Antimicrobial resistance (AMR) has raised concerns that we may no longer be able to rely on antibiotics to cure infectious diseases or to carry out major operative procedures safely, with catastrophic consequences for public health. This situation was exacerbated by the difficulties in undertaking clinical trials, for example as required by the US Food and Drugs Administration (FDA), which prioritized ‘experimental purity’ over ‘clinical pragmatism’ such that it was impractical and unethical to recruit patients into antimicrobial trials, particularly for novel narrow-spectrum antibiotics. The FDA requirements were similar to those of the European Medicines Agency (EMA) at the time.
The 2010 FDA guidance on clinical trials for hospital-acquired and ventilator–acquired bacterial pneumonia required clinicians to avoid prior use of antibiotics effective against the microbe presumed to be causing the infection. They argued that prior antibiotic use would reduce differences between the two treatment arms and bias conclusions in favour of the new drug. However, most trial participants would be drawn from seriously ill hospitalized patients who would already have received prior antibiotics, making it impossible to recruit candidates for a clinical trial.
Other regulatory challenges included shifting targets, statistical hurdles that demanded large trials, and paradoxical situations where no trial design appeared satisfactory, requiring even larger trials and further increasing the cost of drug development, making it impossible to satisfy regulatory guidelines in terms of trial design.
Both the FDA and EMA have now adapted regulatory guidelines to enable practical and ethical trial designs. Changes to statistical requirements allow for smaller trials and changes in recruitment criteria have simplified enrolment. Progress has also been made in reducing regulatory burdens for new drugs for patients with limited treatment options.
In a series of positive moves, the FDA and the EMA have both issued guidelines for the development of drugs for important classes of infection to allow for flexibility in the development paths and labelling for novel antimicrobials for unmet medical needs. Pathogen-specific approval for serious infections with few treatment options was particularly innovative. For the first time, it was permissible for patients in clinical trials to be pooled, even when their infections were in different anatomical locations, if they shared a common infectious agent. Such trials can demonstrate a positive risk-benefit profile against the pathogen without having to prove definitively that the drug has a positive profile for each particular infection caused by the pathogen, making it cheaper to run trials for pathogens that are rare or have rare drug resistance profiles.
This case is an example of proportionate and adaptive regulation, in which regulators, albeit after a delay of a number of years and repeated representations from patient representatives and companies, changed regulatory guidelines to enable more rapid and cost-effective development of new antimicrobial drugs. Regulatory constraints are no longer seen as an important factor inhibiting drug development, given that recent regulatory changes may have more than halved the R&D cost per novel antimicrobial drug.
Tait, J., Bruce, A., Mittra, J., Purves J. and Scannell, J. (2014) Independent review on anti-microbial resistance regulation/innovation interactions and the development of antimicrobial drugs and diagnostics for human and animal diseases: Main Report. 14th December 2014. Report to ESRC for the O’Neill Commission on Antimicrobial Resistance.
Scannell, J. (2015) Four Reasons Drugs Are Expensive, Of Which Two Are False Innogen Working Paper, Opinion piece.