A new guidance document released on 16 October 2013 by the US Food and Drug Administration (FDA) seeks to clarify the standards by which it will assess new applications for pharmaceutical products intended to treat acute bacterial skin and skin structure infections (ABSSSI).
Such infections are distinguishable from other skin infections by their severity, and include wound infections and major (surface area greater than 75 cm2) cutanenous abscesses. FDA said it does not intend for its guidance to address less serious skin infections or those infections that might require "more complex treatment regimens," such as those infections stemming from animal bites, flesh-eating bacteria, diabetic foot infections, or gangrene. Treatments for those conditions should be discussed separately with FDA, the guidance explains.
Basic Efficacy Considerations
"Most drugs for ABSSSI will be studied using non-inferiority trial designs," the guidance added, noting the need for a large infection area to gauge the effect of a treatment under those trial design parameters. "A showing of superiority to an effective control is also readily interpretable and would be acceptable," FDA said.
Under normal conditions, two adequate and well-controlled trials should be used to show evidence of effectiveness. In cases where "other independent evidence, such as a trial in another infectious disease indication," is available, one trial may suffice.
Efficacy will generally be defined as a percent reduction in lesion size equal to or greater than 20% compared to baseline within 72 hours of initiation of treatment. Total resolution should be achieved within 1-2 weeks as a secondary endpoint.
Safety and Enrollment Considerations
Prior to the initiation of efficacy trials, a preapproval safety database of at least 700 patients should be assembled. If the same or greater dose of the same drug was used in patients, even for a different indication, that data may be used to support the safety database, FDA said.
As with many other trials on antibiotics, FDA said an "ideal" design would involve patients who have not received prior antibacterial treatments, "because such therapy can have a number of potential consequences for a clinical trial" by obscuring potential treatment differences or influence efficacy endpoints.
"However, a complete ban on prior antibacterial therapy could have adverse consequences" for some patients, FDA conceded, noting that it would have a negative impact on those patients for whom the effects of the disease are serious or life-threatening. In other cases, trial enrollment procedures could delay treatment, causing some healthcare providers to decline to participate if they can't offer their patients the best standard of care prior to enrollment.
Instead, FDA said it wants sponsors to take a "pragmatic approach" that balances the quality of clinical data with the safety of patients. As a result, patients who have received a single dose of a short-acting antibacterial within 24 hours of enrollment may enroll, but regulators said those patients should not collectively make up more than 25% of all participants. "This would allow patients in the trial to receive prompt antibacterial drug therapy if that was clinically necessary, consistent with the standard of care," FDA said.
Other instances may allow for enrollment after initial treatment, such as a patient whose infection progresses to the point of ABSSSI.
In addition, FDA said concurrent therapy with other antibacterial drug therapies should be avoided unless it can be empirically shown that the other, non-study treatment "has no overlapping antibacterial activity with the investigational drug."
Trial sponsors should also specify which adjunct therapies, such as dressing changes, debridements and hyperbaric oxygen treatments, should be allowed.
Guidance for Industry: Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment