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Development and regulation of monoclonal antibody products: Challenges and opportunities

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Summary

An increasing number of monoclonal antibodies for cancer diagnosis and treatment are in clinical use and in the development pipeline, with more expected as new molecular targets are identified. As with all drugs, product quality, an appropriate pre-clinical pharmacology-toxicology testing program, and well-designed clinical trials are essential for a successful drug development program. However, protein products such as monoclonal antibodies present unique regulatory concerns. The derivation from biological sources as well as the constantly evolving technologies utilized to develop these products demands continuous appraisal of safety concerns, even while the accumulated experience with these protein products has facilitated their safety evaluations. Because of the complex nature of these products and their inherent heterogeneity, a mechanistic understanding of the mode of action along with careful attention to product design and manufacture are critical to assuring a safe, effective and consistent product. Protein products may be highly species specific, thus pharmacologically relevant animal models are an important component in accurately assessing pre-clinical safety and establishing initial dosing. Furthermore, the immunogenicity of protein products can impact its safety profile, dose exposure, and efficacy. Mechanistic insight should form the basis of biological assays used for monitoring efficacy, safety, lot-to-lot consistency and manufacturing changes. The inherent uniqueness of each product necessitates a flexible case-by-case approach for biologics review that is based on a strong scientific understanding of relative risks. This review will provide an overview of approaches used in the development of antibody-based cancer therapeutics and the scientific basis of regulatory reviews.

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Abbreviations

NHL:

Non-Hodgkins Lymphoma

mAb:

monoclonal antibody

IND:

Investigational New Drug application

FDA:

Food and Drug Administration

ADCC:

antibody dependent cell mediated cytotoxicity

CDC:

complement dependent cytotoxicity

Ig:

immunoglobulin

HAMA:

human anti-mouse antibody

CFR:

Code of Federal Regulations

PTC:

Points to Consider

ICH:

International Conference on Harmonisation

PrPsc:

infectious prion protein

BLA:

Biologics License Application

PAS:

Prior Approval Supplement

CEA:

carcinoembryonic antigen

FDAMA:

FDA Modernization Act

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Authors and Affiliations

  1. Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland

    Wendy C. Weinberg, Michelle R. Frazier-Jessen, Wen Jin Wu & Chana Fuchs

  2. Division of Biologic Oncology Products, Office of Oncology, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD

    Andrea Weir, Melanie Hartsough & Patricia Keegan

Authors
  1. Wendy C. Weinberg
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  2. Michelle R. Frazier-Jessen
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  3. Wen Jin Wu
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  4. Andrea Weir
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  5. Melanie Hartsough
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  6. Patricia Keegan
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  7. Chana Fuchs
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Corresponding author

Correspondence to Michelle R. Frazier-Jessen.

Additional information

Disclaimer: The information presented here reflects the current thinking and experiences of the authors. However, this is not an official policy document and should not be used in lieu of regulations, published FDA guidances or direct discussions with the agency.

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Weinberg, W.C., Frazier-Jessen, M.R., Wu, W.J. et al. Development and regulation of monoclonal antibody products: Challenges and opportunities. Cancer Metastasis Rev 24, 569–584 (2005). https://doi.org/10.1007/s10555-005-6196-y

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  • DOI: https://doi.org/10.1007/s10555-005-6196-y

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