Abstract: There are no simple ways to define and assign useful nomenclature (names and other identifiers) to specific biopharmaceutical products, including biosimilars, which add further levels of complexity. This includes names that are unique, unambiguous and useable (relatively short, pronounceable, etc), and generic names that convey information regarding entity, activity, therapeutic equivalence/substitution, class or other relationships among products. Nomenclature systems that work well for chemical substances and drugs fail when applied to biopharmaceuticals and biogenerics. This article discusses problems with conventional drug/chemical nomenclature and registry systems as applied to biopharmaceuticals, and the controversies likely to be associated with selection of official names, both unique and generic, for biopharmaceuticals, particularly biogenerics. Nomenclature, since it directly affects marketing, particularly the names to be officially adopted (for filling of prescriptions) for biogenerics, will be a very contentious issue. [If not familiar with the most basic aspects of biopharmaceutical and biogeneric terminology (basically, like nomenclature, total chaos), consider looking over What is a Biopharmaceutical? and What is a Generic Biopharmaceutical?...].

Background

There has been essentially no development of nomenclature, registry and other taxonomy systems and reference sources in the biotechology, including biopharmaceutical, fields other than concerning primary research data, e.g., bioinformatics, sequence databases, etc. This situation was described in a 1986 report, Biotechnology Nomenclature and Information Organization, by the National Academy of Sciences, and in papers/presentations by this author entitled "The Infrastructure of Information Resources Supporting U.S. Biotechnology," from 1989 (see the "Terminology, Nomenclature and Indexing Schemes" section) and 1988. Two decades later, the situation has not changed! This lack of information infrastructure, including nomenclature systems and the most basic reference sources, is particularly true when biotechnology is viewed from any perspective other than pure research, i.e., when biotechnology is viewed as an industrial and economic activity. This critical lack of resources and underlying infrastructure includes the products of biotechnology, e.g., biopharmaceuticals, and the technologies comprising biotechnology, e.g., bioprocessing technologies. Other than publications by this author, notably Biopharmaceutical Products in the U.S. and European Markets and the ongoing development of The Biotechnologies Directory. Volume 1: Biomanufacturing Technologies, there are no or negligible references concering biopharmaceuticals and biotechnologies. Similarly, there are no nomenclature or registry systems capable of appropriately handling biotechnology or biopharmaceutical products, which as entities exhibit much more complexity than chemical substances and drugs, with this further complicated by their complex and often-changing regulatory and commercial aspects (that combine to define them as products).

Biotechnology and biopharmaceuticals are among the few areas of industry/commerce clearly contributing to both the nation's and world's economy and the health and welfare of its citizens. Biopharmaceuticals constitute a market of nearly $100 billion sales annually, with much more than this being invested in R&D; and biopharmaceuticals are among the few industries still contributing significantly to the U.S. economy and still dominated by the U.S. Despite the importance of biotechnology and biopharmaceuticals, other than bioinformatics and other areas of public sector-supported basic research, nomenclature and other taxonomies concerning biotechnology and biopharmaceuticals have long been ignored. Modern biopharmaceuticals, exemplified by recombinant proteins and monoclonal antibodies, were first introduced in the 1980s, yet none of the existing chemical and pharmaceutical nomenclature systems have been adapted to adequately handle these products, and no new systems have been proposed. These deficiencies are becoming particularly evident as generic biopharmaceuticals (biogenerics) enter the market and the U.S. and other countries consider restructuring their regulatory systems to accomodate these products. The U.S. Biopharmacopeia Registry and nomenclature project seeks to resolve these problems by developing a functional biopharmaceutical products registy and nomenclature system, including candidate official unique and generic nonproprietary names for marketed products and active agents.

Biopharmaceuticals and related nomenclature issues are the last frontier for the fields of chemical and pharmaceutical information. No or negligible attention has been paid to biopharmaceutical nomenclature, including in the chemical/pharmaceutical information communities, and there is no body of literature or consensus on this topic. Due primarily to their complexity, these products defy application of various conventional chemical and pharmaceutical information paradigms, methods and artifices that work well with drugs and other chemical substances. These paradigms are primarily based on primary structure representation, including systematic nomenclature and other linear notations (e.g., protein amino acid sequences), and often trivial nomenclature. Conventional registry systems fail to either assign unique or generic active agent or product names/identifiers, and further complicate the situation by simply compiling the various nomenclature terms in use, many of which are insufficient and/or inaccurate. Add in trying to have generic names reflect the nature of biogeneric similarities, e.g, therapeutic equivalence/substitution, and the situation gets even more chaotic. Further complicating the situation is the transient nature and uncertainties involved with these being commercial products, with the products themselves, their approvals, manufacturing processes, formulations, trade names, manufacturers/owners and every other key aspect that potentially defines and differentiates them subject to constant change; and with much of the entity- and process-related information concerning products as originally approved and subsequent changes (e.g., supplemental approvals) never publicly disclosed.

How Should Biopharmaceuticals Be Named?

Biopharmaceuticals simply do not fit well into established nomenclature and registry paradigms; and there simply has been no work (published) in the area of biopharmaceutical product nomenclature. As with many other commercial products, biopharmaceuticals cannot simply be described from a strict scientific, entity-based perspective. Biopharmaceutical active agents can only be defined/differentiated through consideration of their entity (process=product; further discussed below), regulatory (approvals) and market/commercial aspects. Or, in terms of the products' scientific, technological and commercial aspects. Similarly, finished products must be characterized by their active agent ingredient(s), formulation/presentation, regulatory and commercial aspects. For example, most would consider seemingly identical product formulations containing seemingly identical active agents to be distinct different products (chemical/regulatory/commercial entities), if they were manufactured by different companies, have different trade names (trademarks), are marketed for different indications, and/or were approved as distinct products. For example, interferon beta products containing essentially identical active agents (having the same protein sequence, same activity) and having identical formulations but manufactured by different companies obviously need to be identified as unique/distinct products. However, under current systematic chemical and drug nomenclature systems, each product would be assigned the same chemical, e.g., CAS or IUPAC, name based on its active agent ingredient (with this systematic name essentially becoming a generic name applied to multiple products), and would also be assigned nonproprietary generic names, e.g., USAN and INN, also based on their active agent.

Current nomenclature systems generally fail to differentiate biopharmaceuticals based on aspects other than primary structure of their active agent ingredients. These systems fail to acknowledge that different products have different manufacturing processes (process=product paradigm; further discussed below); different formulations; different manufacturers; different approvals; different trade names; etc. A pertinent change in any of these aspects generally warrants a biopharmaceutical being considered a new, distinct product (or version of a product), such that a new name reflecting this is or may be required. Thus, in some respects, naming biopharmaceuticals may turn out to be like naming/identifying software products, with new products and versions replacing prior ones, the basic nature of the products changing as they are upgraded, etc.

As discussed in What is a Biopharmaceutical? and What is a Generic Biopharmaceutical?..., due to their biological source/nature and manufacturing methods, biopharmaceuticals are inherently very complex, often defying rigorous (bio)chemical analysis and descriptions. Most involve rather large molecules, with these often defying analysis; or in some cases, involve even much larger and more complex entities, including biological structures, cells, organisms and tissues. Most current active agents are protein polymers involving variations in structure that affect their activity (and efficacy and safety), but are rarely reflected in nomenclature, e.g., their having variable attachment of highly variable polysaccharide side chains (glycosylation); intrachain, e.g., S=S, linkages; existing as multimers or noncovalent complexes of chains; complex and highly variable 3-dimenensional structures; variable oxidation states; etc. (with these and other aspects largely dependent on manufacturing process). Few biopharmaceutical active agents are truly homogeneous, pure substances, e.g., readily definable by chemical structure. In fact, if one can draw a structure (or other linear notation) for a molecule without resorting to using symbols for subunits, it is almost certainly not a biopharmaceutical.

Because of their biological nature and manufacture, biopharmaceuticals are largely defined and differentiated on the basis of the product (identity/source), process and specifications paradigm, often referred to at the process=product paradigm, i.e., the nature of these products and their active agent ingredients can be largely defined and differentiated on the basis of their manufacturing process. This is the classic "product, process, specifications" paradigm, often shortened to "process=product," that has been promoted by many in the biopharmaceutical community, usually those associated with innovator companies. See "Biologics: Can There Be Abbreviated Applications, Generics, or Follow-On Products?, BioPharm Intl., July 1, 2003; and "One Product, One Process, One Set of Specifications: A Proven Quality Paradigm for the Safety and Efficacy of Biologic Drugs," BioPharm Intl., 14(3), 14-24, March 2001. For example, the same (seemingly identical) recombinant protein expressed by different organisms, e.g., bacteria vs. human cells, or the same protein purified by different methods, e.g., using conventional chromatography vs. affinity ligand-based chromatography, will likely have discernable differences in structure; composition, impurities profile and other aspects likely to affect biological activity, including safety and efficacy. Specifically, process-associated variations in the 3-dimensional structures of proteins can profoundly affect the immunogenicity and related safety aspects of a biopharmaceutical. "Process = product" is very similar or much the same as the chemistry, manufacturing and control (CMC) aspects of GMP manufacturing. Conventional nomenclature and registry systems ignore this, concentrating on active agent primary structure, much as they also ignore the other complex structural/composition, regulatory and commercial aspects of biopharmaceutical products.

Biopharmaceuticals are generally so complex and require descriptions of so many aspects that they resist assignment of simple (usable), unique and unambiguous names. It becomes much easier to assign or use names, if one ignores the need for them to be considered as unique, i.e., without clear one-to-one correspondence with a specific agent/product (and that sums up the current situation with nomenclature). Thus, conventional systematic chemical nomenclature is generally ambiguous or nonspecific, actually generic, when applied to biopharmaceuticals. Further complicating this chaotic situation, it is very common, even for manufacturers and FDA, to improperly (technically) refer to products by their active agent ingredient names and vice versa, to refer to active agent ingredients by the names of finished products. Use of oversimplified trivial or simply wrong nomenclature is also common. For example, Proleukin from Novartis (previously Chiron) containing recombinant des-alanyl-1, serine-125 interleukin-2, an interleukin-2 (IL-2) mutein or protein with modified amino acid sequence, is commonly referred to simply as IL-2 (not the actual active agent). With biopharmaceuticals and many other commercial products, the cumulative nature of most registry systems, with their concentration on collecting all nomenclature used to reference a chemical substance (e.g., used in the scientific literature), results in these systems collecting and cumulating nomenclature that is often inaccurate or simply wrong.

As discussed above and in What is a Biopharmaceutical?, there is no consensus on what constitutes or how to define a biopharmaceutical. The criteria that define and differentiate unique biopharmaceutical products must be defined before one can progress to even begin to discuss defining, differentiating and assigning nomenclature to biogenerics. The situation get even more complex when considering biogenerics. Biopharmaceuticals can only be described from a number of perspectives, with descriptions often ending up being as complex as the products.

Ultimately, biopharmaceuticals will need to be described and named from multiple perspectives and for different purposes, with registries linking and explaining the limitations of various nomenclature terms to be applied to each active agent and product, with this likely needing to be facilitated by use of various taxonomies, classifications. Even if one presumes that biopharmaceuticals can now be defined based on their analytical profiles (as propounded by some supporters of biogeneric regulations), including ignoring holistic descriptions of the "product-process-specifications" (process=product paradigm) and other aspects defining products, this involves a large set of data not conducive to naming or communication. Uniquely and unambiguously describing a biopharmaceutical product requires elaborating much diverse and complex information. Even then, with much, if not most, relevant information (e.g., manufacturing, specifications) never disclosed, in many respects, biopharmaceuticals are enigmas or black boxes, with just scattered bits and pieces of information available in the public domain. This further complicates the situation. When examined rigorously from a rigorous process=product or other chemical/pharmaceutical information-based perspective, most current discussions and references to biopharmaceutical products are imprecise, ambiguous and are all too often wrong, including in the scientific literature.

There are many types of names and identifiers relevant and applied to pharmaceutical products [e.g., see " The Development and Adoption of Nonproprietary, Established, and Proprietary Names for Pharmaceuticals," by D. Boring (FDA), Drug Information Journal, vol. 31, no. 3, p. 621-34, 1997]. For biopharmaceuticals, current names/identifiers include can trade names, including trademarks; systematic names (e.g., IUPAC and CAS); sequences and sequence database identifiers; ATCC and other culture collection accession numbers; nonproprietary names (e.g., USAN and INN); trivial (common) names; and other types of nomenclature. Currently, essentially all nomenclature and other identifiers as applied to biopharmaceuticals are best thought of as generic index terms or descriptors. For both biopharmaceutical active agents and finished products, current chemical and drug nomenclature systems have simply not been designed to uniquely identify biopharmaceuticals as commercial products. Similarly, nomenclature systems, e.g., USAN, INN and FDA proper names for biologics, designed to provide generic names have serious limitations, problems and appear unlikely to work well with biogenerics. All of these conventional nomenclature systems (except for proper names for biologics) have been primarily designed and used for drugs and other chemical substances, not biopharmaceuticals.

Conventional Systematic Nomenclature and Registry Systems Fail

Current nomenclature systems designed for chemical substances, including drugs, fail to provide names that include consideration of biopharmaceuticals' unique aspects, including those associated with their manufacturing processes, regulatory and their commercial aspects. These drug/chemical nomenclature systems further generally only concentrate on primary structure, which fails to describe all but the simplest biopharmaceuticals. Additionally, the various organizations that provide chemical (e.g., Chemical Abstracts Service) and pharmaceutical product nomenclature [e.g. USP (USAN) and WHO (INN)] appear to be slow and bureaucratic, and their systems too fine tuned and constrained to handling generic and other drugs and chemical, not biological, substances. What works well enough for generic and other drugs fails when applied to biopharmaceuticals and, particularly, biogenerics. Drug and chemical substance nomenclature systems are also inadequate in the sense that they each concentrate on providing just one unique name (and associated identifier, e.g., CAS Registry Number) or generic drug name. With biopharmaceuticals, particularly in the context of biogenerics, it appears that multiple types of official nomenclature are needed, i.e., both unique and generic names for both finished products and active agent ingredients; and the complexities and limitations of names requires annotations not included in current systems.

Assigning nomenclature or other identifiers to biopharmaceutical and biogeneric active agents and finished products involves the seemingly impossible tasks of combining (compromising) the need for unique names vs. the need for these to be usable in the real world vs. the need for names to describe the product vs. the need for names to portray aspects of similarities among products. Biogenerics, like all biopharmaceuticals, are each unique and highly complex, but the whole concept of biogenerics involves similarities and relationships; and, in the case of those therapeutically equivalent, products are ruled to be therapeutically interchangeable in the filling of prescriptions. Incorporating both products' unique aspects and biogeneric similarities into product nomenclature, including nonpropriatary (generic) nomenclature, confounds assigning official or other names.

For many people and purposes, just the trademark or other product name is often unique, unambiguous and sufficient enough to identify a specific biopharmaceutical product. In fact, the trademark is often the best practical way to uniquely identify a product. However, most such commercial and trivial nomenclatures as applied to biopharmaceuticals, with their complexity, are ill- or insufficiently defined, and often unusable. For example, besides trademarks conveying little or no information about a product, and trademarks are all too often only loosely linked to specific products. Trademarks may actually refer to multiple similar but different products in the same or different countries or at different times; may be restricted to marketing for specific indications; and new trademarks often arbitrarily replace established ones in different markets at different times. Also, trademarks are private property and (technically/legally) cannot be systematically used without permission; and similarly, trademarks (technically/legally) are adjectives, and cannot be used as names (nouns). Thus, trademarks are just one of many descriptors that identify biopharmaceutical finished products with varying levels of specificity and precision.

For many biopharmaceuticals, including recombinant proteins, the most basic aspects of their primary structure, i.e., amino acid sequence and, optionally, attachment of carbohydrate of other side chains, cross-linking and other modifications, can be described with varying degrees of success conventionally using linear notations, including lengthy linear representations of linked substructures, e.g., amino acid sequences, and systematic chemical nomenclature. But, these are not conducive to human understanding or communication, and still do not define or differentiate product-specific aspects of structure, much less define and differentiate products based on the process=product paradigm, much less their regulatory or commercial aspects. Systematic chemical nomenclature (names) is similarly a method for linear notation or representation of chemical structures (with trivial/common or derivative names adopted where this fails). However, for most biopharmaceutical products, traditional chemical nomenclature, e.g., IUPAC and Chemical Abstract Service (CAS) names, are of little use or relevance as unique identifiers. Systematic nomenclature simply has not been designed or adapted to uniquely identify either biopharmaceutical active agents or finished products.

Traditional systemic linear notation and nomenclature systems based on chemical structure are useful, but do not even begin to describe the complexity of most biological products, much less take into account unique regulatory and market/commercial aspects. With biopharmaceuticals, structural representations are only a starting point, telling one little about the 3-dimensional aspects of size and shape or about the diversity of distinct molecules and variations present, biological source, or other unique process- and formulation-related aspects. In simplified terms, current structural representations and nomenclature for biopharmaceuticals may be considered more as classifications or index terms, potentially applicable to multiple products, rather than unique identifiers. Chemical structures and systematic nomenclature are simply among the many descriptors relevant to describing and identifying biopharmaceuticals.

Systematic chemical nomenclature currently makes no distinctions between similar biopharmaceutical products, even where the products involve substantially different processing, e.g., sources and expression systems, and related characteristics and final formulations. As commonly used, systematic nomenclature is often unclear/ambiguous, whether it is referring to similar finished products or their component active agents. These systems oriented to serving the needs of the scientific community (e.g., indexing the scientific literature) simply avoid differentiating between commercial products, i.e., different commercial products and their active agent ingredients are treated as the same. For example, under the IUPAC and CAS systems, all similar recombinant hepatitis B surface antigen (HbsAg) protein-based hepatitis B virus vaccines are assigned the same names. Systematic chemical nomenclatures also avoid making distinctions based on regulatory determinations, another problem severely affecting their relevance for biopharmaceuticals and biogenerics. Similarly, nonproprietary pharmaceutical nomenclature systems, e.g., U.S. Adopted Names (USAN) and International Nonproprietary Names (INN), are designed primarily to provide non-trademark-protected generic, not specific names, for drugs, not biopharmaceuticals, a problem further discussed below.

Chemical registry systems, often associated with nomenclature systems, e.g., the CAS Registry System, are authority files linking chemical nomenclature terms for specific chemical substances (and pharmaceutical active agents or products). CAS and other registry systems assign or adopt unique names and numbers for specific chemical substances. Thus, the CAS Registry System assigns a unique CAS Name (usually adopting or adapting systematic/IUPAC nomenclature) and an associated unique CAS Registry Number to a chemical substance exemplified by groupings of nomenclature terms (from various sources and of various types that for biopharmaceuticals varyingly refer uniquely or ambiguously to active agents and formulated products). These groupings (indexing) of nomenclature terms include trivial/common, trade names (e.g., trademarks) and other nomenclature terms in actual use. The CAS Registry concentrates on associating and bringing together names for chemical substances (not commercial products) as used in the scientific literature it indexes. By their very nature, nomenclature systems tend to collect names varying greatly in their specificity and accuracy, often including names that are simply wrong, but have been used in the literature or other source(s) the registry system is intended to serve. Thus, Registry systems contain systematic nomenclature, related unique numbers/identifiers and other names which very rarely can be authoritatively linked to specific biopharmaceutical product active agents and/or finished products (particularly, when multiple similar products exist).

CAS and other nomenclature and registry systems generally work well enough for drugs and other chemical substances, which can be much more precisely identified and described based on primary structure than biopharmaceuticals, but fail when applied to biopharmaceuticals. The CAS and other registry systems and name authority files generally support applying registry names/numbers as indexing terms, with these not really being unique and unambiguous in the case of biopharmaceuticals. These systems' "unique" names and registry numbers are almost always nonunique and ambiguous when multiple biopharmaceuticals are involved. Similar (including seemingly or relatively identical) biopharmaceutical active agents and/or products that would be considered unique in terms of the process=product paradigm or by anyone familiar with them are generally treated as all the same and grouped together in the same record (same systematic name, Registry number, etc.). In these systems, recombinant protein (and other) products from different manufacturers are commonly assigned the same chemical names and registry numbers, irrespective of their being different in diverse aspects other than active agent primary structure (amino acid sequence); and with distinctions between active agents and formulated products often lacking or ambiguous. Another major failing of registry systems, associated with their primarily serving as indexing authority files, is that they contain and present nomenclature terms as used in the literature, commerce or whatever they are tracking. Thus, particularly with biopharmaceuticals, registry systems cumulatively compile many ambiguous, nonunique and erroneous synonyms that have been applied to an active agent or product.

Conventional Generic Drug Nomenclature Systems Fail

Nomenclature systems have also been developed and adapted to provide generic names for pharmaceuticals, primarily just drugs. This includes names for generic drugs with varying types of relationships, including being designated equivalent/substitutable in terms of filling prescriptions. Here, what starts out as a relatively unique name for a pharmaceutical's active agent ingredient is officially or otherwise adopted or used to refer to siimilar finished products containing identical active agents (i.e., presumed to be identical or meeting minimal pharmacopeial standards of identity). Specific systems have been developed and officially adopted by countries for the identification, including labeling, of generic drugs, i.e., drug products containing what is considered to be identical chemical substances as their active agents. This sameness or products being judged identical or all practical purposes are often based on products' active agent ingredients meeting idealized minimal standards/specifications, e.g., those established by the U.S. Pharmacopeia (USP) and European Pharmacopeia (EP).

The predominant systems for nonproprietary and generic nomenclature for pharmaceuticals are U.S. Adopted Names (USAN) assigned by the U.S. Pharmacopeia (USP) and used in the U.S., and International Nonproprietary Names (INN) assigned by the World Health Organization (WHO) and used in the European Union and most countries worldwide. These nonproprietary (not trademark-protected) generic pharmaceutical names are designed to be somewhat descriptive, although these names may be meaningless to most (e.g., alteplase for recombinant tissue plasminogen activator and nonacog alfa for recombinant Factor IX). For nonproprietary (generic) names in the U.S., U.S. Adopted Names (USAN) are assigned by the U.S. Pharmacopeia (USP), and International Nonproprietary Names (INN) assigned by the World Health Organization (WHO/UN) are generally used by the EU and most other countries worldwide. The USAN and INN systems have been developed in the context of their names being recognized as the official nonproprietary (non-trademark-protected) names for drugs. USAN or INN names are assigned to pharmaceutical active agents, with these names then applied to finished drug products, particularly those considered the same/identical, including being bioequivalent and, particularly those considered therapeutically identical/substitutable in terms of filling prescriptions. For example, paracetamol is the INN and acetomenophen is the USAN adopted for similar drugs containing N-(4-hydroxyphenyl)acetamide (IUPAC Name), CAS Registry Number 103-90-2, and synonyms; and Tylenol is one trademark for a branded form of acetomenophen marketed in the U.S., along with other branded versions of the drug (using different trademarks) and others that are simply labeled as generic acetomenophen. Both INNs and USANs are often the same or very similar, with USANs largely based on INNs. Each uses word stems or portions of words to represent structural, activity, class or other characteristics of drug substances, with these descriptors strung together to form a unique INN or USAN for each active agent. Both USANs and INNs are developed by international committees associated with USP and WHO, respectively. The process of selecting and adopting a name can take many months or even years.

INN and USAN nonproprietary names for drug substances have been used for decades, during which these systems have been adapted and finely tuned for handling of generic and other drugs (not biopharmaceuticals and, definitely, not biogenerics). These naming systems are closely associated with pharmacopeia (drug standards compendia), which provide consensual minimum specifications that pharmaceutical (primarily drug) active agents must meet in order for them to be given the same name and considered to be generic (including for the writing and filling of prescriptions). The USP also develops monographs reviewing and evaluating medical/use aspects of each generic drug (i.e., as a grouping of products meeting related pharmacopeial standards and assigned the same USAN).

INN and USAN nonproprietary names have been assigned to essentially all biopharmaceutical active agent ingredients in marketed pharmaceuticalss, particularly those marketed in the U.S and Europe. However, in the case of biopharmaceuticals, unlike with the vast majority of drugs, these names are not used in commerce as generic names as they were designed, since essentially no biopharmaceuticals have been officially recognized by FDA or other authorities as being therapeutically equivalent/substitutable (i.e., USAN and INN names for biopharmaceuticals are not used in filling prescriptions). For example, a U.S. pharmacist encountering an otherwise seemingly good (fully descriptive) prescription specifying Insulin Human, the USAN for regular uncomplexed insulin, in a common presentation (e.g., 1000 Units in a vial) must contact the physician writing the prescription to determine the specific branded product he wants his patient to receive, despite approved products from two manufacturers meeting this description. Similarly, even though a version of recombinant somatropin (Omnitrope) has received FDA approval as a biogeneric (an oversimplification), this did not include designation of equivalence with the innovator product against which it was compared; and all prescriptions for somatropin must specify the exact branded product, e.g., by trade name (trademark). Thus, besides not being designed for biopharmaceuticals, conventional nonproprietary names assigned to biopharmaceuticals have not been used much in commerce.

The underlying paradigms on which INNs and USANs are based, although used successfully for generic drugs, are simply unlikely to work with biopharmaceuticals, including with any new laws expected to eventually be enacted concerning generic biologics. As an indication of the problems with current nonproprietary nomenclature regimes (USAN and INN), particularly their fixation on a single name for an active agent being adopted as the generic name for similar/identical finished products containing these, European Biopharmaceutical Enterprises (EBE, part of EFPIA), the main European biopharmaceutical trade association, has submitted a proposal to WHO that unique (not generic!) INNs be solely adopted as the official names for biopharmaceuticals approved as biosimilars in the European Union, even including where approvals include designation of therapeutic equivalence (although this has not happened yet). This proposal is fundamentally flawed and in conflict with long-established generic drug nonproprietary nomenclature and drug regulation worldwide.

USAN and INN names may work well enough as nonproprietary (generic) names for some of the simplest biopharmaceuticals, notably those regulated in the U.S. as drugs, e.g., insulin and somatropin, but these names were not designed for more complex biopharmaceuticals, including those regulated in the U.S. as biologics (which takes in most biopharmaceuticals). With the decades of baggage these systems carry; their name selection and adoption processes being lengthy; these systems hosted by large, bureaucratic public sector organizations; and, particularly, with these systems adapted, finely-tuned and working well for the needs of generic drugs, e.g., Hatch-Waxman Act-related FDA generic drug approvals, it is hard to believe that they can or even should be adapted or substantially redesigned (which is what is required) for biopharmaceuticals. Besides current USAN and INN systems being slow, bureaucratic and solely oriented to drugs (chemical, not biological, products), any new biopharmaceutical nomenclature system proposing official generic and unique nomenclature for adoption by governments and others may need to retrospectively review and adopt unique and generic nomenclature for currently marketed products, a task for which established both systematic and nonproprietary nomenclature systems are unprepared and unsuited. Also, simply assigning a nonproprietary generic name does little without an explanation of what it does/doesn't cover (i.e., a definition or description of what is covered), including descriptions (and unique names/identifiers) for the products covered, and without inclusion and explanation of the relationships of the assigned nonproprietary name to other nomenclature. Restated, these systems operating independently, providing negligible annotations/explanations and not functioning as Registry systems will not work well with biopharmaceuticals. Neither USAN nor INN are designed to do more than simply provide their own names and associate these with corresponding CAS or systematic nomenclature, CAS Registry Numbers and other nomenclature. Biopharmaceuticals are simply too complex and ill-defined to lump associated names together without explanations/annotations. Further, in this author's opinion, it appears that both unique and (bio)generic names for both finished products and active ingredients will likely be required for biopharmaceuticals, i.e., four nonproprietary names, rather than one generic name, should be available for use with each marketed product; and any nomenclature and registry system will need to track changes in the product, often assigning new names/identifiers, as products evolve, i.e., follow changes that effectively redefine the product as new/different or a new version, including relevant changes in formulations, manufacturing processes, manufacturing and marketing companies, therapeutic equivalence, etc. Current systems work well enough for what they have been designed for, i.e., drug substances and drug products, but these cannot be expected nor should be altered to accommodate biopharmaceutical paradigms.

New Nomenclature and Registry Systems Are Needed

New, not reworked chemical substance and drug, nomenclature regimes are required for biopharmaceuticals. Associated with this, the author is proposing the U.S. Biopharmacopeia Registry and nomenclature system.

Any new biopharmaceutical nomenclature system should start from scratch, with a study of what is needed. This would include developing working definitions for what criteria constitute a unique and differentiate similar biopharmaceutical active agents and products; the information needed to describe this (i.e., how to uniquely define a biopharmaceutical); what relationships define a similar or generically-related biopharmaceutical; the information needed to describe this; a review of current nomenclature systems for what should work and not work for biopharmaceuticals and biogenerics; a survey of current stakeholders, including innovator and biogeneric companies, regulatory agencies and formulary and pharmacy organizations to make sure their needs are met; and, finally, devising a system of consistent, consensually-acceptable guidelines/rules for developing biopharmaceutical nomenclature (both unique and generic names for both active agents and products, and maybe other types of names for other purposes). As with any information system, the resulting nomenclature will involve many compromises. This will not happen overnight, but with Congress expected to get around to considering new laws for generic biologics in 2008, the time to start is now.

With any new biopharmaceutical nomenclature and registry system, it is likely that existing systematic and nonproprietary nomenclature (USANs and INNs) will often be found appropriate and adopted for active agents and/or products, particularly as generic names. Similarly, it will likely be easier to develop (bio)generic names vs. truly unique names. Much as with generic names, unique names/identifiers could be constructed a number of ways. These may end up being a stylized series of descriptors, and/or a unique Registry Number or other unique identifier may be associated with a stylized textual description, various taxnomies/classifications, analytical and other data and/or a series of other identifiers/descriptors, including other nomenclature. No matter how it done, annotations will be required regarding the nuances and limitations of some or all of the nomenclature terms and identifiers applied to each agent and product.

The author recommends that a new system of unique and nonproprietary names be adopted for biopharmaceutical products and active agents, with this being industry-, not public sector or international organization-based; the parent organization being small, adaptable, agile and responsive to the needs of industry (quick turnaround); and providing names that will satisfy both innovator and biogeneric companies (with FDA, other governments and (bio)pharmaceutical information resources adopting the unique and/or (bio)generic nonproprietary nomenclature/identifiers provided as they see fit, or not).

Nomenclature in the Context of Biogenerics: Major Controversies Loom

With most everyone now at least accepting that many biogenerics are in the development pipeline and that related regulations are inevitable, and with FDA, EMEA/EU and other regulatory agencies already having gone through the motions of public input/comment regarding biogeneric regulations (so far, concerning only the simplest biopharmaceuticals), terminology and nomenclature, rather than the need for or impossibility of biogenerics, may become the next major battlegrounds. Nomenclature issues are likely to be very controversial, perhaps, even more than the regulations for biogenerics (abbreviated testing and therapeutic equivalence), since product names directly affect marketing and how everyone refers to and thinks of biogenerics. How will official nonproprietary names, including those used for writing/filling prescriptions, be assigned and by whom? Will these be generic, covering similar products and/or active agents, and/or unique for each product and/or active agent? What information should names for biogenerics convey (or not)? Particularly, what official nonproprietary and/or other names will the medical community and public use for biogenerics, and be used for marketing and filling of prescriptions?

Currently, no biopharmaceuticals, including simpler products regulated as drugs, e.g., insulin, have been designated as officially therapeutically equivalent and substitutable in terms of writing/filling prescriptions. For example, when a U.S. pharmacist processes a prescription specifying recombinant regular insulin, x units, he/she cannot simply fill it with either the matching Eli Lilly (Humulin) or Novo Nordisk (Novolin) product, based on best price, what is in stock or any other factors. If nothing else than to avoid liability and lawsuits, because these products are not designated as therapeutically equivalent (AB rating), the pharmacist must contact the prescribing physician to determine which exact branded product to provide. However, sooner or later, biogenerics, including biologics, will receive approvals with designations of therapeutic equivalence. In such cases, for filling of prescriptions, will unique product names/identifiers be used, or will a common generic name be used for products ruled equivalent/substitutable (the same as with generic drugs)? Will and should biologics be incorporated into the Orange Book (which likely will not work), the current U.S. authority for recognition of specific products and substitutions; or will a new system be required for biologics and other biopharmaceuticals?

Nomenclature Controversies Loom

Official nomenclature for biogenerics will likely be a very contentious issue, potentially pitting the needs of safety vs. economics. One of the main societal goals driving biogenerics is the cost savings they are expected to provide. These cost savings (cheaper products) are associated with the generic manufacturer avoiding original research; conducting abbreviated (shorter, simpler) testing, including bioequivalence/pharmacodynamic rather than Phase III-type safety and efficacy trials; and the generic not requiring marketing and detailing like branded products. Like generic drugs, as envisioned by supporters, many future biogenerics may not be branded products, i.e., marketed or known by their trademark, rather they will be known by their generic names and essentially not marketed, simply stocked by pharmacies, much like current generic drugs. Innovator companies obviously prefer to continue use of unique names, particularly brand (trademarks) for which they have worked years/decades and invested considerable sums to build brand recognition. Official adoption of unique names for biogenerics, e.g., brand names (trademarks), would allow innovators to retain considerable marketing advantage, and put biogenerics at a significant disadvantage. In fact, unique names may effectively require biogenerics to be marketed, detailed, advertised, etc. much the same as branded products, increasing the costs and providing considerable disincentives for companies to even get involved in biogenerics. On the other hand, use of generic names, e.g., conventional USANs and INNs, for biogenerics, particularly those ruled therapeutically equivalent, facilitates pharmacy substitution and supports generic drug-like cost savings. However, post-approval adverse event monitoring will be an important aspect of most biogeneric approvals, and use of generic names, particularly for filling of prescriptions, may make post-approval pharmacosurveillance difficult or impossible. With U.S. adverse event monitoring systems already having a reputation for being dysfunctional, some assert that pharmacosurveillance will be impossible without use of unique names. Until new nomenclature and registry systems are developed for biogenerics, this is an area where compromises appear difficult or impossible, with the decision seemingly involving use of either generic names (based on the active agent) or unique names (for finished products). This has not been an issue with generic drugs, which are presumed similar or identical enough to innovator products that post-approval monitoring has not been an important factor in their approvals. Other related issues may also arise. For example, once a biogeneric equivalent of a product has been approved, if generic names are used officially, is it fair (does this even matter?) and what problems (if any) will be caused by suddenly adopting a generic name for innovator branded products that have been on the market for perhaps several decades?

No matter what, unique names for products, not active agents, will be required, whether they are used in filling of prescriptions or not. Some have proposed that nonproprietary names (USANs and INNs) be modified to construct unique names for products and/or active agents. For example, names could be constructed by appending the trade or company name with a USAN, INN or other name to make it unique. Another option that has been suggested would be to use generic or descriptive names and add unique designations, perhaps, based on order of approval, e.g., human insulin 1, 2, 3. Some presume that generic or other descriptive names, when associated with companies, trade names and, perhaps, other information, e.g., regulatory approvals or indications, are sufficient to uniquely and unambiguously identify biopharmaceutical products. Such linking of multiple descriptors increases the precision in identifying and naming a biopharmaceutical, and could be both functionally descriptive and unique. However, such names will likely look and sound too much alike, making them prone to being mistaken for each other, and ill-suited for medical and prescription uses. Inclusion of company and/or brand names to construct unique names simply may not be acceptable, e.g., officially adopted names may look too much like advertising, and companies might game the system to increase their brand and company name exposure. Or, the health care system could be forced to use unique, meaningless identifiers, e.g., National Drug Code (NDC) or other registry numbers or codes. But pronounceable names are needed, not numbers.

No matter what type of names are assigned to biogenerics, there will be problems. To date, the few similar biophamaceuticals approved by FDA as follow-on proteins (generic drugs) through abbreviated filings have followed the established generic drug-like path of using nonproprietary drug names (USANs and internally-used CBER/FDA proper names for biologics) for both the innovator and follow-on product; and all biologics applications have involved full, not abbreviated filings, with none designated as officially therapeutically equivalent. The EU has not yet issued official names for the few biosimilars (each a recombinant somatropin product) it has approved, nor granted any biosimilars therapeutic equivalence. But, this situation will change sooner or later. FDA appears likely to avoid the difficult and contentious issue of unique vs. generic names for biogenerics, much as it has for years and continues to avoid even releasing proposed guidelines for submission of applications for even the simplest products regulated as drugs, much less more complex products regulated as biologics. This follows the pattern of FDA avodining and going out of its way to not be or be perceived as a source for pharmaceutical product information. Ultimately, there may be different degrees or types of biogenerics and therapeutic equivalence/substitutability, along with various caveats and warnings. Should and how would different classes of biogenerics and complex issues of equivalence/substitution be reflected (or not) in the names to be used?