In conclusion, it is clear that there is tremendous opportunity to improve the design and methodology used

in randomized clinical trials. The recognition of these challenges by the NIMH, the FDA, the European regulatory authorities, as well as industry, implies that important future change is likely to occur.
Phase 1 studies constitute a pivotal step in drug development. TTicir goal is to gather enough information to warrant the scientific value of phase 2 studies. The information to be collected includes the pharmacological actions of the drug, its side effects with increasing doses, its Inhibitors,research,lifescience,medical pharmacokinetics (PK) and metabolism, its mechanisms of action, and, if possible, early evidence of effectiveness.1 ‘The classic method Inhibitors,research,lifescience,medical of conducting phase 1 studies is much more limited (Table I). First-time-in-man, single -dose, and repeated-dose studies are carried out in healthy volunteers (HV), according to a parallel, double -blind (DB), placebocontrolled design. They are focused on PK, safety, and tolerability, seeking the maximal tolerated dose (MTD), which will be the basis for the choice of doses in subsequent patient Inhibitors,research,lifescience,medical studies. Using this scheme, many drugs have been developed in the wrong indication2 or using

inappropriate doses,3 which led to failures or irrelevant studies, which then had to be replicated leading to delays, increased costs, and overexposure of patients to drugs. It seems clear that, gathering data on pharmacodynamics (PD) and PK/PD relationships earlier would minimize these risks, bearing in mind that, in any case, further steps will face other major issues such as patient heterogeneity and placebo response. Table I Three ways of conducting phase 1 studies. MTD, maximal tolerated dose; PK, pharmacokinetics; PD, pharmacodynamics; BBB, blood-brain Inhibitors,research,lifescience,medical barrier. *Basic PD includes BBB crossing, minimal Inhibitors,research,lifescience,medical active dose, dose effect, and non-central nervous system (CNS) PD. **Basic … Our usual way of conducting phase 1 studies takes these

needs into account (Table II). As early as in the first-inman study, in addition to PK and safety/tolerability evaluation, we collect, basic, central nervous system (CNS) PD data, as well as peripheral PD data (eg, evidence of blood-brain barrier crossing, QTc or cardiac PD0332991 ic50 rhythm changes, minimal active dose, and dose effect), and attempt to sketch PK/PD relationships. This information and is expanded in repeated-dose studies, which can be followed by PD studies in HV, conducted according to a crossover, DB, placebo-controlled design and using the most, appropriate tools, such as wake or sleep electroencephalography (EEG), cognition or functional imaging according to the molecule and its putative indication (see, for example, references 4 to 10). This allows patient studies to be undertaken with a better knowledge of the drug profile and the most appropriate doses. In the last years, the necessity for a proof of concept (POC) approach has emerged.