Draft Guidance for Industry on Streamlined Development Program for Antibacterial Drugs: Review of FDA Webinar

by Deborah Toscano 27 Sep 2013
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The FDA has been on a roll with new guidance for industry, this time for an area in dire need of innovation and drug development activity – serious bacterial infections.  The GAIN act (Generating Antibiotic Incentives Now) which was signed into law in July of 2012 authorized a streamlined development process for antibacterial drugs meeting certain criteria.  Initiatives such as this have been undertaken in response to the lagging development of antibacterial drugs which is no longer keeping pace with the development of drug resistance, spurning a concerning increase in unmet medical need.  Among several factors hindering antibacterial drug development, challenges with conducting proper clinical trials is among the most important due to issues such as the urgent need to initiate standard antibacterial therapy which can obscure the effect of the investigational drug, diagnostic uncertainties, and difficulty getting consent from patients with serious infections due to impaired cognitive abilities, etc.  The FDA hosted a webinar today outlining draft guidance for industry for the development of antibacterials for serious diseases.    

Following are the highlights of the proposed streamlined development program:

  • The streamlined program is for drugs for the treatment of serious bacterial infections where there are few or no treatment options and thus unmet need.  Potential candidates are expected to be drugs with a novel MOA or alterations of existing MOAs that address resistance and can include drugs targeting a specific genus and species.  The modification of an existing drug for other purposes such as to reduce hospital stay or dosing frequency would only be considered if the sponsor could justify the meeting of an unmet need
  • The non-clinical development program is just as critical as the clinical program, if not more so, in light of the abbreviated clinical program and cannot be streamlined.  It will be important for sponsors to provide comprehensive data on the MOA, dosing and frequency, PK/PD and tissue distribution.  Also, the agency notes that the “Animal Rule” does not apply in this scenario since it is possible to ethically conduct clinical trials.
  • Trial design:
    • Superiority trials are a definite possibility when appropriate, and in this case the sample sizes can be much smaller as opposed to non-inferiority trials. 
    • Trial centers can be randomized, as opposed to patients
    • Adaptive trial designs such as Bayesian and other approaches can be used
    • A non-inferiority trial might identify a sub-population in which a superiority trial could be conducted
    • Use of a historical control is acceptable if the untreated morbidity is high and the treatment effect is expected to be high
    • Randomization of even a few patients to active control would yield valuable information, such as 3:1, 4:1 or even 5:1 randomization
    • Selection of endpoints should be discussed with the FDA
  • Accelerated approval based on surrogate endpoints may be appropriate, and should be discussed with the FDA.  The agency particularly welcomes comments and suggestions on this aspect of the draft guidance
  • A pre-market safety database of at least 300 patients is considered adequate, with the rationale that this would rule out a 1% or greater risk of a serious or unexpected adverse event in the post-market setting
  • Development of a companion rapid diagnostic would be very useful, and in the setting of a pathogen-focused antibacterial could be crucial/essential
  • Multiple drugs per pathogen can be approved and development is encouraged in the event of unexpected side effects of one drug , or better response of a certain sub-population to one drug, as well as in the event of a drug shortage or emerging public health threat
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