Understanding pharmacology in humans: Phase I and Phase II (Data Generation)

The discovery of novel drugs is a complex and highly regulated process organized around a critical moment, that is, when the novel compound is tested in humans. This process encompasses a series of clinical studies, identified as Phase I and Phase II, whose composite outcome should deliver the data needed for an informed decision about progressing or not the compound in full development (Phase III). Over the last 10 years the global delivery of novel treatments from the pharmaceutical industry has plunged to the level of the ‘70ies in spite of a 10-fold larger investment, the differential mostly due to failures in Phase III. There is the need to improve the decision making at the early clinical stage by using innovation and the high-profile achievements of basic science generated in academic and biomedical labs. A specific attention should be paid to applied biotechnologies, in particular nanotechnology and biomedical devices not only for drug deliver but also for biomarker detection. This path, also supported by regulatory agencies, is calling for an important change of perspective about how drug discovery is made, which we believe should start from the full implementation of the paradigm of Translational Medicine.

Introduction

The early clinical stage of drug discovery consists of a series of studies required by the regulatory agencies and aimed to characterize the basic features of an experimental compound, the Novel Chemical Entity (NCE) [1]. Traditionally these studies are organized as clinical trials subdivided according to their delivery and design into Phase I and Phase II (see Box 1). While these trials are effective in detecting safety-related issues, their capacity to inform about pharmacological effects and clinical efficacy is less than optimal, in particular when the conventional design is implemented. The low efficiency of early clinical trials is compounded by the problem of translating the effects observed in preclinical tests and in animal models into humans, not always a linear process. In fact, specie-specific biologic differences can be so relevant to severely reduce the predictive power of preclinical pharmacological studies, as experienced, for example, in the area of drug discovery for acute ischemic stroke [2]. In this case the incomplete characterization of the NCE during the early clinical stage had catastrophic effects, resulting in failed Phase III trials, with several hundred patients unnecessary exposed to a non-effective treatment. While no simple recipe is available to avoid errors, improvements in the management of the drug discovery process are possible starting exactly from the early clinical stages.