It's no secret that the landscape for developing new antibiotics poses many obstacles for drug companies, both scientific and financial.
To begin with, finding substances with novel mechanisms to combat bacterial pathogens is challenging and expensive. When scientists do identify a promising antibacterial candidate, the subsequent path to regulatory approval of new drugs is long and winding. Then, once these drugs are on the market, they are only used for only short periods.
On top of those challenges, in a time when growing resistance to the current arsenal of antibiotics has illustrated the need for prudent use of this limited resource, there is a desire to withhold new antibiotics until they are absolutely needed. The longer the drugs stay on the shelf, the longer it will take for resistance to develop.
Now, new research by a team from the University of Wisconsin (UW) has put a number on how long some hospitals are delaying the use of these new drugs.
In a study published recently in Diagnostic Microbiology and Infectious Disease, the researchers found that US hospitals on average waited more than a year to prescribe any of six new antibiotics approved by the US Food and Drug Administration (FDA) within the past 5 years.
"When you're in the field, you have a sense that the use of these drugs is delayed," said study co-author Warren Rose, PharmD, a professor in the UW-Madison School of Pharmacy, told CIDRAP News. "But to know, from our results, that it was on average more than a year, was really surprising."
Hospitals slow to use new antibiotics
For the study, Rose, co-author Lucas Schulz, PharmD, of UW Health, and colleagues examined a clinical administrative database of US medical centers from 2014 through 2018 to determine the first use of six new antimicrobials that had received qualified infectious disease product (QIDP) designation from the FDA: ceftazidime-avibactam, ceftolozane-tazobactam, dalbavancin, isavuconazole (an antifungal), oritavancin, and tedizolid.
The aim of QIDP designation, which was created by Congress in 2012 under the Generating Antibiotic Incentives Now (GAIN) Act, is to spur the development of new antibiotics for difficult-to-treat infections by granting companies that develop them an additional 5 years of marketing exclusivity. QIDP products are also eligible to be fast-tracked for approval.
"The idea is to reduce the barriers for approval, and get these drugs out into market," Rose explained.
But Rose said the sustainability of this incentive is in question given what they found in their analysis. Among the 132 hospitals that reported prescribing one of the six QIDP agents, the median number of days to use any of them was 398, with some hospitals using the new drugs within 2 weeks and others waiting more than 4 years.
Hospitals with sicker patients were quicker to use the new antimicrobials, and large hospitals (with more than 400 beds) and academic medical centers—the facilities with a more complex patient population—were more likely to use any of the QIDP agents than smaller hospitals and non-academic medical centers.
The analysis also found that hospitals in the South were quickest to use all six antimicrobials (median 733 days), while hospitals in the Northeast took the longest to use all six (median 1,370 days).
Little difference from existing treatments
Although the study did not delve into the reasons for the delay in using these new drugs, Rose says several factors are likely involved. One is cost. "Some of these drugs cost up to $1,000 a day, so that's certainly a part of it," he said. "Pharmacies have budgets."
Antibiotic stewardship is another factor. "The main issue [with stewardship] is to be able to use drugs appropriately for the patients that need them…and maybe that's leading to some of the delay," he added.
A third issue that may be causing hospitals to hesitate in using these new drugs is that many of them are broad-spectrum and aren't really novel—they're enhanced versions of currently available drugs.
"These are drugs that work against organisms that are resistant, but they’re really not anything different than what we already have," Rose said.
Brad Spellberg, MD, chief medical officer at the Los Angeles County-University of Southern California Medical Center, says cost and the lack of true novelty or superiority to older drugs are big reasons why these drugs aren't selling well.
"They're all terribly expensive, and most don't differentiate from existing treatments," Spellberg, who wasn't involved in the study, said in an email.
Take, for example, ceftazidime-avibactam, which combines a cephalosporin antibiotic that came onto the market in 1984 with a beta-lactamase inhibitor. It received QIDP designation in part because of its ability to treat multidrug-resistant pathogens, including carbapenem-resistant Enterobacteriaceae (CRE).
"Ceftazidime-avibactam is very expensive, and while it is superior to colistin when treating CRE, it is not clear that it is 30 times more effective (it is however, 30 times more expensive!)" Spellberg said. "It also competes with three other CRE-specific antibiotics on the market now (meropenem-vaborbactam, plazomicin, and eravacycline)."
There's also the fact that the population of patients with CRE or other types of multidrug-resistant infections just isn't very large. Rose and his colleagues suggest that rapid diagnostics, early identification of resistance, and clinical decision support tools may be able to better identify the patients that could benefit from these drugs.
Small companies hit hardest
The concern is that the delay in use of these new drugs has a significant financial impact on the companies that are making them. With many of the large pharmaceutical companies having abandoned the antibiotic development market, that space is now being filled by smaller companies that don't have the financial wherewithal to develop products that fail to produce a significant return on investment.
An example is Achaogen, a biopharmaceutical that recently filed for bankruptcy, only 10 months after the FDA approved its antibiotic plazomicin.
"A lot of new, novel drugs are coming from smaller companies, and that's problematic, because they have no capital outside of pre-development funding," Rose said.
Rose isn't sure what the answer is, but he says the growing conversation around "pull" incentives, which would aim to provide companies with better return-on-investment for novel, critically needed antibiotics, is encouraging. "There's some talk in the industry about…providing some backing for these companies until they can maintain a profit or become stable," he said. "I hope [our study] provides some data for how long we need to think about these things."
Along those lines, a bill recently introduced in Congress—the DISARM (Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms) Act—calls for higher Medicare reimbursement for new antibiotics that treat serious or life-threatening infections, while also requiring hospitals that receive the increased payments to monitor their use and establish stewardship programs.
"By improving critical Medicare reimbursement for antibiotics and promoting their appropriate use, the legislation has the potential to stabilize the antibiotics market, spur the development of new infection-fighting drugs, and preserve the effectiveness of existing medicines," the Infectious Diseases Society of America (IDSA) said in a recent statement about the bill.
Other proposed strategies for supporting antibiotic development include a $1 billion market entry reward for developing a novel antibiotic that addresses a defined public health need.
But in a recent paper published in the New England Journal of Medicine (NEJM), Spellberg and co-authors from the University of California, Los Angeles; Loyola University Chicago; Johns Hopkins University; and Oregon Health & Science University argue that relying on financial incentives to prop up antibiotic development is unsustainable. They argue instead that the solution might lie in nonprofit organizations, which don't face shareholder pressure to generate continuous revenue growth.
"Nonprofit organizations could bring antibiotics to the market themselves, or they could license or sell compounds that have been through initial testing or early-stage clinical trials to for-profit partners that could then carry such products through late-stage development," they write.
Spellberg believes the NEJM paper starts a much-needed conversation about how we should approach antibiotic development. "A fundamental transformation in our discovery and development process for new antibiotics is required," he said.
See also:
Jun 22 Diagn Microbiol Infect Dis abstract
Jun 19 N Engl J Med paper on nonprofit antibiotic development
Apr 16 CIDRAP News story "Achaogen bankruptcy raises worry over antibiotic pipeline"
Jun 12 IDSA statement on DISARM Act
