PhRMA to FDA: Antibiotic Guidance Focuses too Much on Superiority

Posted 16 December 2013 | By Alexander Gaffney, RAC 

The US pharmaceutical industry says a recent guidance issued by the US Food and Drug Administration (FDA) and intended to spur the development of new antibacterial therapies relies too heavily on superiority studies, potentially undermining legitimate needs and uses for drugs in light of advancing antimicrobial resistance to existing therapies.


The draft guidance, Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases, was released in July 2013 and comes just as FDA is giving renewed attention to antibacterial products.

Under provisions of the Food and Drug Administration Safety and Innovation Act (FDASIA)-specifically the Generating Antibacterial Incentives Now (GAIN) Act-FDA  was given new authority to grant additional terms of marketing exclusivity and other incentives to antibacterial and antifungal products developed to treat qualified infectious diseases.

The legislation is an attempt to increase incentives for companies to invest in developing new antibiotics, which are needed to outpace rising rates of antimicrobial resistance, and FDA's guidance is meant to explain to sponsors how they can streamline the development of antibacterial products in general.

Superiority or Non-Inferiority?

The guidance is extensive, and Regulatory Focus' explanation of it may be found online here.

Of the guidance's many recommendations, one stuck out to regulatory analysts at the pharmaceutical trade group PhRMA: Trials should generally be focused on providing evidence of superiority, not just non-inferiority.

"The proposed approaches place heavy reliance on demonstration of superiority as the basis for approval," PhRMA noted in comments submitted to the agency in late September 2013.

The problem, the group explained, is that even products with the same degree of efficacy can confer unique advantages to patients in high-need cases. For example, if a microbe becomes resistant to the alternate treatment, a drug that is non-inferior to another would be exceptionally useful.

"Development programs based on non-inferiority and development programs that incorporate alternative approaches to traditional statistical inference testing are both options that are urgently needed make it possible to develop a broad, diverse array of antibacterials," PhRMA wrote. "As is noted in the draft guidance, the approval of one new antibacterial in one particular indication does not guarantee that the unmet medical need has been addressed for that pathogen."

Could Non-Inferior be Superior?

In fact, every drug can be superior given the appropriate set of circumstances, PhRMA argued. "We believe that each new antibacterial will have either some component of intrinsic microbiological superiority or address some situation in which other agents cannot be used (e.g., drug allergies) and thus address an unmet medical need," it wrote.

"Dependence on superiority alone will thus not create a robust approach to development of the urgently needed diverse, vibrant pipeline of novel antibiotics," it added.

Though the group conceded that there are cases in which superiority should be used-when existing therapies don't work well or are toxic, for example-it said FDA should generally look to non-inferiority studies instead.

The bulk of the trade group's other comments reflect a desire for additional examples and specific tweaks within the guidance.

PhRMA Comments

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