By Ronald A. Rader (draft, 9/20/2006)
Introduction
There are no accepted or recognized definitions of biogenerics, biosimilars, follow-on proteins and biologics, biocomparables, off-patent or multi-source biopharmaceuticals and other terms for generic biopharmaceuticals. This is obvious from any review of recent presentations, articles and studies on the topic. [Note, for the moment, the author has adopted the term "biogeneric" to broadly refer to all generic biopharmaceuticals, including biosimilars, follow-on proteins and other related terms]. The definitions and paradigms adopted for biogenerics will profoundly affect the (bio)pharmaceutical industry, healthcare systems and economies worldwide. Just about everything concerning biogenerics is controversial, and there is a lot at stake, since every successful biopharmaceutical will sooner or later face generic competition; and, similarly, sooner or later, every successful biopharmaceutical company will be involved or competing with biogenerics. This article broadly examines some of the basic concepts, paradigms, terms and related issues concerning biogenerics. This article does not get involved in specific definitions or criteria regarding similarities among biopharmaceuticals.
This chaotic situation with biogeneric terminology parallels the situation with the wide diversity of definitions in use for what is/isn't a biopharmaceutical (see related articles by this author in BioExecutive, March and May 2005 issues). For example, some consider biopharmaceutical as referring to obviously biological products manufactured using live organisms (biotechnology), with biopharmaceuticals being the intersection of pharmaceutical and biotechnology. This is the definition adopted and recommended by this author. Others restrict the term to only genetically engineered products (recombinant proteins). Others, including much of the popular and financial press, companies and major trade associations, ignore products' biological nature and involvement of biotechnology and include any pharmaceutical (including small molecule drugs) associated with a smaller, biotech-like company, any pharmaceutical that seems or can be portrayed as high-tech, or simply consider all pharmaceuticals (and companies and industry) to now be biopharmaceuticals (i.e., 'biopharmaceutical' being the union of pharmaceutical and biotechnology).
The concepts and terms used for biogenerics are based on perceived relationships (similarity, comparability, equivalence, etc.), classifications, taxonomies, etc., with these based on judgments and generalizations, currently most often based on unspecified criteria, for relationships among active agents and/or finished products. The basic presumption underlying biogenerics is that active agents and/or finished biopharmaceutical products can be considered to be similar or even the same (for all practical purposes) based on commonalities of their underlying nature (source, structure, composition, specifications, etc.), which are largely dependent on their manufacture, and activity (biological, clinical). These similarities are presumed to enable comparisons and predictions of product safety and efficacy (for regulatory and health care delivery purposes) based on knowledge of one or more related products. In the extreme, these similarities enable designation of therapeutic equivalence, allowing substitution in the filling of prescriptions.
Much as with definitions and views of 'biopharmaceutical' and 'biotechnology,' entity-based and other technically-grounded, including regulatory, definitions for biogenerics are in common use. And, much as with 'biopharmaceutical' and 'biotechnology,' many in the popular press, financial community and even knowledgeable scientists and industry specialists often ignore science, technology and regulations, and base their views and definitions of biogenerics on perceived commercial or other similarities, e.g., including products competing for the same indication, next- or later-generation products, products with similar names, etc. Some consider only later similar products to be biogenerics, while others also consider the first or "innovator" products to be biogenerics (once there are others in its class). Some concentrate on, while others simply exclude or ignore, the hundreds of outright copies/knockoffs already manufactured and marketed primarily in lesser-developed countries, often restricting their interests to products in or destined for the market in highly developed countries, particularly the U.S. and Europe. Others restrict biogeneric terms only to biopharmaceuticals involving simplified or abbreviated regulatory filings/approvals based at least partially on demonstrating chemical, biological and pharmacological similarities with another product(s).
What parameters or criteria make biopharmaceutical active agents and products generic, (bio)similar, (bio)comparable, follow-on proteins, multi-source, etc.? What is actually meant by each of these and other terms? For example, some commonly refer to all insulin-related products in development and in the world market as being biogenerics; including regular insulin, whether recombinant or animal-derived, and insulins with different molecular structures, activities and pharmacological profiles, including fast- and slow-acting insulin analogs/muteins, those with other molecular modifications (e.g., pegylation) and insulin formulations with novel modes of delivery (e.g., recently-approved Exubera involving insulin in glassified mannitol particles for inhalation). To many, considering all of these products to be biogenerics is perfectly proper, while to others it is ridiculous to include so many obviously dissimilar products with vastly different chemical, biological and pharmacological profiles.
Biases and Preconceptions Prevail
With no consensual or other recognized terminology available, the terms and definitions currently being used for biogenerics are often dependent on their context and the intentions of the user, with these often based on individual or corporate biases and vested interests. This does not even begin to take into account that most of what has been written on this topic has used terms inconsistently, improperly and rarely defines the terms being used. Terms and definitions are also often simply made-up or contrived, including by those knowledgeable on the topic, as a means to try to avoid the vagueness and baggage associated with terms as used by others. Many avoid making distinctions based on temporal relationships, considering all similar products as being biogeneric versions of each other, i.e., include the original or "innovator" product as being biogeneric along with other similar products that came later. Others give precedence to the "innovator," and consider only later similar products to be biogenerics.
All current terms used to describe biogenerics have connotations and evoke preconceptions that may be used to support, denigrate or obfuscate various views and discussions of the topic. Even the term generic (and similar, comparable, follow-on, etc.) in the context of biopharmaceuticals can have vastly different connotations. For some, the term "generic" (and biogeneric) applied to biopharmaceuticals is objectionable, rightly or wrongly evoking images of (bio)generics as inherently inferior, linking these products to generic drugs and the generic drug industry, which has its own history, regulations and negative public perceptions. For example, ask yourself, presuming cost was not a factor and you required erythropoietin (EPO) for treatment of anemia associated with kidney failure or cancer chemotherapy, would you prefer to receive Epogen from Amgen or Procrit from Ortho/Johnson & Johnson, products with nearly two decades of manufacturing, clinical and post-marketing experience, or a new biogeneric version ruled by FDA as identical for all practical purposes and, therefore, just as safe and effective, but likely not tested in large-scale safety and efficacy trials, for which little or no post-approval surveillance studies are likely yet available, and likely manufactured by a new entrant to the field, perhaps, even manufactured in Eastern Europe, China or another lesser-developed country? Similarly, terms such as "innovator" and "follow-on" entail connotations and preconceptions, e.g., with follow-on implying to some that biogenerics are newer and better (incorporate newer or current vs. usually decades-old "innovator" technology); and with "innovator" implying that biogenerics are less innovative or of lesser quality.
In this author's view, with no consensus or substantive regulatory guidance, all views and definitions of biogeneric terms are acceptable, provided one sufficiently defines the view/definition being used or makes it clear in context. However, as discussed below, some terms are best avoided or already have official definitions that should be recognized and avoided for other uses.
Commonalities in Views/Definitions of Biogenerics
Biogeneric terms and definitions should, ideally, start with or be based on entity- or regulatory-based (further discussed below) evaluations, i.e., based on structure, composition, source, manufacturing process, biological activity, approvals and other aspects of active agents and finished products to judge uniqueness and similarities. For example, for many purposes, it would be proper to consider new products containing injectable high-purity recombinant regular insulin (with the same primary amino acid sequence, biological activity, etc.) and similar method of manufacture, e.g., E. coli expression, to be biogeneric products (e.g., similar to Humulin from Lilly, originally approved by FDA in 1982), while excluding similar products with different manufacturing processes, e.g., a different expression system, having modified primary structures (muteins), molecular modifications (e.g., pegylation), different formulations (e.g., particles for inhalation) or having different impurity or other analytical profiles. But one could also take a slightly broader entity-based view,, e.g., considering all high-purity injectable regular insulins to be biogeneric or even the same (i.e., insulin is insulin, no matter how it's made), whether the insulin has been isolated from human pancreas, semi-synthetically derived from animal-derived insulin, or is a recombinant product expressed by bacteria, yeast, plant or another expression system. The fact that many insulins are not bioequivalent or have not received approvals as biogenerics does not figure into many peoples' view/definition. Others may take even broader entity-based views and include as biogenerics products involving insulin muteins, molecular modifications, vastly different formulations (e.g., inhalable powders), etc. Thus, seeming rigorously-defined entity-based views of biogenerics can variably include or exclude related products.
Temporal relationships are a common aspect of many views and definitions of biogenerics. Usually, and particularly in regulatory contexts, a later biogeneric product is compared to an earlier, original product often termed the "innovator" product, based on the presumption that its development involved original R&D and innovation on the part of its developer, with innovator products approved based on full, not abbreviated, clinical and other testing, e.g., Phase III-type safety and efficacy trials. [Note, although this author might favor a more neutral term, e.g., "reference," "innovator" is already widely used, including throughout this article].
Closely related to temporal aspects, patents and other government grants of marketing exclusivity, e.g., orphan designation, figure prominently in the commercialization (or not) of biogenerics. Obviously, biogenerics cannot be brought to market, if relevant patents or other grants of exclusivity are held by others, usually the company having developed the innovator product. Thus, most biogenerics cannot be commercialized until related patents expire. Due to variability in the issuance of patents and time in R&D and testing, marketing of most biogenerics will usually follow 10-20 years after launch of the innovator product. However, contrary to many preconceptions, many current blockbusters (sales >$1 billion/year) and other major biopharmaceuticals are very similar and are biogenerics in many respects (other than their regulatory approvals). Many of these products were developed, usually by large (bio)pharmaceutical companies, despite each company clearly infringing patents held by the other developer(s), with the companies engaging in legal disputes that have been almost always settled by cross-licensing, allowing each other's products to enter or remain on the market. This has been the case with the multiple, in many respects, biogeneric versions of recombinant insulin, somatropin, hepatitis B vaccine, interferons alpha, beta and gamma, and certain other recombinant proteins from major manufacturers. In this context, a large number of conventional vaccines and blood/plasma products are biogenerics, although patent disputes have not been involved with many of these mostly older non-recombinant products.
Therapeutic equivalence is another concept commonly applied to biogenerics, much the same as with generic drugs. In the extreme, therapeutic equivalence involves innovator and generic pharmaceuticals (officially in the U.S., currently just drugs) being considered sufficiently identical in terms of their active agents and bioequivalence/pharmacodynamics (from comparative trials) such that the generic may be substituted for the innovator in the writing and filling of prescriptions. Many common drugs may be substituted with generic equivalents, and the majority of drug prescriptions filled in the U.S. are now filled with generics. Although there are many precedents for FDA (and other regulators) approving biopharmaceuticals as generics based on abbreviated filings (further discussed below), these approvals have been restricted to the few relatively simple biopharmaceuticals, e.g., insulin, somatropin and other peptide hormones, that happen to be regulated as drugs, not biologics (which takes in the majority of biopharmaceuticals and which are generally much more complex). Even though they often involve abbreviated and comparative clinical testing vs. a similar innovator product, none of the FDA biogeneric-like drug approvals, to date, has included official designation of therapeutic equivalence/substitutability.
However, in practice, including administration to the patient, a large number of biopharmaceuticals, including complex biologics, are often considered and treated as therapeutically equivalent and interchangeable. For example, many blood-derived products, e.g., Albumin or Red Blood Cells, from hundreds of licensed manufacturers are considered essentially equivalent and interchangeable; and various vaccines are considered similar and bioequivalent enough, such that their approved indications recognize that a series of inoculations started with one product may be finished using another.
Geographic considerations can profoundly affect views and definitions of biogenerics. For many users and uses, the only products that matter are those in the U.S., European Union and, perhaps, a few other major pharmaceutical markets (highly developed countries). However, as discussed below, there are many, apparently hundreds, of biogenerics manufactured and marketed in lesser-developed countries, with these often being direct copies or knockoffs of innovator products. Already, for many, if not most, successful biopharmaceuticals in the U.S and EU markets, there are copies in lesser-developed counties (where lack of issued or active patents and/or their enforcement allows; often seemingly in violation of World Trade Organization (WTO), TRIPS and other international treaties concerning intellectual property). In China (PRC) alone, there are commonly reported to be over 20 manufacturers of recombinant granulocyte-colony stimulating factor (G-CSF; copies of Leukine from Amgen) and many other biopharmaceuticals, e.g., see the Biopharmaceutical Products in China database implemented at one of this author's Web sites. And, there are over 180 insulin products reported to be in the world market.
Contrary to the presumptions of many, development of products as biogenerics may not always save time and/or money, and may complicate and delay development of some products. In some cases, it may turn out that following the traditional non-abbreviated development path, including full Phase III placebo-controlled trials, will be quicker, simpler and cost comparable to trying to gain approval based on proving similarities, which may be scientifically very difficult, and conducting trials comparing the biogeneric with the innovator/reference product. Although very much a special case, it took about three years for FDA to approve Omnitrope (recombinant somatropin) from Sandoz/Novartis, while the product could have been approved and on the market (making money), perhaps, with only about a year delay from filing, if the company had simply filed a traditional, non-abbreviated NDA (like each of the other seven somatropin products already in the U.S. market). Was the delay worth it? - probably not in a monetary sense. But, Sandoz/Novartis did achieve recognition as the leading biogenerics developer, and the company has helped pave the way for other biogenerics. In some cases, traditional full regulatory filings, based largely on placebo-controlled trials, will be less risky than comparative bioequivalence trials. What if your product is shown not to be similar/bioequivalent?). This recentlys happened with BioPartners GmbH's application for approval of a biosimilar recombinant interferon alpha-2a (Alpheon) product, essentially a copy of Roferon-A from Hoffmann-La Roche. In some cases, the lack of access to innovator's in-process and other controls, standards, assays, etc., may make it difficult or impossible to convince regulators of sufficient similarity between products. With innovators generally having already manufactured their product for 10-20 years, the innovator may well have developed proprietary analytical assays, data, processing and knowledge that the biogeneric developer lacks.
Another common biogenerics-related presumption is that introduction of biogenerics will lead to price decreases (probably true) and that newer biogenerics will be less expensive than established innovator products. The later may not be true. With the costs for biopharmaceutical manufacture being much higher than for most drugs, innovators likely have attained economies-of-scale, dominant market share and brand recognition, and likely long ago paid for their R&D and manufacturing infrastructure, etc., such that, as needed, innovators may be able to easily meet or beat the price of new biogenerics while still making a healthy profit from their mature products.
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Much as biopharmaceuticals as commercial products can only be fully defined by considering their entity, regulatory and commercial aspects, there are three basic, underlying paradigms or ways to view and define generic biopharmaceutical products and relationships:
1) Entity-based (product=process) paradigms: Biogeneric products and relationships start with consideration of chemical/biological identities and activities, manufacturing processes and specifications - the aspects that define and differentiate distinct biopharmaceutical products. To the extent that biopharmaceuticals can be defined and differentiated by their identity/source, methods of manufacture and specifications, products and their active agent ingredients can be largely defined and differentiated on the basis of their manufacture 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. "Process = product" is very similar or much the same as the chemistry, manufacturing and control (CMC) aspects of GMP manufacturing.
The process=product paradigm has long been the basis for FDA and other definitions, regulation and approvals of biologics and other complex biopharmaceuticals. A product from one company/establishment, manufactured using a consistent biological source (genes, cell lines, etc.), a consistent set of processes, under a consistent set of conditions, using consistent in-process and other controls and assays, and with a consistent set of final specifications constitutes a unique biopharmaceutical product (with these factors generally defined by the product's approval). Thus, a specific active agent manufactured by a manufacturer from a consistent source (e.g., 'x' gene from 'y' organism), using consistent biological materials (e.g., vectors, cell lines, expression systems, etc.) and processes, including biological and down-stream processing, with consistent composition and activity (purity, potency, etc) and consistently formulated, constitutes a specific biopharmaceutical product. Regulatory approvals concern the associated ranges of allowable variations in these aspects. In many of these respects, products from the same manufacturer often vary from batch-to-batch, but are considered to be the same product and marketable, presuming their many aspects fit within the ranges that have been approved for the product. Thus, many of these aspects of "comparability" used for judging the sameness of products, e.g., different manufacturing lots, also apply to biogenerics from different manufacturers.
In this process=product context, particularly since manufacturing processes are so complex (and never fully publicly disclosed), biopharmaceuticals are considered impossible to exactly replicate by all but their licensed manufacturers (usually the innovators). This forms the basis for assertions that biogenerics (abbreviated approvals) are inherently impossible. The presumption is that only the approved manufacturer can duplicate his own process (and product), with this including proprietary source organisms (e.g., cell lines) and often hundreds of in-process and other assays, reference standards, trade secrets, etc. (and even the same manufacturer often has problems making approvable "comparable" products from batch-to-batch). This is the classic view taken by FDA and regulators in other highly-developed countries, and forms the basis for regulation of all but the simplest biopharmaceuticals.
Biopharmaceuticals, due to their biological nature and source, are inherently very complex, often defying rigorous (bio)chemical analysis and terse descriptions. Even products indistinguishable using all available analytical technologies can be substantially different, e.g., have different safety and efficacy profiles, such as immunogenicity. Hardly any biopharmaceuticals are truly homogeneous pure substances readily definable by the usual chemical information artifices, including chemical structures and systematic nomenclature. Most are very large or macromolecules, usually polymers, particularly proteins. However, unlike synthetic polymers, few proteins are composed of consistently repeating monomers/substructures. Most , including seemingly straightforward well-characterized recombinant proteins, involve considerable (micro)heterogeneity, with the active agents actually comprising a variety of molecular subspecies with variations in structural aspects, e.g., folding and other 3-dimensional conformations, formation of dimers and other associations of chains, S=S and other covalent intra- and inter-chain linkages, variable oxidation states, formation of aggregates, etc. Each molecular subspecies may have different biological activities, including immunogenicity and other safety-related aspects, which may detract from, contribute to or have no effect on the activity, safety and efficacy of the final product. Most mammalian proteins further involve glycosylation or attachment of carbohydrate polymers of varying composition at varying sites. Everything gets much, much more complex when dealing with less well-characterizable products, including some non-recombinant proteins, e.g., many blood plasma-derived products, and hyaluronidase, which is considered to be uncharacterizable. Everything gets even more complex when dealing with more cell- and organism-based biopharmaceuticals, e.g., many vaccines, which involve inactivated or whole live bacteria or viruses; viral and other vector-based gene therapies; cellular therapies; cultured tissues, etc.
Current analytical technology does not allow similar biopharmaceuticals (with different manufacturing processes or manufacturers) to be proven to be identical in all potentially relevant respects, including immunogenicity and other adverse effects. This complicates conclusions regarding similarity and uniqueness.
In many respects, the "process=product" paradigm is already understood by most people, particularly when analogies are made to wine, cheese and other biotechnology products that are similarly defined based on their source, processing and specifications, including often being defined by meeting standards of identity. Everyone appreciates that even identically-named products, e.g., wines and cheeses, from different manufacturers are each unique, e.g., based on flavor, texture and other characteristics. But, people also understant that for many purposes, e.g., regulation and commerce, these products can be considered the same (generics), e.g., cheddar cheese is cheddar cheese, and 'xyz' wines from different manufacturers contain the same amount/range of active ingredient (ethanol), yet each finished product is perceptively unique.
With some products, such as immune globulins and other blood products manufactured from pooled blood/plasma often from 1,000s of donors, the products are so variable and uncharacterizable at the molecular level that they are defined on the basis of their heterogeneity (averaging or balancing out in such complex mixtures; with the product defined primarily by its manufacturing process). Yet, many of these complex biologics are manufactured by hundreds of local blood centers, with sponsors not required to conduct large-scale Phase III-like safety and efficacy trials for approval of each product. In some respects, the composition of these biogeneric-like products is so complex as to defy characterization, making one wonder how they could ever be regulated and considered interchangeable. Shared processes and standards of identity based on diversity of contents averaging out overall variability (based on pooling of source materials from many organisms) form the basis for the definition and regulation of these products.
Thus, the process=product paradigm provides a basis for defining and differentiating particular biopharmaceutical products. However, the real issues with biogenerics involve comparisons and similarities (comparability, equivalence, etc.), not uniqueness Ñ What characteristics, particularly similarities, allow knowledge of one product to be used to make judgments regarding another, particularly concerning safety and efficacy. Thus, determining biogeneric relationships can be more complex and subjective than simply (although, it is not simple at all) trying to define products on the basis of their nature/source, manufacturing and specifications (process=product paradigm). A corollary of process=product is that both active agents and finished products are each unique, with each presenting problems in description, nomenclature, etc.
2) Regulation-based paradigms: For many people and many purposes, the only biogeneric relationships and definitions that matter are those made by regulatory agencies, with many further restricting this to the U.S. and Europe. Here, biogenerics are defined based on their approval or plans for approval under an abbreviated testing/filing scheme and/or involving designation of therapeutic equivalence. Using this simple, strict definition, identifying biogenerics based on regulatory paradigms is very simple - just look at approvals and sponsors' plans for approvals. As discussed below, product approvals, particularly for biologics, essentially are secret pacts between the manufacturer and FDA or other regulatory agency regarding suitable ranges of procedures and specifications to be met throughout the manufacturing process. Regulatory-based views and definitions of biogenerics start with similarities based on entity (process=product) considerations, and then add further regulatory-based restrictions.
With the recent much-publicized FDA 505(b(2) approval of Omnitrope (recombinant E. coli-expressed somatropin) from Sandoz/Novartis as a generic drug (follow-on protein) version of Genotropin from Pfizer, FDA stated, "Follow-on protein products generally refers to protein and peptide products that are intended to be sufficiently similar to a product already approved or licensed to permit the applicant to rely for approval on certain existing scientific knowledge about the safety and effectiveness of the approved protein product. Follow-on protein products may be produced through biotechnology or derived from natural sources." Very important, but unstated here, this definition has been restricted to those few biopharmaceuticals regulated as drugs under the Food, Drug, and Cosmetic Act, not biologics regulated under the Public Heath Service Act of 1946 for which no generic approval mechanisms yet exist. Note that many using the term follow-on proteins ignore or fail to include non-recombinant proteins as included in this class, e.g., recent biogeneric-like FDA approvals of animal-derived hyaluronidase products.
There has been and is nothing to stop a sponsor from obtaining approvals and marketing generic versions, even reverse engineered copies, of marketed biopharmaceuticals (or any pharmaceutical), provided that legal barriers (patents, orphan exclusivity, etc.) are met and the sponsor submits a full-blown (not generic) original application. In major market countries, this would generally require conducting expensive and time-consuming Phase III-type efficacy trials, which are not needed or can be much simplified, quicker, smaller, etc., in the case of formal generic filings. These product development cost and time savings are the main commercial advantages and reasons to even consider biogenerics, in addition to designation of therapeutic equivalence/substitution, which can further reduce or eliminate marketing costs (e.g., pharmacies need only stock the generic, with negligible marketing, detailing and advertising on the part of the marketing company). Biogeneric filings and approvals generally involve a sponsor basing an application largely on knowledge of another, previously-approved ("innovator") product, with this generally enabling abbreviated (simplified, shortened, thus, cheaper, quicker) testing, including bioequivalence trials and other comparative clinical studies with the innovator product. The presumption is that knowledge of the similar innovator product can be extrapolated to that of the biogeneric. With some biopharmaceuticals, this may be more of a challenge than many presume.
The primary goal of the biogeneric developer is to avoid costly and lengthy large-scale Phase III-type safety and efficacy trials and, perhaps, allow substitution in terms of filling prescriptions. These aspects allow the biogeneric to, presumably, have a lower price than the innovator product (which likely involved much more R&D, testing, including safety and efficacy trials, and for which considerable sums have likely been invested in brand name promotion). For example a biogeneric filing for recombinant regular insulin, beyond proving purity, potency, lack of immunogenicity, etc., including in comparison with a similar innovator product, would essentially need only show identical or comparable pharmacokinetics with the innovator to receive approval. The challenge is to prove sufficient relevant similarities between the chemical composition, biological and pharmacokinetic aspects of products such that all relevant aspects concerning the biogeneric's safety and efficacy can be reliably predicted based on knowledge of the innovator product. For example, a 505(b)(2) generic drug NDA for a new synthetically-manufactured sildenafil citrate generic drug would rely on knowledge and comparative testing with the innovator, Viagra, from Pfizer. But to what extent could a generic filing for a complex biopharmaceutical, e.g., recombinant erythropoietin (EPO) or Factor VIII, with purity, potency and pharmacokinetics substantially similar or even judged identical to an innovator's product rely on knowledge of and comparison testing with the innovator product? These and many other questions remain to be resolved by FDA (and regulatory agencies in other countries) and, ultimately, by Congress.
FDA and other regulatory agencies have considerable experience and have approved thousands of generics, nearly all as drugs, based on comparison to and knowledge of earlier innovator products. But, in terms of biopharmaceuticals, this has been restricted to smaller, simpler or other active agents that, due to regulatory history, natural product source and/or their more small molecule drug-like nature, have already been regulated as drugs (vs. biologics, involving much larger and more complex molecules, or even cells, tissues and organisms). Thus, FDA recently approved Omnitrope (recombinant E. coli-expressed somatropin or human growth hormone) from Sandoz/Novartis under 505(b)(2) generic drug regulations, based largely on comparisons with Genotropin from Pfizer; and the European Union has similarly approved Omnitrope and another recombinant E. coli-expressed somatropin (Valtropin) under its new biosimilar regulations based on comparisons with Genetropin and Humatrope from Eli Lilly, respectively. For those taking a restrictive Western-country regulatory-centric view, these are among the few biogeneric products.
Currently, no regulations exist in the U.S. for evaluation and approval of biologics as generics (based on comparative, abbreviated applications; designations of therapeutic equivalence; etc.), and FDA has signaled that it will largely leave this up to Congress to resolve. This is not expected until 2008 (e.g., see "Congressional Fix For Follow-On Biologics Unlikely Until 2008," Washington Drug Letter, vol. 38, no. 26, June 26, 2006, p. 1, 4). FDA has avoided issuing guidelines for even the simplest biopharmaceuticals regulated as drugs (follow-on proteins), e.g., somatropins and insulins, and has signaled it prefers to do even less in terms of guidelines or regulations concerning biogeneric versions of products regulated as biologics. Only recently, after years of delay, did FDA grant approval of Omnitrope (discussed above), but only after being forced to after having lost a lawsuit brought by Sandoz in federal court.
Omnitrope did not set any precedents, since other recombinant and natural protein products have been formally approved as generic drugs (not biologics) under the same Hatch-Waxman Act-derived section 505(b)(2) regulations that have been used for approval of hundreds of conventional, primarily small molecule, generic drugs, and involving abbreviated bioequivalence but not large Phase III-like safety and efficacy trials. Besides Omnitrope, recent examples of such 505(b)(2) biogeneric-like approvals include recombinant calcitonin (Fortical) and glucagon (GlucaGen) and multiple animal-derived (Vitrase and Amphadase) and recombinant hyaluronidase (Hylenex) products. However, to date, none of these approvals has included formal recognition of equivalence/substitutability for filling of prescriptions, a hallmark of most generic drug approvals. Despite approving these drugs based on equivalence for all practical purposes with a prior product, FDA has avoided the issue of therapeutic equivalence/substitution by designating each a New Chemical Entity (NCE), recognizing each as unique, not substitutable in terms of filling prescriptions, forcing each to be marketed as a branded product (i.e., by trade name vs. generic name).
The European Union is much further ahead than the U.S., having developed a new class of products, "similar biotechnology medicinal products" (biosimilars); issued related guidelines for a few classes of biopharmaceuticals, e.g., insulins and somatropins; and having approved two "biosimilar" somatropin products. However, as in the U.S., the EU has yet to issue guidance concerning the great majority of biopharmaceuticals involving much more complexity or for the official nomenclature (unique or generic) to be used with biosimilars.
3) Market/commerce-based paradigms: For many people and purposes, the only biogeneric relationships that matter are those that are market-driven or based on related personal or public perceptions and preconceptions, often with no consideration of entity- or regulatory-based relationships between products. Thus, biogeneric, follow-on protein/biologic and related terms are commonly applied to just about any biopharmaceutical (and sometimes non-biopharmaceuticals) that appear similar, e.g., based on their competing for the same indication/market, coming later (follow-on or next-generation products), or commonalities of active agent names. For example, as discussed above, some consider to be biogenerics all forms of insulin irrespective of differences, including products with otherwise clearly different active agents, formulations, activities and pharmacological profiles, with biogenerics defined as any products containing an insulin-related active agent competing for diabetes indications.
Broad market-based views of biogenerics often include next-generation and other later generation (follow-on) versions and variations of products, irrespective of how (dis)similar they actually are. For example, some would consider all later variations and versions of a recombinant glycoprotein to be biogenerics, irrespective of variations in primary structure (amino acid sequence), glycosylation, multimers (linking of chains), major molecular modifications (e.g., pegylation), formulations (e.g., adjuvant systems, elimination of animal products, additives for improved thermal stability), packaging/delivery systems (e.g., in liposomes, controlled release, transcutaneous), etc. Some view these various products as biogenerics, including their presumably being able to be approved based on abbreviated testing based on the large body of knowledge concerning insulins. On the other hand, most taking a rigorous entity-based (or derivative regulatory) view would consider these to clearly be distinct, dissimilar products that cannot be compared to each other (particularly, for regulatory approvals), negating any possibility of their being biogenerics. Others would simply say they seem and/or sound similar to them, seemingly involve the same basic active ingredient (an oversimplification) and biological and clinical activity and, thus, are biogenerics. Some only consider products involving obvious improvements or technological advances as being later-generation or follow-on biogenerics, not including innovator products as being biogenerics, while others consider all similar products to be biogenerics, including the innovator products, once biogenerics in development are reported in the public domain or are approved. A new term, "super biogenerics," is used by some to refer to follow-on biogenerics involving radical modifications, usually new and improved delivery systems.
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biocomparable | a common synonym for biogeneric; best avoided due to comparability guidelines that apply to manufacturing changes (see comparability below) | |||
biogeneric | refers to any biopharmaceutical considered generic, based on any criteria (which should be stated or clear in context) | |||
biologic(s) | a type of FDA approval for biopharmaceuticals and associated products [best used only to refer to products approved or on track for approval by this mechanism]; generally, includes all but the simplest biopharmaceuticals regulated as drugs by FDA; [the official definition is complex, unwieldy, developed decades ago and based on analogies to terms/concepts at the time (e.g., viruses analogous to toxins, vaccines to serums, etc.)] | |||
biopharmaceutical | a pharmaceutical product or active agent with the active agent biological in nature and manufactured using living organisms (biotechnology) [Note, this does not include small molecule or other drugs, which are inherently chemical, not biological, in their nature and manufacture]. | |||
biosimilar | short name (never actually officially defined) for "similar biotechnology medicinal product," a new type of generic biopharmaceutical approval in the European Union and associated products [best used only to refer to products approved or on track for approval by this mechanism] | |||
comparability | refers to similarities, regulatory acceptability and supplemental approvals of products incorporating a change in the manufacturing process (by the product's current manufacturer or contractors), i.e., judgments of similarities between the same products (presumably) from the same manufacturer incorporating a change in the manufacturing process [best only used in this context, not to refer to biogenerics]. | |||
drug | chemical, not biological, pharmaceutical agents and products manufactured using chemical, not biological, methods. This includes the vast majority of pharmaceuticals. | |||
follow-on | a synonym for biogeneric; often used to describe a later biopharmaceutical, often involving a more technologically advanced version of an innovator product; see also later generation [best avoided due to FDA having adopted the term "follow-on protein"] | |||
follow-on protein (FOP) | a biopharmaceutical approved or on track for approval by FDA as a generic drug, usually under section 505(b)(2), generally restricted to relatively simple proteins, including those with prior versions approved as natural products [best reserved for this use] | |||
follow-on biologic (FOB) | a biopharmaceutical approved or on track for approval by FDA as a generic biopharmaceutical, a regulatory track that does not yet exist [best reserved for this use] | |||
innovator | refers to original products, usually the first to receive approvals, and associated companies; These products are presumed to have involved original and extensive R&D and full (not abbreviated) Phase III-type safety and efficacy testing. | |||
later generation | a biopharmaceutical similar to another prior product; the product often involves technological advances or other modifications such that it may not actually be similar to prior innovator product(s) [recommended for adoption in place of follow-on] | |||
pharmaceutical | any medicinal product, particularly those with therapeutic or in vivo uses; two major subsets are drugs and biopharmaceuticals |
Table 2 above presents a brief glossary of biogeneric and other terms. This author proposes that certain of these terms and definitions be adopted and some avoided in the context of biogenerics. Note, many of these terms can be used as both a noun, e.g., biosimilars, and adjective, e.g., biosimilar products. The author favors use of biogeneric to describe generic biopharmaceuticals in a broad or generic sense. Other common synonyms for biogeneric, e.g., biosimilar and follow-on protein, are best only used in the context of their official regulatory definitions, and some terms, e.g., biocomparable, are best avoided due to conflict with other regulatory-defined terms/concepts.
New terms, concepts, taxonomies/classification schemes, etc. will need to be developed as discussions and regulation of biogenerics become more sophisticated, including new terms/concepts for scientific, medical, public and regulatory use. Presently, there are few terms/concepts available to readily describe biogeneric products and relationships. For example, terms/taxonomies will be needed for these products and for different types and degrees of similarity; for biogenerics with/without different types and degrees of therapeutic equivalence/substitutability; and to differentiate biogenerics developed to be exact copies/knock-offs vs. those either developed not to be copies or clearly different (but still similar) in their nature and specifications. As discussed further below, those who make a concerted effort to define and promulgate these new terms, definitions and taxonomies will be in a good position to influence or control public perceptions, development of regulations and the future of biogenerics.
Beyond the relatively simple issue of terminology for biogenerics, official nomenclature for biogenerics will be a very contentious issue, potentially pitting the needs of safety vs. economics. See related articles, including Nomenclature Systems for Biopharmaceuticals and Biogenerics and the author's proposal for the U.S. Biopharmacopeia Registry and nomenclature system for biopharmaceuticals. Biogeneric developers obviously favor non-unique (ambiguous) generic names, i.e., applying the current generic drug nomenclature regimen to biogenerics, placing all biogenerics ruled equivalent, including innovator products, on the same footing. This facilitates generic substitution. But, as innovator company supporters point out, using a generic name in writing/filling prescriptions complicates or negates post-approval pharmacosurveillance or the monitoring of adverse events, which will be an important aspect of most biogeneric approvals. Using generic names will require much more resources, increasing costs and complicating or even negating effective pharmacosurveillance. 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. Unless new nomenclature 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 or unique names.
Public Relations and Popular Culture Battles Ahead
No matter what happens with the development and implementation of regulations for biogenerics, considerable (re)education of physicians, pharmacists and consumers will likely be required. For example, many still presume that generic drugs are inferior to innovator drugs, including in a recent poll a significantly higher proportion (~25%) of physicians than the general public. Even before getting around to issues such as this, some very basic terminology-related industry public relations and policy problems related to biotechnology may need be resolved before meaningful discussions and debate regarding biogenerics can progress. As discussed in What is a Biopharmaceutical?, everyone wants their company and products to be perceived as being biopharmaceutical or biotechnology (sounds better than pharmaceutical or drug). Companies proclaim this and the popular, business and other press follow along, with many in the industry and the press having adopted aberrant definitions of 'biopharmaceutical' such that they no longer need involve biotechnology, e.g., include small molecule drugs. Along these lines, the Pharmaceutical Research and Manufacturers Association (PhRMA) has been seeking to rebrand the pharmaceutical/drug industry and its products as having been transformed and now 'biopharmaceutical' (as reflected in its recent annual review of the industry and other studies it has funded). The Biotechnology Industry Organization (BIO) similarly has effectively redefined biopharmaceutical (and biotechnology) as now including any pharmaceutical involving a small (biotech-like) company or that can be portrayed as being high tech, including small molecule and other drugs and other diverse technologies, with no need for involvement of actual biotechnology [reflecting its current dominance by drug (vs. biopharmaceutical) discovery, service and development companies].
Biopharmaceutical terminology and nomenclature problems persist at least partially because there are no venues to discuss this. Along these lines, there simply is no U.S. trade association primarily concerning with the biopharmaceutical industry. This has resulted in the industry lacking identity and being susceptible to the rebranding and terminology misappropriation efforts of the broader life/bio sciences and pharmaceutical industries. A problem with both BIO and PhRMA is that companies with substantive involvement in actual biopharmaceuticals/biotechnology are distinct minorities of their members. In the context of biogenerics, it remains to be seen whether either organization can or will even be able to effectively represent the vested interests of the biopharmaceutical industry vs. their broader membership base that covets the positive public image established by the biopharmaceutical (and biotechnology) industry and has little or no interest in biopharmaceutical products (vs. drugs). Neither BIO nor PhRMA now even use or recognize a workable term(s) for actual biopharmaceuticals [pharmaceuticals inherently biological and involving biotechnology (live organisms), in their manufacture vs. drugs that are inherently chemical nature and manufactured using chemical methods]. Presuming these organizations stick to their current terminology and lack of recognition of biopharmaceuticals as distinct from other
pharmaceuticals (drugs), how can either seriously engage in public debate and education concerning biogenerics?
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In the U.S., FDA and Congress are expected to sooner or later develop new regulations concerning all but the simplest biogenerics, particularly those regulated as biologics. Major public relations and lobbying efforts and battles related to this can be expected. The winners may well be those best infiltrating the popular culture. Will biogeneric regulations be driven by rational industry-based debate of the highly technical issues involved; or by image and attack ads, focus-group crafted images, concepts and related terminology; and related spin and hype from opposing industry camps? With innovators and biogeneric companies, ranging from large international pharmaceutical companies to small biotechnology-type companies, having so much on the line and their vested interests in conflict, the later seems likely.
The "process=product" view/definition/paradigm of biopharmaceuticals exemplifies the power and successful popularization of a biogenerics-related concept, terminology and buzz word/catch phrase/slogan. This terminology is now universal. Just about every discussion of biogeneric issues, particularly the development of regulations, uses or cites this. "Process = product" appears to have originated with (or at least was widely promulgated) by innovator companies affiliated with PhRMA starting about five years ago (e.g., see "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). Already, "product = process" has performed incredibly well in promoting and popularizing innovators' views. Both lay and technical publications commonly cite this as a reason for the impossibility of biogenerics (i.e., abbreviated approvals and therapeutic equivalence). Those promoting biogenerics have yet to develop and promote an effective defense against this, other than citing the economic reasons for biogenerics, and have yet to mount effective campaigns to influence public perceptions.
What concepts and terms will be used in the U.S. for biogenerics and their regulation? Who will determine these and through what mechanisms? Who will be the winners and losers? As pointed out at the start of this article, just about every term applicable to biogenerics has connotations or other baggage, such their use often inherently supports, denigrates or obfuscates discussions or views on the topic. Will terms such as "(bio)generic" be used, which for many involves negative preconceptions about generic drugs and the generic drug industry? Will "follow-on" be used, with this already having an official FDA definition, while implying to some the use of more modern technology or other improvements incorporated into biogenerics? Will the term "innovator" product be used, or will a more neutral term, such as "reference," be adopted? Will products be referred to as being "equivalent," "(bio)similar," "(bio)comparable," "identical," "the same," "related," or what? Will qualifiers, such as essentially or substantially be used with these terms? Will new concepts/terms and slogans be developed and promulgated, along the lines of "process = product? Will politicians (Congress) and bureaucrats (FDA) adopt or devise new paradigmss and terms, which may not be useful or workable in the real world? Who will determine the use and adoption of these terms, including in the scientific literature, industry publications and popular press and culture, and, thus, influence politicians, regulators and the public (as consumers and as voters)? Will different camps, e.g., innovator and (bio)generic drug companies, adopt and promote different concepts and terms? Similarly, how will nomenclature for specific biogeneric products be handled? Will new types of nomenclature and pharmacopeia be needed for biogenerics, along with new product references and Web sites for medical community and public education? Who will develop and sponsor these? Will biogenerics become a political issue, e.g., in the 2008 elections? This seem possible.
Simplistically stated, innovator supporters have inertia (current regulations) and science (the complexity of the products, e.g., process = product) on their side, while biogenerics have the irresistible force of economics on their side (cost savings).
Innovator products and companies have the strategic advantage of being in a defensive position, supporting the status quo (no generic biologics), as exemplified by "process = product." Biogeneric supporters are in the more difficult position of seeking change, and have yet to promote their own views, including promulgating concepts, buzz word, slogans, etc., that inherently support their position. But biogeneric supporters need only point to cost savings and the success of generic drugs, with the majority of prescriptions in the U.S. now filled with generics. If nothing else, with the federal government being the single largest purchaser of pharmaceuticals, including biopharmaceuticals, and with the U.S. economy in trouble sooner or later (e.g., with worsening deficits, national debt, balance of trade, social security and the health care system likely to eventually collapse, etc.), biogenerics, including regulations for complex biologics and their therapeutic equivalence, appear inevitable.