Many of today’s most important medications are biologics. Among the notable conditions treated by biologics are rheumatoid arthritis, anemia, low white blood cell counts, inflammatory bowel disease, skin conditions and various forms of cancer. As you probably perceive, biosimilars are to biologics what generic drugs are to brand-name drugs. However, there are major differences between the two.
Biosimilars, also known as follow-on biologics are therapeutic drugs that are highly similar to (or interchangeable with) their approved, brand-name comparators, or Reference Products. Whereas conventional generic drugs (aka small molecules) are comprised of pure chemical substances which may be identically duplicated. This allows for demonstration of bioequivalence to their Reference Listed Drugs (RLDs) through pharmacokinetics (PK) studies. Because of their complexities, biosimilars are never structurally identical. Made from living organisms, biologics are relatively large and complex molecules compared to conventional chemical drugs. Biologics tend to be made up of proteins (and/or constituent amino acids), carbohydrates (e.g. sugars), or nucleic acids (e.g. DNA) and can be derived from many sources, including humans, animals and microorganisms, such as bacteria or yeast., 
The New Biosimilar Pathway
Prior to 2010, there was no regulatory pathway for biosimilar development in the US. Interestingly, in April 2006, Sandoz’s Omnitrope® was approved by the European Medicines Agency (EMA) as Europe’s first ever biosimilar. FDA followed with approval of Omnitrope® also in 2006, but it followed a court ruling that the agency must review the application. In doing so, FDA used the 505(b)(2) pathway but stated that the approval did not establish a pathway for approval of other follow-on biologics, and that Congress would need to change the law in order for the agency to continue doing so.
On March 23, 2010, the President signed the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) into law, which amended the Public Health Service Act (PHS Act) and created an abbreviated review pathway for US biosimilars using Biologic Licensing Applications (BLAs). In addition, Congress authorized FDA to collect associated user fees from industry to compensate them for their review time.
Although the pathway is abbreviated, the similarities must be proven with sound data and the guidelines are strict. Biosimilar sponsors must demonstrate that the proposed compound is highly similar (biosimilar) to or interchangeable with the Reference Product. The distinction between a biosimilar that is “highly similar” and one that is “interchangeable” is an important one: “Under the BPCI Act, a biological product that that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” FDA will only approve a biosimilar product if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product.
The biosimilar 351(k) application may, at the discretion of FDA, require analytical, animal and clinical (PK/PD) studies to bridge the similarity to the reference drug as written in the regulation: “The biological product is biosimilar to a reference product based upon data derived from analytical studies, animal studies (including toxicity), and a clinical study or studies (including immunogenicity and pharmacokinetics or pharmacodynamics). The Secretary of Health and Human Services (the Secretary) may determine that any of these elements is unnecessary…”
Basic Biosimilar Nomenclature
Following are excerpted definitions of commonly used terminology from Background Information: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations (Purple Book):
Under section 351(i)(4), a “reference product” is the single biological product licensed by FDA under section 351(a) of the PHS Act against which a proposed biological product is evaluated in an application submitted under section 351(k).
Under section 351(i)(2), “biosimilar” or “biosimilarity” means that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency of the product.
Under 351(k)(4), an “interchangeable” biological product is a product that has been shown to be biosimilar to the reference product, and can be expected to produce the same clinical result as the reference product in any given patient. In addition, to be determined to be an interchangeable biological product, it must be shown that for a biological product that is administered more than once to an individual the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.
Biosimilar Development Challenges
Because biologics are such complex mixtures, they are inherently more difficult to identify or characterize. However, characterization of both the RLD and proposed biosimilar version are critical to in vitro comparisons, as traditional PK studies alone may not demonstrate substantial similarity.
In addition, complex, large molecule biologics are not easy to manufacture and usually require special handling (e.g. refrigeration) and additional processing (e.g. sterilization). More rigorous development, manufacturing and distribution challenges have resulted in few biosimilar approvals since the program began, a minimal reduction in prices compared to generics and continued monopoly-like markets for biosimilar sponsors willing to take the additional responsibilities and risks.
Following is the short list of biosimilars currently approved for marketing in US. Zarxio® was the first and was based on review of evidence that included “structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data.” Zarxio® was approved as biosimilar, not as an interchangeable product.
Biosimilars Approved for Marketing in the United States by FDA
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Adapted from Johnson J. Biologics and Biosimilars: Background and Key Issues, Congressional Research Service Report. September 7, 2016.
Marketing Challenges of Biosimilars
Based on the variety of challenges associated with the development and manufacturing of biosimilars, it is not surprising that marketing them also poses a unique set of challenges. Specialty Pharmacy Times reports that “Retail pharmacies face significant challenges when entering the specialty pharmacy space. Product pricing information, inventory, and reporting demands for specialty drugs are often more stringent than for primary care medications, and reimbursement issues can introduce new challenges for members of the retail staff. Clinical programs to keep patients compliant with high-cost specialty drugs are also not typically part of a retail pharmacy’s strategy.”
More recently, Fierce Pharma reported that “moving into the biosimilar market will require shrewd out-licensing strategies or long-term investments in required infrastructure”.
As of this writing there are no approved biosimilars in the Purple Book with interchangeable (“I”) rating. Therefore, pharmacists cannot currently substitute biosimilars for the Reference Product (“The Purple Book, in addition to the date licensed, also includes whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product”).
About the Authors
Jodi Hutchins is an Independent Regulatory and Quality Consultant with over 15 years of global medical device registration experience, to include FDA 510(k) submissions. She held her most recent position for 9 years, as QA/RA Director for a Worldwide distributor of medical devices.
Charles Jaap is Vice-President of Operations and Business Development for PDG, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices. Please feel free to contact us for more information.
The opinions and statements in this paper are solely those of Charles Jaap and Jodi Hutchins and do not necessarily reflect those of PDG.