New Regulatory Pathways for Antibacterial Drugs

  • David Shlaes
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)


Starting at the turn of the century, we descended from an open and enlightened approach to regulatory approval of antibacterial drugs back to the middle ages, as requirements for clinical trial stringency increased dramatically. In 2006, we descended even further into the dark ages where, at least for the US Food and Drug Administration, it became infeasible to develop new antibacterial drugs for most infections. However, in 2012, the FDA made a remarkable turnaround, and over the last 5 years, a number of new, feasible, and streamlined pathways for the development of these needed drugs have become available. These new pathways include streamlined non-inferiority trial strategies that allow approval for multiple indications with fewer trials. New endpoints for skin and skin-structure infections and for respiratory infections have been defined, mainly by the FDA for US regulatory approval. Some endpoints remain controversial, but trial designs using these endpoints are now at least feasible. One area in which the regulatory agencies and their partners, such as the Infectious Diseases Society of America, are still working diligently to develop new, feasible pathways for development is that of antibacterial drugs targeting a narrow spectrum of bacterial pathogens. Because of great differences in approach, this chapter does not deal with the development of agents specifically targeting Mycobacterium tuberculosis or Neisseria gonorrhoeae.


Infectious Diseases Society Of America (IDSA) Streamlined Pathways Skin Structure Infections Antibacterial Drug Development Ventilator-associated Pneumonia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Duncan G, Warner WP, Dauphinee JA, Dickson RC. The treatment of pneumococcal pneumonia with Dagenin. CMAJ. 1939;1939:325–32.Google Scholar
  2. 2.
    Lax E. The mold in Dr. New York: Florey’s coat. Henry Holt; 2004.Google Scholar
  3. 3.
    Shlaes DM. Antibiotics – the perfect storm. Springer; 2010.Google Scholar
  4. 4.
    Fleming TR. Current issues in non-inferiority trials. Stat Med. 2008;27(3):317–32.CrossRefGoogle Scholar
  5. 5.
    Everson-Stewart S, Emerson SS. Bio-creep in non-inferiority clinical trials. Stat Med. 2010;29(27):2769–80. Scholar
  6. 6.
    Shlaes DM, Robert CM Jr. Telithromycin and the FDA: implications for the future. Lancet I. 2008.Google Scholar
  7. 7.
    Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP 3rd, Banks PM. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006;144(6):415–420. Epub 2006 Feb 15.CrossRefGoogle Scholar
  8. 8.
    Shlaes DM, Sahm D, Opiela C, Spellberg B. The FDA reboot of antibiotic development. Antimicrob Agents Chemother. 2013;57(10):4605–7.CrossRefGoogle Scholar
  9. 9.
    Rex JH, Eisenstein BI, Alder J, Goldberger M, Meyer R, Dane A, Friedland I, Knirsch C, Sanhai WR, Tomayko J, Lancaster C, Jackson J. A comprehensive regulatory framework to address the unmet need for new antibacterial treatments. Lancet Infect Dis. 2013;13(3):269–75.CrossRefGoogle Scholar
  10. 10.
    Guidance for Industry Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases. 2013.
  11. 11.
    European Medicines Agency. Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. 2013.
  12. 12.
    Guidance for Industry. Antibacterial Drug Products: Use of Noninferiority Trials to Support Approval. 2010.
  13. 13.
    Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment. 2010.
  14. 14.
    Snodgrass WR, Anderson T. Prontosil in the treatment of erysipelas; a controlled 1329 series of 312 cases. BMJ. 1937;17.Google Scholar
  15. 15.
    Snodgrass WR, Anderson T. Sulfanilamide in the treatment of erysipelas; a 1332 controlled series of 270 cases. BMJ. 1937;11.Google Scholar
  16. 16.
    Guidance for Industry. Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment. 2014.
  17. 17.
    Considerations for clinical trial design for the study of hospital-acquired bacterial pneumonia and ventilator associated bacterial pneumonia.
  18. 18.
    Guidance for Industry Hospital-Acquired Bacterial Pneumonia and Ventilator- Associated Bacterial Pneumonia: Developing Drugs for Treatment.
  19. 19.
    Melsen WG, Rovers MM, Groenwold RH, Bergmans DC, Camus C, Bauer TT, Hanisch EW, Klarin B, Koeman M, Krueger WA, Lacherade JC, Lorente L, Memish ZA, Morrow LE, Nardi G, van Nieuwenhoven CA, O'Keefe GE, Nakos G, Scannapieco FA, Seguin P, Staudinger T, Topeli A, Ferrer M, Bonten MJ. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis. 2013;13(8):665–71.CrossRefGoogle Scholar
  20. 20.
    Zarb P, Coignard B, Griskeviciene J, Muller A, Vankerckhoven V, Weist K, Goossens MM, Vaerenberg S, Hopkins S, Catry B, Monnet DL, Goossens H, Suetens C. National Contact Points for the ECDC pilot point prevalence survey, hospital contact points for the ECDC pilot point prevalence survey. The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use. Euro Surveill. 2012;17(46):20316. Available online: Scholar
  21. 21.
    Grohskopf LA, Huskins WC, Sinkowitz-Cochran RL, Levine GL, Goldmann DA, Jarvis WR, Pediatric Prevention Network. Use of antimicrobial agents in United States neonatal and pediatric intensive care patients. Pediatr Infect Dis J. 2005;24(9):766–73.CrossRefGoogle Scholar
  22. 22.
    Alexander EL, Loutit J, Tumbarello M, Wunderink R, Felton T, Daikos G, Fusaro K, White D, Zhang S, Dudley MN. Carbapenem-resistant Enterobacteriaceae infections: results from a retrospective series and implications for the design of prospective clinical trials. Open Forum Infect Dis. 2017;4(2):ofx063. eCollection 2017 Spring.
  23. 23.
    FDA Workshop. Facilitating Antibacterial Drug Development for Patients with Unmet Need and Developing Antibacterial Drugs that Target a Single Species. 2016.
  24. 24.
    Rex JH, Talbot GH, Goldberger MJ, Eisenstein BI, Echols RM, Tomayko JF, Dudley MN, Dane A. Progress in the fight against multidrug-resistant Bacteria 2005–2016: modern noninferiority trial designs enable antibiotic development in advance of epidemic bacterial resistance. Clin Infect Dis. 2017;65 (1):141–146. Scholar
  25. 25.
    Srinivas N, Jetter P, Ueberbacher BJ, Werneburg M, Zerbe K, Steinmann J, Van der Meijden B, Bernardini F, Lederer A, Dias RL, Misson PE, Henze H, Zumbrunn J, Gombert FO, Obrecht D, Hunziker P, Schauer S, Ziegler U, Käch A, Eberl L, Riedel K, DeMarco SJ, Robinson JA. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 2010;327(5968):1010–3. Scholar
  26. 26.
    Boucher HW, Ambrose PG, Chambers HF, Ebright RH, Jezek A, Murray BE, Newland JG, Ostrowsky B, John H, Rex on behalf of the Infectious Diseases Society of America. White paper: developing antimicrobial drugs for resistant pathogens, narrow-spectrum indications, and unmet needs. J Infect Dis. 2017;0000:1–9.Google Scholar
  27. 27.
    Spellberg B, Brass EP, Bradley JS, et al. 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. 2012;55:1031.CrossRefGoogle Scholar
  28. 28.
  29. 29.
    Shlaes DM. Research and development of antibiotics: the next battleground. ACS Infect Dis. 2015;1(6):232–3. Epub 2015 May 5.CrossRefGoogle Scholar
  30. 30.
    Shlaes DM. Antibacterial Drugs; Looking ahead from the past. In Jonathan Cohen, William G Powderly, Steven M. Opal ed. Infectious Diseases 4th Ed. 2016. Springer.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • David Shlaes
    • 1
  1. 1.Retired from Anti-infectives Consulting, LLCStoningtonUSA

Personalised recommendations