Updated Guidance on Clinical Trials for Antimicrobials


EMA’s new release factors in scientific advances, clarity on trial designs.

As concerns over the risks of future international health crises begin to replace the crisis-mode responses to the COVID-19 pandemic, the European Medicines Agency (EMA) has published an update of its 10-year-old guideline on development of antimicrobials.

The revised guideline1 reflects scientific advice that has emerged over the last decade, including modified recommendations for primary endpoints, primary analysis populations, and non-inferiority margins in trials.

As EMA says in its consciously moderate language—a sober contrast to some of the more attention-grabbing statements that have attempted over recent years to trigger concern over anti-microbial resistance—“in the face of increasing problems posed by bacterial resistance, there is a pressing need for new antibacterial agents suitable for treating infections in patients with few remaining therapeutic options.”

The document also clarifies recommended clinical programs for antibacterial agents expected to address an unmet need and for combinations of beta-lactam agents with beta-lactamase inhibitors. Guidance has also been added on clinical trials to support treatment of uncomplicated urinary tract infections and uncomplicated gonorrhoea. The document offers descriptions, too, of situations in which single pivotal trials may be accepted to support infection-site-specific indications.

EMA emphasises the international validity of the document, which takes account of “discussions between regulators in the EU, United States, and Japan. There is a need to ensure that each clinical trial conducted can be designed to meet the requirements of multiple regulatory agencies, it points out, in order to facilitate clinical development programs for new antibacterial agents and to support modifications to the uses or regimens for licensed agents.

According to the new guidance, a non-inferiority trial design is acceptable when there is a licensed treatment for the infection under study for which the magnitude of the treatment effect over placebo is known or can be estimated from existing data. The choice of active comparative regimen “is critical to the overall validity of non-inferiority trials”, and the regimen selected should be considered one of the best available treatments based on clinical trials, medical opinion, infection type-specific treatment guidelines, and the anticipated prevalence of resistance to the comparative agent at the trial sites.

The selection of the non-inferiority margin should consider the need to indirectly demonstrate superiority of the test agent over no antibacterial therapy for the infection under study and how large a difference between the test and reference treatments could be considered clinically important, EMA advises. And it offers a warning over the use of historical data, which “may be used to estimate the no-treatment effect,” but where “the relevance of these data to a prospective randomized trial design reflecting contemporary medical practice may be questionable.” It offers the example of general patient management changes “to such an extent since the historical data were obtained that constancy cannot be assumed.”

A non-inferiority margin of -10% is recommended for primary analysis in trials of treatments for acute bacterial skin and skin structure infections, community-acquired pneumonia, and complicated intra-abdominal infection, but 12.5% in the case of hospital-acquired pneumonia and ventilator-associated pneumonia.


  1. https://www.ema.europa.eu/documents/scientific-guideline/guideline-evaluation-medicinal-products-indicated-treatment-bacterial-infections-revision-3_en.pdf
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