Exploratory development patient studies

A 43-year-old male in the surgical ICU after exploratory laparotomy following a motor vehicle accident develops fever that is unresponsive to broad-spectrum antibacterial therapy (piperacillin-tazobactam 3.75 g every 6 hours, gentamicin 120 mg every 8 hours, and vancomycin 1 g every 12 hours). The patient has a central venous catheter and a Foley catheter. Blood cultures are negative at the time, but the patient has yeast growing in the sputum and urine. Laboratory studies reveal a white blood cell count of 11,300 cells/mm3 (11.3 x 109/L). 

Freidlin and Simon (10) have shown, however, how one pivotal trial can be used potentially for both purposes—if the set of patients used to develop the classifier is kept distinct from the set of patients used to evaluate treatment benefit. Generally, however, the studies should be kept separate. Developmental studies are exploratory, though they should result in completely specified binary classifiers. Studies on which claims of drug benefit are based should be non-exploratory, but should instead test prospectively defined hypotheses about treatment effect in a pre-defined patient population. 

So far we have considered biomarkers whose validity has been either somewhat established or discredited by their use in clinical practice or in clinical trials. However, the utility of biomarkers in aiding both drug development and the diagnosis and management of patients has resulted in the introduction of many new biomarkers, many of which are less well characterized. Innovative but incompletely evaluated biomarkers are particularly likely to play an important role in exploratory studies of a new drug candidate. Unfortunately, the degree of innovation represented by a biomarker is likely to vary inversely with the extent of its validation (53). This is a consequence of the fact that prior use in clinical trials is an important component of biomarker evaluation. 

When a hypothesis has been developed, when a chemical synthesis program has been developed, when an exploratory preclinical program has been completed, and when the clinical study evaluation all contribute to the data that generates an approved NDA, all the disciplines of research and development come together to provide a tool to the physician to improve the life of his or her patients. 

Our intranasal ketamine product candidate is being developed for the management of acute moderate to severe pain, as well as BTP in patients on chronic opioid therapy. Pilot studies in both of these pain models, using the exploratory formulation of Ereska, have yielded encouraging results for safety and efficacy. A randomized, double-blind, singledose parallel study [3] tested 10, 30 and 50 mg IN... 

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