12:00 AM
Nov 11, 2013
 |  BioCentury  |  Regulation

Modeling breakpoints

FDA panel on antibiotic breakpoints could level playing field for old, new drugs

An FDApanel's advice on how to gauge antibiotic resistance could result in a more level playing field for new and old antibiotics. But at least three antibiotics developers contacted by BioCentury are uncertain how the changes will affect uptake of newer drugs.

On Oct. 17, FDA's Anti-Infective Drugs Advisory committee recommended the use of new pharmacokinetic and pharmacodynamic modeling that incorporates microbiologic data and some clinical data to set new susceptibility and resistance breakpoints for older antibiotics to treat serious infections, including acute bacterial skin and skin structure infections (ABSSSI), complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI).

A breakpoint is the concentration of a drug at which a given pathogen is susceptible or resistant to a particular antibiotic when used at the approved dose. The breakpoints are included on the drug's label and are based on preclinical and clinical data that are available at the time of approval.

Clinicians use breakpoints to determine which drug to give a patient.

The problem is that breakpoints for many older drugs are out of date, in part because there is not a process for routinely updating them to account for increasing resistance.

In addition, new PK/PD models that can determine susceptibility and resistance breakpoints with greater accuracy has resulted in a de facto two-class system in which newer antibiotics may be subject to more restrictive breakpoints than older drugs were.

"The breakpoints for older and widely used antibiotics were initially determined with less robust data, thereby possibly overstating effectiveness with emerging resistance. Breakpoints for new antibiotics are often overly conservative, leading a physician to possibly hold back on using a new antibiotic that is more effective," wrote Barry Eisenstein, SVP of scientific affairs at Cubist Pharmaceuticals Inc., in a statement issued ahead of the meeting.

FDA has been under pressure to fix the problem but has been unable to resolve two major issues - whether the new PK/PD models could be used for older drugs, and how to deal with drugs that are approved at different doses for different indications.

While there was no vote on the first issue, last month's FDA panel generally agreed the new models could be used to update breakpoints for older drugs.

The committee had mixed views on whether FDA should define multiple breakpoints for a given drug and pathogen based on different doses or sites of infection, or whether it is preferable to use a simpler approach.

Ten of the 18 members favored a hypothetical scenario in which the agency used PK/PD tools to define a single...

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