Exploring the antibiotic commercial conundrum. ​
Numerous reports have been published on the rising tide of antibiotic resistance across the globe. Most recently the US Centers for Disease Control and Prevention (CDC) released the 2019 update of its comprehensive report, Antibiotic Resistance in the United States. The report, last updated in 2013, highlights the challenges of infectious diseases surveillance. The publication also emphasizes the severe underestimation of resistance rates and dire consequences, pointing to the fact that in the United States 2.8 million individuals have an infection due to a resistant pathogen and 35,000 people die each year in the US alone.
Although the CDC reports that the post-antibiotic era may already be here, it cannot be ignored that despite the numerous challenges to commercialize new antibiotics, industry has responded. In the early years of this millennium we saw a continued exodus from antibiotic development and a depleted pipeline. However, in the last decade, 12 new intravenous antibiotics were approved in the United States. Clearly, we can’t declare victory. Ongoing research and significant investments are needed to address the challenges with Acinetobacter infections, metallo-beta-lactamase-producing pathogens, Mycobacterium, and the ever-evolving resistance profiles of existing treatment options.
Despite remaining challenges, it should be recognized that meaningful advances have been made. In 2015 there were no viable treatment options for carbapenem-resistant Enterobacteriaceae (CRE), an urgent health threat referenced in the CDC’s report. Today, we have 6 new agents with activity against these challenging pathogens. Several studies have since demonstrated a significant improvement in mortality rates with these new options. These meaningful advances should grab the headlines and encourage responsible use.
In any other therapeutic area where significant advances are made that improve survival, investments would be made, company stock prices would go up, and the mainstream media would report on it. Unfortunately, in infectious disease we miss these reports and continue to read about the rising tide of resistance rather than the significant developments that are being made to combat today’s challenges.
Are we really in a post-antibiotic era or are new agents just not being used?
This is the antibiotic commercial conundrum.
If industry develops a mediocre antibiotic, it won’t be used, but a very good antibiotic won’t be used either. This occurs because antibiotics are reserved as a resistance-prevention measure or use is restricted because of cost concerns. Antibiotic developers understand that a new antibiotic is not for everybody with an infection, however it cannot be that the new antibiotic is for nobody—that the older generic antibiotics remain good enough.
It has been accepted that volume-based revenues are not in the best interest of sustained use and long-term effectiveness. However, many studies have demonstrated the negative consequences of delayed appropriate therapy. In an era of antibiotic stewardship, these programs should focus on providing direction and recommendations regarding where new antibiotics should be used versus where they can’t be used (restricting), educate on the appropriate use on newer and older generic agents, and provide access to patients that need them. Stewardship programs that have included diagnostic stewardship and risk stratification tools have made meaningful impact on outcomes such as reduced time to cure and length of stay. Collaboration between healthcare providers, regulatory agencies, and industry in providing early meaningful data on the deployment of new antibiotics for the patients they are intended to be used for may further help direct appropriate use and adoption.
In a recent study, investigators evaluated the use of antibiotics for CRE infections and found that, despite the widely recognized limitation of polymyxins, they were used preferentially over newer CRE active agents and just recently, 5 years after the introduction, these new CRE active antibiotics surpass the use of polymyxins. Schulz et al. reported in a comprehensive survey that on average hospitals take 1-2 years to use a new antibiotic. When we continue to read of superbugs threatening our society, this is extremely surprising. Additionally, they reported that new antibiotics are used more frequently off label, which may imply that their use is not based on the promotional activity but based on a true unmet medical need.
As a result, of all the antibiotics approved in the last 10 years, only 2 will have an annual revenue over $100 million in 2019. The development of a new antibiotic would cost between $800 million and $1 billion. You don’t need a comprehensive net present value model to understand that this is a losing proposition and companies are struggling to survive.
Push incentives have certainly had a positive impact on the antibiotic pipelines; however, it is evident that getting a development program to completion is not enough and getting these large investments to ultimately reach patients remains challenging. Achaogen’s and Melinta's fates are the most recent examples and we can only hope that other companies find a way to survive.
The investment community is challenged to support the therapeutic area when launch uptake and peak year revenues are struggling to reach healthy returns. There is no doubt that this will lead to a return of the time where pipelines are depleted, and research support is shifted again to different therapeutic areas.
A recent meeting with an assembly of stakeholders, including the US Food and Drug Administration, the Infectious Diseases Society of America, Pew Charitable Trusts, Combatting Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, and the National Institutes of Health, made a serious attempt to address this issue. The stakeholders asserted that non-inferiority studies do provide valuable data, other data sources have impact, and updates to guidelines need be more frequent, among many other things. The Centers for Medicare and Medicaid’s final rule on reimbursement changes for new antibiotics are commendable and proposed legislation can further remove barriers and improve the economic viability of new antibiotics, but more needs to be done. No more finger pointing. Volume is already decoupled from revenue. Now, healthcare professionals should be empowered with data to use new antibiotics to provide the best care for patients who need them most, without fear of financial repercussions.
Wagenaar is a senior marketing executive with 25 years of launch and commercialization experience in antibiotic and antifungal marketing of numerous brands in the US.