A first-in-human (FIH) clinical trial is a significant milestone in the development of a potential new drug in that it will be the first opportunity for a drug development sponsor to evaluate the impact of their new chemical entity (NCE) or biologic in humans. Typically, FIH trials with compounds intended for treatment of diseases other than cancers or certain rare non-malignant diseases are conducted using normal healthy volunteers (NHVs), unless there is an ethical concern (such as known toxicity) in administering the investigational drug to an otherwise healthy population.

In Issue 18 of The Altascientist, we provide a stepwise guide for how to plan first-in-human trials to mitigate risk, including:

• Submitting an Investigational New Drug (IND) Application
• Selecting the starting dose
• Designing the trial
• Participant safety
• Identifying and mitigating potential risks
• Recruiting, educating, and retaining study participants
• Resources need for study conduct

Designing a First-in-Human Trial

FIH trials are typically designed as dose-escalation studies, where subjects receive increasing doses of the investigational product based on desired protocol-specified outcomes. Most often, both single ascending dose (SAD) and multiple ascending dose (MAD) studies are included in the early development program. The dose is increased once the safety, pharmacokinetics (PK), or other protocol-specified requirements have been confirmed by a Safety Review Committee (SRC).

During a FIH study, objectives may include:

-    Evaluating safety and tolerance.
-    Determining pharmacokinetics (exposure and dose proportionality).
-    Identifying early pharmacological activity relative to exposure level, either based on measured physiologic responses, or on biomarkers of response identified during preclinical testing.
-    Assessing observed effects on subsets of participants based on age, gender, or ethnicity.
-    Evaluating the therapeutic outcomes in a small group of patients suffering from the targeted disease.

At this stage of the investigational product’s lifecycle, a drug may fail simply because the human participant does not respond to the drug in the same manner suggested by preclinical testing.

Planning for Study Participant Safety in Fist-in-Human Trials

When testing a drug in humans for the first time, detailed consideration must be given to the risks that exist in any early-phase trial, and also the risks that can be extrapolated from observations in the preclinical testing phase.

In addition to demonstrating to regulatory authorities that the trial has been properly designed to ensure participant safety, Institutional Review Boards (IRBs) will assess whether subject risk has been minimized, and that the potential risks are justifiable in relation to any anticipated benefits. In addition to reviewing the protocol, informed consent, and Investigator's Brochure (IB), IRBs will review safety monitoring plans, including the membership and establishment of a Safety Review Committee (SRC), dose escalation criteria, stopping criteria, reporting of dose-limiting toxicity (DLT), and adverse events.

Recruiting, Educating, and Retaining Study Participants in First-in-Human Trials

FIH trials present an interesting challenge when it comes to participant recruitment, mainly due to the lack of human data and information available to respond to subject questions. A lack of any derived medical benefits from the investigational product is another factor that may negatively impact willingness to participate in a FIH trial.

The education of study subjects on the potential risks and safeguards in place during their participation should be built in at every stage of recruitment. The goal is to provide participants with the background on the drug, how to reasonably interpret animal model results, and the decision-making process for continuing dose escalation. Potential participants must have adequate access to study personnel, physicians, and anyone they need to answer questions prior to and during the study. They should be counseled to consult their primary care physician for guidance before joining a trial.

Subjects receive crucial information about the study during the informed consent process, their eligibility interview, their screening visits, study orientations, and throughout the study.

How Altasciences Can Help With Your First-in-Human Trials

Altasciences has the in-depth expertise to fully support your FIH trial management. Scientific and regulatory experts, data management and biostatistical experts, and clinical trial monitoring personnel work together with your team to ensure all important elements are fully addressed. With preclinical, small molecule, and bioanalytical capabilities in-house, we provide a holistic, integrated overview that provides the most efficient, relevant, and robust FIH program for your needs.

A successfully conducted FIH trial provides a solid foundation of knowledge regarding the safety and exposure of an investigational product, at several dose levels, within a relatively short period of time. The data generated can help identify opportunities to accelerate or enhance a compound’s clinical development in the future.

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