Addressing the Need for New Antibacterials--authors' Reply.

Safe and effective new antibiotics are urgently needed, but there is no evidence that the plan outlined by John Rex and colleagues1Rex JH Eisenstein BI Alder J et al.A comprehensive regulatory framework to address the unmet need for new antibacterial treatments.Lancet Infect Dis. 2013; 13: 269-275Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar will improve access to new, beneficial antibiotics. We agree that companies will be more motivated to develop new antibiotics if research and development costs are reduced. This can be achieved with carefully designed smaller or shorter-term studies that clearly measure meaningful outcomes to a well defined group of patients.2Fleming TR Powers JH Biomarkers and surrogate endpoints in clinical trials.Stat Med. 2012; 31: 2973-2984Crossref PubMed Scopus (303) Google Scholar Even small trials will show efficacy for drugs that provide a substantial benefit. Unfortunately, surrogate endpoints often do not reflect important health outcomes, such as mortality or admissions to hospital.3Avorn J Approval of a tuberculosis drug based on a paradoxical surrogate measure.JAMA. 2013; 21: 01-02Google Scholar Moreover, to target patients with resistant bacteria is difficult because rapid diagnostic tests are not available. Until these issues are addressed, ineffective or unproven regimens are most likely to be developed under Rex and colleague's framework. The risk of lowering approval criteria for safety and efficacy is clear. Death and other serious adverse effects had a higher incidence for orphan drugs approved after small trials than similar drugs that had more rigorous testing.4Kesselheim AS Myers JA Avorn J Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer.JAMA. 2011; 305: 2320-2325Crossref PubMed Scopus (166) Google Scholar It would be unethical to approve new antibiotics for targeted populations based on small, short-term studies unless there is strong evidence of health improvements to counterbalance unknown risks. After approval, companies should be held accountable by the US Food and Drug Administration (FDA) for completing safety studies, creating patient registries, and developing rapid diagnostics to identify multidrug-resistant infections. Rex and colleagues' proposal does not meet these criteria. Instead of changing regulations, the FDA should make better use of the five existing pathways to expedite development of beneficial antibiotics. At least one company is using an existing FDA expedited pathway for a drug tested by a superiority trial measuring all-cause mortality in patients with multidrug-resistant pneumonia.5Welch C A new pathway for antibiotic innovation: exploring drug development for limited populations.http://www.pewhealth.org/uploadedFiles/PHG/Content_Level_Pages/Other_Resource/antibiotics-transcript.pdfGoogle Scholar Other companies should follow suit. We declare that we have no conflicts of interest. A comprehensive regulatory framework to address the unmet need for new antibacterial treatmentsTo bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Full-Text PDF Addressing the need for new antibacterials – Authors' replyWe appreciate the opportunity raised by Jennifer Yttri and Diana Zuckerman to discuss further our proposed approach to the crisis of antimicrobial resistance. We agree that the availability of safe and effective antibacterials is essential to the protection of public health. Full-Text PDF