US FDA offers draft guidance on conducting shedding studies for gene therapies

By Zachary Brennan

- Last updated on GMT

For products classified as replication competent, the FDA recommends that sponsors begin collecting shedding data in Phase I trials
For products classified as replication competent, the FDA recommends that sponsors begin collecting shedding data in Phase I trials

Related tags: Virus, Microbiology, Gene, Fda

The draft guidance aims to provide sponsors of virus or bacteria-based gene therapy products (VBGT products) and oncolytic viruses or bacteria (oncolytic products) with recommendations on how to conduct shedding studies during preclinical and clinical development.  

The guidance begins by defining the term “shedding​” as a release of oncolytic or VBGT products from the patient via excreta (feces); secreta (urine, saliva, nasopharyngeal fluids etc.); or through the skin (pustules, sores, wounds).  Shedding, however, should be distinguished from biodistribution because the latter describes how a product is spread within the patient’s body while shedding describes how it is excreted or released from the patient’s body.  Shedding also raises the possibility of transmission of product-based viruses and bacteria from treated to untreated individuals, the FDA says. 

Although oncolytic and VBGT products are not as infectious or as virulent as the parent strain of virus or bacterium, the possibility that infectious product-based viruses and bacteria may be shed by a patient raises safety concerns related to the risk of transmission to untreated individuals.

Our current understanding is that in most cases, the potential for transmission to untreated individuals is extremely low when oncolytic or VBGT products are shed because of the derivation methods and/or modifications that are designed to attenuate the product when compared to the parent strain of virus or bacterium​,” the FDA says.

Shedding Studies

Due to this slight risk, the FDA outlines what it expects to see from shedding studies of oncolytic or VBGT products to determine the likelihood of transmission and ways to prevent transmission.

The agency says the main considerations in the design of shedding studies are:  the choice of clinical samples that are collected from subjects in a trial (feces, urine, nasal swabs etc.); the periodicity of sample collection and duration of the monitoring period; and the assay methodology selected to test for the presence of the shed oncolytic or VBGT product in the clinical sample.

For products classified as replication competent, the FDA recommends that sponsors begin collecting shedding data in Phase I trials.

For VBGT products that are classified either as replication incompetent or replication deficient, the FDA recommends collecting shedding data later in product development, such as during Phase II trials, after a dose and regimen have been determined.

In the analysis of shedding data, the extent of shedding noted for each sample type as a factor of time, dose and regimen should be reported for all the patients monitored in the study, the FDA says.

When clinical samples are scored positive for product in a shedding assay, the subsequent analysis of these samples should provide answers to the following questions:

  • Do the clinical samples contain genomes indicative of the presence of product-based infectious viruses or bacteria or do the clinical samples contain mostly degraded genome fragments associated with product-based non-infectious viruses or bacteria?
  • Can infectivity or growth attributable to the product-based viruses or bacteria be detected in the clinical sample?

The FDA also seeks information on what shedding data can be used to assess the potential for transmission to untreated individuals, as well as how companies plan to monitor untreated individuals for transmission.

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