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Biologics and Biosimilars – Emerging Solutions in Pharmaceutical Care

By Tim Affeldt, PharmD, Director of Specialty and Infusion Operations, Fairview Pharmacy Services

Biologic drug products are cultivated from living organisms, called host cells, which are derived from bacteria, yeast, or mammalian cells. Because their composition is generally more complex and variable than traditional small-molecule drugs, biologics are more challenging to produce. The production process involves inserting a human gene specific for a protein, into a living organism host cell.

Biologics have inherent variability because they are based on multiple isoforms, i.e., they are not a single molecular entity. Further variability is due to the natural shifts in both structure and function across different batches of biologic product. Shifts in glycosylation (structure) patterns result in different potency in cell-based assays (function). Despite these differences across production batches, the shift did not lead to clinically meaningful differences that would impact safety and efficacy.1 Manufacturing changes are another variable affecting biologic production over time.

The comparative properties of biologic versus small molecule entities are significant. Figure 1 highlights the major attributes.1

Figure 1. Major attributes of small molecule entity (aspirin) compared with biologic properties.

  Size Structure Stability Manufacturing Immunogenicity Characterizations
Small Molecule
Aspirin
Small =
180 daltons
Simple and well defined Relatively stable Synthesized using a predictable chemical process; identical copy can be made Lower potential Easy to fully characterize
Biologic Large = 149,000 daltons Complex with numerous sites from post translational modification and the potential for structural variation Sensitive to storage and handling conditions Produced in a unique living cell line; similar (but not identical) copy can be made Higher potential Difficult to characterize due to structural complexity and heterogeneity

A number of biologic classifications address specific disease conditions. These classifications are organized as shown in Table 1.

Biologic Therapeutic Classification2 Biologic Brand Name
Monoclonal antibodies Avastin®, Humira®
Antitoxins Botox®
Blood Products Factor, Immune Globulins
Vaccines Bexsero®
Purified Proteins Cytokines: Rebif®, Avonex® Thrombolytics: Activase®
Enzymes: Vpriv® Growth Hormone: Omnitrope®

Table 1. Biologic classifications

Biosimilar Products

With the recent expiration of patents on biologic products, and in anticipation of more patent expirations in the near term, the timing is right for biosimilars technology to become a viable solution for both therapeutic efficacy and cost savings.

Figure 2. Patent expiration dates and 2013 global sales of various biologic products

Biosimilar products are being introduced to the market in order to address the complexity, variability and higher cost of biologic drugs. A biosimilar product is a biologic that is highly similar to the reference product with no clinically meaningful differences in terms of the safety, purity and potency.

All biologics and biosimilars can and do vary from one another because of enzyme cleavage, phosphorylation, attachment of lipids, attachment of glycans, glycosylation, oxidation, deamidation, formation of protein aggregates and degradation. To address the inherent variabilities of biologic production, analytical and biological characterization technologies can be used to show that the functional integrity and structure of a biosimilar is as close as possible to its reference product.3

Additional terminology in this area of pharmaceutical development includes:4

  • Biologic: Large complex molecules derived from living sources, and comparatively more difficult to manufacture than traditional small molecule drugs.
  • Reference product: The originally FDA-approved licensed biologic product, used for comparison with the biosimilar.
  • Interchangeable biosimilar: A biosimilar to an FDA-approved reference product which also meets additional standards for interchangeability.

Regulatory Approval Pathways for Biosimilars

Regulatory approval pathways for biologics remain rigorous; however, the timeline is shorter for biosimilars because they reference the biologic. The 8-10 year streamlined development process allows biosimilars to cost less than their reference biologic products.6

As of June 2016, the FDA has approved five biosimilars:7

  • Zarxio® (filgrastim-sndz), Sandoz. Reference drug, Neupogen®(filgrastim), Amgen.
  • Inflectra® (infliximab-dyyb), Pfizer. Reference drug, Remicade® (infliximab), Janassen Biotech.
  • Renflexis® (infliximab-abda), Merck. Reference drug, Remicade® (infliximab), Janassen Biotech.
  • Amjevita® (adalimumab-atto), Amgen. Reference drug, Humira® (adalimumab), Abbvie.
  • Erelzi® (etanercept-szzs), Sandoz. Reference drug, Enbrel® (etanercept), Amgen

Furthering the timelines and cost savings of these innovations, interchangeable biosimilar products are those that are approved as biosimilars and also meet three additional criteria:

  1. Expectation of the same clinical result, in any given patient, as the reference product in all of the reference product’s licensed conditions of use.
  2. For a product that is administered more than once, no additional risk to safety or efficacy as a result of switching to the interchangeable product.
  3. An interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

The FDA has published draft guidance on this subject, “Considerations in Demonstrating Interchangeability with a Reference Product8. The FDA has programs in place for biosimilar and interchangeable products: “Stand-Alone” Development Program, 351(a) with the goal to establish safety and effectiveness of a new product (Reference Biologic), and the “Abbreviated” Development Program, 351(k) with the goal to demonstrate biosimilarity or interchangeability9 (Biosimilar or Interchangeable Product).

Nomenclature for Biosimilar Products

FDA guidelines13 utilize the addition of a unique four-character suffix to the product name. This standardized nomenclature helps minimize medication errors caused by incorrect substitution. It also supports best practice pharmacovigilance in terms of safety monitoring and usage tracking in all settings.

Biosimilars’ Impact on Health Care

Biosimilars have the potential to save money and help manage specialty care. The price reductions between a brand name biologic and a biosimilar product are anticipated to range from 10% to 35%. By 2024 biosimilars could reduce the total U.S. health care spend by $250 billion.14 From a managed care perspective, biosimilars align with the goal toward the most cost-effective intervention that provides the desired clinical outcome. There are five biosimilar products currently approved, and more are being reviewed. To achieve biosimilars’ potential savings, widespread adoption and utilization of biosimilars will require education for both prescribers and pharmacists since prescribers would need to write for these products and pharmacists would need to dispense these products according to state laws governing biosimilar substitution.


References

1. Source: Declerck, PJ. Biologicals and Biosimilars: A Review of the Science and its Implications. GaBi J. 2012; 1:13-6. Source: Morrow, T. Defining the Difference: What Makes Biologics Unique. Biotechnol Healthc. 2004; 1(4): 24-29.

2. Aitken, M. Prescription Drug Spending Trends In the United States. Health Affairs; 2009; 28(1): 151-160 Source: Ecker, D. The Therapeutic Monoclonal Antibody Market. Mabs; 2015: 7(1): 9-14.

3. McCamish, M. The State of the Art in the Development of Biosimilars. Clin Pharmacol Ther.

4. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/ Biosimilars/ucm241718.htm Accessed July 9, 2016.

5. gabionline.net/Biosimilars/General/Top-8-blockbuster-biologicals-2013, Accessed July 6, 2016. gabionline.net/ Biosimilars/General/US-67-billion-worth-of-biosimilar- patents-expiring-before-2020, Accessed July 6, 2016.

6. https://www.hospira.com.au/en/about_hospira/biologics/developing_biosimilars

7. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm Accessed Sept. 2016.

8. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ UCM537135.pdf. Accessed Jan. 20, 2017.

9. Jenkins, J. Biosimilars in the US: Progress and Promise. FDA Presentation; October 27, 2016.

10. https://www.revisor.mn.gov/statutes/?id=151, Accessed July 9, 2016.

11. Li, E. J Manag Care Spec Pharm, 2015 Jul;21(7):532- 539.

12. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/default.htm

13. https://blogs.fda.gov/fdavoice/index.php/2015/08/naming-and-biological-products

14. Source: Rovira, J. Andalusian School of Public Health, Granada, Spain. Source: lab.express-scripts.com/insights/industry-updates/the-$250-billion-potential-of-biosimilars

*The patent for the chemical entity has expired, but other patents around formulation and manufacturing may still be active.

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