expanding the horizon for...

EXPANDING THE HORIZON FOR BIOSIMILARSAn overview of biosimilars and their evolving landscape



What is a biosimilar?

A biosimilar is a biological medicinal product that is not identical, but highly similar to an already licensed biological medicinal product (reference product).1-3

Contents03 / What is a bioisimilar?

04 / A biosimilar is not a generic

05 / The value of biosimilars

06 / Biosimilarity based on totality of evidence

08 / Extrapolation of indications

10 / Switching and interchangeability of biosimilars

1 2 / Perceptual evolution in the biosimilar landscape

14 / Summary


The European Medicines Agency (EMA) andU.S. Food and Drug Administration (FDA) define biosimilars as:

A biosimilar is a product similar to a biological medicine that has already been authorised, the so-called reference medicinal product. The active substance of a biosimilar is a known biological active substance and similar to that of the reference medicinal product. A biosimilar

and its reference medicinal product are expected to have the same safety and efficacy profile and are generally used to treat the same conditions.

EMA4

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety

and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

FDA5

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Figure 2. The potential and benefits of biosimilars. Figure 1. Comparison of the size and complexity between generics, low molecular weight biosimilars (1st generation biosimilars) and 2nd generation biosimilars.

Aspirin(acetylsalicylic acid)

180 daltons

1st generation biosimilar

Insulin

5,700 daltons

Generic Generic Generic

1st generation biosimilar

2nd generation biosimilar

Monoclonal antibody

~150,000 daltons

The value of biosimilarsA biosimilar is not a generic

While biologics have markedly improved therapeutic options and outcomes for many life-threatening and chronic diseases, their costs have often been high, and access to potentially lifesaving biologics is limited in many areas of the world.9

Fortunately, biosimilars are emerging as a cost-effective alternative to biologics and have the potential to make important biological therapies widely accessible to a global population, as well as resulting in many other benefits (Figure 2).10

Unlike generics, biosimilars are large, highly complex molecules derived from living cells or organisms. The difference in complexities between biosimilars and generic drugs leads to an important distinction: while generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biosimilars are inherently variable, creating inevitable differences even between subsequent batches of the same product.

For this reason, biosimilars require far more rigorous and complicated steps to manufacture compared to generics, and even within biosimilars, the development of 2nd generation biosimilars such as monoclonal antibodies is much more difficult than that of 1st generation biosimilars of smaller, low molecular weight biologics (Figure 1).6-8

Drive innovation through competition

Provide a wider range of benefits for all stakeholders in the medical community

Cost-effective alternative to biologics

Increase patient access to important biological therapy globally

Reduce pressure on healthcare costs and free up limited budgets

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• Physicochemical analysis: examines similarity in glycosylation, impurity, charge variant, etc. between biosimilar and reference product.

20+ Physicochemical tests

• Biological analysis: assesses comparability of biosimilar and reference product in terms of biological functions such as binding and enzyme activity.

40+ Biological tests

• Clinical trials: demonstrates equivalent PK, efficacy, and comparable safety of biosimilar to those of reference product.

Global randomised controlled trials

*Head-to-head comparison

Table 1. Comparison of the marketing authorisation process for generics, new biologics and biosimilars.

Generic New biologic Biosimilar

Quality Studies (structural and biological characterisation)

Comparability test X X O

Full module O O O

Non-clinical studies (toxicity) X O O

Clinical studies

Safety and efficacy X O O

Pharmacokinetics/Pharmacodynamics O* O O

Pharmacovigilance X O O

*

*

*

*

Biosimilarity based on totality of evidence

The objective of a biosimilar development program is to establish “biosimilarity” supported by totality of evidence from comparative analytical, non-clinical, and clinical studies.11

Biosimilars and generics also differ considerably in terms of the studies taken to demonstrate equivalence to a reference product. Because generics are identical to the reference product, a bioequivalence study in humans is sufficient to prove therapeutic equivalence once molecular identity is demonstrated through analytical tests.12

This does not hold for biosimilars. The regulatory pathway pursued for demonstrating equivalence to reference product is much longer and more complex for biosimilars than for generics, due to their inherent variability (Table 1).12

Biosimilarity

Clinical Studies – Efficacy

Non-Clinical Studies

– In vitro/ In vivo

Clinical Studies – Safety

Clinical Studies

– Immunogenicity

Human Pharmacokinetics and Pharmacodynamics

(PK/PD)

Structural and Functional

Characterisation (CMC)

CMC: Chemistry, Manufacturing, and Controls

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Demonstrating comparability to the reference product is the foundation in the approach to seeking extrapolation.

Comparability exercises must include:

• Comparison of quality (physicochemical and functional) attributes

• Clinical studies assessing any differences in efficacy, safety, or immunogenicity in the most-sensitive patient population

• Assessment of the mechanism of action(s) of the biosimilar in each indication

The primary rationale for data extrapolation is to avoid unnecessary studies in the target population for ethical reasons, efficiency, and to allocate resources to areas where studies are the most needed.

– European Medicines Agency

Figure 3. Extrapolation of indications scientifically justified through extensive comparability studies.

Physicochemical Characterisation ClinicalNon-clinical

Biological Characterisation PK/PD

01 05040302

Extrapolation of indications

Extrapolation of indications is a core principle of biosimilar development. It is the leveraging of safety and efficacy data from clinical studies in the most sensitive indications to support the authorisation of other less sensitive indications. Once extrapolation is granted, the biosimilar can be used for the treatment of all indications for which the reference product has been approved.13,14

Extrapolation must be scientifically justified and is based on the totality of evidence supported by extensive analytical, functional, non-clinical and clinical comparability studies (Figure 3).13,14

Biosimilar manufacturers must submit convincing and compelling data that justifies extrapolation of data to the appropriate regulatory body. Without extrapolation of indications, time-consuming prior authorization would be necessary for certain indications, possibly delaying treatment for patients in need.13,14

Extrapolation of indications is a scientifically based principle, guided by specific guidelines established by regulatory agencies including the European Medicines Agency, the Food and Drug Administration, and Health Canada. Therefore, physicians, payers, and patients should feel confident in the safety and efficacy of a biosimilar in all indications approved by the regulatory agency.13

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A decade of switching experiences with 1st generation biosimilars in the EU has been satisfactory, showing no signs of increased unexpected safety issues, immunogenicity events, or altered effectiveness in real clinical settings.18,19

*Automatic substitution

PHARMACY

Substitution*Interchange medicine

at the pharmacy level without consulting the prescriber.

AND

Interchangeability Switching back and

forth between biosimilar and originator.

Switching

OR

Switch from originator to biosimilar or from

biosimilar to originator.

SwitchingThe concept of switching is referred to as not only the switch from originator to biosimilar (O to B) and from biosimilar to originator (B to O) (narrow sense of switchability), but also from originator to originator (O to O) and from biosimilar to biosimilar (B to B) (broader sense of switchability).15

InterchangeabilityFrom FDA’s perspective, interchangeability includes the concept of switching and alternating between an originator biological product (O) and its biosimilars (B).15

The terms “interchangeable” and “interchangeability” mean that (1) the biological product is biosimilar to the reference product, (2) the biological product can be expected to produce the same clinical result as the reference product in any given patient, and (3) for a product administered more than once, the risks of safety and reduced efficacy from alternating and switching are not greater than the use of the reference product without alternating or switching.15,16

SubstitutionSubstitution is the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber.17

In 2017, the FDA released a biosimilar interchangeability guidance, Considerations in Demonstrating Interchangeability With a Reference Product, establishing recommendations regarding the data and information needed to support interchangeability, as well as considerations for switching study design and analysis. It also states that the FDA will determine the biosimilar to be interchangeable with the reference product if FDA determines that the information submitted by the biosimilar manufacturer is sufficient to show that the biosimilar is “biosimilar to the reference product” and “can be expected to produce the same clinical result as the reference product in any given patient”.21

Figure 4. Definition of switching, interchangeability, and substitution for biosimilars.

Switching and interchangeability of biosimilars

Through randomised controlled trials and various cohort studies, the first biosimilar mAb infliximab demonstrated equivalent clinical efficacy, safety, and immunogenicity to reference infliximab, with no clinically meaningful differences. Further data on switching to biosimilar infliximab are being collected through ongoing trials throughout the EU.13,20

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Many international guidelines are also following this perception evolution towards the expanded biosimilar landscape.

Gastroenterology Societies24,25

OncologySocieties26,27

Pharmacist Societies28

Rheumatology Societies22.23

• Sustained post-market evidence development is necessary to enhance patient and provider confidence in the safe and effective use of biosimilar products.

• To be considered interchangeable by the FDA, a biosimilar has to be “expected to produce the same clinical result as the reference product in any given patient” in addition to fulfilling necessary safety requirements.

• Biologics Price Competition and Innovation Act (BPCIA) provides authority to the Centers for Medicare & Medicaid Services (CMS) to implement reimbursement policies for biosimilars under a patient’s medical benefit.

• A biosimilar is intended to provide an action equivalent to that of the product it attempts to copy and requires a complex developmental process based on all the pre-clinical and clinical trials demanded by European Law.

• A license obtained for one indication allows extrapolation of results to a different disorder, if the EMA considers it based on the results of previous trials.

• SEPD favors the development of biosimilar drugs and therefore, their approval by regulatory agencies.

• The approval process for biosimilars needs to place safety and efficacy, supported by scientifically sound evidence, as the highest priorities.

• With the need for more cost-effective biologic therapeutics, biosimilars offer hope of cost reduction if physicians and patients can be sufficiently reassured of their efficacy and safety through rigorous scientific study of these products.

American Society of Clinical OncologyFebruary 2018

The Spanish Society of Digestive Pathology March 2018

American College of RheumatologyMarch 2018

In addition, regulatory authorities of different countries have reported a positive view on switching and extrapolation based on proven comparability in terms of quality, non-clinical, and clinical requirements.22-26

Perceptual evolution in the biosimilar landscape

2018

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2016 -2017

British OncologyPharmacy AssociationFebruary 2017

European Societyfor Medical OncologyJanuary 2017

British Society for RheumatologyJanuary 2017

• BOPA’s position considers biosimilar monoclonal antibodies (mAbs) to be therapeutically equivalent to the originators, and switching to a biosimilar mAb to be acceptable and recommended.

• Patients starting on or switched to biosimilars should be closely monitored and all adverse events must be reported in line with organisational policy.

• The savings achieved by rapid adoption of biosimilar mAbs represent an opportunity to safeguard NHS budgets and create headroom to ensure that new cancer medicines are affordable and funded.

• BOPA believes oncology pharmacists are key to ensuring the successful and rapid adoption of biosimilar mAbs into clinical practice and ensuring pharmacovigilance monitoring is in place.

• Biosimilars have the potential to improve the financial sustainability of global healthcare systems through cost savings.

• Extrapolation of the indications should be permitted if verified scientifically, while interchangeability and switching should only be permitted if: (1) the physician is well-informed about the products; (2) the patient is fully briefed by the physician and (3) a nurse is closely monitoring the changes and tracking any adverse events.

• Switching to a biosimilar should be carried out with the consent of both the prescribing physician and patient.

• The inclusion of biosimilars as a therapeutic choice for patients initiating a new biologic therapy is recommended.

• Switching to biosimilars should be on a case-by-case basis, and all patients starting or switching to biosimilars should be registered with the BSR Biologic Registers.

• Treatment options and any decisions on potential changes to medicines should be discussed in partnership with the patient and the physician, with the informed consent of the patient.

• Clinical studies of equivalence in the most sensitive indication can provide the basis for extrapolation.

• Switching from the originator to a biosimilar in patients with IBD is acceptable. Studies of switching can provide valuable evidence for safety and efficacy.

• Switching from originator to a biosimilar should be performed following appropriate discussion between physicians, nurses, pharmacists, and patients, and according to national recommendation.

European Crohn´s and Colitis OrganisationDecember 2016


1. European Medicines Agency. Guideline on similar biological medicinal products. 2014 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf Accessed April 2018.

2. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. 2015 Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm291128.pdf Accessed April 2018.

3. World Health Organization. Expert committee on biological standardization. Guidelines on evaluation of similar biotherapeutic products (SBPs). 2009 Available at: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_ WEB_22APRIL2010.pdf Accessed April 2018.

4. European Medicines Agency. EMA Procedural advice for users of the Centralised Procedure for Similar Biological Medicinal Products applications. 2017 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_ procedural_guideline/2012/04/WC500125166.pdf Accessed April 2018.

5. U.S. Food and Drug Administration. Biological Products Definition. Available at: https://www.fda.gov/downloads/Drugs/ DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ Biosimilars/UCM581282.pdf Accessed April 2018.

6. Goncalves J, Araújo F, Araújo F, et al. Clin Exp Rheumatol. 2016 Jul-Aug;34(4):698-705.

7. International Alliance of Patients’ Organizations. Briefing Paper on Biological and Biosimilar Medicines. Available at: https://www. iapo.org.uk/sites/default/files/files/IAPO%20Briefing%20Paper.pdf Accessed April 2018.

8. Mellstedt H. EJC Suppl. 2013;11:1-11.

9. Rugo HS, Linton KM, Cervi P, et al. Cancer Treat Rev. 2016;46:73-79.

10. Henry D and Taylor C. Semin Oncol. 2014;41:S13-S20.

11. Khraishi M, Stead D, Lukas M, et al. Clin Ther. 2016;38:1238-1249.

12. de Mora, F. Br J Clin Pharmacol. 2015;80:949-956.

13. Bressler B and Dingermann T. Biosimilars. 2015;5:41-48.

14. Curigliano G, O’Connor DP, Rosenberg JA, et al. Crit Rev Oncol Hematol. 2016;104:131-137.

15. Generics and Biosimilars Initiative. Interchangeability (switching andalternating) of biosimilars. Available at: http://gabionline.net/ Biosimilars/Research/Interchangeability-switching-and-alternating-of-biosimilars Accessed April 2018.

16. Endrenyi L, et al. Stat Med. 2013;32:434-41.

17. European Commission. What you Need to Know about Biosimilar Medicinal Products. Available at: http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/pdf Accessed April 2018.

18. Weise M, Kurki P, Wolff-Holz E, et al. Blood. 2014;124:3191-3196.

19. Ahmed I, Kaspar B, and Sharma U. Clin Ther. 2012;34:400-419.

20. Vermeer NS, Straus SM, Mantel-Teeuwisse AK, et al. Drug Saf. 2013;36:617-615.

21. U.S. Food and Drug Administration. Considerations in Demonstrating Interchangeability With a Reference Product. Guidance for Industry. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM537135.pdf Accessed April 2018.

22. British Society for Rheumatology. Position statement on biosimilar medicines (January 2017). Available at: https://www.nras.org.uk/data/files/revised_bsr_biosimilars_position_statement_jan_2017.pdf Accessed April 2018.

23. American College of Rheumatology. Position Statement. Available at: https://www.rheumatology.org/Portals/0/Files/Biosimilars-Position-Statement.pdf Accessed April 2018.

24. Danese S, Fiorino G, Raine T, et al. J Crohn’s Colitis. 2017;11:26-34.

25. Argüelles Arias F, Hinojosa del Val J, Vera Mendoza I. Update of the SEPD position statement on the use of biosimilars for inflammatory bowel disease. Rev Esp Enferm Dig 2018. doi: 10.17235/reed.2018.5456/2018.

26. Tabernero J, Vyas M, Giuliani R, et al. ESMO Open 2016;1:e000142. doi:10.1136/esmoopen-2016-000142.

27. Gary HL, Edward B, Michael D, et al. J Clin Oncol. 2018;36:1-8.

28. British Oncology Pharmacy Association. Position statement on implementation of biosimilar monoclonal antibodies (February 2017). Available at: http://www.bopawebsite.org/sites/default/files/publications/BOPABiosimilarPositionStatement05.02.17.pdf. Accessed April 2018.

REFERENCE

A biosimilar is a biological medicinal product that is not identical, but highly similar to an already licensed biological medicinal product. A biosimilar and its reference are expected to have the same safety and efficacy profile with no clinically meaningful differences.

Biosimilars must establish biosimilarity based on totality of evidence; highly comparable physicochemical and functional characteristics, equivalent PK/PD profile, comparable immunogenicity, therapeutic equivalence, and analysis of mechanism of action.

Extrapolation of indications is a scientifically based principle and the core concept of biosimilar development. Extrapolation should be justified based on totality of evidence supported by extensive analytical, functional, non-clinical and clinical comparability studies.

Biosimilars are now a reality, and in Europe biosimilars have been marketed without unintended effects, demonstrating similar safety and efficacy to reference biologics.

An evolving perception towards biosimilars is evident. A change in perception among various medical communities, including rheumatology, gastroenterology, oncology, and pharmacist societies, towards a positive view on biosimilars is opening up new opportunities for biosimilars.

Biosimilars are cost-effective alternatives to originator biologics and may help increase access to high-cost biologics, in particular monoclonal antibodies. A biosimilar approved for the same indications as the reference biologic must demonstrate comparable safety and efficacy results to and is expected to be used interchangeably with the reference biologic.

Summary

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