FDA addresses endotoxin levels in investigational cancer treatments

Regulatory NewsRegulatory News | 29 July 2020 |  By 

Oncology drug and biologics developers received new guidance on setting limits for endotoxins during the clinical trial process, in the form of a draft document from the US Food and Drug Administration.
The draft guidance addresses the reality of oncologic drug development, where investigational therapies are frequently used in combination with other approved treatments, or in conjunction with another investigational drug. Specifically addressed are parenterally administered anticancer drugs under investigation to treat serious and life-threatening cancers.
“This guidance does not apply to the development of drugs for adjuvant or neoadjuvant treatment or for cancer subtypes that can be cured or where prolonged survival can be achieved with available therapy,” clarified the agency.  
When an investigational drug is administered parenterally within 60 minutes of another approved drug, the endotoxin load may present a risk to the patient. Bacterial endotoxins can be contaminants of drugs and biologics; when introduced into the bloodstream or intrathecal space, the toxins can cause severe inflammatory reactions including high fevers and even septic shock and death.
In early clinical development, parenteral (excluding intrathecal or intraocular) administration of investigational products that are small molecules, or certain other therapeutic biological products, the combined endotoxin limits for multiple drugs concomitantly administered should not exceed 5 endotoxin units (EU)/kg/hour, or 100 EU/sq m of body surface area per hour. Approved and licensed products do not have to be taken into account in these calculations.
Calculation of the endotoxin level for all other products under early-stage investigation should take into account both investigational and approved products that are concomitantly administered, and should not exceed the exposure identified in General Chapter 85 of the US Pharmacopeia; “this will allow better identification of adverse reactions of investigational products that may overlap with the onset of and mimic the signs and symptoms of endotoxin exposure,” according to the guidance. Cell and gene therapy products are included in this category.
For intrathecally administered agents, the combined all-drug exposure should not exceed 0.2 EU/kg/hour.
“In the rare case that the combined endotoxin exposure exceeds the limits described above, sponsors should justify that such limits cannot be achieved based on specific aspects of product manufacturing and provide a rationale to support a conclusion that the risks to human subjects are reasonable considering the preliminary evidence of clinical activity of the investigational product, the seriousness of the disease, and the availability of satisfactory alternative therapies,” says the agency.
Sponsors working in later stages of clinical development should “tighten the specifications for endotoxin limits to ensure that by the time they submit a marketing application for that drug, the endotoxin limits will not exceed that specified” in the Pharmacopeia for parenterally administered drug, taking into account the combined investigational and approved concomitant exposures, according to the draft guidance.


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