1 See Fauci, Anthony S. & Marston, Hilary D., The Perpetual Challenge of Antimicrobial Resistance, 311 JAMA 1853, 1853-54 (2014)Google Scholar (“In fact, the challenge of antimicrobial resistance is an enduring threat that likely will never be eliminated. The threat is due, in part, to the inherent ability of microbes to replicate rapidly and mutate, offering them an evolutionary advantage in fending off hazards to their survival. Addressing the threat of antimicrobial resistance is a never-ending challenge.”)

2 CDC, U.S. Dep’t of Health & Human Servs., Antibiotic Resistance Threats in the United States, 2013, at 11 (2013) (“Each year in the United States, at least 2 million people acquire serious infections with bacteria that are resistant to one or more of the antibiotics designed to treat those infections. At least 23,000 people die each year as a direct result of these antibiotic-resistant infections. Many more die from other conditions that were complicated by an antibiotic-resistant infection.”)

3 See, e.g., id.; Neidell, Matthew J. et al., Costs of Healthcare- and Community-Associated Infections with Antimicrobial-Resistant Versus Antimicrobial-Susceptible Organisms, 55 Clinical Infectious Diseases 807, 807-15 (2012)Google Scholar (using administrative data to estimate the additional hospital charges associated with healthcare- and community-associated infections (“CAIs”) among patients with antimicrobial-resistant versus antimicrobial-susceptible bacterial strains).

4 World Health Organization, Antimicrobial Resistance: Global Report on Surveillance, at ix, xi (2014) (“These antibacterials are more expensive, may not be available in resource-constrained settings, and are also likely to further accelerate development of resistance. Of great concern is the fact that K. pneumoniae resistant also to carbapenems has been identified in most of the countries that provided data, with proportions of resistance up to 54% reported.”).

5 U.K. Review on Antimicrobial Resistance, Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations, at 5 tbl.1 (2014).

6 Beardsley, James et al., Show Me the Money: Long-Term Financial Impact of an Antimicrobial Stewardship Program, 33 Infection Control & Hospital Epidemiology 398, 398 (2012)Google Scholar (describing the cost savings that could accrue from stewardship); Dellit, Timothy et al., Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship, 44 Clinical Infectious Diseases 159, 160 (2012)Google Scholar (describing recommendations for stewardship in the hospital setting); Aidan Hollis & Ziana Ahmed, Preserving Antibiotics, Rationally, 369 New Eng. J. Med. 2474, 2475 tbl.1 (2013) (describing the widespread use of antibiotics in agricultural practice); Hwang, Thomas J. et al., Antimicrobial Stewardship and Public Knowledge of Antibiotics, 15 Lancet 1000, 1001 (2015)Google Scholar (describing recent initiatives to improve stewardship of antibiotics in the hospital setting); Hwang, Thomas J. et al., Target Small Firms for Antibiotic Innovation, 344 Science 967, 968 (2014)Google Scholar (describing the need for new antimicrobial agents).

7 See Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144, 126 Stat. 1077, §§ 801-06 (2012). The GAIN Act, or GAIN provisions, was passed as part of this larger statute. See id. Since existing patents may provide for longer exclusivity periods, these periods effectively serve as bare minimum guarantees and are most applicable for approved new drugs lacking much remaining patent protection. See Wang, Bo et al., Variations in Time of Market Exclusivity Among Top-Selling Prescription Drugs in the United States, 175 Jama Internal Med. 635, 635 (2015)Google Scholar (“Recent research has shown that prescription brand-name drugs that eventually face generic competition have, on average, an effective market exclusivity period of 12.4 years.”).

8 PCAST, Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation 39, 62 (2012) (“Another important example is the development of drugs to treat bacteria resistant to current antibiotics, which is an urgent medical need. A small clinical trial might rapidly demonstrate a favorable benefit-risk balance in patients with life-threatening infections caused by antibiotic-resistant bacteria …. The purpose of a new pathway and designation would be to signal to physicians and insurers that, based on current evidence, the FDA considers the drug to be inappropriate for use outside the specific subpopulation.”).

9 See id.

10 21st Century Cures Act of 2015, H.R. 6, 114th Cong. § 2121 (2015); see also Norm Ornstein, A Bipartisan Victory for Medical Research in Congress, Atlantic (July 13, 2015), http://www.theatlantic.com/politics/archive/2015/07/21st-century-cures-act-bipartisan/398369/ [http://perma.cc/5TX6-FMDP].

11 See Stuart J. Pocock, Clinical Trials: A Practical Approach 7 (1983) (“The aim of any clinical trial should be to obtain a truthful answer to a relevant medical issue. This requires that the conclusions be based on an unbiased assessment of objective evidence rather than on a subjective compilation of clinical opinion.”).

12 See Chen, Donna T. et al., U.S. Physician Knowledge of the FDA-Approved Indications and Evidence Base for Commonly Prescribed Drugs: Results of a National Survey, 18 Pharmacoepidemiology & Drug Safety 1094, 1096 (2009)Google Scholar (describing physician attitudes towards the evidence base for new drug approvals); Schwartz, Lisa M. & Woloshin, Steven, Communicating Uncertainties About Prescription Drugs to the Public, 171 Archives Internal Med. 1463, 1466 (2011)Google Scholar (describing public attitudes towards FDA approval of new drugs).

13 See Billstein, Stephan A., How the Pharmaceutical Industry Brings an Antibiotic Drug to Market in the United States, 38 Antimicrobial Agents & Chemotherapy 2679, 2679 (1994)Google Scholar.

14 Id. at 2680.

15 Id.

16 Id.

17 Id. at 2680-81.

18 Id.

19 See Sibbald, Bonnie & Roland, Martin, Understanding Controlled Trials: Why Are Randomised Controlled Trials Important? 316 Brit. Med. J. 201, 201 (1998)Google Scholar (“Randomised [sic] controlled trials are the most rigorous way of determining whether a cause-effect relation exists between treatment and outcome and for assessing the cost effectiveness of a treatment.”)

20 See, e.g., Meissner, Karin et al., Differential Effectiveness of Placebo Treatments: A Systematic Review of Migraine Prophylaxis, 173 JAMA Intern Med. 1941, 1942 (2013)Google Scholar (describing the importance of placebo controls when evaluating the effectiveness of medical treatments).

21 See Scott H. Podolsky, The Antibiotic Era: Reform, Resistance, and the Pursuit of a Rational Therapeutics 13 (2014).

22 See Marshall, Geoffrey et al., Streptomycin Treatment of Pulmonary Tuberculosis: A Medical Research Council Investigation, 2 Brit. Med. J. 4582, 4582 (1948)Google Scholar (presenting the results of the first randomized, controlled trial of streptomycin for the treatment of pulmonary tuberculosis).

23 See 21 C.F.R. § 314.126 (2015).

24 See Kocher, Robert & Roberts, Bryan, The Calculus of Cures, 370 New Eng. J. Med. 1473, 1474 (2014)Google Scholar (“The most expensive step in creating a new drug is conducting clinical trials. Conducting a trial costs $25,000 or more per patient studied.”)

25 See Kantarjian, Hagop M. et al., Cancer Drugs in the United States: Justum Pretium—The Just Price, 31 J. Clinical Oncology 3600, 3602 (2013)Google Scholar (“The cost per patient in a clinical trial has risen from an estimated $25,000 per patient in 2000 to as much as $100,000 in 2012.”); see generally Thomson Reuters, 2012 CMR International Pharmaceutical R&D Factbook (2012) (describing results of a survey of clinical development costs by category) (on file with author).

26 See Hwang, Thomas J., Stock Market Returns and Clinical Trial Results of Investigational Compounds: An Event Study Analysis of Large Biopharmaceutical Companies, Plos One, Aug. 2013CrossRefGoogle Scholar, at 6 (“Our results indicate that clinical development events have material economic implications, even for large biopharmaceutical companies with multidrug portfolios ….”); Rothenstein, Jeffrey M. et al., Company Stock Prices Before and After Public Announcements Related to Oncology Drugs, 103 J. Nat’l Cancer Inst. 1507, 1507 (2011)Google Scholar (“Phase III clinical trials and regulatory decisions by the US Food and Drug Administration (FDA) are high-profile events that are critical for the financial success of new drugs. These events can also have a substantial impact on the market valuation of the companies that might bring these drugs to market. Therefore, these events attract great interest from investors.”)

27 See Downing, Nicholas S. et al., Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012, 311 JAMA 368, 372 (2014)Google Scholar (describing the variation in clinical trial evidence across indications); Duijnhoven, Ruben G. et al., Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis, 10 PLoS Med. e1001407 (2013)CrossRefGoogle Scholar (“For most approved medicines intended for chronic use, the number of patients studied before marketing is insufficient to study safety and long-term efficacy. In light of new scientific and legislative tools to monitor benefits and risks in clinical use, discussion of the long-term exposure requirements for approval of medicines, particularly for medicines intended for chronic use, seems warranted.”); Kesselheim, Aaron S. et al., Characteristics of Clinical Trials to Support Approval of Orphan vs. Nonorphan Drugs for Cancer, 305 JAMA 2320, 2320 (2011)Google Scholar (“Compared with pivotal trials used to approve nonorphan cancer drugs, pivotal trials for recently approved orphan drugs for cancer were more likely to be smaller and to use nonrandomized, unblinded trial designs and surrogate end points to assess efficacy.”); Mitsumoto, Jun et al., Pivotal Studies of Orphan Drugs Approved for Neurological Diseases, 66 Annals Neurology 184, 189 (2009)Google Scholar (describing similar results in orphan-designated versus non-orphan-designated drugs approved for central nervous system disorders).

28 See D’Agostino, Ralph B., Sr. et al., Non-Inferiority Trials: Design Concepts and Issues, 22 Stat. Med. 169, 169 (2003)Google Scholar (“Where possible and justified, [placebo-controlled trials] should be the first choice for medical treatment evaluation …. The non-inferiority trial is appropriate for evaluation of the efficacy of an experimental treatment versus an active control when it is hypothesized that the experimental treatment may not be superior to a proven effective treatment, but is clinically and statistically not inferior in effectiveness.”).

29 See Powers, John H. & Fleming, Thomas R., Noninferiority Trials: Clinical Understandings and Misunderstandings, 3 Clinical Investigations 215, 216 (2013)Google Scholar (“The formulation of the [non-inferiority] margin is often controversial. Sponsors interested in conducting smaller trials and increasing the likelihood of achieving ‘positive’ results prefer large margins. However, to avoid exposing patients to meaningfully less-effective new interventions, there should be rigorous scientific justification for the [non-inferiority] margin.”); Schumi, Jennifer & Wittes, Janet T., Through the Looking Glass: Understanding Non-Inferiority, 12 Trials 106, 112 (2011)Google Scholar (“Although non-inferiority trials are often conceptually desirable, operational difficulties may plague the process of choosing the margin, either because of insufficient data to support a selected margin or a calculated margin that leads to an impractical sample size.”).

30 See DiMasi, Joseph A. et al., Cost of Innovation in the Pharmaceutical Industry, 10 J. Health Econ. 107, 132-33 (1991)Google Scholar (“That clinical trial costs have risen sharply in recent years is attested to in F-D-C [sic] Reports: The Pink Sheet (1989), where an executive of a major pharmaceutical firm reports that the information required to support NDAs has increased dramatically. Clinical trials for one of the firm’s anti-infective NCEs approved in 1979 used 1,493 patients; the trials for a related anti-infective that the firm is currently developing will require testing on 10,000 patients.”).

31 See Gupta, Sandeep Kumar & Nayak, Roopa P., Dry Antibiotic Pipeline: Regulatory Bottlenecks and Regulatory Reforms, 5 J. Pharmacology & Pharmacotherapeutics 4, 6 (2014)Google Scholar.

32 Drugs@FDA, FDA, https://www.accessdata.fda.gov/scripts/cder/drugsatfda/.

33 See id.

34 See Hwang, Thomas J. et al., Assessment of US Pathway for Approving Medical Devices for Rare Conditions, 348 Brit. Med. J. 1, 1–2 (2014)Google Scholar (describing data extraction from FDA’s publicly available regulatory review dossiers) [hereinafter Hwang et al., Assessment]; Hwang, Thomas J. et al., Postmarketing Trials and Pediatric Device Approvals, 133 Pediatrics e1197, e1198 (2014)Google Scholar (describing data extraction methodology) [hereinafter Hwang et al., Postmarketing]; Kesselheim, supra note 27, at 2321 (describing data extraction from FDA’s publicly available regulatory review dossiers).

35 See Wilcoxon, Frank, Individual Comparisons by Ranking Method, 1 Biometrics Bull. 80, 81–82 (1945)Google Scholar.

36 See History, StataCorp LP, http://www.stata.com/company/ [http://perma.cc/K523-DHA5].

37 Warner-Lambert Co. v. Heckler, 787 F.2d 147, 151 (3d Cir. 1986) (“Because the [FDCA] requires ‘investigations,’ the FDA requires drug manufacturers to submit at least two … studies showing the effectiveness of the drug.”); FDA, Final Decision on Benylin, 44 Fed. Reg. 51,512, 51,518 (Aug. 31, 1979) (explaining that the two study requirement is premised on the notion that a study must be capable of reproduction for the results to be reliable). Although the FDA generally requires two adequate and well controlled studies to establish evidence of a drug’s effectiveness, the federal Food, Drug, and Cosmetic Act was amended in 1997 to explicitly allow only one pivotal trial to meet the substantial evidence standard. See Food, Drug, and Cosmetic Act of 1938, 21 U.S.C. § 355(d) (2012) (“If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence.”).

38 21 C.F.R. § 312.84 (2015).

39 See Darrow, Jonathan J. et al., New FDA Breakthrough-Drug Category—Implications for Patients, 370 New Eng. J. Med. 1252, 1252-53 (2014)Google Scholar (describing the history of early-access and expedited-approval programs); Kesselheim, Aaron S. et al., Existing FDA Pathways Have Potential to Ensure Early Access to, and Appropriate Use of, Specialty Drugs, 33 Health Aff. 1770, 1772 (2014)Google Scholar (“The FDA’s expedited review and approval programs have frequently been applied to specialty drugs. In the period 2000–13, 82 drugs were approved under the fast-track designation, which represented 22 percent of the 369 new molecular entities (including biologic drugs) approved by the FDA during that time period.”)

40 Kesselheim et al., supra note 39, at 1772-73.

41 See Investigational New Drug, Antibiotic, and Biological Drug Product Regulations; Procedures for Drugs Intended to Treat Life-Threatening and Severely Debilitating Illnesses, 53 Fed. Reg. 41,516, 41,516 (Oct. 21, 1988); Daniel Carpenter, Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA 457 (2010) (“Today the AIDS crisis seems powerful in U.S. pharmaceutical regulation not just as a cause but also as example. The striking demonstration of the power of patient politics was, at the same time, an historical precedent to which other organizations paid heed. Not just in the case of AIDS and HIV, but more broadly for the politics of disease, the politics of AIDS reframed some of the fundamental issues and controversies buffeting the FDA.”)

42 See 21 C.F.R § 312.500 (2015).

43 Id. § 312.510.

44 Id. §§ 312.530, 312.540.

45 Food and Drug Administration Safety and Innovation Act of 2012, Pub. L. No. 112-144, 126 Stat. 1087, § 902 (2012) (codified as amended at 21 U.S.C. § 356).

46 See Press Release, Rebiotix, Receives Breakthrough Therapy Designation for RBX2660 (Oct. 12, 2015) http://www.rebiotix.com/news-media/press-releases/rebiotix-receives-breakthrough-therapy-designation-for-rbx2660-recurrent-c-diff/ [http://perma.cc/77XP-SBHR]; Press Release, Seres Therapeutics, Seres Therapeutics Receives FDA Breakthrough Therapy Designation for Its Lead Product Candidate, SER- 109 (June 12, 2015), http://www.serestherapeutics.com/pipeline/ser-109 [http://perma.cc/BAB8-9B8H].

47 See Press Release, XBiotech, XBiotech Receives FDA Fast Track Designation for its Novel True Human™ Therapeutic Antibody for Treating Serious Infections Due to Staphylococcus aureus (Oct. 1, 2015), http://www.xbiotech.com/about/news/xbiotech-receives-fda-fast-track-designation-for-its-novel-true-human-therapeutic-antibody.html [http://perma.cc/VP2D-ZSTT].

48 See generally FDA, Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (2014) (describing features of the expedited approval and breakthrough designation programs).

49 See Drug Price Competition and Patent Term Restoration (Hatch-Waxman) Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585, § 505(b)(2) (1984) (codified as amended at 21 U.S.C. § 355(b)(2)). This statute is commonly referred to as the Hatch-Waxman Act or the Hatch-Waxman Amendments, and the relevant subsection is still referred to as § 505(b) even though it is codified in § 355(b). Accordingly, it will be referred throughout this article simply by § 505(b).

50 Compare § 505(b)(1), with § 505(b)(2); see also FDA, Guidance for Industry: Applications Covered by Section 505(b)(2), at 2 (1999), http://www.fda.gov/downloads/Drugs/.../Guidances/ucm079345.pdf [http://perma.cc/6KPZ-LB7Y] (describing the types of evidence that can be accepted as part of a 505(b)(2) application).

51 See FDA, supra note 50, at 3.

52 See Albane D’Argent, The 505(b)(1) and 505(b)(2) Application Process in the US, Life Sci. Connect (Apr. 7, 2015), http://lsconnect.thomsonreuters.com/the-505b1-and-505b2-application-process-in-the-us/ (“Since its introduction, the 505(b)(2) path has become slowly but surely a more and more appealing and lucrative pathway for manufacturers. Not only is this pathway shortening development time and mitigating costs, but it may also qualify for 3 to 5 years of market exclusivity, unlike generics for which exclusivity can be held for only 180 days.”).

53 See Press Release, FDA, FDA Approves New Antibacterial Drug Avycaz (Feb. 25, 2015), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435629.htm [http://perma.cc/6E5Z-SW9R].

54 See Flamm, Robert K. et al., Ceftazidime-Avibactam and Comparator Agents Tested against Urinary Tract Isolates from a Global Surveillance Program, 80 Diagnostic Microbiology Infectious Disease 233, 233 (2014)Google Scholar (“Ceftazidime-avibactam is a combination agent consisting of the non–β-lactam β-lactamase inhibitor avibactam and the broad-spectrum cephalosporin, ceftazidime. In this combination, avibactam protects ceftazidime from hydrolysis by β-lactamases, thus preserving antibacterial activity.”); Sader, Helio S. et al., Antimicrobial Activity of Ceftazidime-Avibactam Against Gram-Negative Organisms Collected from U.S. Medical Centers in 2012, 58 Antimicrobial Agents Chemotherapy 1684, 1684 (2014)Google Scholar (“Avibactam (formerly NXL-104) is a member of a novel class of non-β-lactam β-lactamase inhibitors, the diazabicyclooctanes (DBOs). Compared to current inhibitors available for clinical use, DBOs are more potent and have a broader spectrum and a different mechanism of action.”).

55 Levasseur, Premavathy et al., In Vitro Antibacterial Activity of the Ceftazidime-Avibactam (NXL104) Combination Against Pseudomonas aeruginosa Clinical Isolates, 56 Antimicrobial Agents Chemotherapy 1606, 1606 (2012)Google Scholar (“Avibactam has virtually no intrinsic antibacterial activity, but it efficiently protects β-lactams from hydrolysis in a variety of class A- and class C-producing strains, including ESBL and KPC producers, as well as AmpC-overexpressing strains, many of which are poorly inhibited by clavulanic acid and tazobactam.”).

56 Ctr. for Drug Evaluation & Research, FDA, Application Number: 206494Orig1s000, Summary Review, at 3 (Feb. 25, 2015) (“The Investigational New Drug (IND) application was submitted by Novexel in January 2008. Novexel transferred ownership to AstraZeneca Pharmaceuticals LP in April 2010, who then transferred ownership to Cerexa, Inc., a wholly owned subsidiary of Forest Laboratories, Inc. in October 2011.”).

57 See id. (“In December 2013, the Applicant and the Agency agreed that a New Drug Application (NDA) covered under Section 505(b)(2) of the Food Drug and Cosmetic Act relying in part on the Agency’s previous finding of safety and efficacy of ceftazidime (one of the components of the drug product, ceftazidime-avibactam), could be submitted.”).

58 See id. (“Additional data would include nonclinical data, Phase 1 data, data from two Phase 2 trials, and published ceftazidime data. The application also includes safety data on avibactam, including data from patients who received ceftazidime-avibactam. The contribution of the avibactam component is being assessed primarily in in vitro studies and in animal models of infection, where the addition of avibactam restored the activity of ceftazidime against ceftazidime-nonsusceptible bacteria.”).

59 Bridget Silverman, Flexibility Or Formal Pathway? Avycaz Suggests FDA Doesn't Need Congress To Expedite Limited Use Antibiotics, Pink Sheet (May 18, 2015), https://www.pharmamedtechbi.com/publications/the-pink-sheet/77/20/flexibility-or-formal-pathway-emavycazem-suggests-fda-doesnt-need-congress-to-expedite-limite [http://perma.cc/DB3B-KQRD] (“FDA floated the idea of using accelerated approval regulations to expedite Avycaz’s approval but rejected it in favor of the 505(b)(2) strategy. Minutes of the Dec. 19, 2013 pre-NDA meeting report that, after ‘several internal discussions,’ FDA concluded that ‘there is no surrogate endpoint that is reasonably likely to predict clinical benefit for [ceftazidime-avibactam].’”).

60 See Ctr. for Drug Evaluation & Research, supra note 56, at 2 (“Since submission of the NDA, the Applicant clarified that they were seeking all the above indications when limited or no alternative treatments are available.”).

61 Ctr. for Drug Evaluation & Research, FDA, Application Number: 206494Orig1s000, Statistical Review(s), at 3 (Feb. 11, 2015).

62 Id. at 8, 20 (2015) (“Clinical cure rates were lower in a subgroup of patients with baseline creatinine clearance (CrCL) of 30 to 50 ml/min compared to those with CrCL >50 ml/min. The reduction in clinical cure rate was pronounced in [ceftazidime-avibactam]-treated patients (85% to 45%) compared to meropenem-treated patients (86% to 74%).”).

63 Id. at 20.

64 Id. at 10-11.

65 See AVYCAZ: Indications and Usage, Allergan (2015), https://www.avycaz.com/ [http://perma.cc/6397-RYAV] (“As only limited clinical safety and efficacy data for AVYCAZ (ceftazidime-avibactam) are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options …. To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.”).

66 See FDA, Avycaz (ceftazidime and avibactam): Drug Safety Communication – Dose Confusion and Medication Errors (Sept. 22, 2015), http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm463595.htm [http://perma.cc/4S26-2TC7] (“FDA is warning health care professionals about the risk for dosing errors with the intravenous antibacterial drug Avycaz (ceftazidime and avibactam) due to confusion about the drug strength displayed on the vial and carton labels ….”).

67 See Coates, Anthony et al., The Future Challenges Facing the Development of New Antimicrobial Drugs, 1 Nature Revs. Drug Discovery 895, 895 (2002)Google Scholar (“No new classes of antibiotics were produced in the 37 years between the introduction of nalidixic acid in 1962 and linezolid in 2000; all of the antibacterial agents that entered the market during this period were modifications of existing molecules.”).

68 Cerexa, Inc., Ceftazidime-Avibactam for Injection 8-9 (2014).

69 See 21 C.F.R. § 314.600 (2015).

70 FDA, Guidance for Industry: Product Development Under the Animal Rule 2-3 (2015).

71 See 21 C.F.R. § 314.600.

72 Id. § 314.610.

73 Id.

74 See id.

75 See Gronvall, Gigi Kwik et al., Letter to the Editor, The FDA Animal Efficacy Rule and Biodefense, 25 Nature Biotechnology 1084, 1084-85 (2007)Google Scholar (describing the early experience of the Animal Rule).

76 See Press Release, FDA, FDA Approves Raxibacumab to Treat Inhalational Anthrax (Dec. 14, 2012), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332341.htm [http://perma.cc/6Y8M-DBD5].

77 See Migone, Thi-Sau et al., Raxibacumab for the Treatment of Inhalational Anthrax, 361 New Eng. J. Med. 135, 136 (2009)Google Scholar (“We conducted randomized, placebo-controlled studies in two animal models of inhalational anthrax to assess the efficacy of raxibacumab administered as a prophylactic agent and after the onset of systemic disease.”).

78 See Ctr. For Drug Evaluation & Res., Application Number: 125349Orig1s000, Summary Review, at 6 (Dec. 14, 2012) (“The results of the primary analysis showed survival in 24/37 (65%) NZW rabbits treated with levofloxacin alone, compared to 32/39 (82%) NZW rabbits treated with raxibacumab plus levofloxacin. The 17% difference in survival rates did not reach statistical significance (p=0.0874).”).

79 Id.

80 Id.

81 See Press Release, Human Genome Sciences, Inc., Human Genome Sciences Announces New Order for Raxibacumab (ABthrax™) from U.S. Government (July 22, 2009, 7:00 PM), http://www.prnewswire.com/news-releases/human-genome-sciences-announces-new-order-for-raxibacumab-abthraxtm-from-us-government-62250457.html [http://perma.cc/E6VZ-XWUT] (“Human Genome Sciences, Inc. today announced that the U.S. Government has exercised its option to purchase an additional 45,000 doses of raxibacumab (ABthrax™) for the Strategic National Stockpile, to be delivered over a three-year period, beginning near the end of 2009. HGS expects to receive approximately $151 million from this award as deliveries are completed.”).

82 See Press Release, FDA, FDA Approves New Antibacterial Treatment for Plague (Apr. 27, 2012), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302220.htm [http://perma.cc/F9QM-4664].

83 See Ctr. For Drug Evaluation & Res., Application Numbers: 020634Orig1s061, 020635Orig1s067, 021721Orig1s028, Summary Review, at 8 (Apr. 27, 2012) (“The objective of the study was to determine if treatment with IV levofloxacin improved the survival rate among treated animals compared to those that received placebo.”).

84 See id. at 8-9 tbl.3.

85 See id.

86 See id. at 10.

87 See Press Release, FDA, FDA Approves Additional Antibacterial Treatment for Plague (May 8, 2015), http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm446283.htm [http://perma.cc/7DRS-UK85].

88 See Marion Gruber, Dir., Office of Vaccines Research & Review, Presentation at the Inst. of Med.’s Fast Track Dev. of Ebola Vaccines (Mar. 26, 2015), http://www.nationalacademies.org/hmd/~/media/Files/Activity%20Files/PublicHealth/MedPrep/Gruber%20IOM%20March%2026.pdf [http://perma.cc/YR56-UZNA] (“Ebola vaccines could be licensed based on clinical endpoint efficacy studies, studies that show an effect on a marker reasonably likely to predict clinical benefit, or animal studies. Accelerated Approval and approval under the Animal Rule considered if Ebola infection rates do not permit direct assessment of efficacy in clinical trials, or for vaccines not being evaluated in current efficacy trials.”).

89 See World Health Org., Ebola Situation Report (Oct. 21, 2015), http://apps.who.int/iris/bitstream/10665/190067/1/ebolasitrep_21Oct2015_eng.pdf [http://perma.cc/2XU9-BT2Z].

90 See Henao-Restrepo, Ana Maria et al., Efficacy and Effectiveness of an rVSV-vectored Vaccine Expressing Ebola Surface Glycoprotein: Interim Results from the Guinea Ring Vaccination Cluster-Randomised Trial, 386 Lancet 857, 862-64 (2015)Google Scholar (describing results from an interim analysis of a trial of rVSV-ZEBOV in Guinea, West Africa); J. A. Regules et al., A Recombinant Vesicular Stomatitis Virus Ebola Vaccine—Preliminary Report, New Eng. J. Med. (Online), Apr. 1, 2015, at 2, http://www.nejm.org/doi/pdf/10.1056/NEJMoa1414216 [http://perma.cc/3CZK-ZM69] (“On the basis of the data presented here and additional clinical and preclinical data, the rVSV-ZEBOV vaccine (at the dose of 20 million PFU) was selected for inclusion in the Partnership for Research on Ebola Vaccines in Liberia trial, a recently initiated phase 3 efficacy study in Guinea, and the soon-to-be-initiated phase 3 Sierra Leone Trial to Introduce a Vaccine against Ebola.”)

91 See Joffe, Steven, Evaluating Novel Therapies During the Ebola Epidemic, 312 JAMA 1299, 1299–1300 (2014)Google Scholar (describing key considerations for conduct of clinical trials for Ebola); Kupferschmidt, Kai, As Ebola Wanes, Trials Jockey for Patients, 348 Science 20, 20 (2015)Google Scholar (“But recent successes in reining in the epidemic have created a problem for the international teams running clinical trials: Patients are becoming scarce. That creates moral and scientific quandaries—and even arguments between research teams competing for access to patients.”); Mullan, Zoe, Editorial, Ebola Vaccines: An Uncertain Future?, 3 Lancet Global Health e113, e113 (2015)Google Scholar (“[R]egulators are showing signs of flexibility in terms of accelerated licensure in the event that the waning epidemic delays the ability to demonstrate efficacy.”); Rid, Annette & Emanuel, Ezekiel J., Ethical Considerations of Experimental Interventions in the Ebola Outbreak, 384 Lancet 1896, 1898 (2014)Google Scholar (“Even if clinical trials happen during this Ebola outbreak, additional research will probably be needed in a future epidemic.”).

92 See FDA, Briefing Document: Licensure of Ebola Vaccines: Demonstration of Effectiveness 10 (May 12, 2015), http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM445819.pdf [http://perma.cc/8SKL-ERDJ] (“Preliminary data presented at a December 12, 2014, US government-sponsored workshop indicated that vaccinated humans may achieve immune responses comparable in magnitude to those associated with protection in [non-human primates], suggesting the feasibility of an immunogenicity-based approval, although the thresholds associated with protection may differ for each vaccine candidate.”).

93 See 21 C.F.R. § 314.610 (2015) (“FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when … the animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity.”).

94 21st Century Cures Act of 2015, H.R. 6, 114th Cong., § 2121 (2015).

95 See id.

96 See id.

97 See id.

98 See id.

99 In April 2016, a companion bill covering this proposal passed out of the Senate Health, Education, Labor and Pensions committee. See Zachary Brennan, Senate Committee Advances Five More Bills as Part of Medical Innovation Package, Regulatory Focus, Apr. 6, 2016, at 6, http://www.raps.org/Regulatory-Focus/News/2016/04/06/24714/Senate-Committee-Advances-Five-More-Bills-as-Part-of-Medical-Innovation-Package/ (“S. 185, Promise for Antibiotics and Therapeutics for Health Act, which requires FDA to establish a program to approve as a limited population antibacterial drug intended to treat a serious medical condition and to address an unmet medical need within an identifiable limited population, among other things.”).

100 See, e.g., Hwang, Thomas J. et al., Accelerating Innovation in Rapid Diagnostics and Targeted Antibacterials, 33 Nature Biotechnology 589, 590 (2015)Google Scholar (“[T]he FDA may need to explore other policy mechanisms to ensure that mandatory post-approval trials are completed in a timely fashion. For example, approval via the pilot program could be subject to a ‘sunset’ provision corresponding to the deadline for data submission from any post-approval studies.”).

101 FDA, supra note 70, at 3.

102 This estimate assumes that the study has 80% power to detect, at a significance level of 5%, and a survival rate of 60% in the treatment group versus 40% in the control group. Readers can run their own sample size calculations using online tools. See, e.g., Power (Sample Size) Calculators, Sealed Envelope (2016), https://www.sealedenvelope.com/power/binary-superiority/.

103 See Kevin|Outterson et al., Approval and Withdrawal of New Antibiotics and Other Antiinfectives in the U.S., 1980-2009, 41 J.L. Med. & Ethics 688, 692 (2013)Google Scholar (“Few of the withdrawn antibiotics were commercially successful (n=3, although commercial sales data were available for 1993-2009 only) and most were discontinued from the market several years before formal withdrawal.”).

104 See Hwang, Thomas J. et al., Paying for Innovation: Reimbursement Incentives for Antibiotics, Sci. Translational Med. Feb. 25, 2015Google Scholar, at 1 (“Commercial expectations play a dominant role in how companies prioritize their drug portfolios. Economic factors, such as health-insurance reimbursement levels, act as a signal to current and future drug developers seeking to determine whether the likely market for a new product will be substantial enough to justify costly investments.”); Kesselheim, Aaron S. & Outterson, Kevin, Fighting Antibiotic Resistance: Marrying New Financial Incentives to Meeting Public Health Goals, 29 Health Aff. 1689, 1689 (2010)Google Scholar (“A more rational incentive structure would promote conservation while creating a viable market for investment in antibiotic research and development. In the United States, antibiotics have traditionally been low-price products. The societal value of activities such as hospital infection control programs greatly exceeds the value placed on them by private-sector and government payers.”).