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Information Center

Thank you for visiting our Information Center. This section is meant to provide you with information on issues surrounding biologic medications and offers links to other valuable internet resources on related topics.

The Alliance for Safe Biologic Medicines works to provide information on the safety and quality of biologics, advocate for policies that keep medical decisions between patients and physicians, and seek solutions that ensure affordability and accessibility of biologic medications while never compromising on patient safety.


EU Experience


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.

Biosimilarity

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.

Reference Product

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

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[1]

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.

[1] EU General Guideline, at §2.1 and EMA General Q&A at 1.


Frequently Asked Questions

Q: What Are Biologics?


A: Biologics are complex, large molecule drugs that treat serious illnesses, such as cancer, multiple sclerosis, and rheumatoid arthritis. Unlike drugs derived from chemical synthesis, biologics are manufactured using a unique and proprietary process involving living cells. For this reason, no two biologics made from different cell lines or using different processes will be identical. Biologics are also highly sensitive to the manufacturing process. In fact, altering a single manufacturing parameter can change a compound's identity or the precise effect it has on the human body. Examples of biologics include the cancer drug Avastin and the arthritis drug Enbrel.

Biotech medicine offers the best hope for some of the most devastating medical conditions, such as Alzheimer's and Parkinson's disease, for which there are currently no effective treatments. These drugs are also the fastest-growing segment of the pharmaceutical market and are expected to account for half of the new drugs approved by 2015.

Q: What are Biosimilars?


A: Biosimilars (also known as follow-on biologics) are sometimes mistakenly called "generic" versions of innovative biologics. However, unlike generics, which are copies of chemically synthesized drugs, biosimilars are similar to, but not the same as the innovator's active ingredient. This is an inevitable outcome because they do not utilize the same living cell line, production process, or raw material as the innovator drug.

Q: Why Is Patient Safety A Concern?


A: : Biologics raise some safety concerns above and beyond chemical drugs; commensurately, biosimilars are distinct from oral or injected generic drugs. In contrast to most drugs that are chemically synthesized and their structure is known, most biologics are complex mixtures that are not easily identified or characterized. Small differences in the structure of the innovator and the attempted copy can have effects for patients such as reduced efficacy or changes in safety and tolerance.

In order to make informed choices, patients should understand the complexity of these drugs and the difference between oral or injected generics versus biosimilars and talk with their doctors about the best course of treatment.

Q: Are there places around the world that have already established a so-called "biosimilars pathway?"


A: Yes. In 2004, the European Union authorized the first formal regulatory pathway for biosimilars. The Europeans Medicines Agency (EMA) is the regulatory body of the EU that has guided the implementation of the EU's biosimilar pathway. The EU's process overall was science-driven, transparent and sought the input of major stakeholders.

Other countries that have developed a pathway are:

Q: What are biosimilar "interchangeability" and "substitution"?


A: "Interchangeability" is the determination that a patient can be transferred safely from the innovator/reference product to a biosimilar and expect to have the same experience with no change in safety or efficacy. "Substitution" is the legal authority for a pharmacy filling a prescription or hospital to switch the innovator product to the biosimilar or switch the prescribed product to a different product.

Around the world, substitution decisions are largely handled at the local government level; in the US, the decision of whether a biosimilar is substitutable is made at the state level. In Canada, this decision is made at the provincial level, while within the European Union, the decision is made by individual Member States.

South Africa and Japan have similar guidelines for interchangeability and substitution - South Africa does not allow biosimilars to be interchangeable with their reference product and automatic substitution cannot apply to biosimilars. Japan's approach is similar, but additionally points out that substitution of a biosimilar with it reference or innovator product should be avoided throughout treatment.

The reality, however, is little is known about how the process of interchanging a biosimilar for the reference product and its potential impact on the patient's immune response.

Q: What is "pharmacovigilance"?


A: Pharmacovigilance is the surveillance of a drug's performance, particularly of adverse reactions experienced by patients taking the product after it has been released for marketing.

The overall goal of post-marketing pharmacovigilance plans is to accurately and promptly trace a patient's adverse event to a particular product, manufacturer and lot number. Proper labeling, product tracking and an operational system of reporting and attributing adverse events are all components of a well-functioning pharmacovigilance program.

Labeling remains a concern in the FDA's implementation of biosimilars moving forward, given the fact that no two biologics are identical. A biosimilar should contain the information needed by the doctor to help the patient make an informed decision. For example, the label should identify trials done with the biosimilar medicine, not the product it is copying.

Part and parcel to the pharmacovigilance process is how to identify the product through its unique name. Only the World Health Organization (WHO) and Japan have laid out clear guidelines that specifically address naming biosimilars:

Q: What is "Immunogenicity"?


A: Immunogenicity is a measure of the immune response to a therapeutic drug. Due to the size of the biologic molecule, it is always able to be recognized by the human immune system, where as a small molecule travels through the body unnoticed. Thus the risk of an immune response from a biologic is much more significant than with small molecules. Most health authorities recognize the sensitivity around biologics/biosimilars in causing safety concerns because of immunogenicity.