What is a Biosimilar?
Definitions and Terminology Remain Unclear and Much Abused
See the Glossary of Biosimilar and Related Terms for a simple glossary of proposed terms and definitions. But, as discussed below and in other sections, with these products, nothing is simple or clear, including the most basic terminology and definitions. Biopharmaceuticals are the most complex of all commercial products, and discussing biosimilars adds even more nuances and complications.
There are no broadly-recognized or simple definitions for this subset of biopharmaceutical products, the most complex of all commercial products. 'Biosimilar' and related terms can mean very different things to different users and in different contexts. First, one must understand that these terms involve biopharmaceuticals, i.e., pharmaceuticals manufactured by biotechnology methods, with this involving manufacture by or using living organisms, with biopharmaceuticals involving active bioprocessing and more complex biological molecules/materials. 'Biopharmaceutical' does not include small molecule drugs and natural products, which are drugs (chemical substances) and generally regulated separately from biopharmaceuticals (e.g., in the U.S., as drugs vs. biologics).
Biosimilars (and follow-on biologics, biobetters and other terms) are commonly defined/viewed (and can also be named) on the basis of their:
Defining biosimilars on a regulatory basis is rather simple and clear-cut -- products (or active agents) with current or planned regulatory approvals by an abbreviated 'biosimilar' mechanism. With biosimilars basically being a regulatory concept, the author recommends definitions (but not nomenclature) be based on this.
Biosimilars' are also often defined based on objective entity/structural similarities among active agents. In the U.S. at least, biosimilar approval requires an identical primary amino acid sequence with the reference product, but beyond that, many structural modifications can be involved, e.g., glycosylation. Others, including most in the business community and press, often define biosimilars from a market-centric or real-world view, defining "biosimilars" to include any products that (often simplistically) appear (bio)similar based on their use and/or marketing, including products that share some similarities and compete against other. [If a product looks to be similar to an approved product, e.g., the same product type, e.g., antibody, and will compete for the same indication(s), then it's a biosimilar]. But keep in mind that most everyone, even experts using the strainghtforward regulatory definition, often confound discussions by mixing in terms/concepts, citing products, etc., based on other ways of defining/viewing 'biosimilars.'
There is incredible inconsistency in the application of definitions/criteria for biosimilars. Actually, the situation is even worse, with most everyone involved usually simply avoiding ever reporting their definition or approach. And many organizations that would or should otherwise be leaders in this field have taken broader positions restricting their contributing on these issues or imposing major conflicts of interest. It is difficult to expect clarity and consistency on 'biosimilar' terminology from organizations such as PhRMA, which is now working to rebrand/rename itself, its members and everything 'pharmaceutical' as now being 'biopharmaceutical' (to capitalize on biotech's better public image); and BIO which now often refuses to define biotechnology as involving products manufactured using/by living organisms, reflecting the fact that most of its members are no longer biopharmaceutical or other genuine biotech companies. Rather, BIO vaguely uses 'biotechnology' to encompass everything life sciences- or biomedical-related (BIO simply can't refuse its mass of members that want to be perceived as or associated with biotechology). Similarly, most other organizations that should be involved in resolving biosimilar terminology and nomenclature issues are avoiding this (rightly, with it too complex for those not getting seriously involved) and/or have serious conflicts-of-interest. In the meantime, lack of activity and clarity on these issues favor the status quo (reference products), so established biopharmaceutical manufacturers will likely not get involved until something adverse to their interests comes along.
Besides this author's articles on this subject (see the articles abstracted below), the Biosimilar Medicinal Products Working Party (BMWP) of the EMA, EU, has published an article on the topic of biosimilar terminology, "Biosimilars - Why Terminology Matters," in the August 2011 issue of Nature Biotechnology. In an associated table, the Working Group proposes a set of terminology and definitions. As to be expected from an official EU Working Group, the proposed terms are EU-specific, rather vague, use unexplained jargon (e.g, what exactly is a "copy version?") and is severely limited in scope [useless and best ignored; far from "precise terminology" as claimed]. The intent is to provide some type of actual EU definition of 'biosimilar,' something which EU officials had avoided to date (despite granting over a dozen 'biosimilar' approvals).
For further information about terminology and related issues, see the articles discussed/abstracted below or visit www.biopharmacopeia.com.
BioProcess International, June 2011, by Ronald A. Rader, President,
Biotechnology Information Institute
Abstract: The names to be used for biosimilars (and biogenerics and biobetters) will be highly controversial, including the nonproprietary names to be designated by FDA for U.S. marketing and prescription purposes. Will these be fully unique? Will names reflect biosimilarity and if so, by what criteria (e.g., structure, product class, indications, be indicative of the reference product or not, etc.)? And how will this be done? Should there a system and consistency among official names? What exactly will names be assigned to (What is a product, and when what changes in a product require assinging or new name (or do we need to think in terms of version numbers). Who will coordinate and disseminate nomenclature? The U.S. BIOPHARMACOPEIA Registry of Biophaarmaceutical Products is proposed to help resolve these problems.
published in BioProcess International, March and May 2007, by Ronald A. Rader, President, Biotechnology Information Institute
"What Is a Generic Biopharmaceutical? Biogeneric? Follow-On Protein? Biosimilar? Follow-On Biologic?"
Abstract: The concepts, paradigms, terminology and definitions concerning generic biopharmaceuticals (biogenerics) are still in a primitive state. Use of essentially all current terms may support, denigrate or obfuscate various views and discussions of the topic, e.g., to many 'biogeneric' evokes negative connotations from association with generic drugs and/or suggests that products are identical, rather than similar/related. There are three basic views/paradigms/definitions of generic biopharmaceuticals. Entity-based views concentrate on the products and active agents, including chemical structures and the unique aspects imparted by their biological source/identity, manufacturing process and specifications (process=product paradigm). Regulatory-based views concentrate on biopharmaceuticals as being approved or on track for approval as biogenerics (involving abbreviated filings based on comparative testing, sometimes therapeutic equivalence/substitution). Market/commercial-based views concentrate on products as competing for similar/same indications, having similar names, or any other perceived similarities. Depending on the view/paradigm/definition used and whether one takes a world or just Western (major market)-centric view, there are currently either many (hundreds), some or just a few biogeneric products in commerce; and biosimilars/follow-on biologics/biogenerics have either been around for a century or more, a few decades, a few years or do not yet even exist.
Part 2: Information, Nomenclature, Perceptions, and the Market
Abstract: Because of their complexity, biopharmaceutical products defy use of various conventional chemical and pharmaceutical information paradigms and methods that work well with drugs and other chemical substances. Before one can deal with biogenerics, difficult questions must be answered, e.g., What defines a biopharmaceutical agent or product as unique and distinct from others?; And, what entity-, regulatory-, and/or market-based changes in an agent or product require it to be considered a new, different one? Biopharmaceuticals will have to be defined, named, and tracked. But how should names be assigned, particularly to biogenerics? Should generic/similar names be assigned, facilitating marketing as generics but likely decreasing safety, or should unique names be assigned, favoring safety but likely decreasing the cost savings generic offer? Both unique and (bio)generic names for both finished products and active ingredients will be required for different uses/users. However, current nomenclature systems are inadequent for biopharamceuticals, e.g., with systematic nomenclature (IUPAC and CAS) designed to index the chemical literature, and nonproprietary pharmaceutical nomenclature (USAN and INN) designed to handle small molecule, particularly generic, drugs. New paradigms, terminology, taxonomy, and nomenclature systems are needed for biopharmaceuticals, particularly ones that include biogenerics. This industry maturation will be painful, requiring industry and regulators to define products, their relationships and develop related information resources and educational programs. The U.S. BIOPHARMACOPEIA Registry of Biopharamceuticals will assist in this process by developing new nomenclature systems, candidate names and a public Registry of biopharmaceutical products.