Why so few drugs for Alzheimer's disease? Are methods failing drugs? - PubMed (original) (raw)

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Why so few drugs for Alzheimer's disease? Are methods failing drugs?

R E Becker et al. Curr Alzheimer Res. 2010 Nov.

Abstract

Recent studies of Alzheimer's disease (AD) and other neuropsychiatric drug developments raise questions whether failures of some drugs occur due to flaws in methods. In three case studies of recent AD drug development failures with phenserine, metrifonate, and tarenflurbil we identified methodological lapses able to account for the failures. Errors in complex systems such as drug developments are both almost inescapable due to human mistakes and most frequently hidden at the time of occurrence and thereafter. We propose preemptive error management as a preventive strategy to exclude or control error intrusions into neuropsychiatric drug developments. We illustrate the functions we anticipate for a preemptive error management preventive strategy with a checklist and identify the limitations of this aspect of the proposal with three drug examples. This strategy applies core scientific practices to insure the quality of data within the current context of AD drug development practices.

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Figures

Fig. (1)

Fig. (1)

Swiss Cheese model of error [13]. As illustrated, during processes of planning and executing complex processes, investigators and sponsors allow lapses in defenses against mistakes (Active Failures or Unsafe Acts) opening the processes or outputs to errors. These lapses may be oversights or results from effective interventions at multiple levels being overcome by random shifts and realignments that allow, as the figure illustrates, unexpected errors and consequences.

Fig. (2)

Fig. (2)

Relation between tarenflurbil action in mild to moderate Alzheimer's disease and maximum plasma concentrations of tarenflurbil (Cmax) in a randomized phase II CT trial [reprinted from [6], Figure 3C]. The straight line of the ascending improvements in the outcome measure at the highest dose tested, expressed as the Cmax, allow the possibility that more efficacy may occur at greater doses than those within the tested range that were selected for the Phase II CT. All of these tested doses were described as safe and well tolerated, suggesting that tolerability may not have been an issue in not selecting a higher dose.

Fig. (3)

Fig. (3)

Efficacy and Toxicity with Metrifonate (mg/kg/wk): Weekly Versus Daily Dosing Effects on Percent AChE Inhibition (Assessed in Red Blood Cells (RBC). Legend: These previously mainly unpublished data are from the author's (REB) laboratory and from [5, 15, 16]. These data are based on work completed by the author and the monographs [39, 40]. The distinction exemplified favors the weekly dosing both because the estimated replacement half-lives of acetylcholinesterase of 4 and 14 days [5] and recovery of other enzymes irreversibly inhibited by the organophosphate pro-drug metrifonate activation [5] are thought to allow recovery by new protein synthesis or activation which does not occur adequately with daily dosing.

Fig. (4)

Fig. (4)

Variance Sources and Consequences. Inter-site variance in the placebo data derived from the initial phase III CT of phenserine in mild to moderate AD (Axonyx AX-CL-06) (Data from Axonyx master file by permission of QR Pharma). The further variance around the mean values for each site (intra-site variance) is not shown. In light of the expected moderate improvement in ADAS-cog found for anticholinesterases in AD, a large variance in placebo data may over shadow and mask any drug related efficacy signal.

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