New drug trial regulations proposed by the US Food and Drug Administration (FDA) could discourage pharmaceutical companies from developing new antibiotics for both serious and mild infections. The issues are discussed in the Leading Edge editorial in the April edition of The Lancet Infectious Diseases.
The proposed new rules centre on trials of antibiotics to treat community respiratory tract infections (RTIs), including community acquired pneumonia (CAP). Whereas currently a new drug must only be shown to be at least as good as (ie non-inferior) to existing drugs, the new rules propose that new drugs must be clinically superior (ie, better than existing drugs). Although many RTIs are self-limiting, they represent one of the largest opportunities in the anti-infectives marketplace. The editorial says: "Without a market for common infections there might be little incentive to develop antibiotics for rarer but far more serious infections." Perhaps not surprisingly, these new rules have met with considerable opposition from both doctors and the pharmaceutical industry.
In October 2007, the FDA issued draft guidance for non-inferiority studies, proposing that they would not be acceptable for drugs for RTIs such as acute bacterial sinusitis*, otisis media (inflammation of the middle ear), and exacerbation of chronic bronchitis. Instead, superiority trials should be used, and the FDA is now considering applying this reasoning to CAP -- which is not a trivial condition and is already resistant to many antibiotics on the market.
The editorial suggests that the FDA's experience with telithromycin "probably provided the impetus for this change." This antibiotic was approved for acute bacterial sinusitis and exacerbation of chronic bronchitis after non-inferiority trials, but approval was subsequently withdrawn over concerns that the side-effects outweighed the benefits of treating these self-limiting infections. Similarly, gemifloxacin for sinusitis, and faropenem for bronchitis, both of which had been tested in non-inferiority trials, failed to gain FDA approval.
Doubts over whether any antibiotic is better than no treatment for mild infections seem to lie at the heart of the FDA's proposed new rules, and use of antibiotics to treat self-limiting infections without evidence of benefit might promote antibiotic resistance. But the editorial points out the European Medicines Agency did not follow the FDA's lead in changing its indication for telithromycin, and also shows no signs of recommending superiority trials over non-inferiority ones. The editorial says: "Such differences in interpretation suggest the need for dialogue between the FDA, European Medicines Agency, and other regulatory agencies."
The editorial concludes: "The FDA needs urgently to issue definitive guidelines on the design of trials it deems acceptable for approving new antibiotics. No one design will fit all circumstances…The practicalities of running trials and encouraging industry participation in antibiotic development should not be forgotten in the desire for theoretical perfection."
The Lancet Infectious Diseases Press Office T) +44 (0) 20 7424 4949 E) pressoffice@lancet.com
Notes to editors: *A paper on the use of antibiotics to treat sinusitis was published in the most recent edition of The Lancet (March 15 edition). Please contact the press office for a copy of this paper.
http://www.eurekalert.org/jrnls/lance/TLIDAprilleadingedge.pdf
Journal
The Lancet Infectious Diseases