Objective: To evaluate the safety, tolerability, and drug exposure (pharmacokinetics) of the compound in healthy adult subjects.

Before the completion of preclinical development, determine where the study will be conducted (e.g., US, EU, AU). Regulatory requirements (e.g., extent and type of documentation, review time) cost, and related study start-up timelines differ (link to regulatory websites for each region; potential to link to a table listing requirements for each region).

Phase 1 FIH Protocol

  • A clinical trial protocol should concisely state what will be done in the study and provide justification for the study design.
  • Clinical protocols include required sections as detailed in ICH E6 (R2) (link). The EMA also has a guidance that outlines specific requirements for FIH studies to ensure subject safety.
  • It is essential for a sponsor to have their own experienced clinical pharmacologist and clinical operations specialist (distinct from the CRO clinical team) to represent their interests during the conduct of the trial. These individuals may be employees, consultants, or contractors.

Study design considerations for first in human (FIH) studies: dosing strategy, dose selection, and endpoints (laboratory/clinical)

  • The FIH study is usually double-blind, randomized, placebo-controlled, escalating dose design
    • This design minimizes bias through blinding and randomization, provides a comparison of safety to no treatment (placebo), and minimizes potential risk by initially evaluating the safety of low doses.
  • The FIH study may either be a single ascending dose (SAD) study or a combined SAD and multiple ascending dose (MAD) study
    • Combining the SAD and MAD in one study decreases the overall cost and can be completed in a shorter timeframe than if conducted as two
      separate studies.
    • The SAD part of the study is conducted first and is followed by MAD if safety and tolerability are acceptable. Overlap of SAD and MAD parts of the study may be acceptable if prospectively defined and supported by the data generated in early SAD cohorts.
    • Orally administered drugs should be evaluated for a potential the drug exposure is influenced by food (food effect) early in clinical development.
      This may be incorporated in the FIH study.
  • Dose ranging studies
    • The number of cohorts included should be designed to determine safety and tolerability of the drug and an estimated therapeutic margin without exposing large numbers of subjects to drug unnecessarily.
      • The starting dose in the SAD part is calculated based on NOAEL from preclinical toxicology studies using an algorithm defined in FDA guidance
      • The maximum dose/exposure is also guided by the NOAEL: in general, the exposure in the FIH study should target doses/exposures that do not exceed the NOAEL. However, if no adverse safety or tolerability findings are evident as the NOAEL is reached, the study may continue to escalate doses to achieve exposures higher than the NOAEL. The specific data for each investigational agent must be taken into consideration as the study is designed. The determination of therapeutic margin is based on the comparison of the estimated efficacious exposure from microbiology/PKPD data to the safety/tolerability at exposures obtained in the FIH study.
    • Safety and tolerability data from each cohort is used to inform the decision for dose escalation.
    • Procedures for dose escalation and stopping rules must be included.
  • Endpoints: safety, tolerability, and pharmacokinetics. Specific assessments and timing must be included in the protocol
    • Safety evaluation typically includes physical examination, vital signs, adverse events, laboratory safety testing, electrocardiograms, and any compound specific safety measurements identified as potential risks in preclinical development studies.
    • Pharmacokinetic assessments.