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Leveraging Novel and Existing Pathways to Approve New Therapeutics to Treat Serious Drug-Resistant Infections

Published online by Cambridge University Press:  06 January 2021

Thomas J. Hwang  and
Aaron S. Kesselheim
Thomas J. Hwang*
Affiliation:
Harvard University, and Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
Aaron S. Kesselheim
Affiliation:
Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
*
Email: tjhwang@post.harvard.edu
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Abstract

Accelerating the development and approval of novel therapeutics has emerged as a key public health priority given the mortality, morbidity, and economic costs associated with infections caused by drug-resistant bacteria. However, there is limited empirical evidence to guide policymaking, such as the factors that may disadvantage antibiotics compared to other classes of drugs. In this Article, we empirically examine characteristics of the key clinical trials underpinning FDA's approval of antibiotics and other drugs over the past decade. Despite perceptions that antibiotic trials are larger and more difficult to conduct, we find that antibiotic trials are no larger than those conducted for drugs approved in other disease areas with high unmet medical needs, suggesting that policymakers may need to target other levers to meaningfully stimulate innovation. We discuss the risks and benefits of harnessing new and existing regulatory pathways to speed the approval of new drugs, particularly those intended to treat patients with serious and life-threatening infections, and we evaluate ways that proposals for new regulatory pathways could be improved to better prioritize and expedite the approval of therapies with the greatest potential for patient health benefits.

Type
Articles
Information
American Journal of Law & Medicine , Volume 42 , Issue 2-3: Global Infectious Diseases: New Challenges and Solutions , May 2016 , pp. 429 - 450
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2016

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15 Id.

16 Id.

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18 Id.

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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.

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33 See id.

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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].

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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.”).