FDA’s New Antibiotic Guidance: A Flexible Pathway for Urgent Therapies

Antibiotic-resistant bacteria are a significant public health challenge, with nearly three million infections and 35,000 resulting deaths reported annually in the United States (U.S.).¹ To help address this growing problem, in June 2025, the FDA issued finalized guidance on developing new antibacterial therapies for patients with unmet medical needs. The guidance, titled “Antibacterial Therapies for Patients with an Unmet Medical Need for the Treatment of Serious Bacterial Diseases – Questions and Answers,”² is a strategic response to a growing public health crisis in which common infections can turn deadly when existing antibiotics fail. It signals a shift in how such infections are approached. Initially released as a draft in 2022, the guidance lays out a flexible framework for developing and approving new antibacterial treatments for patients who have no effective options left. The core concept of the guidance is simple: if a therapy targets a serious bacterial disease with no current cure, the FDA is willing to be flexible to bring that therapy to patients faster, while still ensuring its safety and efficacy.

As outlined in the guidance, new antibacterial therapies should be aimed at serious, life-threatening infections for which standard antibiotics have failed or would likely fail. The therapy should also offer something new in the fight against resistance. For example, a novel antibiotic that evades known resistance mechanisms would qualify. Notably, narrow-spectrum drugs that may kill only one or a few species of bacteria are also acceptable under this guidance. Such precision may be advantageous in certain cases.

Importantly, the FDA will apply these special flexibilities only when the product is being developed for use in patients at significant risk because existing treatments are ineffective. Sponsors need to clearly justify the unmet need. For example, by using data to show how poor outcomes are with current care, researchers open the door to a more streamlined development and approval process.

Streamlining Development

For therapies that meet these criteria, the FDA’s guidance outlines several ways to accelerate clinical development and review. The goal is to gather enough evidence to approve the drug as efficiently as possible, given the urgent need. The flexibilities highlighted by the guidance include:

• Smaller (or single) clinical trials: The guidance underscores that in cases of urgent need, the FDA is willing to consider approving a drug based on much smaller trials than usual. In fact, the guidance says even a single pivotal study might suffice if it provides compelling evidence. This is a departure from the norm. Yet enrolling thousands of patients with serious drug-resistant infections is impractical, and waiting years to accumulate data could cost lives. The approach outlined in the guidance is exemplified by Xacduro®, which was approved by the FDA in 2023 to treat highly resistant Acinetobacter baumanniiinfections based largely on a single trial of about 180 participants.³
• Flexible trial designs: In the guidance, the FDA is also encouraging sponsors to be creative in how they approach trials for these products, emphasizing flexibility in trial design. For example, rather than running separate trials for pneumonia, sepsis, and urinary tract infections caused by a single bacterial species, sponsors can conduct one combined trial encompassing patients with any of those infections. The FDA even discusses using nested trial designs, where one part of a study is designed to demonstrate non-inferiority to existing treatments in a general population, and another part of the study is designed to show that the new drug works better specifically in patients with resistant infections. The importance of using and/or developing rapid diagnostic tests is also highlighted in the guidance, particularly in the context of pathogen-specific treatments.
• Relaxed efficacy benchmarks: In many antibiotic trials, the goal is to show the new drug is non-inferior to an existing one, generally within a tight margin of approximately 10%.⁴ But for unmet needs, the guidance indicates the FDA may accept a wider margin when comparing the new therapy to an existing treatment. The FDA recognizes that a small trade-off in efficacy is acceptable if the new drug works in patients for whom existing drugs do not. For example, the Xacduro® trial noted above was allowed a 20% margin on mortality, with the understanding that being slightly less effective in a mixed patient group is acceptable if the drug is addressing a critical gap in a subset of otherwise untreatable patients.⁵
• Use of external or historical control data: When a standard randomized controlled trial is unfeasible, the FDA is open to using other sources of evidence to support approval. For example, if a trial cannot have a placebo arm because giving someone with a life-threatening infection a placebo would be unethical, sponsors could compare the outcomes of patients on the new drug to historical data from similar patients. Real-world evidence (RWE) or registry data might also be considered, in line with the FDA’s broader acceptance of RWE in other areas.
• Iterative development: The FDA also encourages an adaptive, learning-oriented approach to development under this guidance. Sponsors are urged to start a dialogue with the agency early and adjust their plans as new data is generated, rather than following a rigid pre-set road map. An initial small study showing promise might be expanded, or the drug could even receive a form of early approval with requirements to gather more evidence afterward. For example, the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) offers an additional approval pathway.⁶

Ensuring Evidence and Safety

With these streamlined, flexible development pathways come equally important measures to ensure that the evidence is sound and that research participants are protected. The FDA’s guidance emphasizes several points about supporting evidence and safety oversight:

• Strong lab and animal data: When human data is limited, preclinical data becomes even more crucial. Accordingly, the FDA expects a robust package of laboratory and animal research to support the therapy before it is tested or approved for use in humans. This means developers should show a combination of in vitro evidence that the new drug reliably kills target bacteria and use animal infection models to demonstrate efficacy in a living organism. These studies should be designed based on an understanding of how the new therapy works and how bacteria might become resistant to it to inform longer-term risks.
• Pharmacokinetics/pharmacodynamics and dose optimization: In addition to efficacy assessments, pharmacokinetic/pharmacodynamic (PK/PD) analyses help ensure that the dose level and treatment regimen chosen for the trial are optimal. While larger drug development programs may test multiple dose levels and/or dosing schedules, smaller programs for new targeted antibiotics do not have that luxury. The FDA will therefore expect thorough PK/PD modeling based on animal data and any early human data to justify the proposed dose.
• Safety measures and follow-up: In the guidance, the FDA acknowledges that with fewer patients studied pre-approval, there is a chance that some risks will not be evident until later. To manage this, the FDA may put special safety oversight measures in place. This could involve requiring post-marketing studies to continue evaluating safety and effectiveness in a larger or more diverse population. Use of the drug may also be restricted initially. Under the LPAD pathway, for instance, a drug’s labeling will clearly state that it is only for a specific limited group of patients, and physicians are expected to prescribe it only for those individuals. In practice, this might mean the drug is primarily distributed to hospitals or specialists where such high-need patients are treated. The FDA might also implement a Risk Evaluation and Mitigation Strategy (REMS) for certain products. The REMS could require prescribers to undergo training or certification, patients to sign an informed consent, or pharmacies to verify certain criteria before dispensing the drug.⁷

These steps collectively ensure that even as the FDA facilitates a faster path to approval, it is not losing sight of patient safety. The agency still demands that the benefits outweigh the risks, even if the evidence comes from a more patchworked quilt of data sources. And it has mechanisms to keep collecting data and protecting patients after the drug hits the market.

A Balanced Path Forward

The new guidance represents a significant shift for the FDA that could have far-reaching implications for public health. By balancing the urgent need for new antibiotics with caution and scientific rigor, the FDA aims to bring lifesaving antibiotics to patients faster without sacrificing safety. For patients and clinicians, the impact is straightforward: when facing an infection that no existing drug can cure, there is now a better chance that an innovative treatment will be available in the future. For drug developers and researchers, the message of flexibility and collaboration from the FDA is encouraging: the agency is showing its willingness to think outside the box and collaborate with sponsors on innovative trial designs and endpoints to facilitate the development of effective new treatments.

With an emphasis on preclinical data, flexibility, and safety, the principles outlined in this guidance can be applied to other treatments. Targeted bacteriophage therapies, for example, have been used to treat antibiotic-resistant pathogens in compassionate use scenarios with positive results.⁸ Even though phage therapies are regulated by Center for Biologics Evaluation and Research (CBER) and not directly subject to this guidance from Center for Drug Evaluation and Research (CDER), application of the framework outlined in this guidance will be beneficial for developers. It will be beneficial because nearly all of the difficulties in testing new small molecule antibiotics also exist for targeted phage therapies.

At a broader level, this guidance is part of a recognition by the FDA that inflexible protocols and traditional approaches will not facilitate the development of new treatments for evolving threats like antibiotic-resistant bacteria. The FDA is still upholding its gold-standard principle, that therapies must be proven safe and effective, but it is acknowledging that the way we arrive at that proof can be modernized and made more efficient. If successful, the impact of this guidance will be a win-win for patients and regulators. Patients in dire need will get access to treatments sooner, while regulators and providers will gather the data needed to be confident those treatments work and to monitor their risks. The lessons learned from each drug developed using this guidance will further inform and streamline future efforts. In the ever-present battle against antibiotic-resistant bacteria, this is exactly the kind of adaptive, innovative approach needed.

Learn more about how WCG can support your antibacterial development program by completing the form below. Our biosafety experts, backed by WCG’s ISO 9001 certified IBC, are here to help you navigate the FDA’s latest guidance and accelerate your path to approval—safely, efficiently, and with confidence.

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References

1. Guidance for Industry: Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases – Questions and Answers. US Food and Drug Administration. https://www.fda.gov/media/158589/download.
2. Antibiotic Resistance Threats in the United States, 2019. US Centers for Disease Control and Prevention. https://www.cdc.gov/antimicrobial-resistance/media/pdfs/2019-ar-threats-report-508.pdf.
3. Drug Approval Package: XACDURO. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216974Orig1s000TOC.cfm.
4. Guidance for Industry: Non-Inferiority Clinical Trials to Establish Effectiveness. https://www.fda.gov/media/7850.
5. Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Kaye, Keith S et al. The Lancet Infectious Diseases, Volume 23, Issue 9, 1072 – 1084.
6. Limited Population Pathway for Antibacterial and Antifungal Drugs – the LPAD Pathway. US Food and Drug Administration. https://www.fda.gov/drugs/development-resources/limited-population-pathway-antibacterial-and-antifungal-drugs-lpad-pathway.
7. Risk Evaluation and Mitigation Strategies | REMS. US Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems.
8. Hatfull GF, Dedrick RM, Schooley RT. Phage therapy for antibiotic-resistant bacterial infections. Annu Rev Med 2021; 73:197–211.