Have we made progress in the 10 X' 20 Initative?

At least 2 million people are infected with antibiotic-resistant bacteria, and more than 35,900 die each year in the United States, costing over $20 billion per year. Combating this evolving threat requires multiple stakeholders working together via a One Health approach. Antibiotics make procedures including joint replacement, transplantation, cancer chemotherapy, and premature newborn care possible. Recent reports have warned of the dangerously failing antibiotic pipeline; on January 18, the World Health Organization issued an unprecedented warning, declaring that “only government intervention can fix the broken market for antimicrobial drugs.”¹

The Infectious Diseases Society of America (IDSA) has worked since 2002 to sound the alarm about the antimi­crobial resistance crisis and the need for progress in devel­oping medicines to treat resistant infections. The 2004 report “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates…a Public Health Crisis Brews” proposed legislative, regulatory, and funding solutions.² IDSA then published an update on the concerning status of the development pipeline and a call to action from the medical community.³ Major pharmaceutical companies left the antibiotics space, and most research and development work moved to small biotech companies with limited capacity and budgets. Leaders reported difficulty in securing funding for antibiotic development because the return on investment was low.^4,5

In 2010, IDSA issued a call for 10 new efficacious and safe antibacterial agents by the year 2020.⁶ With 14 new systemically available antibiotics becoming available from 2010 to 2019, IDSA’s 10×’20 goal was achieved (Figure). However, these medications are entering a failing market. Achaogen filed for bankruptcy protection in April 2019, shortly after the US Food and Drug Administration (FDA) approval of their drug, sending a chill across the antibiotic marketplace. Limited use and poor reimbursement, as well as the cost of maintaining the supply chain and mandatory postapproval work, were cited as contributing causes. In June 2019, a foreign company purchased Achaogen’s assets for $16 million, and Tetraphase Pharmaceuticals announced significant layoffs. In December 2019, Melinta Therapeutics declared bankruptcy, bringing the total to 4 recently FDA-approved antibiotics in jeopardy.⁷

Reasons for the broken market are complex and include the relatively low price of antibiotics and delayed uptake of newly approved antimicrobials, as well as the fact that they are held in reserve in the interest of good steward­ship and preserving efficacy. IDSA leaders and others have called for a rapid “fix” of the broken antibiotic market via pull incentives, in addition to addressing delayed uptake and the other areas of policy work and advocacy already advancing.^7-9

Prior to the bankruptcies of Achaogen and Melinta, stakeholders worked to advance policy and regulatory solutions. Accomplishments included the 2012 Generating Antibiotic Incentives Now (GAIN) Act, an important first step toward support of antibiotic research and develop­ment. GAIN granted an additional 5 years of exclusivity to new antibiotics and antifungals that treat serious or life-threatening infections. The 21st Century Cures Act established the Limited Population Antibacterial Drug (LPAD) pathway in 2016. Under LPAD, such antibiotics can be studied in smaller, more rapid clinical trials.10 Paired with these efforts were measures to preserve and optimally use the few available antibiotics via antibiotic stewardship and optimize infection prevention and surveillance.¹⁰

At the same time, efforts were made to facilitate study of drugs for resistant pathogens, narrow-spectrum indica­tions, and unmet medical needs.¹⁰ To date, it has proved difficult for new antibiotics to achieve indications for MDR organisms. IDSA is working closely with other orga­nizations and the federal government on initiatives to streamline clinical trials for agents that treat serious or life-threatening infections.¹¹ This collaboration also led to progress in incentives for antibiotic development, including push incentives such as the Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH) and the public-private partnership Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), both of which have significantly stimulated discovery and early-phase development.¹² We now have evidence of promise in the antimicrobial discovery pipe­line: CARB-X lists 36 early-development programs, including drugs, vaccines, and nontraditional therapies in early clinical trials and diagnostic tests being developed. Many of these target novel mechanisms of action, and all have potential to treat antimicrobial-resistant pathogens.¹²

Delayed uptake of new antibiotics has been cited as a multifaceted issue contrib­uting to the broken market.^13,14 At the recent FDA-IDSA-NIH-Pew Public Workshop, there was a call for improved sharing of clinical data on drug performance in patients with drug-resistant infections so physicians would be better informed.14 Even if data are deemed insufficient for a label indication, clini­cians called for including them in the FDA package insert, making clear the limits on data generation.¹⁴

At the same time, clinicians must under­stand the power of standard FDA indications. Modern noninferiority studies are powerful tools; they detect inferior agents, provide clear safety and efficacy comparisons, facilitate initial FDA approval, and provide a basis for additional indications in more severe infec­tions. Goals of future work include better use of other data that are available or can be readily obtained; learning to “borrow” data across indications, using different thresholds for different settings; and applying patient-oriented outcome measures.¹⁴

Antimicrobial stewardship programs provide “coordinated interventions designed to improve and measure the appropriate use of antibi­otic agents by promoting the selection of the optimal antibiotic drug regimen including dosing, duration of therapy, and route of administration.”¹⁵ Benefits of antibiotic stew­ardship include improved patient outcomes, reduced adverse events, and optimized resource use. Successful stewardship programs often help save money, but cost savings are not included in official definitions. Vickers et al and others have suggested that an unintended consequence of some stewardship programs may be focusing too much on cost savings and thereby discouraging appropriate use of newly FDA-approved antimicrobial agents.¹³

Delayed publication of pivotal trials and updating of guidelines, as well as failure to update antimicrobial susceptibility break­points, also contribute to delayed uptake of newly approved antimicrobial agents.^13,16 In addition, failure to update breakpoints can affect uptake of new agents. In the case of colistin, an old and toxic drug, breakpoints had not been updated in years. Recently, the Clinical & Laboratory Standards Institute updated colistin breakpoints for key gram-negative pathogens. As a result, virtually all resistant gram-negative pathogens now test as colistin intermediately susceptible or resistant.¹⁷

Finally, fixing the broken market will require financial incentives. IDSA supports robust, predictable, and understandable incentives that target areas of greatest unmet need and align fully with principles of antibiotic stewardship and appropriate access. Incentives including reimbursement reform and market entry rewards seem to have gained the most trac­tion to date. Importantly, both of these unlink the incentive from sales of antibiotics, thereby supporting stewardship and avoiding overuse.

In August 2019, CMS released its final Hospital Inpatient Prospective Payment System rule for fiscal year 2020.¹⁸ It includes an increase in the Medicare bundled payment (also known as Diagnosis Related Group, or DRG) severity level designation for the diagnosis codes that specify antimicrobial drug resistance, which should result in higher Medicare payments to the hospital for these cases, hopefully allowing the use of newer, costlier drugs when neces­sary. The rule also provides for an increase in the new technology add-on payment (NTAP) and automatically considers all qualified infec­tious diseases product antibiotics as meeting the substantial clinical improvement criterion. This makes it easier for antibiotics to qualify for NTAP, but many hospitals still find the associ­ated administrative burden too great and do not seek these payments except in cases of very costly drugs or devices (not antibiotics).

The bipartisan Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act was introduced in the House and Senate in 2019. This bill would carve new antibiotics that treat serious or life-threatening infections out of the DRG and pay for them separately to boost their reimbursement, require hospitals to establish antibiotic stewardship programs that align with US Centers for Disease Control and Prevention recommendations, and require hospitals to report antibiotic use and resistance data to the CDC. The goal is to help ensure that patients can access new antibiotics when necessary, as well as stabilize the antibiotics market for developers and ensure that these precious resources are used in the best way possible.

Although reimbursement reform and the proposed DISARM Act are encouraging first steps, salvaging the antibiotic research and devel­opment infrastructure will require more. Long-term solutions such as market entry rewards are gaining traction but require further work. The time is now for clinicians to be the voice for patients, telling patients’ stories and urging action. Advocate for prompt publishing of data and updating of guidelines and for availability of new drugs. Most of all, reach out to legislators in support of DISARM and get colleagues involved. Antimicrobial resistance affects us all, and we each have a role in responding to the crisis.

Boucher is chief of the Division of Geographic Medicine and Infectious Diseases and director of the Tufts Center for Integrated Management of Antimicrobial Resistance.

References

1. Jacobs A. WHO Warns That Pipeline for New Antibiotics Is Running Dry. New York Times. 1-17-20 https://www.nytimes.com/2020/01/17/health/antibiotics-resistance-new-drugs.html

2. America IDSA. Bad Bugs, No Drugs: As Antibiotic R&D Stagnates A Public Health Crisis Brews. IDSA. 6-04. https://www.idsociety.org/ 1-37.

3. Spellberg B, Guidos R, Gilbert D, et al. The Epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(2):155-164. doi: 10.1086/524891.

4. Boucher HW, Talbot GH, Benjamin DK, Jr., et al. 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(12):1685-1694. doi: 10.1093/cid/cit152

5. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12.doi: 10.1086/595011.

6. Talbot GH, Jezek A, Murray BE, et al. The Infectious Diseases Society of America's 10 x '20 initiative (Ten new systemic antibacterial agents FDA-approved by 2020): Is 20 x '20 a possibility? Clin Infect Dis. 2019. Jun 18;69(1):1-11. doi: 10.1093/cid/ciz089.

7. Jacobs A. Crisis Looms in Antibiotics as Drug Makers Go Bankrupt. The New York Times. 12-25-19. https://www.nytimes.com/2019/12/25/health/antibiotics-new-resistance.html

8. Outterson K, Boucher HW. Medicare payment rules hinder the fight against superbugs. STAT. 4-17-19. https://www.statnews.com/2019/04/17/medicare-payment-antibiotics-hinder-superbug-fight/

9. IDSA, Spellberg B, Blaser M, et al. Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52 Suppl 5:S397-428. doi: 10.1093/cid/cir153.

10. Boucher HW, Ambrose PG, Chambers HF, et al. White Paper: Developing Antimicrobial Drugs for Resistant Pathogens, Narrow-Spectrum Indications, and Unmet Needs. J Infect Dis. 2017;216(2):228-236. doi: 10.1093/infdis/jix211.

11. Administration USFD. Enhancing the Clinical Trial Enterprise for Antibacterial Drug Development in the United States. 11-18-19. www.fda.gov/news-events

12. CARB-X Antibacterial Treatment and Prevention Product Portfolio. 02-18-20.

13. Vickers RJ, Bassetti M, Clancy CJ, et al. Combating resistance while maintaining innovation: the future of antimicrobial stewardship. Future Microbiol. 2019;14:1331-1341. doi: 0.2217/fmb-2019-0227.

14. Rex JH, FDA-IDSA-NIH-Pew. A Pivotal Point in Time: What Do We Need, What Should We Be Doing, Who Should Be Doing It? 11-19-19.

15. Fishman, N. Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infection Control & Hospital Epidemiology 2019; 33(4), 322-327. doi:10.1086/665010

16. Clancy CJ, Potoski BA, Buehrle D, Nguyen MH. Estimating the treatment of carbapenem-resistant Enterobacteriaceae infections in the United States using antibiotic prescription data. Open Forum Infect Dis. 2019;6(8):ofz344.doi: https://doi.org/10.1093/ofid/ofz344

17. Hindler JA, Schuetz AN. CLSI Subcommittee on Antimicrobial Susceptibility Testing

CLSI AST News Update. CLSI. 2018;3(2):1-19.

18. Fiscal Year (FY) 2020 Medicare Hospital Inpatient Prospective Payment System (IPPS) and Long Term Acute Care Hospital (LTCH) Prospective Payment System (CMS-1716-F) CMSgov. 8-2-19.