FDA publishes Guidance for Setting Endotoxin Limits During Development of Investigational Oncology Drugs and Biological Products

End of July the FDA (CDER) published a draft guidance document for setting endotoxin limits during the development of drugs for oncology and biological products.

Objective of the Guidance Document

Especially in the field of oncology, new approvals are often based on already known treatment regimens to which new drugs are added or new combinations of drugs are developed. This results in multidrug approaches with increased efficacy. The present draft guideline contains FDA's current recommendations for setting endotoxin limits for investigational drugs intended for use in combination with other approved drugs or for the codevelopment of two or more investigational drugs. The scope of this guidance is limited to anticancer drugs, including combination products as defined in 21 CFR Part 3, as further described in this document and administered parenterally (except for intraocular administration) to treat serious and life-threatening cancers based on histology or stage of disease.

This document does not apply to the development of drugs for adjuvant or neoadjuvant treatment or for cancer subtypes that can be cured or for which prolonged survival can be achieved with the available therapies.


In order to prolong survival of patients with incurable cancers, attempts are being made to identify suitable multidrug or multimodality regimens. Since the manufacturing processes for such investigational products are usually not yet optimised and the administration of one or more drugs often occurs within the same 60-minute timeframe, endotoxin limits for this investigational product may pose a problem. This guidance gives orientation for setting endotoxin limits for investigational medicinal products for the treatment of advanced cancer when evaluated in early (pilot) clinical trials as part of a multidrug regimen. The FDA acknowledges that, based on the potential benefits or enhanced efficacy of investigational products in the treatment of life-threatening, incurable cancers, the potential exposure of these patients to elevated endotoxin levels may be seen as an acceptable risk, although it goes beyond the recommendations provided in the USP General Chapter Bacterial Endotoxins Test. The objective of this document is to discuss FDA's considerations regarding the setting of endotoxin limits for investigational medicinal products during early product development for incurable cancers. The recommendations are in line with the abbreviated product review for feasibility studies of monoclonal antibodies used for patients with severe or immediately life-threatening conditions for whom there is no effective alternative treatment. In this guidance, the FDA recommends a risk-based approach that weighs the potential risks of potential exposure to higher endotoxin levels in all components of a multidrug regimen against the potential benefits to patients with severe and life-threatening cancers.
For further details please refer to the draft Guidance document entitled Setting Endotoxin Limits During Development of Investigational Oncology Drugs and Biological Products.

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