Regulatory Coverage

Complement measurements are recommended and widely applied for the hemocompatibility testing of medical devices, as regulated in ISO 10993-4. ISO-1093

The U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) lists testing for complement activation among the recommended immunotoxicological assays in Guidance for Industry 2002
Quoting from the document: „A pseudoallergic reaction can result from activation of inflammatory or anaphylactic mechanisms independent of antigen-specific immune responses. Pseudoallergy is known to have several causes, including but not limited to direct histamine release and complement activation (Descotes, 1986; Szebeni, 2001). This reaction is likely to be dose-related. If signs of anaphylaxis are observed in animal studies, follow-up studies should be considered. Anaphylactoid reaction can be differentiated from true IgE mediated anaphylaxis by various methods, including in vitro testing (e.g., drug-induced histamine release using a mast cell line) (Baxter et al., 1993; Toyoguchi et al., 2000). Biochemical markers of an anaphylactoid reaction can be observed in nonclinical toxicology studies (e.g., detection of serum anaphylactic complement products in animals showing signs of anaphylaxis) (Szebeni, 2001). Careful evaluation of these reactions has resulted in valuable information on biochemical markers used in clinical trials.”

A peer-reviewed publication referencing the above guideline also specifically comments on the phenomenon (Hastings KL 2002 Int Immunopharmacol).

The EMA refers to complement activation as a potential mechanism when adverse reactions occur upon administration of biotechnology-derived products in ICH guideline S6 (R1) . EMA CHMP ICH 731268 1998
Quoting from the document: ”incidence and/or severity of adverse effects, complement activation, or the emergence of new toxic effects should be considered when interpreting the data”.

The most explicit recommendations for CARPA tests are found in a recent „Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product”  reflection paper.
Quoting from the document: „Use of in vitro and in vivo immune reactogenicity assays such as complement (and/or macrophage/basophil activation assays) and testing for complement activation-related pseudoallergy (CARPA) in sensitive animal models should be considered to evaluate the extent of potential adverse events.”

Reference to hypersensitivity is also made in the „New recommendations to manage risk of allergic reactions with intravenous iron-containing medicines” ().

A recent review concludes that „complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response” (Rampton D, Folkersen J 2014 Haematologica). Rampton-Haem2014-1


ISO 10993-4: Biological evaluation of medical devices — Part 4: selection of tests for interaction with blood, ANSI/AAMI/ISO 10993-4:2002/(R) 10 March 2009, 2009.

Guidance for Industry, Immunotoxicology Evaluation of Investigational New Drugs”, October 2002

Hastings KL, Center for Drug Evaluation and Research, US Food and Drug Administration. Implications of the new FDA/CDER immunotoxicology guidance for drugs. Int Immunopharmacol. 2002 Oct;2(11):1613-8

Preclinical safety evaluation of biotechnology-derived pharmaceuticals EMA/CHMP/ICH/731268/1998; Committee for medicinal products for human use (CHMP); June 2011)

Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product. EMA/CHMP/806058/2009/Rev. 02; Committee for Human Medicinal Products (CHMP); 21 February 2013).
Rampton D, Folkersen J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, Patni S, Szebeni J, Weiss G. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99(11):1671-6.