First-in-human trial: The first phase of clinical development
The journey of drug development is filled with excitement and challenges, with one of its most critical milestones being the first human trials, known as "first-in-human" (FIH) clinical studies. This pivotal phase marks the transition from lab and animal testing to human testing. The primary aim of these Phase I trials is to evaluate the safety, tolerability, and pharmacokinetics of a new drug in healthy volunteers. Participants are carefully selected based on strict medical and psychological criteria to minimize the risk of adverse events. These volunteers play a crucial role in advancing promising compounds to the next stages of clinical development, bringing potential treatments closer to patients. Let's explore what first-in-human trials entail!
The structure of first-in-human trials
Designing Phase I trials requires meticulous planning, as this is the stage where a drug candidate is tested on humans for the first time. In Phase I/a, the focus is on selecting single ascending doses, a critical aspect for ensuring safety. Experts often determine the starting dose based on the NOAEL (No Observed Adverse Effect Level) and adjust it using a safety margin. Another approach is the MABEL (Minimum Anticipated Biological Effect Level) concept, which estimates a safe starting dose based on pharmacodynamic effects.
The strategy for dose escalation is also carefully considered. The Fibonacci sequence, or its modified versions, are popular choices because they allow for larger initial increments, followed by gradually smaller ones. In Phase I/b, studies involve repeated dosing, potentially lasting several weeks. During this time, participants' physiological functions and side effects are closely monitored. To determine pharmacokinetic parameters, regular blood sampling is needed to monitor the drug levels in the body. These studies are essential to obtain a comprehensive picture of the safety and behavior of the drug candidate in the human body, laying the foundation for further clinical development.
Key considerations in the first phase of drug development
In first-in-human trials, participant safety and well-being are of utmost importance. Selection is based on stringent inclusion and exclusion criteria. Typically, only completely healthy males aged 18 to 50, who do not regularly take medication, smoke, or use drugs, are eligible.
Women are usually excluded from this phase to avoid complications related to early pregnancy, and because reproductive toxicity studies are often incomplete at this stage. This exclusion is crucial, as the potential for the new drug to harm a fetus remains unknown.
However, there are ethical considerations that sometimes necessitate the involvement of patients instead of healthy volunteers, such as with anti-cancer or anti-HIV drugs. In these cases, trials can begin with patients from the outset. In some cases, Phase I and Phase II trials can be merged. This approach allows for continued treatment of the same patients with the dose determined by tolerability, now also assessing efficacy. This method can speed up the development process and reduce the burden on participants.
Throughout the first phase, ensuring safety is paramount, whether the subjects are healthy volunteers or patients. The strict selection criteria and ethical considerations are all geared towards minimizing risks to the participants.
Safety and conduct of trials
First-in-human studies are conducted under stringent safety regulations at specialized clinical pharmacology units. These facilities operate separately from traditional healthcare settings and are equipped with state-of-the-art medical equipment. The staff at these sites are highly experienced in clinical research and are prepared to detect and manage any adverse effects immediately.
Continuous monitoring ensures participant safety, with 24/7 observation and meticulous documentation of even the slightest changes. The facilities are equipped with the necessary life-saving equipment and medications to respond promptly in case of emergencies.
The design and operation of clinical pharmacology units adhere to strict guidelines. These sites must meet regulatory requirements and possess the necessary licenses.
Phase I trials are a crucial step in the journey of developing a new drug. They serve as a bridge between preclinical findings and larger-scale clinical studies. The primary goal is to assess safety and tolerability, as well as to understand the drug's behavior in the human body.
Inthera plays an important role in the smooth running of Phase I clinical trials when a new drug is given in combination with an existing drug (e.g. new anticancer agents in combination with chemotherapy). Our company specializes in sourcing medications for these tests. Our experienced team ensures that these studies are conducted according to the highest professional and ethical standards, always prioritizing the safety of the volunteers involved