Dalia Deak, MPH; Kevin Outterson, LLM, JD; John H. Powers, MD; Aaron S. Kesselheim, MD, JD, MPH
Disclosures: Prof. Outterson reports grants from the European Union—DRIVE-AB and other from Roche-Genentech Anti-Infectives Advisory Board and Pure Tech outside the submitted work. Dr. Powers reports personal fees from Cardeas, Contrafect, Gilead, Johnson & Johnson, MedImmune, Novartis, Otsuka, Pfizer, and Trius outside the submitted work. Dr. Kesselheim reports grants from the Greenwall Foundation, Harvard Program in Therapeutic Science, U.S. Food and Drug Administration Office of Generic Drugs and Division of Health Communication, and Laura and John Arnold Foundation outside the submitted work; further, he is an unpaid member of the governance board of the DRIVE-AB consortium, which is a venture of the European Innovative Medicines Initiative. Ms. Deak has disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0291.
Financial Support: By the Greenwall Faculty Scholars in Bioethics Program, the Laura and John Arnold Foundation, and the Harvard Program in Therapeutic Science (Dr. Kesselheim). Prof. Outterson is a partner in DRIVE-AB, which is funded by the European Union's Innovative Medicines Initiative.
Requests for Single Reprints: Aaron S. Kesselheim, MD, JD, MPH, Program on Regulation, Therapeutics, and Law (PORTAL), Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, Massachusetts 02120; e-mail, firstname.lastname@example.org.
Current Author Addresses: Ms. Deak and Dr. Kesselheim: Program on Regulation, Therapeutics, and Law (PORTAL), Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120.
Prof. Outterson: School of Law, Boston University, 765 Commonwealth Avenue, Boston, MA 02215.
Dr. Powers: George Washington University School of Medicine, 2300 Eye Street, NW, Washington, DC 20037.
Author Contributions: Conception and design: D. Deak, K. Outterson, J.H. Powers, A.S. Kesselheim.
Analysis and interpretation of the data: D. Deak, K. Outterson, J.H. Powers, A.S. Kesselheim.
Drafting of the article: D. Deak, J.H. Powers.
Critical revision of the article for important intellectual content: D. Deak, K. Outterson, J.H. Powers, A.S. Kesselheim.
Final approval of the article: D. Deak, K. Outterson, J.H. Powers, A.S. Kesselheim.
Statistical expertise: D. Deak, J.H. Powers.
Obtaining of funding: A.S. Kesselheim.
Collection and assembly of data: D. Deak, K. Outterson.
A weak antibiotic pipeline and the increase in drug-resistant pathogens have led to calls for more new antibiotics. Eight new antibiotics were approved by the U.S. Food and Drug Administration (FDA) between January 2010 and December 2015: ceftaroline, fidaxomicin, bedaquiline, dalbavancin, tedizolid, oritavancin, ceftolozane–tazobactam, and ceftazidime–avibactam. This study evaluates the development course and pivotal trials of these antibiotics for their innovativeness, development process, documented patient outcomes, and cost. Data sources were FDA approval packages and databases (January 2010 to December 2015); the Red Book (Truven Health Analytics); Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (FDA); and supplementary information from company filings, press releases, and media reports. Four antibiotics were approved for acute bacterial skin and skin-structure infection. Seven had similar mechanisms of action to those of previously approved drugs. Six were initially developed by small to midsized companies, and 7 are currently marketed by 1 of 3 large companies. The drugs spent a median of 6.2 years in clinical trials (interquartile range [IQR], 5.4 to 8.8 years) and 8 months in FDA review (IQR, 7.5 to 8 months). The median number of patients enrolled in the pivotal trials was 666 (IQR, 553 to 739 patients; full range, 44 to 1005 patients), and median trial duration was 18 months (IQR, 15 to 22 months). Seven drugs were approved on the basis of pivotal trials evaluating noninferiority. One drug demonstrated superiority on an exploratory secondary end point, 2 showed decreased efficacy in patients with renal insufficiency, and 1 showed increased mortality compared with older drugs. Seven of the drugs are substantially more expensive than their trial comparators. Limitations are that future research may show benefit to patients, new drugs from older classes may show superior effectiveness in specific patient populations, and initial U.S. prices for each new antibiotic were obtained from public sources. Recently marketed antibiotics are more expensive but have been approved without evidence of clinical superiority.
Deak D, Outterson K, Powers JH, Kesselheim AS. Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration–Approved Antibiotics, 2010–2015. Ann Intern Med. [Epub ahead of print 24 May 2016]165:363–372. doi: 10.7326/M16-0291
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Published: Ann Intern Med. 2016;165(5):363-372.
Published at www.annals.org on 24 May 2016
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