In 2004, the European Union (EU) became the first jurisdiction in the world to authorize a formal regulatory pathway for biosimilars. The statuary and regulatory provisions have been adopted over time through a public and scientific process and now the EU’s rigorous guidelines, requirements, and experiences provide an instructive reference to the United States and other regions.
The development of general and product class-specific guidelines in the EU began with concept papers and draft guidelines. Throughout the public review and comment process, the European Medicines Agency (EMA) decision making process was driven by robust and thoughtful scientific discussion and deliberation. The guidelines for biosimilars sought to balance patient safety and sound science with the goal of delivering biologic therapies at lower cost.
The EU’s biosimilar framework has been adopted by Australia and provided foundational principles for pathways in Canada, Japan, Malaysia, South Africa and others. The World Health Organization (WHO) recently issued guidelines for national regulatory authorities (NRAs) which heavily rely on EU biosimilar principles.
The EMA guides applicants to use the same reference product throughout the analytical, nonclinical, and clinical development of the biosimilar product. Similarly, they state that the reference produce used must be authorized in the European Community on the basis of a complete dossier, and data generated from comparability studies using reference products not authorized in the European community may only provide supportive information.
In practice, EMA have required analytical, nonclinical, and clinical studies to be carried out to detect any significant differences in efficacy and safety between the biosimilar and reference product before biosimilar products have been approved for use in patients.
The EMA guides applicants to use the same reference product be used throughout the analytical, nonclinical, and clinical development of the biosimilar product. Similarly, they state that the reference produce used must be authorized in the European Community on the basis of a complete dossier, and data generated from comparability studies using reference products not authorized in the European community may only provide supportive information.
Analytical and Clinical Data
Anticipating that there may be safety and efficacy difference between seemingly similar products, the EU guidelines require rigorous head-to-head analytical evaluation of physiochemical and biological properties of the products.
As it is expected that a biosimilar will have minor differences in product-related components as well as product-and process-related impurities, clinical equivalence studies designed to demonstrate comparable efficacy, safety and immunogenic potential are necessary. In addition to clinical equivalence studies, the EU guidelines acknowledge that—even where bioequivalence and equivalence with regard to efficacy have been demonstrated—the safety profile of the biosimilar still may differ from that of the reference product. A comparison of the type, severity, and frequency of adverse reactions between the products must be conducted over an adequate duration. In many cases, additional monitoring is necessary in the post-marketing phase to ensure ongoing safety.
Interchangeability refers to a regulatory determination that a biosimilar may be substituted for its reference product without the consent of the physician. In the European Union, interchangeability determinations are made at the Member-State level. Most EU countries have rules prohibiting automatic substitution (eg. without the consent of the treating physician).
Names and Labels
Product identification is an important part of patient safety. We should learn from the EU’s failure to effectively ensure products are uniquely identified. The EMA does not have a formal rule requiring unique names for biosimilars and subsequently had to change some product labels to emphasize the importance of knowing specifically which biological product a patient received. The overarching EU guideline states that products given to the patient should be clearly identified and that the name, appearance and packaging of a biosimilar medicine differ from the innovator product.
The World Health Organization’s guidelines, by contrast, states that biosimilars should be clearly identifiable by a unique brand name; that where an INN is defined, it should be provided, and that a lot number is essential for traceability. Japan, similarly, distinguishes the innovator product from the follow-on biologic with numbers and letter stamps in the product name.
The European Union does not explicitly address the issue of biosimilar product labeling, unlike Canada and the World Health Organization (WHO), but there is a question as to whether it is appropriate for the biosimilar product to have the same labeling as the reference product.
Safety and Pharmacovigilance
All biologic products can potentially cause safety and/or efficacy problems because of the interactions of the product with a patient’s immune system (immunogenicity). The EU explicitly states that studies conducted prior to marketing approval are generally insufficient (due to study size) to identify all safety concerns or differences between the reference product and the biosimilar. Post-marketing surveillance is a core component of ensuring patient safety.
European Union Resources
Annals of the Rheumatic Diseases: Biosimilars in rheumatology: the wind of change
European Medicines Agency (EMA) Guidelines — Including Draft & Adopted Guidelines
Once a medicine has been granted a European Community marketing authorization by the European Commission, the European Medicines Agency publishes a full scientific assessment report called a European Public Assessment Report (EPAR). In the EPAR, you will find key information for a medicine including a Q&A on the medicine and the patient leaflet. You will also find information on medicines which were refused a marketing authorization or have been suspended or withdrawn post-approval. Please be aware that the Agency does not evaluate all medicines currently in use in Europe, therefore no EPAR will be available for medicines approved prior to 2004.
Each EPAR record provides information on individual medicines including: general information about the medicine, a summary of the EPAR, authorization details, product information (including clinical trial summaries) and an assessment history. An example of how the information available for each medicine is displayed can be viewed here.
|International Non-proprietary Name (INN)||Trade Name||Owner||Approval Date||Ref. Product|
Epoetin Alfa Hexal
|International Non-proprietary Name (INN)||Trade Name||Owner||Refusal Date||Ref. Product|
|International Non-proprietary Name (INN)||Trade Name||Owner||Withdrawn Date||Ref. Product|
|Insulin – Human||Insulin Rapid||Marvel LifeSciences||6-16-08||Humulin|
|Insulin – Human||Insulin 30/70 Mix||Marvel LifeSciences||6-16-08||Humulin|
|Insulin – Human||Insulin Long Acting||Marvel LifeSciences||6-16-08||Humulin|