Continuing Education Lesson
Biosimilars: An Emerging Category of Biologic Drugs
Biologics represent the fastest growing segment of annual United States (U.S.) drug expenditures. Biologics are complex proteins derived from living sources that are important therapies for a variety of diseases. The U.S. is now poised to introduce biosimilars, which are copies of biologics that are not manufactured by the innovator company and are approved under an abbreviated regulatory process. Biosimilars are intended to offer comparable safety and efficacy to the reference biologic at a lower cost. Because of the complexity of producing biologics, the manufacturing process for biosimilars may differ from that of the reference biologic, which may result in subtle changes in biological characteristics and clinical activity. Questions exist regarding whether these slight differences allow the products to be interchanged with the reference product and if unique adverse events will occur with use. While the Biologics Price Competition and Innovation Act outlined the abbreviated approval pathway for biosimilars, guidance from the U.S. Food and Drug Administration (FDA) is needed on specific details of the approval process. The FDA has recently provided guidance about the scientific and quality requirements for demonstrating biosimilarity, but a number of unanswered questions still remain, including concerns about immunogenicity, product naming, and the exact cost savings from biosimilars. In Europe, regulations and an approval pathway have been established and at least 14 biosimilar medications are available in the marketplace. Pharmacists must lead the way with regard to the appropriate introduction of biosimilars to the U.S. market by understanding these issues and assisting other clinicians and patients with making informed decisions about the use of biosimilars.
Annual spending on prescription medications is forecasted to reach $372 billion in the United States (U.S.) and $1.2 trillion worldwide by 2016.1 Biologics, medications synthesized through biotechnology, represent the fastest growing segment of the pharmaceutical market. Biologics are generated by cells or living organisms through recombinant deoxyribonucleic acid (DNA) technology, controlled gene expression, or antibody production and encompass a wide range of substances, including hormones, vaccines, growth factors, blood products, monoclonal antibodies, and advanced technology products (protein-antibody combinations, gene therapy biological products).2
The FDA approved the first biologic human insulin (Humulin) in 1982.3 Since then, the pharmaceutical industry has developed many biologics for the treatment of acute life-threatening diseases, such as cancer and cardiovascular illness, and for chronic conditions like diabetes, anemia, rheumatoid arthritis, and multiple sclerosis, as well as for rare genetic conditions, such as Gaucher's disease and Fabry disease. Health providers are now trying to balance the pressures of prescribing these agents early, when the disease course may be prevented or modified, with the challenges of patient and insurer affordability.
After 30 years, the patents on many of these recombinant biologics will soon expire (Table 1).4,5 The U.S. pharmaceutical marketplace is now poised for the introduction of biosimilars, which are simply described as copies of biologics that are not manufactured by the innovator company and are approved under an abbreviated regulatory process. Since it is not possible to copy a biologic in the precise manner that small molecules can be replicated, the term "generic biologic" is inappropriate. Therefore, a variety of other terms have been used for these products, such as follow-on biologics, biogenerics, and postpatent biologics. During the last several years, and especially after the introduction of the legislation described below, the term biosimilar has become the standard term, but definitions are not standardized. Recently, a more detailed consensus definition was proposed: "A biosimilar is a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise."6
|Product||Brand Name||Category||Use(s)||Global Sales||Year Launched||Patent Expiration|
|Somatotropin (human growth hormone)||Humatrope||Recombinant human protein||Growth disorders||$420 million||2002||Expired|
|Alteplase, t-PA||Activase||Recombinant human protein||Myocardial infarction, stroke, pulmonary embolism, catheter clearance||$440 million||1985||2005|
|Filgrastim||Neupogen||Recombinant human protein||Neutropenia||$1.3 billion||1991||2013|
|Imiglucerase||Cerezyme||Protein||Gaucher's disease||$720 million||2013|
|Etanercept||Enbrel||Dimeric fused protein and antibody||Rheumatoid arthritis, psoriasis, JIA, ankylosing spondylitis||$7.3 billion||1998||2014|
|Erythropoietin alpha||Epogen/Procrit||Recombinant human protein||Anemia||$4.5 billion||1989||2014|
|Infliximab||Remicade||Recombinant chimeric antibody||Rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis||$6.5 billion||1998||2014|
|Trastuzumab||Herceptin||Recombinant humanized antibody||Breast cancer||$5.2 million||1998||2014|
|Glatiramer||Copaxone||Peptide||Multiple sclerosis||$3.3 billion||1997||2014|
|Certolizumab||Cimzia||Recombinant chimeric antibody||Rheumatoid arthritis, Crohn's disease||$260 million||2008||2014|
|Rituximab||Rituxan||Recombinant chimeric antibody||Rheumatoid arthritis, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple sclerosis||$6.1 million||1997||2015|
|Pegfilgrastim||Neulasta||Pegylated human G-CSF||Neutropenia||$3.3 billion||2002||2015|
|Palivizumab||Synagis||Antibody||Respiratory syncytial virus||$900 million||1998||2015|
|Dornase||Pulmozyme||Protein||Cystic fibrosis||$513 million||1994||2015|
|Adalimumab||Humira||Recombinant humanized antibody||Rheumatoid Arthritis, JIA, ankylosing spondylitis, Crohn's disease, psoriasis||$6.7 billion||2003||2016|
|Abatacept||Orencia||Rheumatoid arthritis||$850 million||2019|
|Bortezomib||Velcade||Dipeptide bound to boronic acid||Multiple myeloma, lymphoma||$1.7 billion||2003||2017|
|Omalizumab||Xolair||Antibody||Allergic asthma||$960 million||2003||2018|
|Bevacizumab||Avastin||Recombinant humanized antibody||Colorectal, non-small cell lung, kidney cancers, glioblastoma||$6.2 billion||2004||2019|
|Darbepoetin alfa||Aranesp||Recombinant variant of erythropoietin||Anemia||$2.5 billion||2004||2019|
|Interferon alfa-2a||Pegasys||Pegylated recombinant human interferon||Hepatitis B, hepatitis C||$670 million||2002||2019|
|Interferon beta 1a||Avonex||Recombinant human protein||Multiple sclerosis||$2.5 billion||1996||2026|
|Interferon beta 1a||Rebif||Recombinant human protein||Multiple sclerosis||$6.7 billion||2002||2026|
|Golimumab||Simponi||Recombinant human antibody||Rheumatoid arthritis||$320 million||2009||2026|
|Interferon beta-1b||Betaseron||Recombinant human protein||Multiple sclerosis||$1.6 billion||1993||2026|
|JIA = juvenile idiopathic arthritis; G-CSF = granulocyte-colony stimulating factor|
SCOPE AND IMPACT
Global biologics sales accounted for approximately $93 billion in 2009 and are expected to be worth more than $167 billion by 2015.7 Biologics sales are expected to continue to grow at least twice as fast as those of conventional, chemical based, small molecule medications. Of the biologics products, monoclonal antibodies are the largest and fastest growing market. By 2016, 10 biologics are expected to occupy the top 20 positions in pharmaceutical industry sales. Of these, 8 are antibodies (adalimumab, bevacizumab, rituximab, trastuzumab, infliximab, denosumab, ranibizumab, and etanercept).8,9 The top 6 biologics already consume 43% of the drug budget for Medicare Part B.10 As a result of the clinical and commercial success, pharmaceutical companies have invested heavily in the development of biologics. Approximately 30% of the industry's research and development pipeline is composed of biologics, with nearly one-third being monoclonal antibody medications.2,9
While Europe enacted legislation in 2004 for the approval of biosimilars, the U.S. only passed legislation to create an approval pathway in 2010. The first biosimilars reached the European market in 2006. The goals for encouraging the development of generic biologics are the same as those for encouraging generic small molecule drugs, which is to reduce costs by fostering price competition and provide patients treatment access at an affordable price. Generic drug use is common.11 In 2011, approximately 80% of the 4 billion drug prescriptions issued in the U.S. were dispensed using generic medications. Estimated savings to the consumer and to the U.S. health care system from generic drug use reached $193 billion in 2011. The introduction of biosimilars is projected to generate $9 to $12 billion in savings for the U.S. Medicare program during the next decade.12,13
Small Molecule, Biologic, and Biosimilar Manufacturing
The manufacturing process for biologics is more complex than the chemical synthesis used for conventional small molecule pharmaceuticals. Small molecule medications have a molecular weight typically between 100 and 1000 daltons (Da) (Table 2).14 In contrast, biologics are large, complex, and heterogeneous proteins with molecular weights ranging from 18,000 to 145,000 Da (Figure 1).15 Biologics can consist of primary (linear amino acid sequence) and secondary (helix and pleated sheet) structures, or fold into complicated three-dimensional tertiary structures.16 The tertiary structure subunits can then interact to form a more complex protein or quaternary structure.
|Characteristic||Small Molecule Drugs||Biologics|
|Production||Chemical synthesis||Through biotechnology and host cell lines|
|Size||Low molecular weight||High molecular weight|
|Physiochemical properties||Well defined||Complex|
|Stable||Sensitive to heat, sheer stress (aggregation)|
|Manufacturing||Single entity, high chemical purity, standards well established||Heterogeneous mixture, broad specifications which may change during development, difficult to standardize|
|Not affected by slight changes in production process and environmental conditions||Highly susceptible to changes in production process and environmental conditions|
|Analytic assays||Completely characterized by analytic methods||Difficult to characterize, assays not standardized|
|Decontamination||Easy to purify||Lengthy and complex purification process|
|Quality assurance and detection||Contamination can be avoided and easily detected and removable||High possibility of contamination, detection hard, and removable impossible|
|Pharmacokinetic properties||Administered through different routes||Parenteral route of administration most common|
|Rapidly enters systemic circulation through capillaries||Larger molecules enter circulation through lymphatic system, subject to proteolysis and lymphatic transit|
|Distributes to any organ and tissue||Distribution limited to plasma and extracellular fluid|
|Toxicity||Organ specific toxicity||Mostly receptor mediated toxicity|
|Allergenicity||Often not antigenic||Usually antigenic|
After an initial DNA sequence of a desired protein product is identified, it is inserted into a suitable vector and then into the appropriate cell line (Figure 2). From the cell line, a master bank is created, where the cell culture replicates the cells and exponentially increases protein production. During the production process the end product proteins must be recovered, purified, and characterized. After synthesis many proteins undergo further transitional modifications, such as glycosylation or pegylation, which may alter receptor binding affinity, efficacy, duration of action, and other properties.16-19 For example, different glycosylation patterns with epoetin result in different isomers, whereas the addition of polyethylene glycol bridges (PEGylation) to filgrastim extends its duration of action and metabolic removal.19 Glucocerebrosidase, a protein used in the treatment of Gaucher's disease, in its natural form is 12% glycosylated by weight; whereas, in its recombinant form glycosylation represents 6% of its total weight. Administration of the recombinant form is clinically superior to the naturally extracted product.
The production of biologics and their subsequent pharmacologic activity are dependent on the manufacturing processes, which, in turn, are very sensitive to changes in production.20 Any changes occurring to the expression systems used for production, culture conditions (e.g., temperature and nutrients), equipment, purification and processing, formulation, storage, or packaging may result in subtle changes in biological characteristics, clinical activity, and toxicity profile (Table 3).15,17 In addition, while producing complex biologics, there are formulas and processes as well as a substantial amount of tacit knowledge (i.e., knowledge or functions that have not been reduced to instruction or recipe) that may impact the final product. Even when biologics are produced from the same process, technique, formulation, and packaging as the reference product, there is no guarantee that they will be identical to the reference product. To uphold their patents, innovator pharmaceutical companies have argued that there can never be a generic equivalent to a biological medication, only a similarity.
|Medication Class||Comparator||Difference||Molecular Difference or Cause|
|Imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), taliglucerase alfa (Elelyso)||Natural glucocerebrosidase||Clinically superior||Enhanced glycosylation|
|Somatropin (Genotropin, Nutropin, Saizen, Norditropin)||Natural human growth hormone||Varying half-lives (1.5 to 10 hours)||None|
|Coagulation Factor VII||Natural Factor VII||Antibody production||Pasteurization process|
|Interferon alfa-2a (Intron-A, Roferon-A)||Itself||Antibody production||Human serum albumin diluent and room storage|
|Epoetin (Eprex)||Same protein, different formulation||Antibody production causing anemia (pure red blood cell aplasia)||Change in stabilizer from human serum albumin to glycine and polysorbate 80|
With recent biotechnology advances, manufacturers are able to create accurate protein copies by using microbial rather than mammalian cell lines. Proteins created through microbial fermentation in Escherichia coli, without post-translational modifications, can be produced cheaply and easily, with high purity and reliability. Most of the early biologics (e.g., insulin, growth hormone, filgrastim, and interferons) can be produced in this fashion. Future advances in microbial cell lines may remove the need for mammalian cell cultures altogether.17
For conventional, chemical based, small molecule medications, generic approval hinges on pharmaceutical equivalence (i.e., identical active substances) and bioequivalence (i.e., comparable pharmacokinetics) to the innovator agent. Chemical identity can be confirmed by exact analytical techniques, such as high performance liquid chromatography (HPLC), mass spectrometry (MS), nuclear magnetic resonance (NMR), and x-ray diffraction. Bioequivalence and rate and extent of absorption is usually established in a single study involving 24 to 36 healthy volunteers.18
The larger molecular size and structural complexity poses a challenge for the characterization of biosimilar medications. While techniques, such as HPLC, MS, NMR, are still employed, newer techniques, such as capillary electrophoresis and peptide mapping, have been introduced to identify protein structure and function. Collectively these advances have improved molecular understanding, yet it is unclear whether they are capable of detecting all structural differences or if these differences impact clinical efficacy and safety.19 Consequently, analytical tests for characterizing structure and physicochemical properties may provide an incomplete picture. For example, the helical, pleated, folded, and interactive conformational states of a protein can be difficult to detect and the assays may be limited to a particular fingerprint region of the product. Furthermore bioassays measuring receptor binding and cell response have not been standardized, which prevents the comparison of results between different laboratories. These limitations broaden the obstacles in establishing equivalence between a biosimilar and a reference product.15
Legislative History, Approval Process, and New Approval Pathways for Biosimilars
The FDA approves and licenses conventional small molecule medications under the Federal Food, Drug, and Cosmetic Act (FD&C), enacted in 1938 (Figure 3). In contrast, permission to introduce a biologic requires a Biologic License Application (BLA). A BLA for vaccines, toxins, antitoxins, blood, blood components or derivatives, allergens, or analogous products is approved through the 1944 Public Health Services Act (PHS). Large, complex biologics are required to follow the BLA process for approval and licensure.21
The FD&C Act was hastened into law in response to a series of patient deaths, which resulted from diethylene glycol poisoning after the compound was used as a solubilizing agent for the antibiotic sulfanilamide.22 Until that time, drug laws did not require the completion of safety studies on new agents. Since both laws are more than 50 years old, they have been amended over time. As new compounds are synthesized in the laboratory, they must clear a series of scientific and clinical hurdles to ensure they are safe and effective. A large number of chemically or biologically active compounds show early promise as medications in preclinical trials. However, few emerge through the FDA approval process and become established as safe and effective therapies.
The Drug Price Competition and Patent Term Restoration Act (also commonly known as the Hatch-Waxman Act) amended the FD&C Act in 1984, establishing the current system of generic drug approval. The revision provided two abbreviated pathways for the approval of generic small molecule drugs, a small number of natural source products, and simple recombinant proteins. More importantly, the pathways eliminated preclinical and human studies in the New Drug Application (NDA) of a generic drug. For a new small molecule entity to be approved, it must follow the 505(b)1 pathway, complete clinical trials (Phase I, II, III), and demonstrate safety and efficacy in the treatment of the targeted disease state (Table 4). The 505(j) pathway sets forth the process by which the manufacturer of a generic drug, one that is bioequivalent to a previously approved product, can file an Abbreviated New Drug Application (ANDA) to seek FDA approval. An ANDA allows the applicant to rely on the FDA's previous finding of safety and efficacy for the already approved drug and bypass clinical trials. The 505(b)(2) pathway also allows an existing medication to be approved by using study data from a prior application and either limits clinical studies (3 to 6 months in duration) or avoids them completely. However, because of the size and complexity of the biologic molecules, manufacturers have not been able to demonstrate that their biologic is identical to an already existing, approved product. Therefore, the abbreviated 505(j) approval pathway has not been routinely available for biosimilar protein products. Similarly, the FDA has limited the 505(b)(2) pathway, which allows direct comparison of the generic drug with a product already approved, to a small number of natural source products and recombinant proteins (e.g., human and bovine hyaluronidase, salmon calcitonin, human glucagon, and human growth hormone). In these instances, while data about each biologic were provided, the structural characterization, comparative pharmacokinetics, pharmacodynamics, and immunogenicity were well known. The approval was based on the knowledge about the safety and effectiveness of a similar, already approved product.23 In at least one case where a non-innovator human growth hormone was approved under this pathway, the FDA made it clear this was not a pathway for future approvals.24
|Product Designation||Application Type||Application Pathway||Clinical Studies|
(Federal Food, Drug, and Cosmetic Act)
|New Drug Application (NDA)||New molecular entity||505(b)(1)||Full evaluation of safety and efficacy|
|Existing molecular entity||505(b)(2)||Studies do not have to be done by the application sponsor|
|Abbreviated New Drug Application (ANDA)||Existing molecular entity||505(j)||No, but must demonstrate bioequivalence|
(Public Health Service Act)
|Biologics License Application (BLA)||New molecular entity||351(a)||Yes, full evaluation of purity, safety, and potency|
|Biosimilar Application||Existing molecular entity||351(k)||Yes, but abbreviated process|
In March 2010, the Biologics Price Competition and Innovation Act (BPCI) became law as section of the Patient Protection and Affordable Care Act (PPAC). The BPCI Act amended the PHS Act by adding subsection (k), which finally established an abbreviated approval pathway for copies of biologic medications.23 The legislation permits a biological product to be evaluated against only a single reference biological product and outlines the requirements for achieving biosimilarity (Table 5). Based on data derived from analytical, animal, and clinical studies, the biologic product must be "highly similar to the reference product" and have "no clinically meaningful differences in safety, purity, and potency." The FDA is given flexibility in the approval process and can determine that one or more of these data requirements are not needed. The Health and Human Services (HHS) secretary will then decide whether the biologic is licensed as biosimilar to or interchangeable with the reference product. (While the law is written that the HHS secretary will make this decision, these decisions are expected to be delegated to the FDA). Therefore, it is important to note that the BPCI Act establishes a framework where 2 types of biosimilars may reach the U.S. market – those that are biosimilar and products that are biosimilar and interchangeable.
|Domain||Characteristic of biosimilar|
|Pharmacology||Utilizes the same mechanism or mechanisms of action for the condition(s) of use prescribed, but only to the extent the mechanism or mechanisms of action are known for the reference product|
|Delivery||Utilizes the same route of administration|
|Formulation||Same dosage form, same purity|
|Indications for use||The condition or conditions must be previously approved for the reference product|
|Data supporting safety and efficacy||Analytical studies that demonstrate that the biological product is highly similar to the reference product;
Animal studies (including an assessment of toxicity);
Clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed
|Excipients||Minor differences in clinically inactive components are allowable|
|Manufacturing facilities||Must follow "good manufacturing practices"|
|Substitution||Product may be biosimilar or deemed interchangeable|
|Patent protection||Innovator is granted 12 years of exclusive use to manufacture the reference product;
6 month extension is granted for pediatric studies;
Biosimilar is granted exclusive use for 1 year if licensed as the first interchangeable biosimilar
|Guidance||FDA may issue general or specific guidance on the science and experience required for the product or product class;
The issuance or nonissuance of such guidance does not preclude approval of a biosimilar;
FDA establishes a process through which the public can provide FDA with input regarding priorities for issuing guidance
|Risk Evaluation Mitigation Strategy programs (REMS)||Same REMS programs required of the innovator agent are applied to the biosimilar|
The BPCI Act includes provisions for exclusivity for economic protection. The FDA may not approve a BLA for a biosimilar until 12 years after the reference product was first licensed. The exclusivity period can be extended by 6 months, if studies involving pediatric patients are completed. In addition, the BPCI Act encourages biosimilar development by granting 1 year of exclusive marketing rights to the first biosimilar that is approved as being interchangeable with a reference product.21
In July 2012 President Obama signed the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, which reauthorized the Prescription Drug User Fee Act (PDUFA). PDUFA allows the FDA to collect user fees for new drug applications. FDASIA, the recent reauthorization, contained provisions for biosimilars, which are referred to as the Biosimilar User Fee Act of 2012 (BsUFA). This new legislation authorizes the FDA to assess and collect fees from biopharmaceutical manufacturers seeking approval for biosimilars. These resources will be used to hire staff that can provide feedback to companies seeking to develop biosimilars, expedite the application review process, and ultimately speed up the arrival of biosimilars to the marketplace.25
FDA Guidance Documents
Guidance from the FDA on biosimilars is critical since the BPCI Act provides the FDA with flexibility to define specific details of the biosimilar approval process. In February 2012 the FDA released a 3-part draft guidance to the industry regarding the development and approval processes of biosimilars.26-28 The FDA emphasizes that they will consider the totality of evidence to support a demonstration of biosimilarity. Each part outlines the complexity and challenges of developing and securing FDA-approval for a biosimilar medication. The FDA recommends a stepwise approach to demonstrating biosimilarity that includes scientific, animal, and human studies, where the evidence supports safety and effectiveness comparable to the reference product (Figure 4). The FDA stresses the importance of each step in the developmental process and how it will influence the type and amount of data required to move on to the next step; each sponsor should work closely with the FDA to solidify plans and establish milestones.
In addition, the FDA describes the quality requirements for biosimilarity. Manufacturers must ensure their expression system codes the same protein sequence as the reference product. The manufacturer must understand all manufacturing steps with physiochemical assessments identifying structures (primary, secondary, tertiary, and quaternary) and post-transitional modifications. Functional bioassays should complement all analytic activities and when receptor binding is critical, comparison studies must be completed versus the reference product. Manufacturers are required to characterize, identify, and quantify impurities in both the reference product and their biosimilar. Finally, a complete characterization of the finished product, including stability testing under accelerated stress study conditions (i.e., high temperature, light exposure, agitation, etc) is required to ensure product degradation and clinical performance are comparable to the reference product. Manufacturers are expected to generate reference standards or databases of scientific knowledge that can be relied upon for both the biosimilar and the reference product.27,28
Immunogenicity is the major safety concern for biosimilars and can be described as either classic immune reactions to foreign proteins or as a breakdown of immune tolerance (Table 6). Classic immune reactions are associated with products of human, animal, microbial, or plant origins and occur immediately, usually after a single injection. The clinical consequence, in most cases, is loss of medication efficacy; in addition, the reaction itself may force the patient to stop their treatment.29 The second mechanism leads to the development of neutralizing antibodies against the biosimilar. While the mechanisms by which the breakdown of immune tolerance is induced are not completely understood, it appears that aggregation in protein drugs and impurities are the most important factors in precipitating the generation of neutralizing antibodies.30
|Classic Reaction||Breakdown of Immune Tolerance|
|Antigen Properties||Human (growth hormone, blood clotting factor VII)||Human recombinant proteins
(epoetin, interferons, colony stimulating factors, interleukin-2)
|Animal (bovine and porcine insulins, heparins)|
|Bacteria (streptokinase, staphylokinase)|
|Antibody formation||Neutralizing antibodies||Neutralizing antibodies|
|Duration||Long||Disappear after treatment stops or after prolonged treatment|
|Cause||Foreign, nonself-antigens||Impurities and presence of aggregates|
|Consequences||Loss of efficacy, discontinuation of treatment||Larger doses|
Factors affecting the immunogenicity of a biologic include structural properties (e.g., sequence variation and glycosylation),29 patient's genetic background, the route of administration (evidence suggests that intravenous administration is less likely to elicit an immune response than subcutaneous or intramuscular administration), and the product formulation. Appropriate formulation, handling, and storage of a biologic is important, particularly with respect to stabilization. With inadequate stabilization, the protein may aggregate or denature, increasing its immunogenic potential. In a study of interferons, the most immunogenic formulation was a freeze-dried human serum albumin (HSA)-containing formulation, which was kept at room temperature. The interferon reacted with HSA to form aggregates, which in turn induced immune responses. Changing to an HSA-free formulation and storing it in a refrigerator reduced the product's immunogenicity.29
Antibodies can impact biologic pharmacokinetics and efficacy. Both increases and decreases in half-life have been reported, resulting in enhancement or attenuation of activity. In a study of hepatitis C virus (HCV) treatment, patients with the highest antibody titers had the lowest response rates to interferon treatment. Furthermore, neutralizing antibodies will inhibit the efficacy of all products in the same class, which can result in serious consequences for patients if there is no alternative treatment. Finally, antibody neutralization of naturally occurring proteins can have more serious consequences for the patient. Megakaryocyte-derived growth factor (MDGF), a native thrombopoietin protein, was administered to patients with cancer to stimulate platelet production. It produced MDGF antibodies, which neutralized native thrombopoietin, and produced severe thrombocytopenia. Patients required platelet transfusions to survive.29
Similarly, pure red cell aplasia was associated with the production of erythropoietin-neutralizing antibodies that resulted from exogenous epoetin (Eprex-Ortho Biotech LLC, Manati, Puerto Rico) administrated to patients with anemia from chronic kidney disease (CKD). The immune reaction appeared to be related to changes in product formulation. The Eprex formulation in Europe was changed when the HSA stabilizer was replaced by polysorbate 80 and glycine. Protein aggregates generated from the vial rubber stoppers were blamed for eliciting the immune reactions.31
The ability to predict immunogenicity in patients is limited. Sensitivity and specificity of assays for testing immunogenic responses are inadequate to predict rare cases of immunogenicity. The lack of standardization and validation of assay methods makes it virtually impossible to differentiate antibodies across laboratories. Conventional animal models may be useful for studying the relative immunogenicity of different biologic formulations and may be useful for screening different formulations or structural differences between products during product development and during the assessment of storage and handling.32
Naming of Biosimilar Products
Concerns exist that adverse events unique to biosimilars may appear, therefore adequate mechanisms for tracing and determining if a patient received the reference biologic or the biosimilar are needed. Several approaches exist to track the use of biosimilars for pharmacovigilance, and one approach that has been suggested is assigning unique nonproprietary names to biosimilars. The United States Adopted Names Council (USANC) approves nonproprietary (generic) names for all pharmaceuticals in the U.S. The World Health Organization (WHO) coordinates the International Nonproprietary Name (INN) program that standardizes drug nomenclature for new agents, worldwide. Small molecule manufacturers do not have to go through the USANC process because their generic products are identical to and have the same nonproprietary name as the innovator drug. While the WHO INN program is planning to develop, establish, and promote international standards for "biological, pharmaceutical, and similar products," the FDA has not decided whether biosimilars and innovator biologics will share nonproprietary names.23 The WHO INN Program advises that biosimilars should have a unique brand name and use lot numbers to ensure traceability, but they oppose unique generic names to identify nonglycosylated biosimilars. Furthermore, they recommend that glycosylation differences should be indicated by unique Greek letters (e.g., epoetin α, epoetin β) when naming epoetins and other glycoproteins, both reference products and biosimilars.
Several options in the U.S. have been proposed for the surveillance of biologic and biosimilar medications; these include 1) assigning different nonproprietary names to biosimilar and innovator compounds, 2) developing different physician-administered billing codes (Healthcare Common Procedure Coding System [HCPCS] codes), 3) utilizing National Drug Codes (NDC), and 4) establishing prospective electronic health data registries.23 Unique biosimilar names could prevent the substitution of one product for another. Clinicians and patients may interpret different names to mean that the products do not have similar efficacy and safety, even if regulatory agencies have determined that they meet biosimilarity requirements. Unique names could also cause confusion among prescribers, which may lead to prescribing errors and adverse events. Confusion of drug names has been frequently cited as a cause of medication errors.19 HCPCS, NDC, and lot numbers are not captured uniformly in electronic health records in health care institutions and office practices. However, NDCs can be used for tracking small-molecule generics dispensed through outpatient pharmacies; they are included as a reporting element in the FDA's MedWatch Safety Information and Adverse Drug Event Reporting Program and are often available on the packaging of patient medications. Patients and clinicians may require additional education about the possible use of NDCs for reporting events.23
The European Medicines Agency (EMA) has issued a number of guidelines for biosimilar approval, with specific recommendations for individual classes of biologics. Their guidelines advocate preclinical and clinical testing to demonstrate safety and efficacy as well as pharmacovigilance plans to monitor for adverse effects. The EMA has approved a number of biologics (Table 7), including both epoetin and granulocyte colony-stimulating factor (G-CSF) filgrastim biosimilars, after the patent expiration of the innovator products.33 The approvals of these biosimilar products, however, did not support interchangeability with the reference products. Two epoetin alfa (recombinant erythropoietin) products (Epogen [Amgen] and Procrit [Centocor Ortho Biotech]) received marketing approval in the U.S. in 1989. A third innovator epoetin alfa product (Erypo/ Eprex [Janssen-Cilag GmbH]) is approved in Europe.33 Five biosimilar epoetin alfa products, manufactured by 2 companies, are available in Europe: Retacrit and Silapo were given the INN epoetin zeta rather than epoetin alfa. Their approvals were based on comparability with Eprex in terms of structure, quality, safety, and efficacy. Despite differences in glycosylation levels on chromatography, all were deemed representative of the active substance isolated from Eprex. Comparable safety and efficacy between these biosimilar epoetin products and Eprex was demonstrated in clinical trials involving hemodialysis patients with anemia. In addition, supportive data, not intended to demonstrate equivalence, in patients with chemotherapy-induced anemia were supplied for both products.15 The EMA approved the biosimilar epoetins for anemia associated with chronic renal failure.33 It approved indications in cancer patients and those patients planning to undergo surgery (for autologous blood transfusions) via data extrapolation, without full clinical data supporting the indications.30
|Reference product||Marketing authorization holder||European medicines agency approval||Brand name||Substance or Molecule|
|Epoetin alfa||Sandoz GmbH||2007||Binocrit||HX575|
|Hexal GmbH||2007||Epoetin Hexal||HX575|
|Epoetin zeta||Hospira UK||2007||Retacrit||SB309|
|Stada Arzneimittel GmbH||2007||Silapo||SB309|
|Teva Generics GbmH||2008||TevaGrastim||XM02|
|CT Arzneimittel GmbH||2008||Biograstim||XM02|
|Hexal GmbH||2009||Filgrastim Hexal||EP2006|
Neupogen was used as the reference product for the approval of filgrastim biosimilars. Filgrastim is indicated in adults and children to shorten the duration of neutropenia and to reduce the incidence of febrile neutropenia following receipt of cytotoxic chemotherapy. It is also used to aid in the delivery of chemotherapy to maintain dose intensity and to support dose-dense chemotherapy. Filgrastim is also indicated to mobilize peripheral blood progenitor cells (PBPC) in both cancer patients and healthy donors and to support engraftment and neutrophil recovery after stem cell transplantation. Outside the oncology setting, filgrastim is indicated for the treatment of severe chronic neutropenia and to maintain neutrophil counts or for the reversal of neutropenia in patients infected with human immunodeficiency virus (HIV).
The biosimilars were compared with Neupogen through physicochemical, pharmacokinetic, pharmacodynamic, and clinical studies. Comparability was assessed in a single indication for which Neupogen is approved for, the reduction of chemotherapy-induced neutropenia (CIN) in accordance with EMA guidelines. Safety and efficacy was assessed in a comparative study involving breast cancer patients at high risk for CIN, with supportive studies providing safety data for patients with other malignancies (e.g., lung cancer, non-Hodgkin's lymphoma). Duration of neutropenia, time to white blood cell recovery, incidence of febrile neutropenia, and adverse events were similar and led the EMA to extrapolate the data and approve these biosimilars across all indications of the reference product.33
The EMA has not approved all biosimilar applications. Biosimilar interferon was recently rejected because of quality concerns (i.e., inadequate stability data and process validation for the finished process), insufficient immunogenicity testing, and clinical differences from the reference product.15 Biosimilars have been introduced in countries without a structured regulatory approval processes. Quality concerns may exist with these products and, therefore, it is important to differentiate non-innovator biologics approved in countries with limited or no regulations from products approved in countries with well-developed regulatory structures. In a comparative study of 11 different epoetin products sold in East Asia and South America, none of them had the same molecular patterns as the reference product.18
It is estimated that the use of generic medications have saved the U.S. health care system an estimated $824 billion over the past decade.23 The introduction of generic medications for conventional small molecule drugs offered price reductions of up to 80% compared with their branded counterparts. However, the economics surrounding biosimilars are different and the number of successful companies are expected to be limited. Because of higher development, facility, and manufacturing costs, biosimilar profits are expected to be more modest. It is estimated that the costs of developing a biosimilar product in the U.S. may range from $75 to $250 million. For more complex monoclonal antibodies, costs of up to $500 million have been projected. Government regulations and potential requirements for comparative studies that prove biosimilarity to the reference biologic enhance the risk and uncertainty of this investment and years may be required for a company to recoup its initial investment.34
The U.S. Congressional Budget Office has estimated biosimilars will provide a discount of up to 40% off the price of the reference product. In Europe, epoetin biosimilars have provided a 25% to 30% cost savings compared with their innovator products.23 While the savings from biosimilars have been modest compared with the savings from small molecule generics, they are still meaningful since they are expensive therapies.
Filgrastim biosimilars have captured about 50% of the total market share.34 The use of filgrastim has increased dramatically, which is thought to be a consequence of improved access and the increase in use among patients who had been untreated previously. Innovator companies have remained competitive with price, focusing on brand loyalty and marketing the uncertainties of biosimilars in the areas of safety and efficacy. The automatic substitution of a reference product with a biosimilar in the U.S., a practice which has not been employed in Europe, would facilitate the rapid penetration and market share uptake of biosimilars.16
The Pharmacist's Role
A recent survey of oncology clinicians suggests that practitioners who care for cancer patients are unfamiliar with issues surrounding biosimilar medications.23 Since patents are expiring on many biologics, it is crucial for pharmacists to become familiar with recent advances surrounding biosimilars and lead their appropriate introduction. In addition, pharmacists must understand the existing U.S. approval process for biosimilars, especially with the development and introduction of more complex biosimilars.
Biosimilar development is more complicated when compared with that of conventional small molecule medications. Pharmacists will be asked to evaluate biosimilars, and the data that support their FDA approval, for formularies at hospitals and for health care insurance plans. Evaluation through the formulary system will be necessary for the introduction of biosimilars, which is in contrast to the use of new small molecule generics that do not receive formulary review. Pharmacists should be prepared to lead the evaluation of comparability regarding manufacturing differences, pharmacokinetics, and immunogenicity, as well as clinical data comparisons. Pharmacists must assist with educating the medical community, and patients, about recognizing that biosimilars are not exact copies of their reference products, as well as explaining both the benefits and the potential pitfalls involved with use. Pharmacists are responsible for continuous patient monitoring and follow-up to ensure optimal outcomes and the avoidance of adverse events during treatment. This is especially important if treatment with existing products is changed or if biosimilar products are switched. If unique safety and efficacy problems occur with biosimilars, pharmacists are well positioned to monitor and identify these issues. The FDA has yet to define detailed standards for interchangeability or whether unique names will be used for specific biologics. Pharmacists must be aware of the manufacturer's handling and storage requirements for biologics, be comfortable with providing patients with instruction, and intervening when a medication may be questioned or a product's integrity compromised.
The arrival of biosimilar products in the U.S. represents an important opportunity for cost savings for essential, but expensive, therapies. Pharmacists must lead the appropriate introduction of biosimilars by understanding the issues that surround biosimilars. Biosimilars present pharmacists with another opportunity to plan an active role in advising other clinicians and patients, empowering them to make informed decisions about the use of biosimilars.
On August 29, 2012 the U.S. Food and Drug Administration (FDA) announced the approval of tbo-filgrastim, a recombinant human growth factor (Sicor Biotech UAB, a member of Teva Corporation).1 tbo-filgrastim is expected to be launched in the United States by the fourth quarter of 2013. The agent is available in Europe under the proprietary name Tevagrastim.
This approval highlights many of the recent issues surrounding biologics and biosimilar medications. The original tbo-filgrastim review application was filed in November 2009, when no legislative pathway existed for biosimilar drugs. Therefore, tbo-filgrastim was considered a new biologic, which followed the biologic license application (BLA) pathway at the FDA.2 When compared with the innovator or reference product (Table 1), tbo-filgrastim is a protein, produced from an Escherichia coli cell culture.3-4 While the World Health Organization (WHO) has an international reference standard for granulocyte colony stimulating factor (G-CSF), bioassays differ across manufacturers.5 As a new drug, tbo-filgrastim could not rely on any prior proprietary data and had to be evaluated in clinical studies for efficacy and safety. In the efficacy trial, tbo-filgrastim was compared with a non-FDA-approved filgrastim agent and placebo in adult patients with advanced breast cancer; tbo-filgrastim improved patient recovery from neutropenia. In the safety study tbo-filgrastim was evaluated in 3 trials, involving more than 600 patients, with a variety of malignancies. Side effects were minimal and bioassays suggested no patient developed neutralizing antibodies during treatment. Based on the totality of data submitted, coupled with a rigorous postmarketing drug stability surveillance program, tbo-filgrastim was approved as a new drug. Its indications are limited to the treatment, by subcutaneous injection, of severe neutropenia in patients with nonmyeloid malignancies, the population treated during trials for this medication.
Pharmacists should recognize that tbo-filgrastim is not a biosimilar, nor is it interchangeable with, Neupogen (filgrastim), the innovator product. Pharmacists can expect that within hospitals, under pharmacy and therapeutics (P&T) policies and procedures, pharmacies may seek to therapeutically interchange tbo-filgrastim for Neupogen for a number of indications. Pharmacists must be prepared to explain the potential differences between this agent and the innovator product.
- IMS (Institute for Healthcare Informatics) News. IMS Study Forecasts Rebound in Global Spending on Medicines, Reaching Nearly $1.2 Trillion By 2016. IMS Web site (July 12, 2012). http://www.imshealth.com/portal/site/ims/menuitem.d248e29c86589c9c30e81c03 3208c22a/?vgnextoid=4d47d1822e678310VgnVCM10000076192ca2RCRD&vgnextchannel=437879d7f269e210VgnVCM10000071812ca2RCRD&vgnextfmt=default. Accessed July 1, 2012.
- Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21-39.
- Genentech, Inc. Corporate Chronology: 1982. Genentech Web site. http://www.gene.com/gene/about/corporate/history/timeline.html. Accessed July 1, 2012.
- EvaluatePharma, LTD (Web site). Surveying Tomorrow's BioPharma Landscape: The NASDAQ Biotech Index Up Close. https://www.evaluatepharma.com/secure/FileResourceDownload.aspx?id=847d4 5d7-07a9-4171-9085-d1a2584b0b29. Accessed July 1, 2012.
- Drug patent watch (Web site). Drug patent expirations and intelligence. http://www.drugpatentwatch.com/subs/. Accessed July 1, 2012.
- Weise M, Bielsky MC, De Smet K, et al. Biosimilars - why terminology matters. Nat Biotechnol. 2011;29:690-693.
- International Market Analysis Research and Consulting (IMARC) Global Biopharmaceutical Market Report (2010-2015). October 29, 2010:234 Pages. Pub ID: IMRC2849563.
- ICIS (Reed Business Information Limited). Pharmaceutical innovators aim to be major players in the market for follow-on biologics, or biosimilars. ICIS Chemical Business. ICIS Web site http://www.icis.com/Articles/2010/02/15/9333235/follobw-on- biologicspresent-opportunity-to-big-pharma.html. Accessed July 1, 2012.
- Sekhon BS, Saluja V. Biosimilars: an overview. Biosimilars. 2011;1:1-11.
- McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3):405-417.
- Generic Pharmaceutical Association (GPhA). The Generic Pharmaceutical Industry--Improving Lives for Less. www.gphaonline.org/about-gpha/about-generics/case/generics-providing-savings-americans. Accessed August 9, 2012.
- Medicare Payment Advisory Commission (MedPAC). Report to the Congress: Improving Incentives in the Medicare Program (MedPAC, Washington, DC, June 15, 2009). http://www.medpac.gov/documents/jun09_entirereport.pdf. Accessed July 1, 2012.
- Hennessy S, Leonard CE, Platt R. Assessing the safety and comparative effectiveness of follow-on biologics (biosimilars) in the United States. Clin Pharmacol Ther. 2010;87(2):157-159.
- Lacaná E, Amur S, Mummanneni P, et al. The emerging role of pharmacogenomics in biologics. Clin Pharmacol Ther. 2007;82:466-471.
- Schellekens H. Biosimilar therapeutics—what do we need to consider? NDT Plus. 2009;2(suppl 1):i27-i36.
- Crommelin D, Bermejo T, Bissig M, et al. Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals. Euro J Hosp Pharm Science. 2005;11(1):11-17.
- Roger SD. Biosimilars: how similar or dissimilar are they? Nephrology (Carlton). 2006;11(4):341-346.
- Genazzani AA, Biggio G, Caputi AP, et al. Biosimilar drugs: concerns and opportunities. BioDrugs. 2007;21(6):351-356.
- Chirino AJ, Mire-Sluis A. Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol. 2004; 22:1383-1391.
- Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19(3):411-419.
- Kay J. Biosimilars: a regulatory perspective from America. Arthritis Res Ther. 2011;13(3):112.
- Ballentine C. Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide
Incident. U.S. Food and Drug Administration (FDA) Consumer magazine: 1981. FDA Web site. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/Sulfanilamide Disaster/default.htm. Accessed July 20, 2012.
- Zelentz AD, Ahmed I, Braud EL, et al. NCCN biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Cance Netw. 2011;9 (suppl 4): s1-s22.
- Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures-2007. Am J Health-Syst Pharm. 2007;64:298-314.
- U.S. Food and Drug Administration (FDA). Biosimilar User Fee Act (BsUFA). FDA Web site. http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/default.htm. August 9, 2012.
- U.S. Food and Drug Administration (FDA). 2012 Guidance for Industry: Scientific
Considerations in Demonstrating Biosimilarity to a Reference Product. FDA Web site. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G uidances/UCM291128.pdf. August 9, 2012.
- U.S. Food and Drug Administration (FDA). Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product: 2012. FDA Web site. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G uidances/UCM291134.pdf. Accessed August 9, 2012.
- U.S. Food and Drug Administration (FDA). 2012 Guidance for Industry: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. FDA Web site.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM273001.pdf. Accessed August 9, 2012.
- Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol
Dial Transplant. 2005;20 (suppl 6):vi3-vi9.
- Schellekens H. The first biosimilar epoetin: but how similar is it? Clin J Am Soc Nephrol. 2008;3(1):174-178.
- Schellekens H. Follow-on biologics: challenges of the "next generation". Nephrol Dial
Transplant. 2005;20(suppl 4):iv31-iv36.
- Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol
Dial Transplant. 2006;21(suppl 5):v13-v16.
- Niederwieser D, Schmitz S. Biosimilar agents in oncology/haematology: from approval to practice. Eur J Haematol. 2011;86(4):277-288.
- Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies: regulatory, clinical and commercial considerations. Drugs. 2011;71(12):1527-1536.