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Surveillance has been promoted as an important tool to monitor the prevalence of antimicrobial resistance. Beyond this purpose, surveillance is conducted to identify the increase in prevalence of certain pathogens, monitor the impact of prescribing habits and evaluate changes caused by infection control practices and public health guidelines. It is also used to direct drug developers to the priority target pathogens and provide data for new drug submissions to regulatory agencies.
Surveillance studies have different designs according to their goals. It is often difficult to compare data arising from the programs that focus on public health questions with those that are designed to evaluate new treatments. Programs created to evaluate new antimicrobial agents usually have a focus that is tailored to address the target organisms, site of infection, and comparators for that new agent. These programs rely on centralized testing that is performed by one or a few laboratories using the same methodology, common reagents, and rigorous quality assurance processes. Alternatively, public health surveillance programs are likely to use data generated in clinical or sentinel microbiology laboratories to keep the cost of the program to a minimum. They can employ different methodologies, follow different national or regional guidelines and on occasion their own organization’s unique quality control requirements.
How can we get the most out of antimicrobial surveillance?
For antimicrobial developers, surveillance programs are important for understanding the current susceptibility patterns of bacteria or fungal isolates circulating in the target population that they want to evaluate. These studies can include the evaluation of pathogen prevalence if isolates are consecutively collected and to monitor the spread of resistance genes. These studies have the advantages to support centralized testing that can employ reference methods and rigorous quality control processes. The organisms, regions and comparator antimicrobial agents can be tailored to the study compound and the data can be timely reported to the sponsor of the program.
Despite the importance and the advantages of surveillance programs for new antimicrobial agents, there have been criticisms of these studies. The denominators of the surveillance collections are not always clear or determined. This may be due to the collection of isolates being limited to a few species and not capture the overall isolates diverse types of organisms recovered in different medical institutions. Also, it is difficult to feature all types of institutions in any surveillance study; usually large teaching hospitals with academic interests are the most likely to participate.
While surveillance studies are a regulatory requirement, they also offer data that aids the decision-making process for the development of any antimicrobial agent.
To avoid evaluating duplicate isolates, surveillance collections focus on one isolate per patient episode, which can then limit understanding for how resistance develops. Lastly, the information these studies generate can take time to result in publications. However, advances in technology allow for many surveillance study databases to be hosted online for public queries and more timely publications in scientific journals.
The United States Food and Drug Administration (FDA) and the European Medical Agency (EMA) guidelines recommend the inclusion of surveillance data for new drug applications. Both agencies suggest that surveillance should be tailored to address the properties of the agent or combination, require new drugs to incorporate isolates of the bacterial species intended for the label, and analyze major drug metabolites separately. They also request the inclusion of rare pathogens, genotypes, serotypes, biotypes, and isolates with known drug-resistance mechanisms. However, the FDA and EMA differ on the timing in which the isolates should be collected and the origin of the isolates. The US FDA requires three years from the date of culture to the EMA’s five years; the US FDA also recommends inclusion of isolates of mostly USA origin, while the EMA requires representation across all European countries and isolates from other regions without proposing a prevalence.
Factors to consider when designing a surveillance study
In order to design a surveillance study intended to support the development of a new drug, developers need to answer the questions that are relevant to their antimicrobial agent. These questions include the data variables that are the most important to collect and capture. These include geographic region, infection site in the patient, and comparator agents as well as indicating the target organisms and their respective phenotypes and genotypes.
A study’s geographic regions are usually chosen by where the drug will be brought to market. Although, it is important to include representative isolates from a broad number of hospitals and regions as including too many medical centres while collecting too few isolates might not represent the overall bacterial populations in that institution or be cost-effective.
Species or groups of species to be analyzed should be based on the spectrum of activity of the drug and indication pursued. It is also important to analyze off-label organisms that might be common to that infection site or indication pursued despite the limited activity of the new agent. The timing for starting a surveillance program is also important. Traditionally, pharmaceutical companies initiate their surveillance after phase 1 clinical trials are complete, but this can be as late as phase 2. However, with accelerated pathways for drug approval recently provided by regulatory agencies, some companies are compelled to start surveillance shortly after their Investigational New Drug (IND) application is approved. This is done to have sufficient data for their regulatory application submission.
Despite the importance and the advantages of surveillance programs for new antimicrobial agents, there have been criticisms of these studies.
Lastly, the genetic characterization of surveillance isolates is an asset to understand the strengths and weaknesses of antimicrobial agents. Genetic data has been used to support drug label claims of efficacy against isolates exhibiting resistance genes that can be threatening to available therapies.
While surveillance studies are a regulatory requirement, they also offer data that aids the decision-making process for the development of any antimicrobial agents. These studies help select clinical trial sites and provide complementary survey data for clinical studies. Additionally, surveillance programs may generate support for the package insert label providing sufficient isolates for species that were not broadly represented in the clinical trials for that agent, also known as list 2 pathogens. They may also establish a robust minimum inhibitory concentration (MIC), frequency distribution (distribution of isolates by antimicrobial MIC values) required for target attainment (probability to achieve a certain concentration) and other pharmacokinetic/pharmacodynamic (PK/PD) analyses. This information will also allow for the creation of challenge collections that support diagnostics for the new agents and validate tests by clinical laboratories. These collections should include organisms that are a target for that antimicrobial agent and have MIC values around the expected breakpoints.
Making surveillance an asset for an antimicrobial agent development program requires knowing how to construct appropriate study designs taking in consideration all points discussed and consulting with experts or surveillance contractors that have vast experience in creating these programs. More important is to utilize the resulting data to guide the development pathway, understand and monitor the strength and weakness of that agent and lastly, to disseminate information about the utility of that agent and how it compares with other agents in the market.
- Critchley IA and Karlowsky JA. Optimal use of antibiotic resistance surveillance systems. Clin. Microbiol. Infect. 2004; 10: 502-511.
- European Medical Agency, Draft Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections, Revision 3. 2018.
- U.S. Food & Drug Administration, Guidance for industry postmarketing studies and clinical trials – Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. 2011.
- U.S. Food & Drug Administration, Microbiology data for systemic antibacterial drugs-development, analysis, and presentation guidance for industry. 2018.
- Sader HS, Rhomberg PR, Fuhrmeister AS, Mendes RE, Flamm RK and Jones RN. Antimicrobial resistance surveillance and new drug development. Open Forum Infect. Dis. 2019; 6: S5-S13.