title: A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
authors.affiliation: Department of Clinical Pharmacology, Theravance Biopharma U.S., Inc., South San Francisco, CA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA. blum@gene.com.
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D006801:Humans; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011358:Product Surveillance, Postmarketing; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents
keywords: Dose selection; Food and Drug Administration; Maximum tolerated dose; Modeling; Oncology; Pharmacodynamics; Pharmacokinetics
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