The effect of generic market entry on antibiotic prescriptions in the United States

Might static consumption of antibiotics upon generic entry require new policies to ensure predictable supply?

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Effective antibiotics are a part of the foundation of modern medicine, not only treating infections but also enabling surgeries and cancer treatments. Antibiotic resistance threatens this foundation but can be hindered through effective infection prevention and control and antibiotic stewardship. Done well, these can allow countries to continually use older antibiotics. For example, the most commonly used antibiotics in Scandinavian countries are narrow-spectrum penicillins, developed in the 1940s. Yet bacteria will always evolve, including resistance mechanisms to antibiotics. Therefore, innovation also plays an important role to ensure that multi-drug resistant infections can be treated.

Antibiotic innovation is struggling, with no new antibiotic classes discovered since the 1980s. In a recent assessment, the World Health Organization (WHO) concluded that “the clinical pipeline and recently approved antibiotics are insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.” The primary reason is that the economics are unattractive. Since the development of resistance is hastened with use, new antibiotics are saved as a last resort, translating to minimal unit sales. For complex reasons, new antibiotics cannot charge high unit prices. The result is that large pharmaceutical companies have largely exited the therapeutic space, and small companies are struggling to cover their operational expenses. Four small companies with marketed antibiotics have gone bankrupt in the last two years.

This paper is a part of the DRIVE-AB research project, supported by the Innovative Medicines Initiative, a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. DRIVE-AB was tasked with developing new economic models designed to stimulate antibiotic innovation, while ensuring appropriate use and access. Our article, the effect of generic market entry on antibiotic prescriptions in the United States, is an important contribution to this research, since economic incentives have primarily focused on the monopoly time period, but appropriate and continued access is critical beyond the generic transition.

Previous research on the impact of generic entry on antibiotic use is inconsistent, often looking at only one antibiotic or one antibiotic class, in some cases arguing that generics caused significant increases in both use and resistance. Yet antibiotics are diverse. Depending on target pathogen, formulation, and health care setting, the effect of generic entry would likely differ. As such, we were uncertain of the merits of generalizing these findings. Therefore, we decided to include all antibiotics that transitioned to generic status in the US between 2000 and 2012, acquiring the monthly prescription data. Out of 13 antibiotics that were included in the study, five showed significant increases in use within two years after generic entry, one showed a significant decrease, and seven experienced no significant changes. Two of the five with increases, ciprofloxacin and levofloxacin, represented negative prescription trends that turned positive after generic entry, while the other three represented trends that eventually levelled out.

Our findings suggest that generic entry has limited and inconsistent effects on antibiotic use in the United States. The reason for increasing levels of antibiotic prescriptions (and thereby use) and resistance is multifactorial and complex, and models should not assume that generic entry will automatically increase antibiotic prescriptions. However, fluoroquinolones stood out by representing three of the five antibiotics that showed a significant increase. This was surprising since FDA had issued label warnings for this class, and CDC recommended reduced use due to high levels of resistance.

Since there could be other factors impacting our findings, we searched for potential events, drawing from the combined experience of the members of our research team including medicine, pharmacology, economics, and law. We found that the anthrax attacks had occurred in the same timeframe that ciprofloxacin became available as a generic, which at the time was the only antibiotic approved for anthrax. The US reacted to the attacks by stockpiling ciprofloxacin, which likely contributed to its change in use.

This study has implications for future policymaking. DRIVE-AB and others recommended delinked incentives for new antibiotics, meaning that new and important antibiotics should be rewarded for their accessibility and not their consumption. This study demonstrates that this strategy may also be necessary for generic antibiotics. Shortages of older antibiotics are common, which often necessitate doctors to use broad-spectrum antibiotics instead of the preferable narrow-spectrum ones. Six of our studied antibiotics are included in WHO’s Essential Medicines List: azithromycin, cefuroxime, ciprofloxacin, clarithromycin, meropenem, and piperacillin/tazobactam. Yet only one of these antibiotics, ciprofloxacin, saw an increased consumption after generic transition, and this may have been due to stockpiling efforts. It is desirable from a supply resilience perspective that multiple generic manufacturers produce each antibiotic. In this way, unexpected production problems at one factory will not impact global supply. For this to be successful, generic manufacturers must receive revenues commensurate with their expectations. If not, accessibility may be in jeopardy, unless countries are willing to invest in generic production to cover their own need. Indeed, one of our studied antibiotics, piperacillin/tazobactam, has experienced frequent shortages as a generic medicine. In 2017 a fire at one factory manufacturing its active pharmaceutical ingredients resulted in a global shortage.

Our study only assessed consumption in the US, but other studies have demonstrated that access to important new antibiotics is often delayed in other countries, especially low and middle-income countries. In addition, more people die from lack of access to effective antibiotics than from antibiotic resistance, again, primarily in low and middle-income countries. If antibiotic consumption of important antibiotics in high-income countries remains relatively static (as is desirable to hinder the development of resistance), it may result in an insufficient generic supply of the antibiotic globally. Affordable and accessible generics are necessary to effectively treat patients. New policies may be needed to maintain a predictable supply of important, generic antibiotics.

Cecilia Kållberg

MD, Norwegian Institute of Public Health