Safety, Tolerability, and the Challenge of the Initial Dose
"First-in-Human" (FIH) clinical trials, also known as first-in-human administration studies, represent the first time a new drug, therapy, or medical device is tested in humans. These studies are part of Phase I clinical trials and have as their main objective the evaluation of the safety, tolerability, and pharmacokinetics of the investigated substance or technology.
Objectives of a First-in-Human Study
FIH studies are designed to answer essential questions before a drug or therapy can advance to larger-scale testing:
Safety and Tolerability: Determine whether the substance is safe for humans and identify potential adverse effects.
Pharmacokinetics: Understand how the body processes the drug, including absorption, distribution, metabolism, and excretion.
Initial Dose and Dose Escalation: Evaluate the safe starting dose and define a possible dose range for future studies.
Characteristics of a First-in-Human Study
Participants: Typically conducted in small groups of healthy volunteers (for non-oncology drugs) or patients with the target disease (for oncology drugs or advanced therapies).
Controlled Environment: Carried out in highly monitored clinical centers to ensure participant safety.
Dose Escalation: The drug dose is gradually increased, starting at a very low level, to minimize risks.
Intensive Monitoring: Participants are continuously monitored to identify adverse effects and physiological responses to treatment.
Challenges and Risks of FIH Studies
Uncertainty: As this is the first time the drug is tested in humans, effects may be unpredictable.
Serious Adverse Events: Although based on preclinical studies (in cells and animals), some compounds may trigger unexpected reactions.
Strict Selection Criteria: Participants must meet specific requirements to minimize risks, such as being in good health and having no preexisting conditions (when applicable).
Examples and Regulation
Regulatory authorities, such as the FDA (United States), EMA (European Union), and Anvisa (Brazil), establish strict guidelines for conducting FIH studies. A notable example was the FIH trial of the monoclonal antibody TGN1412 in the 2000s, which resulted in severe adverse reactions in healthy volunteers, reinforcing the need for even stricter protocols.
Conclusion
"First-in-Human" clinical trials are a crucial milestone in the development of new drugs and therapies. Although they present challenges and risks, their careful execution and rigorous monitoring ensure that only the safest and most promising treatments advance to the subsequent phases of clinical development.
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