A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a
biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's
patent
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...
expires.
Reference to the innovator product is an integral component of the approval.
Unlike with
generic drugs of the more common
small-molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
type, biologics generally exhibit high molecular complexity and may be quite sensitive to changes in manufacturing processes. Despite that heterogeneity, all
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
s, including biosimilars, must maintain consistent quality and clinical performance throughout their lifecycle.
Drug-related authorities such as the
European Medicines Agency (EMA) of the European Union, the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA), and the
Health Products and Food Branch The Health Products and Food Branch (HPFB) of Health Canada manages the health-related risks and benefits of health products and food by minimizing risk factors while maximizing the safety provided by the regulatory system and providing information ...
of
Health Canada hold their own guidance on requirements for demonstration of the similar nature of two biological products in terms of safety and efficacy. According to them, analytical studies demonstrate that the biological product is highly similar to the reference product, despite minor differences in clinically inactive components, animal studies (including the assessment of toxicity), and a clinical study or studies (including the assessment of
immunogenicity
Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:
* Wanted immunogenicity typically relates to vaccines, where the injectio ...
and
pharmacokinetics or
pharmacodynamics
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...
). They are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and is intended to be used and for which licensure is sought for the biological product.
The
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
(WHO) published its "Guidelines for the evaluation of similar biotherapeutic products (SBPs)" in 2009. The purpose of this guideline is to provide an international norm for evaluating biosimilars.
The EMA has granted marketing authorizations for more than 50 biosimilars since 2006, (first approved biosimilar Somatropin (Growth hormone)). The first biosimilar of a
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
to be approved worldwide was a biosimilar of
infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
in the EU in 2013.
On March 6, 2015, the FDA approved the United States' first biosimilar product, the biosimilar of
filgrastim
Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count. Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause. It may ...
called filgrastim-sndz (trade name Zarxio) by
Sandoz
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loca ...
.
Approval processes
United States
In the United States, the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. Additional Congressional hearings have been held. On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House.
See th
Library of Congress websiteand search H.R. 1548 in 111th Congress Session. Since 2004 the FDA has held a series of public meetings on biosimilars.
The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the
Patient Protection and Affordable Care Act signed into law by President Obama on March 23, 2010.
The FDA has previously approved biologic products using comparability, for example,
Omnitrope in May 2006, but this like
Enoxaparin
Enoxaparin sodium, sold under the brand name Lovenox among others, is an anticoagulant medication (blood thinner). It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following c ...
was also to a reference product,
Genotropin, originally approved as a
biologic drug under the FD&C Act.
On March 6, 2015,
Zarxio obtained the first approval of FDA. Sandoz's Zarxio is biosimilar to Amgen's Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates
Zarxio is biosimilar to Neupogen.
In March 2020, most protein products that were approved as drug products (including every insulin currently on the market ) are scheduled to open up to biosimilar and interchangeable competition in the United States.
[ ] However, "chemically synthesized polypeptides" are excluded from this transition, which means that a product that falls within this category won't be able to come to market as a biosimilar or interchangeable product, but will have to come to the market under a different pathway.
Background
Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any
recombinant DNA
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be fo ...
based biological substance for eventual development of a drug.
Monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines.
Gene- and
cell-based therapies are emerging as new approaches.
Recombinant therapeutic
proteins are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.
After the expiry of the patent of approved recombinant drugs (e.g.,
insulin, human
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
,
interferons
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
,
erythropoietin, monoclonal antibodies and more) any other biotech company can develop and market these
biologics
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, th ...
(thus called biosimilars).
The typical reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and was approved by the EMA.
The current concept of development of biosimilar
mAbs follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical "model" indication that is most sensitive to detect any minor differences (if these exist) between the biosimilar and its reference mAb also at the clinical level.
The EMA has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same.
Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed
pharmacovigilance
Term Given By Tushar Sharma (UPES Batch 2025)
Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharma ...
plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status.
Generally, once a drug is released in the market by the FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years. Afterward, re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by the EMA are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies.
Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator's product versus antibodies from a biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population.
Nomenclature
In the European Union, no unique identifier of a biosimilar medicine product is required, as the same rules are followed as for all biologics.
The US decided on a different approach, requiring the assignment of a four-letter suffix to the nonproprietary name of the original product to distinguish between innovator drugs and their biosimilars. Japan has similar requirements.
The suffix approach has been criticized on the grounds of compromising the INN system and delaying the marketing of biosimilars.
Australia decided not to use a 4-letter suffix.
A version of the four-letter suffix has been proposed to the WHO as the biological qualifier (BQ). It is not part of the
international nonproprietary name (INN), but is proposed to be managed under the same registry. The report 1 of the May 2017 WHO Expert Consultation on Improving Access to and Use of Similar Biotherapeutic Products, published in October 2017, revealed on page 4, that following the outcome arising from the meeting: "No consensus was reached on whether WHO should continue with the BQ… WHO will not be proceeding with this at present."
Australia
Biosimilars available in Australia include adalimumab, bevacizumab, enoxaparin, epoetin lambda, etanercept, filgrastim, follitropin alfa, infliximab, insulin aspart, insulin glargine, pegfilgrastim, rituximab, teriparatide, and trastuzumab.
European Union
Biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar.
United States
BPCI Act
The
Biologics Price Competition and Innovation Act
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
of 2009 (BPCI Act) was originally sponsored and introduced on June 26, 2007, by Senator
Edward Kennedy
Edward Moore Kennedy (February 22, 1932 – August 25, 2009) was an American lawyer and politician who served as a United States senator from Massachusetts for almost 47 years, from 1962 until his death in 2009. A member of the Democratic ...
(D-MA). It was formally passed under the
Patient Protection and Affordable Care Act (PPAC Act), signed into law by President Barack Obama on March 23, 2010. The BPCI Act was an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved biological product. The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 (also referred to as the "Hatch-Waxman Act") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. The FDA has released a total of four draft guidelines related to biosimilar or follow-on biologics development. Upon the release of the first three guidance documents the FDA held a public hearing on May 11, 2012.
In 2018, the FDA released a Biosimilars Action Plan to implement regulations from the BPCI, including limiting the abuse of the Risk Evaluation and Mitigation Strategy (REMS) system for
evergreening
Evergreening is any of various legal, business, and technological strategies by which producers (often pharmaceutical companies) extend the lifetime of their patents that are about to expire in order to retain revenues from them. Often the practice ...
and transitioning insulin and human growth hormone to regulation as biologics rather than drugs.
US approved biosimilars
Proposed reforms
In the United States, biosimilars have not had the expected impact on prices, leading a 2019 proposal to price regulate instead after an exclusivity period. Another proposal requires originators to share the underlying
cell lines
An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...
.
In 2019, the proposed Biologic Patent Transparency Act would help address
evergreening
Evergreening is any of various legal, business, and technological strategies by which producers (often pharmaceutical companies) extend the lifetime of their patents that are about to expire in order to retain revenues from them. Often the practice ...
"
patent thicket
A patent thicket is "an overlapping set of patent rights" which requires innovators to reach licensing deals for multiple patents. This concept is associated with negative connotations and has been described as "a dense web of overlapping intellect ...
s" by requiring that all patents protecting a biosimilar be disclosed.
Biosimilars have found it difficult to get market share, which led biosimilar developer
Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
to sue
Johnson & Johnson over anticompetitive contracts with
pharmacy benefit managers
In the United States, a pharmacy benefit manager (PBM) is a third-party administrator of prescription drug programs for commercial health plans, self-insured employer plans, Medicare Part D plans, the Federal Employees Health Benefits Program, ...
which
bundle
Bundle or Bundling may refer to:
* Bundling (packaging), the process of using straps to bundle up items
Biology
* Bundle of His, a collection of heart muscle cells specialized for electrical conduction
* Bundle of Kent, an extra conduction pat ...
discounts; these are sometimes called the "rebate wall", and the rebates are generally unavailable to customers.
Market implications
![Biosimilars Patent Cliff](https://upload.wikimedia.org/wikipedia/commons/4/46/Biosimilars_Patent_Cliff.png)
The legal requirements of approval pathways, together with the costly manufacturing processes, escalates the developing costs for biosimilars that could be between $75–$250 million per molecule.
This market entry barrier affects not only the companies willing to produce them but could also delay availability of inexpensive alternatives for public healthcare institutions that subsidize treatment for their patients. Even though the biosimilars market is rising, the price drop for biological drugs at risk of patent expiration will not be as great as for other generic drugs; in fact it has been estimated that the price for biosimilar products will be 65%-85% of their originators.
Biosimilars are drawing market's attention since there is an upcoming
patent cliff The term patent cliff refers to the phenomenon of patent expiration dates and an abrupt drop in sales that follows for a group of products capturing a high percentage of a market. Usually, these phenomena are noticed when they affect ''blockbuster p ...
, which will put nearly 36% of the $140 billion market for biologic drugs at risk (as of 2011), this considering only the top 10 selling products.
The global biosimilars market was in 2013, and is expected to reach by 2020, driven by the
patent expiration of additional ten blockbuster biologic drugs.
Companies
Certain companies (in some cases subsidiaries) tend to operate as generic drug manufacturers, with major ones including
Teva,
Mylan
Mylan N.V. was a global generic and specialty pharmaceuticals company. In November 2020, Mylan merged with Upjohn, Pfizer's off-patent medicine division, to form Viatris. Previously, the company was domiciled in the Netherlands, with principal e ...
, and Sandoz and may also extend that focus to biosimilars. Sandoz, for example, introduced the first biosimilar in the United States, and plans to introduce another in 2020. Newer companies such as India-based
Cadila Pharmaceuticals,
Sun Pharma,
Aurobindo PharmaLupinand
Dr. Reddy's Laboratories
Dr. Reddy's Laboratories is an Indian multinational pharmaceutical company based in Hyderabad. The company was founded by Kallam Anji Reddy, who previously worked in the mentor institute Indian Drugs and Pharmaceuticals Limited. Dr. Reddy's ...
as well as Canada-based
Apotex
Apotex Inc. is a Canadian pharmaceutical corporation. Founded in 1974 by Barry Sherman, the company is the largest producer of generic drugs in Canada, with annual sales exceeding . By 2016, Apotex employed over 10,000 people as one of Canada's ...
have taken share in traditional generics, which has led older companies to shift their focus to complex drugs such as biosimilars.
References
Further reading
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External links
Overview of Biosimilar ProductsU.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
Biosimilar Regulatory Review and Approval U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
Interchangeable Biological Products U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
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