Chemical drugs, like aspirin, are small molecules that are synthesized in a laboratory. Because they are derived from chemicals with fixed structures, they can be fully characterized by analytical techniques.

In contrast, biologic drugs, or biologics, are large, complex molecules designed to specifically interact with other protein molecules in the body. Due to their complexity, biologics can only be manufactured in living cells.

Because of this, biologics cannot be fully characterized, as can chemical drugs. Consequently, biologics require robust, extensive testing programs to ensure quality and consistency.

molecule molecule

What Is A Biosimilar?

In the U.S., a biosimilar is a biological product that is highly similar to a previously approved or reference product notwithstanding minor differences in clinically inactive components. An approved biosimilar will have no clinically meaningful differences from the reference product in terms of safety, purity and potency.

To be highly similar, extensive analytical characterization to demonstrate similarity of structure in combination with safety and immunogenicity studies must be performed. Additional comparative clinical studies may be required if residual uncertainty regarding similarity in structure remains. Because a licensed biosimilar has demonstrated it is highly similar to the reference product, it can be approved to treat the same medical conditions as the reference product.

Where Are
Biosimilars Currently Available?

Biosimilars are already available worldwide through biosimilar approval pathways implemented in countries across the globe.

The European Union has been approving biosimilars since 2006. Other highly regulated markets such as Japan, Australia, and Canada have been approving biosimilars since 2010.

Millions of patients have already received treatment in highly regulated markets with the same level of safety and efficacy as the reference biologics.1

The first biosimilar was approved in the United States in 2015. As biosimilars become more prevalent and accessible, experts predict savings to the U.S. healthcare system could range from $44B to $250B through 2025.2

Global Biosimilar Activity

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How Are Biosimilars Defined By Regulatory Bodies?

While definitions of biosimilars are worded differently among global regulatory bodies, they agree that biosimilars are highly similar in terms of quality, safety, and efficacy to the reference biologic.

The US Food and Drug Administration3:

To demonstrate biosimilarity, a sponsor must provide sufficient data and information to show that the proposed product and the reference product are highly similar notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the two products in terms of safety, purity, and potency.

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The European Medicines Agency4:

A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the EEA. Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established.

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The World Health Organization5:

A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.

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How Does The FDA Assess Biosimilars?

The Biologics Price Competition and Innovation Act (BPCIA) of 2009 created an abbreviated licensure pathway for biosimilars as an amendment to section 351(k) of the Public Health Service (PHS) Act. It was enacted with the passage of the Affordable Care Act (ACA) in 2010. The BPCIA allows for the approval of biological medicines shown to be biosimilar or interchangeable with a reference biologic. After the FDA approves a biosimilar through the 351(k) pathway, the biosimilar may be indicated for some or all of the medical therapies as the reference biologic.

How Do The 351(A) And 351(K) Regulatory Approaches Differ?

The new paradigm for biosimilar approval can be demonstrated as an inverted version of the requirements typical of a novel biologic. The foundation of approval for a new biologic is traditionally a large clinical program to test safety and efficacy of a novel treatment. By contrast, the foundation of approval for a biosimilar is a large analytical program to test similarity in molecule structure to the previously approved reference product. The same type of safety and immunogenicity studies are required for both types of products.

What Is The Approval Process For Biosimilars?

In the 351(k) approval pathway, the manufacturer collaborates with the FDA at each milestone in a stepwise approach. The result is an abbreviated but robust process in which the FDA reviews the biosimilar application numerous times prior to final approval.

351(A) Vs. 351(K)

The 351(k) biosimilar approval pathway was created to increase competition and patient access to potential alternatives to reference biologics. Because a biosimilar is not a new molecular entity, there are differences in the approval pathway. Additionally, the law includes a pathway for an interchangeable biosimilar that, once approved, can be substituted for the reference product at the pharmacy level. Biosimilars will require additional studies to receive the interchangeable designation.

FDA Similarity Definitions

In May 2014, the FDA issued guidance on the clinical pharmacology data needed to support biosimilarity to a reference product. One of four assessments will be given to a biosimilar candidate as a result of the foundational comparative analytical characterization. This assessment should inform the next steps in the demonstration of biosimilarity. The amount of residual uncertainty remaining decreases as the confidence in analytical similarity increases, reducing the need for additional supporting evidence including large scale comparative clinical trials. Clinical pharmacology studies can add to the totality of evidence and reduce residual uncertainty.

Biologics Categories
Originals Non-Originals
Type Reference Biobetter Non-Original Biologic Biosimilar
Approval pathway 351(a) 351(a) 351(a) 351(k)
Classification New biologic New biologic Treated as new biologic Follow-on biologic
Indication New indication(s) Same indication(s), clinical trial for each indication Same indication(s), clinical trial for each indication Same indication(s) as reference
Molecular category New molecular entity New molecular entity Treated as new molecular entity Analytical comparability to reference biologic
Target New therapeutic target New therapeutic target Same target Same target
Biologic category New biologic New biologic Clinically similar biologic Analytically and clinically equivalent biologic
  Originals
Type Reference Biobetter
Approval pathway 351(a) 351(a)
Classification New biologic New biologic
Indication New indication(s) Same indication(s), clinical trial for each indication
Molecular category New molecular entity New molecular entity
Target New therapeutic target New therapeutic target
Biologic category New biologic New biologic
  Non-Originals
Type Non-Original Biologic Biosimilar
Approval pathway 351(a) 351(k)
Classification Treated as new biologic Follow-on biologic
Indication Same indication(s), clinical trial for each indication Same indication(s) as reference
Molecular category Treated as new molecular entity Analytical comparability to reference biologic
Target Same target Same target
Biologic category Clinically similar biologic Analytically and clinically equivalent biologic

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References

  1. Abraham I, Tharmarajah S, MacDonald K. Clinical safety of biosimilar recombinant human granulocyte colony-stimulating factors. Expert Opin Drug Saf. 2013;12(2):235-246.
  2. Mulcahy AQ, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Available at: http://www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed July 29th, 2015.
  3. Food and Drug Administration (FDA). Scientific considerations in demonstrating biosimilarity to a reference product: Guidance for industry. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed July 29, 2015.
  4. European Medicines Agency. Guideline on biologic medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf. Accessed July 29, 2015.
  5. World Health Organization. Expert Committee on Biological Standardization, Geneva 19-23, 2009. Guidelines on evaluation of similar biotherapeutic Products (SBPs). Available at: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. Accessed July 29, 2015.