SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 provides guidance for clinical trial protocol writing. However, neither the original guidance nor its extensions adequately cover the features of early phase dose-finding trials. The SPIRIT Dose-finding Extension (DEFINE) statement is a new guideline that provides recommendations for essential items that should be provided in the protocols of these trials. It details extensions to the SPIRIT 2013 guidance, incorporating 17 new items and modifying 15 existing items. The purpose of this guideline is to promote transparency, completeness, reproducibility of methods, and interpretation of early phase dose-finding trial protocols. It is envisioned that the resulting improvements in the design and conduct of early phase clinical trials will ultimately reduce research inefficiencies and inconsistencies, driving transformational advances in clinical care.
Developing an intervention is a lengthy process pursued in stages where decisions are based on balance of benefits and risks or harms of the intervention under investigation. Lack of efficacy or evidence of harm due to adverse safety profiles are common reasons for phase 2 and phase 3 trials to be unsuccessful.12 Phase 3 trial failures can reflect incorrect decisions made at earlier stages, including in early phase dose-finding (EPDF) trials (commonly known as phase 1, phase 1/2, or first-in-human trials). Reasons why interventions do not progress or succeed in later stages of clinical development include misleading preclinical studies, inadequate participant selection, inefficient trial design, suboptimal biomarker or outcome choices, and poor dose selection. The same reasons can also contribute to early discontinuation of promising interventions.
EPDF trials typically evaluate new interventions that can be used in different doses and can be pharmacological (chemical or biological—eg, drugs, vaccines, cell therapies, gene therapies), non-pharmacological (eg, radiotherapy, devices, rehabilitation, digital therapies), or a combination of both. They usually include a small number of …