November 17, 2009 – Issue 7 “Bridging the Gap” – Part 2 We’ll conclude this 2-part series with a look at an approach to early phase research that has proven promise and potentially huge dividends. For the last several years, CRI has advocated and been successful with bridging studies that fill the gap between working with the drug in normal individuals to patients with an acute psychiatric impairment.  (i.e., from conventional phase I to conventional phase II studies). The first is done in normal volunteers but is generally without any assessment of the behavioral pharmacology of the drug in man. We at CRI advocate using minimally symptomatic volunteers as soon as one can.  The reason is that the salient pharmacology of the drug may only be apparent in patients suffering from the target illness.  This approach involves using volunteers who have a mild variant of the initial target condition for which the NCE is being developed.  The researchers at CRI have considerable expertise with such studies having done them using volunteers with mildly symptomatic schizophrenia, major depression, generalized anxiety disorder and senile dementia of the Alzheimer's type. These studies have generally employed a double-blind, placebo-controlled, fixed-dose design with fewer patients being enrolled. The number of doses can be considerably greater than usual because of the use of computer algorithms to assess response in real time and assign subsequent patients preferentially to the most meaningful part of the dose-response curve.  These studies are generally done at one or two sites to reduce the signal-to-noise problem inherent in large multisite studies. While the studies typically involve fixed doses, they can also be done sequentially in a manner analogous to a traditional phase I study. After each dose group has been completed, the results are assessed typically without breaking the blind and a decision is made as to whether and how to alter the original study plan to pursue an advantageous lead or avoid a potential pitfall. This approach makes such studies highly efficient from both time and cost perspectives. We have often been able to accomplish, in a fraction of the time and in a single study, what would require multiple traditional phase II studies and save millions in research expenses at the same time. Examples of the findings from such studies include: Patients with the target illness could tolerate five times the dose of a NCE compared to a traditional normal volunteer. A NCE being considered as a possible antipsychotic might actually be better as an antidepressant. An immediate release preparation of a NCE on a twice-a-day schedule was not sufficiently well tolerated, despite a number of different dosing strategies, to permit an assessment of efficacy. On the other hand a four-times-a-day dose was well tolerated and had good preliminary evidence of efficacy. With that result, the company canceled the development of the immediate-release preparation and instead pursued the development of a sustained-release preparation. However, another short half-life NCE could be used once-a-day with good tolerability and preliminary evidence of efficacy, but that was only after a twice-a-day dosing regimen to permit the development of tolerance to acute dose dependent tolerability problems. With that result, the company could pursue their pivotal phase II study with the immediate release preparation using an initiation phase with twice-a-day dosing and then a conversion to once-a-day dosing for the remainder of the study. At the same time, they could proceed with the development of a sustained-release preparation as either a backup agent or as a product extension strategy. We are excited by the results we have had to date with such studies. You might find this approach useful in the efficient development of your promising NCE's in the CNS development arena. If so, let's talk.

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