ASSESSING BIOSIMILARITY

Development Pathway

A biosimilar must demonstrate it is highly similar to the originator biologic.1

THE DEVELOPMENT PATHWAYS FOR ORIGINATOR BIOLOGICS AND BIOSIMILARS ARE DIFFERENT

ORIGINATOR BIOLOGIC BIOSIMILAR
  • In addition to the information required for other drugs, biologics must include more detailed chemistry and manufacturing information.2
  • Analytical and functional testing is used to identify the physical, chemical, and biological characteristics of the candidate biologic medicine.5,6
  • With originator/reference biologics, clinical trials are performed to demonstrate clinical benefit compared to placebo/standard of care.11
  • Where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, in vivo non-clinical studies may not be necessary.
  • In most cases, a comparative clinical trial(s) is important to rule out clinically meaningful differences in efficacy and safety between the biosimilar and the reference biologic drug.
  • A biosimilar relies in part, on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the originator biologic.1
  • This influences the amount and type of original data required.1
  • A final determination of similarity will be based on all relevant data from structural, functional, non-clinical and clinical studies.1

DEVELOPMENT PATHWAY: ORIGINATOR BIOLOGIC VS. BIOSIMILARS

The scientific evidence of originator biologics

Key evidence is focused on collecting sufficient scientific evidence to show that it is safe, efficacious and of suitable quality.2

 

Development Pathway for Originator Biologics

Analytical studies: Used to verify the physical structure and stability of the candidate biologic medicine as well as the quality of the manufacturing process.5

Functional assays: Used to characterize biological activity, including pharmacokinetic (PK)/ pharmacodynamic (PD) studies, toxicity, dose-response relationship and immunogenicity.6

Clinical trials: In humans show demonstrated efficacy and safety in controlled trials conducted in each indication.11,12

Key evidence for biosimilars

The weight of evidence needed to demonstrate biosimilarity to an originator biologic drug is based largely on structural and functional studies.1

 
  • Preclinical Studies

     

    COMPARATIVE STRUCTURAL AND FUNCTIONAL TESTS

    STRUCTURAL TESTS FUNCTIONAL TESTS

    Structural tests are performed in vitro, and a wide range of comparative physicochemical assays are performed to ensure that the differences relative to the originator biologic may be detected.1

    • Comparing:
    • Structure: to determine that higher order structure ( secondary, tertiary, and where applicable, quaternary) is comparable.1
    • Purity/Impurity: a combination of analytical procedures selected should provide data to allow evaluation of relevant differences in the purity and impurity profiles.1
    • Immunochemical Properties: to confirm that the biosimilar is comparable to the originator biologic when immunochemical properties are part of the characterization (i.e. for antibodies).1

    These functional tests ensure that the biological activity of a biosimilar is highly similar to the originator biologic.1

    • Comparing:
    • Biological Activity: These tests may confirm product quality attributes that are useful for characterization and batch analysis, and in some cases, could serve as a link to clinical activity.1
  • Clinical Development

     
  • Immunogenicity

     
  • Extrapolation

     

Glossary:

Analytical: separating something into component parts or elements13

Anaphylaxis: an acute allergic reaction to an antigen (i.e. a bee sting) to which the body has become hypersensitive14

Biosimilarity: a demonstration of biosimilarity using a step-wise approach beginning with structural and functional studies, and continuing with clinical studies10

Functional: of, connected with, or being a function15

Immunochemical: of, relating to, or utilizing immunochemistry, a branch of chemistry that deals with the chemical aspects of immunology16

Immunocompetence: the capacity for a normal immune response17

Immunogenicity: the quality or state of being immunogenic, something related to or promoting a response from the immune system18

Immunosuppressant: a chemical agent that suppresses immune response19

Impurity: something that is impure (not pure) or makes something impure20

Pathophysiological: the functional changes that accompany a particular syndrome or disease21

Pharmacodynamics (PD): a branch of pharmacology dealing with the reactions between drugs and living systems22

Pharmacokinetics (PK): the branch of pharmacology concerned with the movement of drugs within the body23

Purity: the quality or state of being pure24

Quaternary (structure): consisting of, containing, or being an atom bonded to four other atoms25

Secondary (structure): characterized by or resulting from the substitution of two atoms or groups in a molecule26

Structural: of or relating to the physical makeup of a thing27

Tertiary (structure): (of an organic compound) having its functional group located on a carbon atom which is itself bonded to three other carbon atoms28

In vitro (studies): outside a living body and in an artificial environment29

In vivo (studies): in the living body of a plant or animal30

References:

1. Health Canada. Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. Revised November 14, 2016. Available online: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/brgtherap/applic-demande/guides/seb-pbu/seb-pbu-2016-eng.pdf (Accessed December 2016). 2. Health Canada. Biologics, Radiopharmaceuticals and Genetic Therapies. December 02, 2016. Available online: https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies.html. 3. Health Canada. Preparation of the Quality Information for Drug Submissions in the Guidance for Industry. Effective May 25, 2004. 4. Health Canada. Guidance Document: Biomarkers Related to Drug or Biotechnology Product. 5. European Medicines Agency. ICH Topic M4Q. Common Technical Document for the Registration of Pharmaceuticals for Human Use. Quality Overall Summary of Module 2 and Module 3: Quality. 6. ICH Harmonised Tripartite Guideline. Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals; S6(R1). June 12, 2011. 7. Pandya, N. Regulatory Affairs Professionals Society. Chapter 19, “Regulation of Subsequent Entry Biologics”; pg 147-58. 8. Piaggio G, et al. Reporting of Noninferiority and Equivalence Randomized Trials. JAMA. 2012;308(24):2594-2604. 9. Walker E and Nowacki A. Understanding Equivalence and Noninferiority Testing. J Gen Intern Med 26(2):192–6. 10. Health Canada. Drugs and Health Products. Fact Sheet: Biosimilars. Available at: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/biosimilars-biosimilaires-qa-qr-eng.php. Accessed on Feb 6, 2017. 11. ICH Harmonised Tripartite Guideline. Structure and Content of Clinical Study Reports; E3. November 30, 1995. 12. ICH Harmonised Tripartite Guideline. The Common Technical Document for the Registration of Pharmaceuticals for Human Use; Efficacy – M4E(R1). Module 5: Clinical Study Reports. Sept. 12, 2002. 13. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/analytical Accessed July 16, 2017. 14. English Oxford Living Dictionaries. Available at: https://en.oxforddictionaries.com/definition/anaphylaxis Accessed July 19, 2017. 15. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/functional Accessed July 16, 2017. 16. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/immunochemical Accessed July 16, 2017. 17. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/immunocompetence Accessed July 16, 2017. 18. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/immunogenicity and http://c.merriam-webster.com/medlineplus/immunogenic Accessed July 16, 201 19. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/immunosuppressant Accessed July 16, 2017. 20. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/impurity Accessed July 16, 2017. 21. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/Pathophysiological Accessed July 16, 2017. 22. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/pharmacodynamics Accessed July 16, 2017. 23. English Oxford Living Dictionaries. Available at: https://en.oxforddictionaries.com/definition/pharmacokinetics Accessed July 19, 2017. 24. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/purity Accessed July 16, 2017. 25. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/quaternary Accessed July 16, 2017. 26. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/secondary Accessed July 16, 2017. 27. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/structural Accessed July 16, 2017. 28. English Oxford Living Dictionaries. Available at: https://en.oxforddictionaries.com/definition/tertiary Accessed July 19, 2017. 29. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/in%20vitro%20%20%20%20 Accessed July 16, 2017. 30. Webster Medical Dictionary. Medline Plus. Available at: http://c.merriam-webster.com/medlineplus/in%20vivo Accessed July 16, 2017.