Strategic, feasibility, economic, and cultural aspects of phase 0 approaches: Is it time to change the drug development process in order to increase productivity?

Abstract

Research conducted over the past 2 decades has enhanced the validity and expanded the applications of microdosing and other phase 0 approaches in drug development. Phase 0 approaches can accelerate drug development timelines and reduce attrition in clinical development by increasing the quality of candidates entering clinical development and by reducing the time to "go-no-go" decisions. This can be done by adding clinical trial data (both healthy volunteers and patients) to preclinical candidate selection, and by applying methodological and operational advantages that phase 0 have over traditional approaches. The main feature of phase 0 approaches is the limited, subtherapeutic exposure to the test article. This means a reduced risk to research volunteers, and reduced regulatory requirements, timelines, and costs of first-in-human (FIH) testing. Whereas many operational aspects of phase 0 approaches are similar to those of other early phase clinical development programs, they have some unique strategic, regulatory, ethical, feasibility, economic, and cultural aspects. Here, we provide a guidance to these operational aspects and include case studies to highlight their potential impact in a range of clinical development scenarios.

FIGURE 1

Phase 0 and phase I timelines. It is recommended that preparations for phase I continue in parallel to the conduct of the phase 0 study. This will allow for seamless transition to phase I or, alternatively, early termination of phase I based on the phase 0 results. The costs of additional preclinical preparations, that might be lost in the event of termination of development, are minimal compared with the savings in time that such parallel development allows (see text). The contribution of in vivo human testing (i.e., in humano ⁷ ) to the selection of preclinical candidates is highlighted. This has the potential to reduce false negatives (i.e., the good drugs wrongly deselected based on inappropriate animal or in vitro data), and also discover earlier, and therefore in a less expensive manner, those false positives that may be discovered only at the end of expensive phase I in healthy volunteers, or phase II in patients. Phase 0 approaches can provide human data for developmental decision 8–12 months prior to traditional phase I. In the case of adaptive phase 0/phase I design the phase 0 application must be withdrawn prior to initiation of the phase I study (required by the FDA but not in the EU). The traditional drug development approach uses phase I as the first‐in‐human (FIH) approach. The parallel phase 0/phase 1 approach is an adaptive design. Abbreviations: API, active pharmaceutical ingredients; CMC, chemistry; manufacturing, and controls; CS, candidate selection; EU, European Union; FDA, US Food and Drug Administration; GMP, Good Manufacturing Practices; LO, lead optimization. Reprinted with permission from Burt et al.

FIGURE 2

Intra‐Target Microdosing (ITM)., , In this illustration, using an intra‐arterial administration method, administering a microdose (≤100 μg, or pharmacologically active dose, or 1/100^th the NOAEL) temporarily surpasses the therapeutic‐level exposure in a small target (≤1/100^th of the body mass) and may allow collection of PD, biomarker, and MOA data, as well as systemic microdose PK. Reprinted with permission from Burt et al. Abbreviations: MOA, mechanism of action; NOAEL, no observed adverse effect level; PD, pharmacodynamic; PET, positron emission tomography; PK, pharmacokinetic

FIGURE 3

Higher clinical approval success rates can reduce developmental costs significantly. Costs defined as “out‐of‐pocket” clinical period costs. Source: DiMasi et al.