Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Phase I-IIa in Neuropsychopharmacology.
Is the Proof of Concept Feasible?

M.J. Barbanoj, R.M. Antonijoan, C. García-Gea, M. Valle and F. Jané

Centre d´Investigació de Medicaments, Institut de Recerca; Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau; Departament de Farmacologia i Psiquiatria, UAB, Barcelona, Spain

Over the last decade, the objectives and processes of clinical drug development have been changing in response to an altered regulatory, medical and business environment. Companies are increasingly willing to test novel compounds in humans in order to obtain an early indication of its clinical and commercial viability, abandoning the compound if the target profile is not likely to be met. Such an approach has changed the traditional view of clinical drug development. Instead of comprising three phases, drug development is divided into two phases, "exploratory" and "full". "Exploratory" development consists of all clinical work required to demonstrate the likeliness of therapeutic success. Frequently this is referred to as "proof-of-principle" or "proof-of-concept". This may only require one study, but typically covers Phase I and Phase IIa in the traditional scheme. "Full" development consists of completion of the registration dossier.

Attempts have been made to differentiate between different approaches: i) proof of mechanism; ii) proof of viability; and iii) proof of efficacy. These three types of trials have several features in common: i) they are performed at an early stage of clinical development; ii) they involve a limited number of subjects (volunteers or patients); iii) they do not take into account the full complexity of the clinical situation; and iv) their goal is not to give a definitive answer on the efficacy and safety of the drug under investigation, but rather to guide decisions on further development.

Definitions and characteristics of the following terms within the conceptual framework of clinical drug development will be provided: biomarkers (characteristics that are measured and evaluated as indicators of normal biological processes, pathogenic processes or pharmacological responses), surrogate endpoints (biomarkers that may serve as a substitutive for a clinical endpoint), clinical endpoints (indicators of "how a patient feels, functions or survives"); and models (experimental systems or paradigms used to simulate some aspects of the disease of interest in which the effects of the drug are examined). There is often confusion between the aspects of validation that relate to the statistical performance of a measurement (precision, accuracy, observer bias, and others, which are really measures of reliability) and the more difficult issue of the predictive utility of a measurement. Given that many new treatments are for areas in which the detailed pathophysiologic characteristics of the condition are still poorly understood, their biomarkers are likely to have near-certain predictive utility. Despite this, they may still be of value when incorporated into a range of other information (which may of course include several other biomarkers) to make informed decisions about the likely benefit of an investigational treatment. There is no consensus on what term should be used instead of validation in this context; terms such as verification, stage-appropriate validation, fit for purpose, and qualification have been suggested, but not universally accepted. Due to the importance of the type of linkage between biomarkers and clinical endpoints in view of their usefulness for predicting drug efficacy and safety, mechanistic and empirical linkage will be introduced, together with the utility of PK/PD modeling as a tool to optimise the process of their selection and evaluation making use of scientific grounds.

A simple classification of biomarkers used in neuropsychopharmacology can be based on the type of measurement employed, e.g., biochemical measurements, measurements obtained from imaging techniques, electrophysiology, psychophysiological measures, psychomotor performance, mood scales. In the recent past, genetic markers, in particular the expression of known genes, have provoked much interest. Models can be classified depending on whether they are "natural" (genetic/ phenotypic differentiation) or "induced" (drug or whichever). These types of classifications can be useful, particularly in view of the techniques used for data collection, pre-processing and analysis. An algorithm for decision making in drug development, defining five broad "strategies" (three drug-related questions: brain access distribution, pharmacology at the target site, functional effects in the brain; two disease-related questions: molecular pathology known or system pathophysiology known) rooted in a framework related to the therapeutic pathways (curative, reversing or compensatory) and the pharmacodynamic evaluations will be presented and exemplified with examples from the neuropychiatric field.

Specifically, the pharmaco-EEG model (the study of drug effects on the electroencephalogram of animals, healthy volunteers or patients with respect to the possibility of applying the information obtained to drug effects on human brain function and disease) will be presented. Its tenets, underlying hypotheses, together with the main uses that have been proven to be of valuable interest in clinical neuropsychopharmacology, will be discussed. An example dealing with drug interactions in Phase I (buspirone and fluoxetine) will be set out in detail to show the usefulness of such evaluations.

ACKNOWLEDGEMENTS

This work has been partially financed by a grant from the Fundació La Marató de TV3 (01/3310).

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com