Lack of financial incentives, and problematic biology are two big reasons for the lack of new antibiotics. The third is the difficulty of gaining regulatory approval.
To be marketed in the US, drugs must be cleared by the FDA, which requires proof that they are safe and effective. The highest-quality evidence of safety and efficacy comes from randomized and blinded placebo-controlled clinical trials: patients are randomly assigned to be treated with the new agent or a placebo. Neither the patient nor the caregivers know who is given a placebo and who is given the drug - this insures that all aspects of treatment and evaluation are unbiased. Trials of new antibiotics are never done this way, for reasons I'll explain below.
Doing clinical trials has an inherent ethical danger - they are essentially experiments on human beings. The Nuremburg code was developed after World War II in response to the horrors of human experimentation carried out by the Nazis. One of the principles of the code is that there must be informed consent. Another, one that is particularly relevant to the conduct of antibiotic trials, is that the participants must have some expectation of therapeutic benefit commensurate with risk. Both of these principles were violated by the notorious Tuskeegee syphilis experiment. Effective treatment was withheld from the subjects without their knowledge, so that the natural course of the disease could be better understood.
When no treatment exists, or if it is relatively ineffective, clinical trial design is fairly straightforward. One group of patients is given the current ineffective therapy, and the other is given the new therapy. Demonstrating the superiority of the new treatment in these circumstances is quite feasible.
Antibiotics have historically been very effective, curing the large majority of patients who have bacterial infections. Thus withholding antibiotic therapy from one group of patients (as in the Tuskeegee experiments) is simply out of the question. The control group in an antibiotic clinical trial typically receives an antibiotic that is expected to be effective against the infection. In this type of trial, the most that the new treatment can hope to show is that it is not inferior to the control treatment. This is not the sort of conclusion that gets your new drug breathless write-ups about being a breakthrough - the kind of publicity that new anti-cancer therapies that extend survival by a few weeks or months often get. This publicity matters because it affects our willingness to pay premium prices, and thus create financial incentives.
Noninferiority is a complex statistical concept with a somewhat arbitrary definition, and it often relies on historical comparisons to trials that may have been performed decades earlier. And again, what you'd really like from a newly approved drug is a demonstration that it's better than the current standard of care. Otherwise, why bother to switch?
This aspiration, among others, has led the FDA to ask for demonstrations of superiority as a condition for clearance, even when demonstrating superiority was not really feasible. Replidyne's application to clear faropenem for bronchitis, pneumonia and wound infections was deemed not sufficient for approval, despite data from 11 clinical trials that enrolled 5000 patients. These trials were designed to show non-inferiority; by the time they were done the FDA decided it wanted superiority. Replidyne did not survive this raising of the bar and eventually folded, taking many millions of investors dollars with it.
Given the difficulty of finding new antibiotics, the relatively low return on investment, and the considerable regulatory risk, it is no surprise that many pharma companies have terminated their antibiotic development programs.
The Infectious Disease Society of America is particularly troubled by regulatory roadblocks, and particularly determined to to provide alternative pathways to clear drug candidates. The IDSA is pushing for Limited Population Antibacterial Drug (LPAD) labeling, which would require less extensive clinical validation, and be restricted to seriously ill patients with few therapeutic options. In addition, IDSA has published a white paper proposing improved and feasible clinical trial designs.
Both of these approaches would benefit greatly from the availability of rapid diagnostics that could determine antibiotic resistance and susceptibility in a few hours. These companion diagnostics would identify patients who are at risk of treatment failure for first-line antibiotics, and thus are most likely to see a benefit from new drug entities. More about that in future posts.
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