Biosimilars - 10 year update for Healthcare Professionals

Biosimilars - 10 year updatefor Healthcare Professionals

January 22, 2021

Dr. Axel Tosikyan

Hopital du Sacré-Coeur de Montreal

NON-2019-0170E-FE2019

Introduction to Biological Medicines and Biosimilars

• A biosimilar is an approved version of a biological medicine with an identical primary amino acid sequence to the originator and developed with the intention to be as close to the originator as possible

• Like biological medicines, biosimilars are complex protein molecules that are produced by living organisms

• During the past 15 years, biological medicines have had a profound impact on healthcare in oncology and inflammatory diseases

• Many of the world’s top-selling medicines are now biological medicines

• However, biological medicines are expensive (sometimes by several orders of magnitude more than small-molecule chemical drugs), limiting patient access

• As many biological medicines come off patent globally, there is great interest in the development of biosimilars, which are likely to improve access to high-quality therapies

What Are Biosimilars? The Regulatory Definitions

What Are Biosimilars? Health Canada Definitions

• A biosimilar sponsor is eligible to apply for the indication(s) and condition(s) of use

that are held by the reference biologic drug authorized in Canada

Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016

What Are Biosimilars? Health Canada Definitions(Cont’d)

• A “biosimilar” is a biological product that is

• Highly similar in quality attributes to the reference originator biologic, with minor differences in clinically inactive components

• Has no clinically meaningful differences from the reference in terms of safety, purity, and potency

• Can a biosimilar be used interchangeably with its reference biologic drug?

• Health Canada’s (HC) authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug

• There are varying definitions of interchangeability. In Canada, the term often refers to the ability for a patient to be changed from

one drug to another equivalent drug by a pharmacist, without the intervention of the doctor who wrote the prescription

• In Canada, the authority to declare two products interchangeable rests with each province and territory according to its own rules and regulations

Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016

How Do Biosimilars Differ from Generics?

Biosimilars Are Not…

1. Anour R. GaBI J. 2014;3:166-167. 2. Dörner T, Kay J. Nat Rev Rheumatol. 2015;11:713-724. 3. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016.4. Wolf DC. Inflamm Bowel Dis. 2016;22:994-997.

generic drugs are small molecules that are chemically synthesized and contain identical medicinal ingredients to their brand name reference products

Biosimilars Are Highly Similar to Reference Products

1. Woodcock J, et al. Nat Rev Drug Discov. 2007;6:437-442.2. Weise M, et al. Nat Biotechnol. 2011;29:690-693.

The Unique Vocabulary of Biosimilars

1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry. April 2015. 2. Royal Dutch Pharmacists Association. Guideline for Generic Substitution. February 2012. 3. EuropaBio. Guide to Biological Medicine. 2014. 4. Pater C. Curr Control Trials Cardiovasc Med. 2004;5:8. 5. FDA. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. Guidance for Industry. April 2015. 6. Health Canada Definition and website. https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/applications-submissions/guidance-documents/fact-sheet-biosimilars.html.

5-6

Biologicals Are Complex Proteins

Voynov V, et al. mAbs. 2009;1:580-582. Lipman NS, et al. ILAR J. 2005;46:258-268. FDA. Information for Consumers (biosimilars). www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm.

Manufacturing of Biologicals Is a Complex Process

Adapted from Mellstedt H, et al. Ann Oncol. 2008;19:411-419.

Biosimilars Represent an Opportunity for Additional Treatment Options for Patients

1. Dörner T, Kay J. Nat Rev Rheumatol. 2015;11:713-724. 2. Dörner T, et al. Ann Rheum Dis. 2016;75:974-982. 3. Federal Trade Commission. Emerging Health Care Issues: Follow-on Biologic Drug Competition. June 2009. 4. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for IndustryApril 2015.

The Potential Impact of Biosimilars: Cost-Savings

Drug Low Estimate+ High Estimate#

Trastuzumab $15M $86M

Filgrastim $18M $62M

Insulin glargine $23M $130M

Rituximab $21M $122M

Bevacizumab $8M $47M

PMPRB. Potential Savings from Biosimilars in Canada. http://www.pmprb-cepmb.gc.ca/view.asp?ccid=1304 accessed Jan 18th, 2019

ESTIMATED POTENTIAL SAVINGS IN THE THIRD YEAR FOLLOWINGBIOSIMILAR ENTRY, CANADA

+ 13% savings for Filgrastim, 8% for all other drugs listed in table# 43% savings for all drugs listed in table

Biosimilar Pathway Represents a Paradigm Shift from Standard Originator Registration Pathway

Biosimilar Development Program Objective: Establish Biosimilarity Based Upon Totality of Evidence, Not Re-Establish Benefit

Originator Pathway

Clinical Pharmacology

Preclinical

Clinical Studies

Biosimilar Pathway

Analytical

Preclinical

Clinical Pharmacology

PK/PD

Analytical

Clinical Studies

PK, pharmacokinetics; PD, pharmacodynamics.Schneider CK, et al. Nat Biotechnol. 2012;30(12):1179-1185. Kozlowski S, et al. N Engl J Med. 2011;365(5):385-388. Macdonald J. Presented at: APEC Biotherapeutics Workshop; September 25, 2013; Seoul, Republic of Korea. McCamish M. Presented at: EMA Workshop on Biosimilars; October 31, 2013; London, UK. Health Canada. How drugs are reviewed in Canada. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/fact-sheets/drugs-reviewed-canada.html accessed Jan 17th, 2019

Conducted in sensitive patient population with sensitive end points; Designed to detect a difference, if there is one

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/fact-sheets/drugs-reviewed-canada.html

The Biosimilar Development Pathway

Leung LK, et al. Chin J Cancer. 2016;35:91.

A Stepwise Approach in Demonstrating Biosimilarity

1. www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski - Biomanufacturing Summit.pdf. 2. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016.3. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues.December 18, 2014.

Step 1: Analytical Characterization: The Foundation for Biosimilarity Assessment1

1. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016.2. www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski - Biomanufacturing Summit.pdf. 3. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues.December 18, 2014.

Step 2: In Vivo Preclinical Studies


Step 3: Comparative Clinical Pharmacology Studies

1. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016. 2. www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski - Biomanufacturing Summit.pdf. 3. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues.December 18, 2014.

Step 4a: Comparative Clinical Safety and Efficacy Assessments

1. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016. 2. www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski - Biomanufacturing Summit.pdf. 3. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues.December 18, 2014.

Step 4b: Immunogenicity


Clinical Studies May Also Be Designed to Address Switching Treatments

Dörner T, Kay J. Nat Rev Rheumatol. 2015;11:713-724.

Summary of the Requirements for Clinical Studies with Biosimilar Candidates

• Once a phase 1 study establishes that a biosimilar possesses comparable PK/PD attributes in human subjects to the reference biological medicine, a phase 3 study of safety, efficacy, and immunogenicity is usually initiated

• Phase 3 studies use the most sensitive, homogeneous patient population and clinical end point to establish the similarity of the biosimilar to the reference and to be able to detect product-related differences

• If the mechanism of action (MOA) for the reference medicine is known, the biosimilar medicine is expected to have the same MOA for the prescribed conditions based on labeling

Gravel P, et al. Target Oncol. 2012;7(Suppl 1):S3-S16.Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016

Regulatory Considerations: Postmarketing Pharmacovigilance

1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.2. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010.3. MRHA. Pharmacovigilance - how we monitor the safety of medicines. www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/Pharmacovigilance/index.htm4. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016.

A risk management plan is required by HC, FDA and EMA guidelines, which may need to include post-marketing

observational studies, inclusion of the biosimilar in biologic registries and/or Phase IV comparative studies1,2,4

➢ Post-marketing surveillance is critical1,2,4

http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/Pharmacovigilance/index.htm

What Does Extrapolation Mean?

RA, rheumatoid arthritis; AS, ankylosing spondylitis; PsA, psoriatic arthritis; PsO, psoriasis.

1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.2. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010. 3. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016.

Theoretical example.Figure created from 1-3

Extrapolation Is Based on Knowledge of the Reference Product, Totality of Evidence, and Scientific Justification1,2,3

1. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. December 18, 2014. 2. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry. April 2015. 3. Health Canada Guidance Document - Information and Submission Requirements for Biosimilar Biologic Drugs: Nov 14-2016.

Global Guidelines on Extrapolation

TOPIC Reference

HC EU US WHO

Extrapolation of Indication

Where similarity has been established, indications may be granted even if clinical studies are not conducted in each indication. A detailed rationale that scientifically justifies authorization of the biosimilar in each indication should be provided taking into consideration mechanism(s) of action, pathophysiological mechanism(s) of the disease(s) or conditions involved, safety profile, dosage regimen, clinical experience with the reference biologic drug, and any case-by-case considerations. Certain situations may warrant additional clinical data for a particular indication.

For recombinant proteins, in certain cases, it may be possible to extrapolate therapeutic similarity to other indications. Justification of extrapolation depends on clinical experience, available literature, whether the same mechanism of action or receptor is involved in both indications, and possible safety issues in different subpopulations.

The sponsor will need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarityfor each condition of use for which licensure is ought. Such scientific justification should address, for example, the flowing issues for the tested and extrapolated conditions of use.The MOA(s) in each condition of use for which licensure is sought. The PK and bio-distribution of the product in different patient populations; PD measures may provide important information on the MOA.

Extrapolation may be possible if a sensitive clinical test model has been used that is able to detect potential differences between the products, that the mechanism of action and/or receptors are the same, and that the safety and immunogenicity of the biosimilar have been characterized and there are no special safety issues expected with the extrapolated indication.

Regulatory Considerations: Interchangeability

• HC: In Canada, the authority to declare two products interchangeable rests

with each province and territory according to its own rules and regulations1.

• EMA: Allows member countries to regulate2

• FDA: Requires additional data to classify a product as ‘interchangeable’ as well as

‘biosimilar’3

• FDA allows an “interchangeable” designation for biosimilars, provided that, in

any given patient, the biosimilar can be expected to produce the same clinical results

as the reference product and that the safety and efficacy observed when alternating

or switching between the two remain the same4

1. Health Canada Fact Sheet: Biosimilars. 2017-08-032. EMA. Questions and answers on biosimilar medicines EMA/837805/2011. 3. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. 4. Biosimilars. US Food and Drug Administration. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm.

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm

Regulatory Considerations: Naming

INN, international nonproprietary name.

Dorner T, et al. Ann Rheum Dis. 2013;72:322-328.

Summary

• Biosimilars are biopharmaceuticals that are highly similar to their reference products;

they are not generics

• Current analytical technologies allow for extensive characterization of both the reference

product and biosimilar molecules

• Biosimilars undergo a rigorous regulatory approval process: A stepwise and comprehensive

comparative approach to claim biosimilarity must demonstrate a totality of evidence

with respect to:

• Physicochemical molecular characteristics and biologic activity

• Pharmacokinetics, immunogenicity as well as clinical safety and efficacy

• Rigorous pharmacovigilance programs must be established to monitor safety and

efficacy issues during the postapproval period

Summary (Cont’d)

• The totality of evidence will be considered when evaluating a

biosimilar product for approval by a regulatory agency

• Extrapolation leverages safety and efficacy data from the studied

biosimilar indication, in addition to knowledge of the reference product

and scientific justification

Documents

Biosimilars - 10 year update for Healthcare Professionals