Considerations on the dose determination for first-in-human clinical trials with novel biopharmaceuticals / 药物评价研究

ABSTRACT

In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.