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Evaluation of genotoxicity testing of FDA approved large molecule therapeutics

Satin G Sawant1, Mark R Fielden1, Kurt A Black1

  • 1Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA 91320, United States.

Regulatory Toxicology and Pharmacology : RTP
|June 17, 2014
PubMed

Insights

Genotoxicity testing is generally not required for large molecule therapeutics, as they typically do not enter cells. A review of FDA-approved drugs found no genotoxic concerns, supporting current regulatory guidance.

Area of Science:

  • Pharmacology and Toxicology
  • Drug Development
  • Regulatory Science

Background:

  • Large molecule therapeutics (MW > 1000 daltons) are generally not expected to enter cells, limiting their potential to interact with DNA.
  • Consequently, genotoxicity studies are typically considered irrelevant and not required for these drug candidates.
  • Existing regulatory guidance reflects this understanding, although some sponsors have voluntarily conducted such studies.

Purpose of the Study:

  • To perform a retrospective analysis of genotoxicity studies for large molecule therapeutics approved by the U.S. Food and Drug Administration (FDA) since 1998.
  • To provide a data-driven rationale for the necessity and value of genotoxicity evaluations in the risk assessment of large molecule therapeutics.
  • To assess the relevance of genotoxicity testing for various large molecule modalities, including peptides and conjugated products.

Main Methods:

  • Identification of FDA-approved large molecule therapeutics using the Drugs@FDA database (1998-present).
  • Retrospective analysis of genotoxicity study data for identified therapeutics.
  • Evaluation of outcomes to determine the necessity and value of genotoxicity testing.

Main Results:

  • Out of 99 identified large molecule therapeutics, 53 underwent genotoxicity testing.
  • No significant positive genotoxic outcomes were observed across the tested therapeutics.
  • An exception was the peptide glucagon (GlucaGen®), which showed equivocal in vitro results as per its product labeling.

Conclusions:

  • The data support current regulatory guidance, indicating that genotoxicity testing for most large molecule modalities does not add significant value to risk assessment.
  • Testing is not supported for peptides composed solely of natural amino acids.
  • Genotoxicity testing may still be warranted for peptides containing non-natural amino acids and for small molecules within conjugated products.
Keywords:
Antibody-drug conjugateBiologicsGenetic toxicity studiesICH S6(R1)Large molecule therapeuticsMonoclonal antibodiesPeptides

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