining.
• Can I leave the trial if I am experiencing side effects or if my condition worsens?Yes, participants can withdraw from a Phase I trial at any time and for any reason<sup>2</sup>. It is essential to communicate your concerns with the study team to help guide decision-making. If you decide to leave a trial, it's important to discuss alternative treatment options with your healthcare provider.
• Will my participation in a Phase I trial affect my future treatment options?Participating in a Phase I trial typically does not restrict a patient's access to future treatments<sup>3</sup>. However, it's important to discuss your individual situation with your healthcare provider and explore how participating in a trial may affect your future treatment choices.

The decision to participate in a Phase I trial is a personal one and should be made after discussing your options with your healthcare provider, reviewing the informed consent document<sup>2</sup>, and considering your personal preferences and goals. By asking questions and addressing your concerns, you can make an informed decision about whether participating in a Phase I trial is right for you.

Learn more about SurvivorNet's rigorous medical review process.