A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience
Issue link: http://innovationscns.epubxp.com/i/499434
Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 10S to determine the number of subjects required for Phase III success of the compound. This sample-size issue is important as protection to avoid false n egative findings. Hence, there are multiple aspects to Phase II trials that require optimization and constant attention during drug development. Optimizing Phase II trials remains critically important. An overall development plan should be in place and the portfolio of the compound should be considered. Compounds that meet the three-pillars criterion should be favored over those that do not. Ultimately, enhancing this design – and an understanding of effects from earlier phases – will likely result in targeting the most likely agents to be successfully developed. CONCLUSION In summary, there are a wide range of strategies aimed at optimizing the drug development process. Specifically, the translation of compounds from Phase I to Phase III clinical trials was emphasized here. The translational pharmacology, including PK/PD data should be quantitatively characterized across species. Stringent a priori decision-making criteria should be identified to aid go/no-go decision-making for a compound. Furthermore, the tests used when translating preclinical to Phase I through III studies should be as consistent as possible, enhancing the likelihood that the same mechanism is being assessed when taking the treatment into human testing. Another critical point is to employ model-based analyses to understand dose-response and effect sizes of particular doses. Utilizing biomarker data to examine efficacy of a compound across disease states may also be an efficient strategy and use of resources. Finally, while using a positive control is vital in many studies, the strength of this control should be carefully weighed against possible costs. In summary, while treatment development for serious m ental illness sufferers has been limited, many lessons have been learned and future studies will be more informative for these complex diseases. REFERENCES 1. Morris SE, Cuthbert BN. Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior. Dialogues Clin Neurosci. 2012;14:29–37. 2. Morgan P, Van Der Graaf PH, Arrowsmith J, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today. 2012;17:419–424. 3. Olofsen E, Romberg R, Bijl H, et al. Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain. Anesthesiology. 2005;103:130–139. 4. Polianskis R, Graven-Nielsen T, Arendt-Nielsen L. Computer- controlled pneumatic pressure algometry--a new technique for quantitative sensory testing. Eur J Pain. 2001;5:267–277. 5. Jones SF, McQuay HJ, Moore RA, Hand CW. Morphine and ibuprofen compared using the cold pressor test. Pain. 1988;34:117–122. 6. Cohen AF. Developing drug prototypes: pharmacology replaces safety and tolerability? Nat Rev Drug Discov. 2010;9:856–865. 7. Esbenshade TA, Fox GB, Cowart MD. Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders. Mol Interv. 2006;6:77–88, 59. 8. Kruk M, Miszkiel J, McCreary AC, Przegalinski E, Filip M, Biala G. Effects of the histamine H(3) receptor antagonist ABT-239 on cognition and nicotine-induced memory enhancement in mice. Pharmacol Rep. 2012;64:1316–1325. 9. Brown JW, Whitehead CA, Basso AM, Rueter LE, Zhang M. Preclinical evaluation of non- imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia. Int J Neuropsychopharmacol. 2013;16:889–904. 10. Burban A, Sadakhom C, Dumoulin D, et al. Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists. Psychopharmacology (Berl). 2010;210:591–604. 11. Cho W, Maruff P, Connell J, et al. Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans. Psychopharmacology (Berl). 2011;218:513–524. 12. Herring WJ, Liu K, Hutzelmann J, et al. Alertness and psychomotor performance effects of the histamine-3 inverse agonist MK- 0249 in obstructive sleep apnea patients on continuous positive airway pressure therapy with excessive daytime sleepiness: a randomized adaptive crossover study. Sleep Med. 2013;14:955–963. 13. Egan MF, Zhao X, Gottwald R, et al. Randomized crossover study of the histamine H3 inverse agonist MK-0249 for the treatment of cognitive impairment in patients with schizophrenia. Schizophr Res. 2013;146:224–230. 14. Egan M, Yaari R, Liu L, et al. Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD. Curr Alzheimer Res. 2012;9:481–490.