Biosimilar


A biosimilar 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 expires. Reference to the innovator product is an integral component of the approval.
Unlike with generic drugs of the more common small-molecule type, biosimilar drugs generally exhibit high molecular complexity and may be quite sensitive to changes in manufacturing processes. Despite this heterogeneity, all biopharmaceuticals, including biosimilars, must maintain consistent quality and clinical performance throughout their lifecycle.
Drug-related authorities such as the European Medicines Agency of the European Union, the United States Food and Drug Administration, and the Health Products and Food Branch 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, and a clinical study or studies. 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 published its "Guidelines for the evaluation of similar biotherapeutic products " 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. The first biosimilar of a monoclonal antibody to be approved worldwide was a biosimilar of infliximab in the EU in 2013. On March 6, 2015, the FDA approved the United States' first biosimilar product, the biosimilar of filgrastim called filgrastim-sndz by Sandoz.

Approval processes

United States

In the United States, the Food and Drug Administration 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. Since 2004 the FDA has held a series of public meetings on biosimilars.
The FDA gained the authority to approve biosimilars as part of the Biologics Price Competition and [Innovation Act of 2009].
The FDA has previously approved biologic products using comparability, for example, Omnitrope in May 2006, but this like Enoxaparin was also to a reference product, Genotropin, originally approved as a biologic under the FD&C Act.
In March 2015, Zarxio obtained the first biosimilar approval from the FDA. Sandoz's Zarxio is biosimilar to Amgen's Neupogen, which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009, 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 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 based biological substance for eventual development of a drug. Monoclonal antibody 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. These proteins are made in living cells. 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 any other biotech company can develop and market these biologics.
The typical reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process was substantiated with appropriate data and was approved by the EMA.
The current concept of development of biosimilar monoclonal antibodies 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 between the biosimilar and its reference monoclonal antibody 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 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 regulations as its reference product. Thus biosimilars approved by the EMA are required to submit a risk management plan 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, 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. It is not part of the international nonproprietary name, 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."

Bioparallel

Different from biosimilars, many new antibodies are being developed with the goal to be structurally different but functionally very similar to their reference drugs. Similarly, in advanced therapy medicinal products, such as Chimeric Antigen Receptor T-cell therapy, the exchange of one component by a similar component, generates structurally different, but functionally similar copies of drugs. There is no established term for such biologics, but the terms "bioparallels" or "me-too biologics" have been proposed. Within the current frameworks of the US and EU approval processes, these drugs require evaluation as new biological entities. Bioparallels compete with their reference medicines on price but have the advantage of being able to enter the market earlier.

Biobetter

The term biobetter refers to a biological drug that is an improved version of an existing biological drug. Unlike biosimilars, the term biobetter is used informally without any official and universally accepted definition. While biosimilars try to copy an existing biological drug as closely as possible, biobetters try to improve on it. Since the term biobetter is informal, there is no rule which regulatory pathway they need to go through to be approved. When the improvement to the original drug is merely in the formulation, the drug might be regulated as a biosimilar. However, if the active pharmaceutical ingredient has been modified, the drug needs to be evaluated as a new biological entity. Even without changes to the API, the biobetter needs to be evaluated as a new biological entity, if it shows better clinical outcomes compared to the reference medicine. The latter happened e.g. to Zymfentra, an antibody biosimilar that can be given subcutaneously, whereas its reference medicine infliximab was only approved for intravenous administration.

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.

Egypt

A research article about "Maximizing the benefits of using biosimilars in Egypt" proposed a regulatory framework for biosimilars in Egypt. The article summarized the recommendations of a number of stakeholders.
;Key Findings and Recommendations of the article
  1. Pricing: The experts suggested a mandatory discount of 30–40% on the price of the first biosimilar compared to its originator, with subsequent biosimilars receiving additional discounts. It was also recommended that biosimilar prices be revised periodically, either annually or biennially.
  2. Reimbursement: A significant emphasis was placed on using Health Technology Assessment, specifically cost-effectiveness analysis and budget impact analysis, when manufacturers seek to extend reimbursement indications beyond those of the originator. Additionally, experts proposed that the first biosimilar, offering a minimum 50% discount compared to the originator, be granted immunity from removal from the formulary for a specified period.
  3. Uptake: The study highlighted the need for policies that enhance both prescriber and patient acceptance of biosimilars. Strategies include disseminating educational materials, implementing financial incentives for prescribing biosimilars as first-line therapy, and using co-payments to encourage the choice of less expensive biosimilars over more costly biologics.
  4. Post-Marketing and Pharmacovigilance: The importance of establishing registries and conducting real-world evidence studies to monitor biosimilar efficacy and safety was also emphasized. A pharmacovigilance framework specific to biosimilars and biologics was suggested to be more effective than the existing general framework.

European Union

Biosimilar medicines approved in the European Union are interchangeable with their reference medicine or with an equivalent biosimilar.
Active substanceReference productBiosimilar medicines
AdalimumabHumiraAmgevita, Amsparity, Cyltezo, Halimatoz, Hefiya, Hukyndra, Hulio, Hyrimoz, Idacio, Imraldi, Kromeya, Libmyris, Solymbic, Trudexa, Yuflyma
BevacizumabAvastinAbevmy, Alymsys, Aybintio, Equidacent, Mvasi, Onbevzi, Oyavas, Vegzelma, Zirabev
Enoxaparin sodiumClexaneInhixa, Thorinane
Epoetin alfaEprex/ErypoAbseamed, Binocrit, Epoetin Alfa Hexal, Retacrit, Silapo
EtanerceptEnbrelBenepali, Erelzi, Lifmior, Nepexto
FilgrastimNeupogenAccofil, Biograstim, Filgrastim Hexal, Filgrastim ratiopharm, Grastofil, Nivestim, Ratiograstim, Tevagrastim, Zarzio
Follitropin alfaGonal-FBemfola, Ovaleap
InfliximabRemicadeFlixabi, Inflectra, Remsima, Zessly
Insulin aspartNovoRapidFiasp, Insulin aspart Sanofi, Kirsty, NovoMix, Ryzodeg
Insulin glargineLantusAbasaglar, Semglee
Insulin lisproHumalogInsulin lispro Sanofi
PegfilgrastimNeulastaCegfila, Fulphila, Grasustek, Pelgraz, Pelmeg, Udenyca, Stimufend, Ziextenzo
RanibizumabLucentisByooviz, Ranivisio, Ximluci
RituximabMabTheraBlitzima, Ritemvia, Rituzena, Rixathon, Riximyo, Ruxience, Truxima
SomatropinGenotropinOmnitrope
TeriparatideForsteoMovymia, Terrosa
TocilizumabRoActemraTyenne
TrastuzumabHerceptinHerzuma, Kanjinti, Ogivri, Ontruzant, Trazimera, Zercepac

United States

As of October 2024, the US FDA has approved 60 biosimilars.

BPCI Act

The Biologics Price Competition and Innovation Act of 2009 is an amendment to the Public Health Service Act to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar to a Food and Drug Administration approved biological product. The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 which created biological drug approval through the Federal Food, Drug, and Cosmetic 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 Act, including limiting the abuse of the risk evaluation and mitigation strategy system for evergreening and transitioning insulin and human growth hormone to regulation as biologics rather than drugs.

US approved biosimilars

Date of Biosimilar FDA ApprovalBiosimilar ProductOriginal Product
March 2015filgrastim-sndz/Zarxiofilgrastim/Neupogen
April 2016infliximab-dyyb/Inflectrainfliximab/Remicade
August 2016etanercept-szzs/Erelzietanercept/Enbrel
September 2016adalimumab-atto/Amjevitaadalimumab/Humira
April 2017infliximab-abda/Renflexisinfliximab/Remicade
August 2017adalimumab-adbm/Cyltezoadalimumab/Humira
September 2017bevacizumab-awwb/Mvasibevacizumab/Avastin
December 2017trastuzumab-dkst/Ogivritrastuzumab/Herceptin
December 2017infliximab-qbtx/Ixifiinfliximab/Remicade
May 2018epoetin alfa-epbx/Retacritepoetin alfa/Procrit
June 2018pegfilgrastim-jmdb/Fulphilapegfilgrastim/Neulasta
July 2018filgrastim-aafi/Nivestymfilgrastim/Neupogen
October 2018adalimumab-adaz/Hyrimozadalimumab/Humira
November 2018pegfilgrastim-cbqv/Udenycapegfilgrastim/Neulasta
November 2018rituximab-abbs/Truximarituximab/Rituxan
December 2018trastuzumab-pkrb/Herzumatrastuzumab/Herceptin
January 2019trastuzumab-dttb/Ontruzanttrastuzumab/Herceptin
March 2019trastuzumab-qyyp/Trazimeratrastuzumab/Herceptin
April 2019etanercept-ykro/Eticovoetanercept/Enbrel
June 2019trastuzumab-anns/Kanjintitrastuzumab/Herceptin
June 2019bevacizumab-bvzr/Zirabevbevacizumab/Avastin
July 2019rituximab-pvvr/Ruxiencerituximab/Rituxan
July 2019adalimumab-bwwd/Hadlimaadalimumab/Humira
November 2019pegfilgrastim-bmez/Ziextenzopegfilgrastim/Neulasta
November 2019adalimumab-afzb/Abriladaadalimumab/Humira
December 2019infliximab-axxq/Avsolainfliximab/Remicade
June 2020pegfilgrastim-apgf/Nyvepriapegfilgrastim/Neulasta
July 2020adalimumab-fkjp/Hulioadalimumab/Humira
December 2020rituximab-arrx/Riabnirituximab/Rituxan
July 2021insulin glargine-yfgn/Semgleeinsulin glargine/Lantus
September 2021ranibizumab-nuna/Byoovizranibizumab/Lucentis
December 2021insulin glargine-aglr/Rezvoglarinsulin glargine/Lantus
December 2021adalimumab-aqvh/Yusimryadalimumab/Humira
February 2022filgrastim-ayow/Releukofilgrastim/Neupogen
April 2022bevacizumab-maly/Alymsysbevacizumab/Avastin
May 2022pegfilgrastim-pbbk/Fylnetrapegfilgrastim/Neulasta
August 2022ranibizumab-eqrn/Cimerliranibizumab/Lucentis
September 2022pegfilgrastim-fpgk/Stimufendpegfilgrastim/Neulasta
September 2022bevacizumab-adcd/Vegzelmabevacizumab/Avastin
December 2022adalimumab-aacf/Idacioadalimumab/Humira
May 2023adalimumab-aaty/Yuflymaadalimumab/Humira
August 2023natalizumab-sztn/Tyrukonatalizumab/Tysabri
September 2023tocilizumab-bavi/Tofidencetocilizumab/Actemra
October 2023ustekinumab-auub/Wezlanaustekinumab/Stelara
December 2023bevacizumab-tnjn/Avzivibevacizumab/Avastin
February 2024adalimumab-ryvk/Simlandiadalimumab/Humira
March 2024denosumab-bbdz/Jubbontidenosumab/Prolia
March 2024denosumab-bbdz/Wyostdenosumab/Xgeva
March 2024tocilizumab-aazg/Tyennetocilizumab/Actemra
April 2024ustekinumab-aekn/Selarsdiustekinumab/Stelara
April 2024trastuzumab-strf/Hercessitrastuzumab/Herceptin
May 2024aflibercept-yszy/Opuvizaflibercept/Eylea
May 2024aflibercept-jbvf/Yesafiliaflibercept/Eylea
May 2024eculizumab-aeeb/Bkemveculizumab/Soliris
June 2024ustekinumab-ttwe/Pyzchivaustekinumab/Stelara
June 2024filgrastim-txid/Nypozifilgrastim/Neupogen
June 2024aflibercept-mrbb/Ahzantiveaflibercept/Eylea
July 2024eculizumab-aagh/Epysqlieculizumab/Soliris
August 2024aflibercept-abzv/Enzeevuaflibercept/Eylea
August 2024aflibercept-ayyh/Pavbluaflibercept/Eylea
September 2024ustekinumab-aauz/Otulfiustekinumab/Stelara
October 2024ustekinumab-srlf/Imuldosaustekinumab/Stelara
November 2024ustekinumab-kfce/Yesintekustekinumab/Stelara
December 2024Ustekinumab-stba/Steqeymaustekinumab/Stelara
January 2025tocilizumab-anoh/Avtozmatocilizumab/Actemra
February 2025denosumab-dssb/Ospomyvdenosumab/Prolia
February 2025denosumab-dssb/Xbrykdenosumab/Xgeva
February 2025insulin aspart-szjj/Meriloginsulin aspart/Novolog
February 2025denosumab-bmwo/Osenveltdenosumab/Xgeva
February 2025denosumab-bmwo/Stoboclodenosumab/Prolia
March 2025omalizumab-igec/Omlycloomalizumab/Xolair
March 2025denosumab-bnht/Bomyntradenosumab/Xgeva
March 2025denosumab-bnht/Conexxencedenosumab/Prolia
April 2025bevacizumab-nwgd/Jobevnebevacizumab/Avastin
May 2025ustekinumab-hmny/Starjemzaustekinumab/Stelara
July 2025insulin aspart-xjhz/Kirstyinsulin aspart/Novolog
August 2025denosumab-nxxp/Bildyosdenosumab/Prolia
August 2025denosumab-nxxp/Bilprevdadenosumab/Xgeva
September 2025denosumab-kyqq/Aukelsodenosumab/Xgeva
September 2025denosumab-kyqq/Bosayadenosumab/Prolia
September 2025denosumab-qbde/Enobydenosumab/Prolia
September 2025denosumab-qbde/Xtrenbodenosumab/Xgeva
October 2025aflibercept-boav/Eydenzeltaflibercept/Eylea
October 2025denosumab-desu/Jubereqdenosumab/Xgeva
October 2025denosumab-desu/Osvyrtidenosumab/Prolia
November 2025pertuzumab-dpzb/Poherdypertuzumab/Perjeta
November 2025pegfilgrastim-unne/Armlupegpegfilgrastim/Neulasta
December 2025ranibizumab-leyk/Nufymcoranibizumab/Lucentis
December 2025denosumab-mobz/Boncresadenosumab/Prolia
December 2025denosumab-mobz/Oziltusdenosumab/Xgeva