Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products

The EMA methodological guideline is the first revision of the 2007 guidance, extended to cover first-in-human (FIH) and early-phase trials using integrated protocols that combine multiple study parts. It has been adopted by the Committee for Medicinal Products for Human Use (CHMP) in July 2017 and effective from February 2018 and also applies to Clinical Trial Applications under EU CTR 536/2014 and related EU/ICH guidelines.

Scope and Content:

• Executive summary and structured sections covering: quality aspects, non-clinical aspects, dosing selection, and planning and conduct of FIH/early clinical trials.
• Quality aspects: IMP strength and potency determination, qualification of invetigational material, and the reliability of small doses.
• Non-clinical aspects: relevance of animal models, target biology, pharmacodynamics (PD), pharmacokinetics (PK), toxicokinetics (TK), safety pharmacology and toxicology, with emphasis on integrating these data into an overall risk assessment and on managing uncertainty when human‑specific mechanisms are involved.
• Dosing selection: starting dose calculation using NOAEL and MABEL approaches for healthy volunteers and patients; dose escalation steps and maximum exposure; moving from single to multiple dosing.
• Clinical trial design: detailed recommendations for integrated protocols, subject selection, cohort size and precautions, sentinel dosing, spacing between subjects and cohorts, data‑review procedures for dose escalation, explicit stopping rules, and monitoring and communication of adverse events (AEs) and suspected unexpected serious adverse reactions (SUSARs), particularly in multicentre trials
• Operational requirements: sponsor and investigator responsibilities; documentation of decision-making and safety review structures, and minimum infrastructure and staffing for early-phase units.

Useful for investigator-initiated early-phase studies to:

• Structure non-clinical-to-clinical risk assessments- Align starting dose and dose escalation strategies with current EMA expectations.
• Design stopping rules and operational safeguards proportionate to the specific IMP risk profile.
• Ensure that protocol design, site capabilities and safety‑oversight processes are proportionate to the specific risk profile of the IMP.