Certainly! Here is a comprehensive, consolidated answer to the question:

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What non-clinical data has EMA accepted for the assessment of the toxicity of medicinal products consisting of human polyvalent immunoglobulins?

Overview

The European Medicines Agency (EMA) has generally accepted a minimal and highly justified set of non-clinical toxicity data for medicinal products consisting of human polyvalent immunoglobulins. This approach is based on the products’ nature as naturally occurring human proteins with extensive clinical experience and established safety profiles, as well as the limited predictive value and feasibility of animal studies due to immunogenicity and lack of relevant animal models.

Key Principles and Rationale

• Limited Value of Animal Studies:
  Animal models often mount immune responses to human proteins, making interpretation of toxicity data unreliable. The EMA and ICH S6 guidelines recognize that animal studies may be impractical or not meaningful for these products ⁵¹¹.
• Reliance on Clinical Data and Product History:
  The EMA places significant weight on clinical data and the established safety record of these products, often superseding the need for extensive preclinical studies ⁴¹¹.
• Case-by-Case Approach:
  The extent of non-clinical data required is determined individually, especially when manufacturing changes occur or when comparability to an existing product is in question ^8131417.

Types of Non-Clinical Data Accepted

Study Type	Accepted/Required	Rationale/Notes
Single-dose toxicity (in animals)	Yes (limited)	Sometimes performed in rodents; deaths, if any, due to volume overload, not substance toxicity 2622
Repeat-dose toxicity	Not required	Omitted due to immunogenicity and limited relevance 26112022
Pharmacokinetics (PK)	Sometimes limited	Comparative PK studies in animals may be performed for comparability, but standard PK studies are generally omitted 251722
Safety pharmacology	Limited	Some studies (e.g., cardiovascular, respiratory) may be performed; no significant concerns found 22
Genotoxicity	Not required (for product)	Not expected for human proteins; sometimes performed for excipients (e.g., Ames test for residual solvents/detergents) 622
Carcinogenicity	Not required	Omitted; not expected for plasma-derived immunoglobulins 6112022
Reproductive/developmental toxicity	Not required	Omitted; not expected for plasma-derived immunoglobulins 6112022
Local tolerance	Sometimes	Performed in some cases (e.g., rabbits), especially for new excipients or formulations 5
Immunogenicity assessment	Limited	Animal models not predictive; assessment mainly clinical 18
Risk assessment of impurities, leachables, excipients	Yes (literature or in vitro)	Toxicological risk assessment expected; literature data or in vitro studies often suffice 61820
Use of literature and data from similar products	Yes	Accepted to support safety, especially for excipients and impurities 61620

Justification for Omission of Certain Studies

• Repeat-dose, reproductive, genotoxicity, carcinogenicity, and local tolerance studies are generally not required for human polyvalent immunoglobulins, justified by:
  • Immunogenicity in animals,
  • The product’s endogenous human origin,
  • Extensive clinical experience and established safety profile,
  • Lack of pharmacological relevance in animal models ^2611152022.

Comparability and Manufacturing Changes

• When manufacturing changes occur, the EMA may require limited non-clinical studies (e.g., comparative PK studies) to demonstrate comparability, but not full toxicity programs. If physico-chemical and biological comparability is established, further non-clinical or clinical studies may not be needed ^8131417.

Environmental Risk Assessment (ERA)

• For products consisting of amino acids or proteins unlikely to pose environmental risks, the EMA may accept a justification for not conducting ERA studies ¹⁹.

Examples from Product Assessments

• Kiovig: Single-dose toxicity in rodents, limited PK studies, no repeat-dose or reproductive toxicity studies, genotoxicity testing for excipients, and safety pharmacology studies ²²².
• Flebogamma DIF: No non-clinical toxicity studies required; reliance on clinical data ⁴¹¹.
• ImmunoGam: No full toxicology program; single-dose toxicity in mice; literature data for excipients; no repeat-dose, genotoxicity, carcinogenicity, or reproductive toxicity studies ⁶²⁰.

Summary Table

Scenario	Non-clinical data accepted/required	Source
Standard product (no major changes)	Generally not required	41115
Manufacturing change (comparability)	May require limited studies (e.g., PK)	8131417
Well-established use (bibliographic app.)	Bibliographic data may suffice	16

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Conclusion

The EMA generally does not require standard non-clinical toxicity studies for medicinal products consisting of human polyvalent immunoglobulins. Instead, the agency relies on clinical experience, bibliographic data, and, in cases of manufacturing changes, may request limited non-clinical studies focused on comparability (such as PK studies), rather than full toxicity assessments. The minimal non-clinical data package is justified by the endogenous nature of the products, their established safety record, and the limitations of animal models for human proteins ^{2456811131415161718192022}.

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References
² EMA Assessment Report: Kiovig
⁴ EMA Assessment Report: Flebogamma DIF
⁵ EMA Assessment Report: Hizentra (IgPro20)
⁶ EMA Assessment Report: ImmunoGam
⁸ EMA Guideline Comments on IVIg
¹¹ EMA Assessment Report: Flebogammadif
¹³¹⁴¹⁷ ICH Q5E Guideline and EMA Guideline Comments on Comparability
¹⁵ EMA Immunogenicity Guideline
¹⁶ EMA Well-Established Use Guideline
¹⁸¹⁹ EMA Guidelines on Non-Clinical Requirements for Biologicals
²⁰²² EMA Assessment Reports: ImmunoGam, Kiovig

(References correspond to those cited in the original answers and have been merged where appropriate.)