Biosimilars: the future of prescribing

biological medicines
PHA758 – Biomanufacturing in Pharmaceutical Development of Drugs

Sahar Al Toufaily

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Outline
• Introduction
• First biosimilar to be approved
• Definition of biosimilar
• What does it mean to be “highly similar”?
• What does it mean to have “no clinically meaningful differences”?
• Differences between generic and biosimilar drugs
• Differences between biological and biosimilar drugs

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Outline (ct’d)
• Benefits of using a biosimilar over a biological
• Comparative tests
• Immunogenicity
• Interchangeability
• How are biological and biosimilar products named?
• Biological Drift
• Example from the Lebanese market
• The Future of Biosimilars
• References

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Brief Introduction
• Biological medicines are complex molecules produced by living cells
that target specific receptors or proteins involved in disease
progression

 e.g. rheumatoid arthritis, Crohn’s disease, multiple sclerosis and

some cancers

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Brief Introduction
• Biologicals are one of the fastest growing therapeutic classes

• A biosimilar is exactly what its name implies — it is a biologic that is

“similar” to reference product

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First biosimilar to be approved
• The first biosimilar to approved is in EU 2006 (somatropin)

• The drug is a biosimilar of Eli Lilly's recombinant human growth

hormone Humatrope, which is used for the treatment of growth
failure in children.

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What is a Biosimilar
• A biosimilar is a biological product that is “highly similar” to and has
“no clinically meaningful differences” from an existing FDA-approved
reference product.

• Biosimilars are those biologics which are developed after patent

expiration of innovator biopharmaceuticals (12 years)

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What does it mean to be “highly similar”?
• A biosimilar is granted approval only in the case of being highly
similar to the reference drug.

• This is done by extensively analyzing the structure and function of

both the reference product and the proposed biosimilar.

• State-of-the-art technology is used to compare characteristics of the

products, such as purity, chemical identity, and bioactivity.

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What does it mean to be “highly similar”?
• The manufacturer uses results from these comparative tests, along
with other information, to demonstrate that the biosimilar is highly
similar to the reference product.

• Minor differences between the reference product and the proposed

biosimilar product in clinically inactive components are acceptable.

• For example, these could include minor differences in the stabilizer or

buffer compared to what is used in the reference product.

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What does it mean to have “no clinically
meaningful differences”?

• Also, a biosimilar product must be proven to have no clinically

meaningful differences from the reference product in terms of safety,
purity, and potency.

• This is generally demonstrated through:

• human pharmacokinetic studies
• pharmacodynamic studies
• assessment of clinical immunogenicity
• additional clinical studies (if needed)
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Differences between generic and biosimilar
drugs
Generic Drug Biosimilar Drug
Produced by chemical synthesis Produced by living cell cultures

Low molecular weight High molecular weight

Well defined structure Complex, heterogeneous structure

Unstable, sensitive to external
Stable
conditions
Mostly non-immunogenic Immunogenic

Price is 80% less than brand Price is up to 20% less than reference
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Differences between generic and biosimilar
drugs

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Differences between biological and biosimilar
drugs
Biological Drug Biosimilar Drug
• Novel therapy • Highly similar competitor
• 15 years to develop • 8-10 years to develop
• $1.2 Billion cost • $100-200 Million cost
• Patentable (12 years) • Not patentable
• Reference price • Reduced price (10-20 % less)

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Differences between biological and biosimilar
drugs

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Differences between biological and biosimilar
drugs

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Differences between biological and biosimilar
drugs

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Benefits of using a biosimilar over a biological

COST REDUCTION BY ENHANCED PATIENT INCENTIVE FOR

COMPETITION ACCESSIBILITY INNOVATION

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Tests that are done to prove bio-similarity
Comparative Tests

• Quality:
All aspects of quality and heterogeneity should be assessed, including head-to-
head comparisons with the reference biotherapeutic product.

• Pharmacovigilance:
A pharmacovigilance plan at the post-marketing phase should be considered to
supplement the limited clinical data.

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Tests that are done to prove bio-similarity
Comparative Tests

• Non-clinical studies:
Data should include pharmacodynamics, pharmacokinetics, and comparative
repeat-dose toxicity studies in a relevant species.

• Clinical studies:
Similarity of the efficacy of the similar biotherapeutic product and the reference
biotherapeutic product will usually have to be demonstrated in powered,
randomized, and controlled clinical trials.
Immunogenicity should always be investigated in humans before authorization.

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Immunogenicity
• Immunogenicity is a measure of the immune response to a
therapeutic drug.

• ADA (anti-drug antibodies) reaction can occur because of:

• High molecular size
• Route of administration which is usually parenteral (IV>IM,SC)
• Non-human sequence

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Immunogenicity
• An immunogenicity reaction can decrease efficacy and safety of the
product

• Biosimilars should not have a higher immunogenicity reaction than

the reference biological drug

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Interchangeability
• Interchangeability is the possibility of exchanging one medicinal
product for another that is expected to produce the same clinical
effect

• Only physician has the right to do so if and only if this switch is

clinically proven to have no loss in efficacy nor a decrease in safety

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 Switching between Biologics:

• common practice

Interchangeability
Switching Biologic to biosimilar

• Controversial modality( intermittently

vs. chronically treated patients)

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How are biological and biosimilar products
named?

• According to the published guide of the FDA in March 2019:

• Both the reference products and biosimilar products should have

nonproprietary names, also called a proper name, that include a core
drug substance name and, to facilitate safe use and
pharmacovigilance, a designated suffix that is unique to each
product.

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How are biological and biosimilar products
named?

Core drug
Proper Unique
substance
name suffix
name

• As an example, the proper names for hypothetical products sharing

the fictitious core name replicamab may be displayed as follows:

• Reference Product: Repam® (replicamab-cznm).

• Biosimilar Product: Lijix® (replicamab-hjxf).
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Biological Drift

• Process and product consistency should be founded on rigorous

design and control of manufacturing processes, but consistency is
ultimately ensured through robust quality systems.

• Even a minor change in any component of a quality system could lead

to product drift, evolution, and divergence, which may impact the
quality, safety, efficacy, and/or interchangeability of biologics.

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Biological Drift

• With the advent of biosimilars, similar biologics will be produced by

multiple manufacturers with different quality systems

• Different patterns of product drift and evolution could contribute,

over time, to clinically meaningful differences among biologics
(divergence), including:
1. among originator products across regions
2. among originator products and biosimilar products

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Biological Drift
• Manufacturers and policymakers can minimize the potential impact
of divergence by:

1. establishing robust pharmacovigilance systems

2. requiring distinguishable names for all biologics, including both
originator products and biosimilars
3. adhering to high standards for designations of interchangeability
4. ensuring that patient medical records accurately reflect the specific
biologic dispensed, especially if the biologic could be sourced from
multiple manufacturers.
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Example from the Lebanese market

• Biologic product

• Herceptin containing Trastuzumab

• Used for breast cancer that is HER2 receptor positive
• Injectable concentrated powder+ diluent
• Price: 3,526,565 LBP

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Example from the Lebanese market

• Biosimilar product

• Mabtin containing Trastuzumab (r-DNA origin) is manufactured locally by

Benta
• Used for breast cancer that is HER2 receptor positive
• Injectable concentrated powder+ diluent
• Price: 1,635,164 LBP

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The Future of Biosimilars
• In the near future, some of the most prescribed biologics will have
their patent expired

the biosimilars market will face an added growth

The market competition driven by biosimilars can pose threat to the

monopoly of the brand pharmaceutical industry.

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The Future of Biosimilars
• In the coming years, the regulatory authorities need to provide a
more tangible framework to address some grey areas in the
marketing and prescription of biosimilars

• This, accompanied with:

1. practitioner/consumer education
2. new development and commercial models can set the stage for creating
new blockbuster biosimilars.

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References

• Biosimilars. U.S. Food and Drug Administration. https://www.fda.gov/drugs/therapeutic-biologics-

applications-bla/biosimilars. Published on September 23, 2019.
• Bren L. The Road To The Biotechnology Revolution: Highlights of 100 Years Of Biologics
Regulation. U.S. Food and Drug Administration; Published on January 2006.
https://www.fda.gov/files/about%20fda/published/The-Road-to-the-Biotech- Revolution--
Highlights-of-100-Years-of-Biologics-Regulation.pdf.
• U.S. Food and Drug Administration. (2019). Designating an Orphan Product: Drugs and Biological
Products. [online] Available at: https://www.fda.gov/industry/developing-products-rare-diseases-
conditions/designating-orphan-product-drugs-and-biological- products.

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References

• Kabir, E., Moreino, S. and Sharif Siam, M. (2019). The Breakthrough of Biosimilars: A Twist in the
Narrative of Biological Therapy. Biomolecules, 9(9), p.410.
• Biosimilars Council. (2019) Leading Resources on Biosimilars. [online] Available at:
https://biosimilarscouncil.org/
• Amgen Biosimilars. (2019). Biosimilars Update 2019 Report [online] Available at:
https://www.amgenbiosimilars.com/
• Vyas, D. (2018). Biosimilars: Review of current applications, obstacles, and their future in
medicine. World Journal of Clinical Cases, 6(8), pp.161-166.
• E, O. (2019). Biosimilars: Rationale and Current Regulatory Landscape.. [online] Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26947438.
• EMA, WHO, and MOPH Guidelines

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Thank you

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