A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities.
The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure-response modeling methods.
['Lu|Dan|D|', 'Lu|Tong|T|', 'Stroh|Mark|M|', 'Graham|Richard A|RA|', 'Agarwal|Priya|P|', 'Musib|Luna|L|', 'Li|Chi-Chung|CC|', 'Lum|Bert L|BL|', 'Joshi|Amita|A|']
D000970:Antineoplastic Agents D004305:Dose-Response Relationship, Drug D017277:Drug Approval D006801:Humans D020714:Maximum Tolerated Dose D058990:Molecular Targeted Therapy D009369:Neoplasms D011358:Product Surveillance, Postmarketing D014481:United States D014486:United States Food and Drug Administration
Oncology Pharmacokinetics Pharmacodynamics Food and Drug Administration Dose selection Modeling Maximum tolerated dose