Accumulating Evidence and Research Organization (AERO) model: a new tool for representing, analyzing, and planning a translational research program

Trials

Charles Weijer²  Charles M Heilig³  Spencer Phillips Hey¹ 

[1] Studies for Translation, Ethics, and Medicine (STREAM) Group, Biomedical Ethics Unit, McGill University, Montreal, QC H3A 1X1, Canada;Rotman Institute of Philosophy, Department of Philosophy, Western University, 1151 Richmond Street, London, ON, N6A 5B8, Canada;, Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd, NE, MS E10, Atlanta, GA, 30333, USA

关键词: Decision-making;    Research planning;    Research coordination;    Tuberculosis;    Moxifloxacin;    Robustness;    Graph-theoretic model;    Research efficiency;    Translational medicine;   

Others  :  1093810
DOI  :  10.1186/1745-6215-14-159

 received in 2013-01-05, accepted in 2013-05-08,  发布年份 2013

【 摘 要 】

Background

Maximizing efficiency in drug development is important for drug developers, policymakers, and human subjects. Limited funds and the ethical imperative of risk minimization demand that researchers maximize the knowledge gained per patient-subject enrolled. Yet, despite a common perception that the current system of drug development is beset by inefficiencies, there remain few approaches for systematically representing, analyzing, and communicating the efficiency and coordination of the research enterprise. In this paper, we present the first steps toward developing such an approach: a graph-theoretic tool for representing the Accumulating Evidence and Research Organization (AERO) across a translational trajectory.

Methods

This initial version of the AERO model focuses on elucidating two dimensions of robustness: (1) the consistency of results among studies with an identical or similar outcome metric; and (2) the concordance of results among studies with qualitatively different outcome metrics. The visual structure of the model is a directed acyclic graph, designed to capture these two dimensions of robustness and their relationship to three basic questions that underlie the planning of a translational research program: What is the accumulating state of total evidence? What has been the translational trajectory? What studies should be done next?

Results

We demonstrate the utility of the AERO model with an application to a case study involving the antibacterial agent, moxifloxacin, for the treatment of drug-susceptible tuberculosis. We then consider some possible elaborations for the AERO model and propose a number of ways in which the tool could be used to enhance the planning, reporting, and analysis of clinical trials.

Conclusion

The AERO model provides an immediate visual representation of the number of studies done at any stage of research, depicting both the robustness of evidence and the relationship of each study to the larger translational trajectory. In so doing, it makes some of the invisible or inchoate properties of the research system explicit – helping to elucidate judgments about the accumulating state of evidence and supporting decision-making for future research.

【 授权许可】

   
2013 Hey et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

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Figure 4.

【 参考文献 】

• [1]Tall AR, Yvan-Charvet L, Wang N: The Failure of Torcetrapib: Was it the molecule or the mechanism? Arteriosclerosis, Thrombosis, Vasc Biol 2007, 27:257-260.
• [2]Joy TR, Hegele RA: The failure of torcetrapib: what have we learned? British J Pharmacol 2008, 154:1379-1381.
• [3]Zhao L, Jin W, Rader D, Packard C, Feuerstein G: A Translational Medicine perspective of the development of torcetrapib: Does the failure of torcetrapib development cast a shadow on future development of lipid modifying agents, HDL elevation strategies or CETP as a viable molecular target for atherosclerosis? A case study of the use of biomarkers and Translational Medicine in atherosclerosis drug discovery and development. Biochem Pharmacol 2009, 78:315-325.
• [4]Arrowsmith J: Phase II failures: 2008-2010. Nat Rev Drug Discov 2011, 10:1.
• [5]Morgan P, Graaf PHVD, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SDA: Can the flow of medicines be improved? Fundamental pharamacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today 2012, 17:419-424.
• [6]Kola I, Landis J: Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004, 3:711-715.
• [7]Arrowsmith J: Phase III and submission failures: 2007–2010. Nat Rev Drug Discov 2011, 10:1.
• [8]Boucher HW, Talbot GH, Bradley JSJr, JEE Gilbert D, Bartlett J, Rice LB: Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America. Clin Infect Dis 2009, 48:1-12.
• [9]Seymour L, Ivy SP, Sargent D, Spriggs D, Baker L, Rubinstein L, Ratain MJ, Blanc ML, Stewart D, Crowley J, Groshen S, Humphrey JS, West P, Berry D: The design of phase II clinical trials testing cancer therapeutics: consensus recommendations from the clinical trial design task force of the National Cancer Institute Investigational Drug Steering Committee. Clin Cancer Res 2010, 16:1764-1769.
• [10]StopTBPartnership: The global plan to stop TB. World Health Organization 2010[http://www.stoptb.org/assets/documents/global/plan/TB_GlobalPlanToStopTB2011-2015.pdf webcite]
• [11]Hey SP: Meta-heuristic strategies in scientific judgment. University of Western Ontario; 2011.
• [12]Kimmelman J: A theoretical framework for early human studies: Uncertainty, intervention ensembles, and boundaries. Trials 2012, 13:173.
• [13]Prinz F, Schlange T, Asadullah K: Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov 2011, 10:712-713.
• [14]Begley CG, Ellis LM: Raise standards for preclinical cancer research. Nature 2012, 483:531-533.
• [15]Ji B, Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J: In Vitro and In Vivo activities of Moxifloxacin and Clinafloxacin against mycobacterium tuberculosis. Antimicrob Agents Chemother 1998, 42:2066-2069.
• [16]Gillespie S, Billington O: Activity of Moxifloxacin against Mycobacteria. J Antimicrob Chemother 1999, 44:393-395.
• [17]Shandil RK, Jayaram R, Kaur P, Gaonkar S, Suresh BL, Mahesh BN, Jayashree R, Nandi V, Bharath S, Balasubramanian V: Moxifloxacin, Ofloxacin, Sparfloxacin, and Ciprofloxacin against Mycobacterium tuberculosis: evaluation of In Vitro and Pharmacodynamic indices that best predict In Vivo efficacy. Antimicrob Agents Chemother 2007, 51:576-582.
• [18]Miyazaki E, Miyazaki M, Chen J, Chaisson R, Bishai W: Moxifloxacin (BAY12-8039), a new 8-methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob Agents Chemother 1999, 43:85-89.
• [19]Lounis N, Bentoucha A, Truffot-Pernot C, Ji B, O’Brien R, Vernon A, Roscigno G, Grosset J: Effectiveness of once-weekly Rifapentine and Moxifloxacin regimens against Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother 2001, 45:3482-3486.
• [20]Yoshimatsu T, Nuermberger E, Tyagi S, Chaisson R, Bishai W, Grosset J: Bactericidal activity of increasing daily and weekly doses of Moxifloxacin in Murine tuberculosis. Antimicrob Agents Chemother 2002, 46:1875-1879.
• [21]Nuermberger E, Yoshimatsu T, Tyagi S, O’Brien R, Vernon A, Chaisson R, Bishai W, Grosset J: Moxifloxacin-containing regimen greatly reduces time to culture conversion in Murine tuberculosis. Am J Respir Crit Care Med 2004, 169:421-426.
• [22]Gosling R, Uiso L, Sam N, Bongard E, Kanduma E, Nyindo M, Morris R, Gillespie S: The bactericidal activity of Moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003, 168:1342-1345.
• [23]Pletz M, Roux AD, Roth A, Neumann K, Mauch H, Lode H: Early bactericidal activity of Moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 2004, 48:780-782.
• [24]Gillespie S, Gosling R, Uiso L, Sam N, Kanduma E, McHugh T: Early bactericidal activity of a Moxifloxacin and Isoniazid combination in smear-positive pulmonary tuberculosis. J Antimicrob Chemother 2005, 56:1169-1171.
• [25]Johnson J, Hadad D, Boom W, Daley C, Peloquin C, Eisenach K, Jankus D, Debanne S, Charlebois E, et al.: Maciel E, et al.: Early and extended early bactericidal activity of Levofloxacin, Gatifloxacin and Moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006, 10:605-612.
• [26]Nijland HMJ, Ruslami R, Suroto AJ, Burger DM, Alisjahbana B, van Crevel R, Aarnoutse RE: Rifampicin reduces plasma concentrations of Moxifloxacin in patients with tuberculosis. Clin Infect Dis 2007, 45:1001-1007.
• [27]Peloquin CA, Hadad DJ, Molino LPD, Palaci M, Boom WH, Dietze R, Johnson JL: Population Pharmacokinetics of Levofloxacin, Gatifloxacin, and Moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother 2008, 52:852-857.
• [28]Burman W, Goldberg S, Muzanye JJG, Engle M, Mosher A, Choudhri S, Daley C, Munsiff S, et al.: Zhao Z, et al.: Moxifloxacin versus Ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006, 174:331-338.
• [29]Rustomjee R, Lienhardt C, Kanyok T, for TB (OFLOTUB) study team G: A phase II study of the sterilising activities of Ofloxacin, Gatifloxacin and Moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2008, 12:128-138.
• [30]Conde M, Efron A, Loredo C, Souza GD, Gracxa N, Cezar M, Ram M, Chaudhary M, Bishai W, Kritski A, Chaisson R: Moxifloxacin versus Ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet 2009, 53:1314-1319.
• [31]Dorman S, Johnson J, et al.: Goldberg S, et al.: Substitution of Moxifloxacin for Isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009, 180:273-280.
• [32]Wang JY, Wang JT, Tsai T, Hsu C, Yu C, Hsueh P, Lee L, Yang P: Adding Moxifloxacin is associated with a shorter time to culture conversion in pulmonary tuberculosis. Int J Tuberc Lung Dis 2009, 14:65-71.
• [33]Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, Tunis S, Bergel E, Harvey I, Magid DJ, Chalkidou K: A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol 2009, 62:464-475.
• [34]Langan D, Higgins JPT, Gregory W, Sutton AJ: Graphical augmentations to the funnel plot assess the impact of additional evidence on a meta-analysis. J Clin Epidemiol 2012, 65:511-519.