Abstract
Every decision a drug discovery scientist makes along the way will impact the ultimate product to emerge from the long and arduous discovery and development process. To meet this challenge, an innovator must have a basic understanding of those steps in this process that demand far more than knowledge of basic bench science. Perhaps the most difficult of these steps involves an understanding of regulatory and clinical development issues that only become relevant years after the potential product has overcome its initial scientific hurdles. This chapter provides a review of currently available clinical development paradigms for antibacterial drugs including non-inferiority trials and various approaches to superiority trials. The thorny problem of how pathogen-specific antibiotics can be developed is explored. The goal of this chapter is simply to familiarize the bench scientist with the challenges ahead for any project and to provide a framework for assessing risk in that context.
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References
Sutterlin HA, Malinverni JC, Lee SH, Balibar CJ, Roemer T (2017) Antibacterial new target discovery: sentinel examples, strategies and surveying success. Top Med Chem. (this volume). doi:10.1007/7355_2016_31
Silver LL (2016) Appropriate targets for antibacterial drugs. Cold Spring Harb Perspect Med 6:a030239. doi:10.1101/cshperspect.a030239
O’Shea R, Moser HE (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51(10):2871–2878. doi:10.1021/jm700967e
Silver LL (2016) A gestalt approach to gram-negative entry. Bioorg Med Chem 24:6379–6389. doi:10.1016/j.bmc.2016.06.044
Sertkaya A, Eyraud JT, Birkenbach A, Franz C, Ackerley N, Overton V, Outterson K (2014) Analytical framework for examining the value of antibacterial products. https://aspe.hhs.gov/report/analytical-framework-examining-value-antibacterial-products. Accessed 24 Jan 2017
Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40. doi:10.1038/nrd2201
Walsh CT, Wencewicz TA (2014) Prospects for new antibiotics: a molecule-centered perspective. J Antibiot 67:7–22. doi:10.1038/ja.2013.49
Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, Woodford N (2011) Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 55:390–394. doi:10.1128/AAC.00756-10
Stachyra T, Péchereau MC, Bruneau JM, Claudon M, Frère JM, Miossec C, Coleman K, Black MT (2010) Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-β-lactam β-lactamase inhibitor. Antimicrob Agents Chemother 54:5132–5138. doi:10.1128/AAC.00568-10
Mushtaq S, Warner M, Livermore DM (2010) In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother 65:2376–2381. doi:10.1093/jac/dkq306
Singh MP, Petersen PJ, Weiss WJ, Janso JE, Luckman SW, Lenoy EB, Bradford PA, Testa RT, Greenstein M (2003) Mannopeptimycins, new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98: antibacterial and mechanistic activities. Antimicrob Agents Chemother 47:62–69. doi:10.1128/AAC.47.1.62–69.2003
O’Dwyer K, Spivak AT, Ingraham K, Min S, Holmes DJ, Jakielaszek C, Rittenhouse S, Kwan AL, Livi GP, Sathe G, Thomas E, Van Horn S, Miller LA, Twynholm M, Tomayko J, Dalessandro M, Caltabiano M, Scangarella-Oman NE, Brown JR (2015) Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrob Agents Chemother 59:289–298. doi:10.1128/AAC.03774-14
Van Bambeke F, Tulkens PM (2016) Editorial commentary: colistin and a new paradigm in drug development. Clin Infect Dis 62:559–560. doi:10.1093/cid/civ968
Drusano GL (2016) From lead optimization to NDA approval for a new antimicrobial: use of pre-clinical effect models and pharmacokinetic/pharmacodynamic mathematical modeling. Bioorg Med Chem 24:6401–6408. doi:10.1016/j.bmc.2016.08.034
Guidance for Industry (2010) M3(R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. http://www.fda.gov/downloads/drugs/guidances/ucm073246.pdf. Last accessed 23 Jan 2017
Shlaes DM (2010) Antibiotics – the perfect storm. Springer-Verlag, New York, NY
Spellberg B, Lewis RJ, Boucher HW, Brass EP (2011) Design of clinical trials of antibacterial agents for community-acquired bacterial pneumonia. Clin Investig (Lond) 1:19–32. doi:10.4155/CLI.10.1
Guidance for Industry (2014) Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia: developing drugs for treatment. Draft guidance. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm234907.pdf
Guidance for Industry (2013) Acute bacterial skin and skin structure infections: developing drugs for treatment. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm071185.pdf
Guidance for Industry (2013) Codevelopment of two or more new investigational drugs for use in combination. U.S. Department of Health and Human Services Food and Drug Administration. Center for Drug Evaluation and Research (CDER). http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm236669.pdf+%26cd=1%26hl=en%26ct=clnk%26gl=us. Last accessed 30 Dec 2016
US Food and Drug Administration (2016) Facilitating antibiotic drug development for patients with unmet need and developing antibacterial drugs that target a single species. http://www.fda.gov/Drugs/NewsEvents/ucm497650.htm. Last accessed 28 Dec 2016
Dougherty TJ, Pucci MJ (2011) Antibiotic discovery and development. Springer Science & Business Media, New York, NY
Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, McGee WT, Reisman A, Chastre J (2012) Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 54(5):621–629. doi:10.1093/cid/cir895
Clinical Laboratory Improvement Act (1988) https://wwwn.cdc.gov/clia/. Last accessed 23 Jan 2017
Clinical trials transformation initiative (2016) Streamlining hospital acquired and ventilator associated bacterial pneumonia trials. https://www.ctti-clinicaltrials.org/projects/streamlining-habpvabp-trials. Last accessed 23 Jan 2017
Shlaes DM, Spellberg B (2012) Overcoming the challenges to developing new antibiotics. Curr Opin Pharmacol 12:522–526. doi:10.1016/j.coph.2012.06.010
Infectious Diseases Society of America (2012) White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens. Clin Infect Dis 55:1031–1046. doi:10.1093/cid/cis688
Clinical trials for emerging infectious diseases (2015) https://videocast.nih.gov/summary.asp?Live=17597&bhcp=1. Last accessed 28 Dec 2016
Byar DP, Schoenfeld DA, Green SB, Amato DA, Davis R, De Gruttola V, Finkelstein DM, Gatsonis C, Gelber RD, Lagakos S et al (1990) Design considerations for AIDS trials. N Engl J Med 323(19):1343–1348. doi:10.1056/NEJM199011083231912
Bass SN, Bauer SR, Neuner EA, Lam SW (2015) Impact of combination antimicrobial therapy on mortality risk for critically ill patients with carbapenem-resistant bacteremia. Antimicrob Agents Chemother 59:3748–3753. doi:10.1128/AAC.00091-15
Guidance for Industry (2013) Antibacterial therapies for patients with unmet medical need for the treatment of serious bacterial diseases. Draft guidance. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm359184.pdf
Achaogen Press Release (2016) Achaogen announces positive results in phase 3 cUTI and CRE clinical trials of plazomicin. http://investors.achaogen.com/releasedetail.cfm?ReleaseID=1003671. Last accessed 30 Dec 2016
Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, LaVange L, Marinac-Dabic D, Marks PW, Robb MA, Shuren J, Temple R, Woodcock J, Yue LQ, Califf RM (2016) Real-world evidence – what is it and what can it tell us. N Engl J Med 375:2293–2297. doi:10.1056/NEJMsb1609216
The 21st Century Cures Act (2016) A section-by-section summary. https://rules.house.gov/sites/republicans.rules.house.gov/files/114/PDF/114-SAHR34-Sxs.pdf. Last accessed 30 Dec 2016
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Shlaes, D.M. (2017). The Clinical Development of Antibacterial Drugs: A Guide for the Discovery Scientist. In: Fisher, J.F., Mobashery, S., Miller, M.J. (eds) Antibacterials. Topics in Medicinal Chemistry, vol 25. Springer, Cham. https://doi.org/10.1007/7355_2017_8
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DOI: https://doi.org/10.1007/7355_2017_8
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