New Regulatory Pathways for Antibacterial Drugs
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.
- 1.Duncan G, Warner WP, Dauphinee JA, Dickson RC. The treatment of pneumococcal pneumonia with Dagenin. CMAJ. 1939;1939:325–32.Google Scholar
- 2.Lax E. The mold in Dr. New York: Florey’s coat. Henry Holt; 2004.Google Scholar
- 3.Shlaes DM. Antibiotics – the perfect storm. Springer; 2010.Google Scholar
- 6.Shlaes DM, Robert CM Jr. Telithromycin and the FDA: implications for the future. Lancet I. 2008.Google Scholar
- 10.Guidance for Industry Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases. 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM359184.pdf.
- 11.European Medicines Agency. Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC500153953.pdf.
- 12.Guidance for Industry. Antibacterial Drug Products: Use of Noninferiority Trials to Support Approval. 2010. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070951.pdf.
- 13.Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment. 2010. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071185.pdf.
- 14.Snodgrass WR, Anderson T. Prontosil in the treatment of erysipelas; a controlled 1329 series of 312 cases. BMJ. 1937;17.Google Scholar
- 15.Snodgrass WR, Anderson T. Sulfanilamide in the treatment of erysipelas; a 1332 controlled series of 270 cases. BMJ. 1937;11.Google Scholar
- 16.Guidance for Industry. Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment. 2014. https://www.fda.gov/downloads/drugs/guidances/ucm123686.pdf.
- 17.Considerations for clinical trial design for the study of hospital-acquired bacterial pneumonia and ventilator associated bacterial pneumonia. https://www.regulations.gov/document?D=FDA-2010-D-0589-0027.
- 18.Guidance for Industry Hospital-Acquired Bacterial Pneumonia and Ventilator- Associated Bacterial Pneumonia: Developing Drugs for Treatment. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM234907.pdf.
- 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.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: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20316.CrossRefGoogle Scholar
- 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. https://doi.org/10.1093/ofid/ofx063. eCollection 2017 Spring.
- 23.FDA Workshop. Facilitating Antibacterial Drug Development for Patients with Unmet Need and Developing Antibacterial Drugs that Target a Single Species. 2016. https://www.fda.gov/Drugs/NewsEvents/ucm497650.htm.
- 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. https://doi.org/10.1093/cid/cix246.CrossRefGoogle Scholar
- 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. https://doi.org/10.1126/science.1182749.CrossRefGoogle Scholar
- 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
- 28.Shlaes DM. Superiority trials for antibiotics. http://antibiotics-theperfectstorm.blogspot.com/2014/04/superiority-trails-for-antibiotics.html.
- 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