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Drug-resistant bacteria, or superbugs, present a serious and worsening threat to human health. According to a report from the Centers for Disease Control and Prevention, 2 million Americans acquire serious infections caused by antibiotic-resistant bacteria each year, and 23,000 of them die as a result. Doctors routinely encounter patients with infections that do not respond to available treatment, and when new drugs come to market, bacteria can quickly develop resistance. To ensure that the supply of new antibiotics keeps pace with these evolving pathogens, it is necessary to have a robust pipeline of new drugs and innovative pathways to bring this medicine to the patients who need it most.
Developing new drugs involves a great deal of time, effort, scientific research, and expense. Historical data show that, generally, only 1 out of 5 drugs that reach the initial phase of testing in humans will receive approval from the Food and Drug Administration. Developing antibiotics to treat highly resistant bacterial infections is especially challenging, because only a small number of patients contract these infections and meet the requirements to participate in traditional clinical trials.
To shed light on the antibiotic pipeline, evaluate public policies, and monitor the potential impact on public health, The Pew Charitable Trusts has assessed antibiotics currently in clinical development. The list, which is updated regularly, identifies each drug, manufacturer, potential targets, and stage in the development process. (See the methodology for the criteria used to select the drugs.)
The current assessment of the pipeline shows 42 new antibiotics in development. These drugs would potentially address many, but not all, resistant bacteria. However, given the inevitability that some of these antibiotics will fail to win approval, it is clear that there are too few drugs in development to meet current and anticipated patient needs. As of June 2018:
- Of the 42 antibiotics in development, 15 were in Phase 1 clinical trials, 12 in Phase 2, 11 in Phase 3, and four have had new drug applications submitted. Two drugs had been approved by the FDA since Pew’s last analysis. Historically, about 60 percent of drugs that enter Phase 3 will be approved. (See the glossary of terms for descriptions of each phase.)
- At least 17 of the antibiotics in clinical development have the potential to treat infections caused by Gram-negative ESKAPE pathogens—a critical area of unmet need. Infections caused by these pathogens are not only difficult to treat, but finding new therapies to overcome Gram-negative resistance is also particularly challenging. And of these, at least 11 have potential activity against carbapenem-resistant Enterobacteriacae, Acinetobacter baumannii, and Pseudomonas aeruginosa, pathogens the World Health Organization considers critical threats because they are resistant to all or nearly all of the antibiotics available today.
- Additionally, at least eight of the antibiotics, if approved, could address infections caused by Neisseria gonorrhoeae or Clostridium difficile, both considered an urgent threat to public health by the CDC.
- Fewer than 1 in 4 drugs in the pipeline represent a novel drug class or mechanism of action. Only one is potentially active against Gram-negative ESKAPE pathogens or WHO critical threat pathogens, and almost a third of the novel products are in development for C. difficile.
- Of the 39 or so companies with antibiotics in clinical development, only five rank among the top 50 pharmaceutical companies by sales. Over 80 percent of the products in development today are being studied by small companies rather than the large pharmaceutical firms that once dominated this field. Additionally, roughly half of the companies are considered pre-revenue, meaning that they have no products on the market.
Pew and other organizations studying the issue of antibiotic resistance advocate for policies that address scientific, regulatory, and economic challenges to the development of new antibiotics. These efforts aim to keep the pipeline primed with a variety of potential treatments that have the best chance of making it to patients.
Pew supported approval of the Generating Antibiotic Incentives Now (GAIN) Act to stimulate the development of new antibiotics. The law increased the commercial value of antibiotics intended for serious or life-threatening infections by extending the period during which the drugs can be sold without competition from generic drugs by five years. Drugs that benefit from GAIN are now in the antibiotic pipeline.
A recent development is the limited-population antibacterial drug pathway (LPAD) authorized in the 21st Century Cures Act, which will provide a unique mechanism for FDA to review and approve new antibiotics specifically for use in patients with unmet medical needs. This process will make the development of the most needed antibiotics more feasible while maintaining FDA standards for safety and effectiveness.
A strong pipeline also requires focused efforts to boost basic scientific research and encourage cooperation between academia and industry. Pew is working with key stakeholders to identify ways to effectively address top scientific priorities for the discovery of new antibiotics. To address a key challenge, Pew launched the Shared Platform for Antibiotic Research and Knowledge (SPARK), a cloud-based, virtual laboratory that enables scientists to share data and insights, learn from past research, and generate new insights into how molecules enter and stay inside Gram-negative bacteria.
An initial list of antibiotics in clinical development was provided by Citeline Inc.’s Pharmaprojects pipeline drug intelligence service.
The pipeline includes antibiotics intended to treat serious infections that act systemically, or throughout the body, but excludes locally acting drugs such as topical, ophthalmic, and inhaled products. It also does not include biological products, vaccines, new indications or different formulations for previously approved drugs, and drugs used to treat mycobacterial infections such as tuberculosis, Mycobacterium avium complex, Helicobacter pylori, and biothreat pathogens.
Also included in the pipeline are treatments for C. difficile infections, many of which act locally in the intestines. C. difficile is often the consequence of systemic antibiotic use, and, while these bacteria are not yet widely resistant to antibiotics, the CDC considers this pathogen an urgent threat. Thousands of Americans contract the illness each year, and an estimated 15,000 die as a result.
Pew supplemented the data provided by Citeline with other public information—specifically, trials registered in government clinical trial registries (United States, https://www.clinicaltrials.gov, Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, European Union Clinical Trials Register, https://www.clinicaltrialsregister.eu, Japan Pharmaceutical Information Center, http://www.clinicaltrials.jp), posters and presentations presented at conferences, articles published in scientific literature or trade press, and company communications. Pew also works with external experts who advise on certain determinations, such as the potential impact of drug candidates on resistant Gram-negative pathogens.
This pipeline will be updated biannually, beginning with the March 2015 update. With the September 2017 update, the pipeline was expanded to include global development of antibiotics. To submit additions, updates, or comments, please contact [email protected].
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