Clinical efficacy and safety of biosimilar epoetin: focus on epoetin zeta

Figures & data

Table 1 FDA criteria of an acceptable biomarker for a biosimilar evaluation

• The time of onset of a biomarker relative to dosing

• The dynamic range of the PD marker over the exposure range to the biological product

• The sensitivity of the PD marker to differences between the proposed biosimilar product and the reference product

• The relevance of the PD marker to the mechanism of action of the drug and

• The relationship between changes in the PD marker and clinical outcomes

Note: Data from Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product.⁴

Abbreviations: FDA, US Food and Drug Administration; PD, pharmacodynamic.

Table 2 Comparison of general regulatory requirements for approval of biosimilars (EU vs USA)

Subject	EU	USA	Clinical significance
Definition	• Focus on origin “biotechnologically derived protein”^Citation1	• Focus on difficulty in characterizing the group “mixture of 100 closely related, complex biological substances that, in aggregate, make up the active component”^Citation8^* • Excludes carbohydrate derived preparations	• Difference in definition may affect the approach required to provide regulatory approval: the extent and content of development program needed, pharmacovigilance requirement
Guidelines	• Overarching guidelines • Class specific guidelines^Citation5	• Overarching guidelines only	• More clarification will be needed during any future biosimilar development, depending on complexity of the preparation, mechanism of action, target population, and current experience with the reference product
Exemptions	• No exemptions	• Biosimilars of certain preparations may be exempt from vigorous regulatory approval and licensed via the generic drug regulatory pathway in the US^Citation6	• Some preparations may not be subject to the vigorous biosimilar evaluation process. • Different approach to post-marketing pharmacovigilance should be adapted
Clinical data for biosimilar EPO: PK	• Single dose trial	• Multiple dose trial	• Inconsistencies in defining trial specification may lead to difficulties in establishing the safest licensing policy
Clinical data for biosimilar EPO: PD	• Data from two separate clinical trials	• One or multiple trials • Clear and specific definition of the reference PD marker	• Neither of the bodies has established clear guidelines to ensure safe interchangeability
Labeling and interchangeability	• Product has to be identified on basis of the common name (INN) and the brand name of the product • Interchangeability is not discussed in the guidelines, but is not allowed in most of EU member states	• Under the BPCI Act, the FDA can make a determination of interchangeability^Citation7 • Based on current experience, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original application given the statutory standard for interchangeability and the sequential nature of that assessment	• Inconsistencies in defining the requirements for interchangeability may lead to difficulties with traceability and establishing causality of any future unexpected adverse events • Labeling of biosimilars should combine information on both the biosimilar and the reference product, so that it is clear whether the data presented was generated for the reference or the biosimilar product

Notes:

* Copyright © 2013 Pro Pharma Communications International. Modified with permission from Pro Pharma Communications International. Blank T, Netzer T, Hildebrandt W, Vogt-Eisele A, Kaszkin-Bettag M. Safety and toxicity of biosimilars – EU versus US regulation. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(3):144–50; doi: 10.5639/gabij.2013.0203.039.⁸

Abbreviations: FDA, US Food and Drug Administration; PK, pharmacokinetic; PD, pharmacodynamic; BPCI, Biologics Price Competition and Innovation; EPO, erythropoietin; INN, international nonproprietary name.

Table 3 Potential untoward immunological responses to therapeutic proteins

Reaction	Mechanism	Example
Anaphylaxis	IgE against therapeutic protein, basophil activation or other mechanisms	Peginesatide^Citation36
Cytokine storm	Receptor cross linking leading to lymphocyte proliferation, release of several inflammatory cytokines	TGN1412^Citation37
Lupus like syndrome Antidrug antibody	Drug-induced immune complex causing organ damage Neutralizing antibodies, binding to the therapeutic protein and the normal endogenous protein	Anti-cytokine therapy, Adalimumab^Citation38 ESA induced pure red cell aplasia (PRCA)^Citation34

Abbreviations: IgE, immunoglobulin E; ESA, erythropoiesis-stimulating agent.

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