Dose-Limiting Toxicities (DLTs) in Phase 1 Clinical Studies – Prepare for Regulatory Success

Dose selection and its justification are critical for the regulatory success of a new investigational medicinal product (IMP). Thoughtfully defining the DLTs during Phase 1 is key to identifying a safe and clinically active dose.

Definition: DLTs comprise a category of adverse events or abnormal laboratory findings observed during a Phase 1 clinical study; they are used to assess the safety and tolerability of a dose of an IMP and inform dose escalation.  

Timing: DLTs are usually assessed over the first month of treatment although the DLT observation period can be longer depending upon the drug’s half-life, dosing schedule, and potential for late or cumulative side effects.

Selection: DLTs are often severe (grade ≥ 3) adverse events or clinical laboratory findings which would preclude continued treatment with the drug. Typically, DLTs are events which are assessed by the investigator as being unrelated to underlying disease and potentially related to the IMP; the determination of relatedness to the IMP may be informed by the mechanism of action or results of animal toxicology studies.

By selecting DLTs that ensure subject safety while excluding those that are easily manageable and/or expected based on underlying disease, will enable a robust and safe dose escalation, and help establish a firm basis for dose selection justification down the road. Based on the results of Phase 1 studies, once a dose is selected for continued clinical development, it is time consuming and costly to revisit that process – so getting it right the first time is critical.   

Justin McLaughlin, CEO