- Email: [email protected]
C.14.01 Ensuring data quality in multi-national clinical trials
C.14 The failure ofmulti-national placebo-controlled studies
episodes). This consolidation during sleep relies on a dialogue between neocortex and hippocampus which is essentially regulated by the <1 Hz EEG slow oscillation (SO). Episodes experienced during waking are encoded in the neocortex, but the more important part of the representations is encoded in hippocampal networks serving as a rapidly encoding buffer in this system. The SOs characterising SWS originate from neocortical networks. Their amplitude depends partly on the use of these networks for encoding of information, i.e., the more information is encoded during waking, the higher the SO amplitude during subsequent SWS. The SOs temporally group neuronal activity into up-states (of strongly enhanced activity) and down-states (of neuronal silence). This grouping is induced not only in the neocortex but also, via efferent pathways, in other structures relevant to consolidation, i.e., in the thalamus, generating spindle activity, and in the hippocampus, generating sharp-wave ripples which are well-known to accompany a replay of the newly encoded memories taking place in hippocampal circuitries during SWS. The synchronizing effect of the SO enables inputs to be fed back from these structures to the neocortex, i.e., the thalamocortical spindle activity and the hippocampo-to-neocortical memory replay activity arrive synchronously at respective neocortical networks. We propose that SO-induced co-occurrence of inputs from thalamus (spindles) and hippocampus (ripples plus memory replay) is critical to the redistribution of memory representations to neocortical networks for long-term storage. References [1] Diekelmann, S., Wilhelm, I., Born, 1. 2009 The whats and whens of sleep-dependent memory consolidation. Sleep Med Rev Feb 28 [Epub ahead of print]. [2] Marshall, L., Born, 1. 2007 The contribution of sleep to hippocampusdependent memory consolidation. Trends Cogn Sci 11:442--450.
IC.13.041 Clinical implications of increasing SWS in insomnia
IK. Walsh1 ", I Saint Louis University, Department ofPsychology, St. Louis, USA Several pharmacological agents with different mechanisms of action increase slow wave sleep (SWS) as measured classically or in a more quantitative fashion as NREM slow wave activity (SWA). Studies with three SWS-enhancing drugs conducted to evaluate the impact of enhanced slow wave sleep (SWS) on established consequences of sleep restriction in healthy adults have demonstrated that pharmacological SWS enhancement reduces selective aspects of the behavioral, psychological, and physiological impact of sleep restriction. In one investigation, SWS enhancement during sleep restriction reduced the homeostatic response to sleep loss during recovery sleep. These findings suggest that pharmacologic SWS enhancement in healthy individuals intensifies some of the processes of physiologic sleep. Many observations suggest that reduced SWS may be associated with symptoms or the pathophysiology of insomnia. SWS is decreased in primary insomnia and major depressive disorder, chronic alcoholics, in older adults and Alzheimer's patients. Physiologically, it is well-established that awakenings and arousals are least frequent in SWS. It seems logical, therefore, to explore the potential role of SWS-enhancing drugs for the treatment of insomnia. However, investigations of SWS-enhancing medications in primary insomnia patients generally find inconsistent and less robust effects on traditional hypnotic efficacy measures, relative to benzodiazepine receptor
S717
agonists. Nevertheless, the effectiveness of SWS enhancing-drugs for treating insomnia may be inadequately assessed in shortterm studies emphasizing traditional hypnotic efficacy measures in primary insomnia. Moreover, the mechanism of action through which SWS is increased may be a differentiating factor for both effectiveness and risk-benefit ratio. References [1] Walsh, 1.K., Griffin, K.S., Hall, 1.M., Dodson, E., Forst, E., Schweitzer, P.K. 2009 Slow wave sleep enhancement during sleep restriction reduces the homeostatic response to sleep loss. Sleep, abstract in press.
C.14 The failure of multi-national placebo-controlled studies IC.14.011 Ensuring data quality in multi-national clinical trials C. Hoschl" ", Republic
I
Charles University, Psychiatry, Prague, Czech
Data quality is a critical issue for Central Nervous System (CNS) clinical trials which frequently rely on subjective outcome measures. Data must be collected appropriately, understood and analyzed in a way to show appropriate results. Good clinical judgment and adequate experience with the indicated population must be combined with adherence to administrative guidelines and scoring conventions to obtain accurate data sets and minimize placebo responses [1,2]. Globalization of clinical trials further jeopardizes data quality due to cultural, ethnic and educational inter-country differences [3]. These differencesmay be responsible for failed international trials, and could also affect placebo response. The role of the clinical rater in reducing placebo response and improving signal detection in CNS trials is paramount to improving success rates. Addressing the inherent variability across sites in global studies is a required step to improving the quality of clinical ratings in global trials. A comprehensive rater training program to address cultural differences in rating patterns as well as differences in global practices will be discussed. Through rater training programs, a standard approach to rating scales can be developed and enhance efficacy of the scale. In the session, the speaker will present data supporting the effectiveness of rater training, certification and rater monitoring as proven methodologies to ensure data quality in multi-national CNS clinical trials. These approaches have been used successfully in many multinational CNS clinical trials to enhance efficacy. References [1] Khan A, Kolts RL, Rapaport MH, Ranga Rama Krishnan K, Brodhead AE, Brown WA. Magnitude of placebo response and drug-placebo differences across psychiatric disorders. Psychological Medicine, 2005:35:743-749 [2] Perkins DO, Wayatt RI, Bartko JJ. Penny-wise and pound-foolish: The impact of measurement error on sample size requirements in clinical trials. Biological Psychiatry, 2000:47:762-766. [3] Muller M, Szegedi A. Effects ofInterrater Reliability of Psychopathologic Assessment on Power and Sample Size Calculations in Clinical Trials. Journal of Clinical Psychopharmacology. 2002:22(3):318-325
episodes). This consolidation during sleep relies on a dialogue between neocortex and hippocampus which is essentially regulated by the <1 Hz EEG slow oscillation (SO). Episodes experienced during waking are encoded in the neocortex, but the more important part of the representations is encoded in hippocampal networks serving as a rapidly encoding buffer in this system. The SOs characterising SWS originate from neocortical networks. Their amplitude depends partly on the use of these networks for encoding of information, i.e., the more information is encoded during waking, the higher the SO amplitude during subsequent SWS. The SOs temporally group neuronal activity into up-states (of strongly enhanced activity) and down-states (of neuronal silence). This grouping is induced not only in the neocortex but also, via efferent pathways, in other structures relevant to consolidation, i.e., in the thalamus, generating spindle activity, and in the hippocampus, generating sharp-wave ripples which are well-known to accompany a replay of the newly encoded memories taking place in hippocampal circuitries during SWS. The synchronizing effect of the SO enables inputs to be fed back from these structures to the neocortex, i.e., the thalamocortical spindle activity and the hippocampo-to-neocortical memory replay activity arrive synchronously at respective neocortical networks. We propose that SO-induced co-occurrence of inputs from thalamus (spindles) and hippocampus (ripples plus memory replay) is critical to the redistribution of memory representations to neocortical networks for long-term storage. References [1] Diekelmann, S., Wilhelm, I., Born, 1. 2009 The whats and whens of sleep-dependent memory consolidation. Sleep Med Rev Feb 28 [Epub ahead of print]. [2] Marshall, L., Born, 1. 2007 The contribution of sleep to hippocampusdependent memory consolidation. Trends Cogn Sci 11:442--450.
IC.13.041 Clinical implications of increasing SWS in insomnia
IK. Walsh1 ", I Saint Louis University, Department ofPsychology, St. Louis, USA Several pharmacological agents with different mechanisms of action increase slow wave sleep (SWS) as measured classically or in a more quantitative fashion as NREM slow wave activity (SWA). Studies with three SWS-enhancing drugs conducted to evaluate the impact of enhanced slow wave sleep (SWS) on established consequences of sleep restriction in healthy adults have demonstrated that pharmacological SWS enhancement reduces selective aspects of the behavioral, psychological, and physiological impact of sleep restriction. In one investigation, SWS enhancement during sleep restriction reduced the homeostatic response to sleep loss during recovery sleep. These findings suggest that pharmacologic SWS enhancement in healthy individuals intensifies some of the processes of physiologic sleep. Many observations suggest that reduced SWS may be associated with symptoms or the pathophysiology of insomnia. SWS is decreased in primary insomnia and major depressive disorder, chronic alcoholics, in older adults and Alzheimer's patients. Physiologically, it is well-established that awakenings and arousals are least frequent in SWS. It seems logical, therefore, to explore the potential role of SWS-enhancing drugs for the treatment of insomnia. However, investigations of SWS-enhancing medications in primary insomnia patients generally find inconsistent and less robust effects on traditional hypnotic efficacy measures, relative to benzodiazepine receptor
S717
agonists. Nevertheless, the effectiveness of SWS enhancing-drugs for treating insomnia may be inadequately assessed in shortterm studies emphasizing traditional hypnotic efficacy measures in primary insomnia. Moreover, the mechanism of action through which SWS is increased may be a differentiating factor for both effectiveness and risk-benefit ratio. References [1] Walsh, 1.K., Griffin, K.S., Hall, 1.M., Dodson, E., Forst, E., Schweitzer, P.K. 2009 Slow wave sleep enhancement during sleep restriction reduces the homeostatic response to sleep loss. Sleep, abstract in press.
C.14 The failure of multi-national placebo-controlled studies IC.14.011 Ensuring data quality in multi-national clinical trials C. Hoschl" ", Republic
I
Charles University, Psychiatry, Prague, Czech
Data quality is a critical issue for Central Nervous System (CNS) clinical trials which frequently rely on subjective outcome measures. Data must be collected appropriately, understood and analyzed in a way to show appropriate results. Good clinical judgment and adequate experience with the indicated population must be combined with adherence to administrative guidelines and scoring conventions to obtain accurate data sets and minimize placebo responses [1,2]. Globalization of clinical trials further jeopardizes data quality due to cultural, ethnic and educational inter-country differences [3]. These differencesmay be responsible for failed international trials, and could also affect placebo response. The role of the clinical rater in reducing placebo response and improving signal detection in CNS trials is paramount to improving success rates. Addressing the inherent variability across sites in global studies is a required step to improving the quality of clinical ratings in global trials. A comprehensive rater training program to address cultural differences in rating patterns as well as differences in global practices will be discussed. Through rater training programs, a standard approach to rating scales can be developed and enhance efficacy of the scale. In the session, the speaker will present data supporting the effectiveness of rater training, certification and rater monitoring as proven methodologies to ensure data quality in multi-national CNS clinical trials. These approaches have been used successfully in many multinational CNS clinical trials to enhance efficacy. References [1] Khan A, Kolts RL, Rapaport MH, Ranga Rama Krishnan K, Brodhead AE, Brown WA. Magnitude of placebo response and drug-placebo differences across psychiatric disorders. Psychological Medicine, 2005:35:743-749 [2] Perkins DO, Wayatt RI, Bartko JJ. Penny-wise and pound-foolish: The impact of measurement error on sample size requirements in clinical trials. Biological Psychiatry, 2000:47:762-766. [3] Muller M, Szegedi A. Effects ofInterrater Reliability of Psychopathologic Assessment on Power and Sample Size Calculations in Clinical Trials. Journal of Clinical Psychopharmacology. 2002:22(3):318-325