FDA Should CAP Its Superiority Trial Requirement For Antibiotics, Journal Says

FDA should refrain from extending its moratorium on non-inferiority trials to antibiotics for the treatment of community-acquired pneumonia, an editorial in The Lancet Infectious Diseases advocates.

"The practicalities of running trials and encouraging industry participation in antibiotic development should not be forgotten in the desire for theoretical perfection," the article concludes.

As part of a larger effort to improve guidance on anti-infective clinical trial design, FDA issued a draft guidance in October discouraging the use of non-inferiority trials for several self-resolving community respiratory tract infections that has been the subject of much criticism from industry (¹ , p. 17). The agency has expressed skepticism about non-inferiority trials for CAP as well, and recently held a workshop on clinical trial design for CAP (² (Also see "FDA Still Needs Convincing On Use Of Non-Inferiority Trials For CAP – Temple" - Pink Sheet, 4 Feb, 2008.), p. 30).

The Lancet's appeal, which appears in the April issue, coincides with an Anti-Infective Drugs Advisory Committee meeting April 1-2 to further discuss CAP trials, including non-inferiority trial designs.

The article encourages FDA to look beyond methodological concerns with non-inferiority trials and consider the ethical implications and market impact of its proposed rules.

"Without a market for common infections there might be little incentive to develop antibiotics for rarer but far more serious infections. Furthermore, community-acquired pneumonia is not a trivial illness and Streptococcus pneumoniae, the leading cause of CAP, is increasingly resistant to existing antibiotics," the article states.

The Lancet Infectious Diseases is "not yet persuaded that placebo control is suitable for CAP trials," and the editorial encourages FDA to find common ground with industry and other regulatory bodies, such as the European Medicines Agency, in determining appropriate trial design for antibiotics.

However, the article counsels companies to accept superiority trials as the standard for some infections. "No one design will fit all circumstances. For certain indications, the pharmaceutical industry will likely have to accept placebo-controlled, superiority designs with endpoints such as time to resolution of symptoms, as it did in the 1990s with trials of neuraminidase inhibitors for uncomplicated influenza. Such endpoints should be phased in alongside ones that are already considered standard," the editorial says.

- Brian Marson ([email protected])