Regulatory Focus™ > News Articles > Extensive New Guidance Explains FDA's Recommendations for Streamlined Antibiotic Development

Extensive New Guidance Explains FDA's Recommendations for Streamlined Antibiotic Development

Posted 01 July 2013 | By Alexander Gaffney, RAC

A new draft guidance document released by the US Food and Drug Administration (FDA) provides extensive recommendations regarding the streamlined development of antibacterial products for patients with untreatable, serious infections.


The draft guidance, released 1 July 2013, comes just as FDA is giving renewed attention to antibacterial products under the new Generating Antibacterial Incentives Now (GAIN) Act, a piece of legislation that was bundled into the FDA Safety and Innovation Act (FDASIA) in June 2012. The legislation was prompted largely by a slowdown in the development of antibacterials, even as rates of antibiotic resistance to existing therapies have increased dramatically in recent decades.

The law directs FDA to grant special incentives to sponsors of antibacterial products intended to treat serious or unmet needs, such as additional years of market exclusivity and more assistance during the development process. The incentives aren't available to just any antibiotic product, however. Under the law, FDA was tasked with generating a list of "qualifying pathogens," which it released in June 2013.

The Guidance

And while the list may encompass many dangerous pathogens, FDA's new draft guidance, Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases, is focused on how sponsors may streamline the development of an antibacterial product regardless of its qualifying status under the GAIN Act.

Of particular interest to FDA are patients with unmet medical needs, either because a drug is resistant to multiple treatments or because the bacteria itself is relatively new. Accordingly, FDA explained that its guidance encompasses two types of products:

  1. drugs to treat serious bacterial diseases in patients with unmet medical need
  2. drugs that are pathogen-focused antibacterial drugs (e.g., drugs that have a narrow spectrum of activity or are only active against a single genus and species of bacteria) and are used for the treatment of serious bacterial diseases in patients who have an unmet medical need

In still other cases, a patient's unique needs, such as allergies to an existing therapy, may limit an existing therapy's efficacy, putting them into the former category.

And while FDA notes that the guidance "is not intended to establish a new approval pathway or standard for such drug products," it is supposed to "serve as a focus for continued discussions" between FDA's Division of Anti-Infective Products and members of industry.


The guidance goes on to note the myriad challenges associated with antibiotic drug development: Patients that must undergo treatment quickly, often leading to prior treatment before enrollment in a clinical trial; Seriously ill patients who can make obtaining informed consent and trial enrollment difficult; Obtaining an exact etiology of the pathogen in a timely manner is difficult; A need for concomitant antibacterial therapy can complicate studies on the drug.

The question for regulators and industry both, then, is how the process can be expedited, improved and otherwise made more appealing for investment.

To assist industry, the draft guidance goes on to list a number of questions and answers about the streamlined development process for certain antibacterial drugs. Some notable explanations from FDA include:

  • Drugs eligible for the streamlined review process are likely to act through new mechanisms of action, have added inhibitory mechanisms or have an altered structure to avoid antibiotic resistance. The drugs must also meet an unmet medical need, including products that avoid common allergic reactions to an existing drug.
  • Drugs with slightly greater potency are not eligible for the streamlined review process
  • Drugs that treat a serious bacterial disease are eligible for streamlined development status.
  • Enriched trials may be used, such as patients affected by an infection at a particular body site, but pre-specified endpoints should first be discussed with FDA
  • Trials may use a best-available active-control therapy as a comparator in the trial
  • Approximately 100 patients would be, at minimum, necessary to show evidence of substantial superiority.
  • For trials in patients with unmet medical need, sponsors may randomize centers instead of patients to streamline trial enrollment and reduce the need to pre-treat a patient with a drug before they can be enrolled into the trial.
  • Some patients could be enrolled into a trial before their infection type is confirmed. Confirmation would then come later, with patients in the confirmed group forming a distinct subgroup for superiority, and non-confirmed patients forming another group for the purposes of non-inferiority analysis.
  • A trial design reliant upon historical or external controls may be acceptable in populations with an unmet medical need, and particularly if the current standard of care isn't suitable and withholding the drug to patients would be considered unethical.
  • For patients where treatments are available, non-inferiority trials may be used to establish efficacy based on an acceptable non-inferiority margin.
  • Surrogate endpoints may be used if its use can be scientifically supported. FDA should be consulted before such an endpoint is used.
  • Nonclinical development programs cannot, in general, be streamlined.
  • FDA is willing to accept more uncertainty about a drug's adverse events during review, but will likely require monitoring in post-market settings to further define a drug's safety profile. The drug's labeling will also need to outline the limitations of the drug's approved uses, populations and available data.
  • Use of the so-called "Animal Efficacy Rule" is not proper for this type of development since human subjects are available for ethical studies.
  • The approval of an initial drug to treat a patient population with unmet needs does not automatically preclude the use of the streamlined pathway by another drug, even for the same indication. It will, however, need to show key differences, such as in its mechanism of action or structural improvement to prevent resistance. In addition, if the drug is found to be safer or could address an "emerging or anticipated public health need, such as a drug shortage or the development of antimicrobial resistance," it could also obtain streamlined approval.
  • Special labeling considerations will apply to the drug, and are meant to explain the limitations of the drug's approval, including the specific pathogens for which the drug has obtained approval.

Comments on the draft guidance are due by 1 October 2013.

Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases

Federal Register


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