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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2931-4) contains supplementary material, which is available to authorized users.

Reverse Translation of US Food and Drug Administration Reviews of Oncology New Molecular Entities Approved in 2011–2017: Lessons Learned for Anticancer Drug Development

“…This was identified as a key review issue for several oncology NMEs, as 23% of the oncology NMEs in this survey were issued a PMR or PMC related to dose optimization (i.e., to conduct exposure‐response analyses and/or clinical trials to further evaluate dose). Lu et al . reported similar results in a survey of new oncology drug approvals by the FDA from 2010–2015 that focused on PMRs/PMCs relating to outcomes associated with initial dose selection; in this survey, 27% of drugs were approved with PMRs/PMCs issued related to dose justification/optimization.…”

Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

“…This assumes that the maximal effect is linked to achieving the maximum dose/exposure approaching early toxicity in a small number of patients but often does not consider long-term safety as well as efficacy outcomes in justifying the selected dose. This has resulted in a large number of post-marketing requirements and commitments for dose optimization investigations for many newly registered agents [16, 19]. With the goal of dose selection to maximize the expected efficacy benefit while minimizing the expected toxicity, it is critical to investigate the relationship between exposure and long-term outcomes for justifying the selected dose.…”

“…Identification of optimal dose selection is a challenging task during drug development, particularly in the field of oncology, where first-in-human studies primarily use conventional approaches originally tailored for cytotoxic chemotherapeutics and subsequent development programs focus on speed to approval [16–18]. The challenges associated with optimizing dose selection for oncology NMEs is highlighted in recent reviews of regulatory evaluations of NDAs [16, 19]. Indeed, in one review it is cited that more than one quarter of approved new oncology agents within an investigated period required further dose optimization investigations, with a greater trend reported for approved TKIs [19].…”

“…The challenges associated with optimizing dose selection for oncology NMEs is highlighted in recent reviews of regulatory evaluations of NDAs [16, 19]. Indeed, in one review it is cited that more than one quarter of approved new oncology agents within an investigated period required further dose optimization investigations, with a greater trend reported for approved TKIs [19]. Thus, there is regulatory expectation to maximize the benefit/risk of the NME for approval and use in the intended patient population by justifying or investigating optimal dose selection.…”

Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

“…[1][2][3] Safety and efficacy data from clinical trials remain the pillars of the risk-benefit assessment for regulatory approval and therapeutic implementation into the clinic. However, a thorough understanding of PK, including the effects of intrinsic variables such as ethnicity and weight, and pharmacometric evaluations that identify relationships between drug exposure and measures of efficacy and toxicity, are the cornerstones of dose justification and complete the risk-benefit assessment ( Figure 1).…”