Is the language of biologics confusing you? Interchangeability, interchangeable product, reference product, pharmacy-level substitution, and switching studies are unique to biologics and biosimilars. Understanding biologics and biosimilars is essential whether you are a medical science liaison or medical affairs team member.

In 2021, the global biologics market value was approximately $366 billion, and the market is expected to reach a value of $719.84 by 2030. One of the reasons for the anticipated growth is the approval and commercialization of a record number of biosimilars, which are generally less expensive versions of the biologic drug or reference drug. In 2023, biosimilars will enter the market at a record number, with approximately 10+ biosimilars for the blockbuster drug, Humira®(adalimumab) becoming available. In a survey of pharmacists in 2021, only 11% of pharmacists answered correctly that all 12 biosimilars on a list were not interchangeable. The survey was conducted before the approval of the first interchangeable biosimilar in July 2021. The survey also found awareness of interchangeable biosimilars was highest among managed care pharmacists. As the biologics and biosimilars market expands, biologic and biosimilar education for health care providers (HCPs), industry, and medical affairs will be in high demand. The U.S. government passed the , requiring the FDA to provide HCPs with in response to market growth. This article will provide you with basic knowledge of biologics and biosimilars. After reading this article, you will be able to answer the following questions:

1. What is a biologic?
2. What is a biosimilar?
3. What is a reference product?
4. What is an interchangeable biosimilar?
5. What is pharmacy-level substitution?
6. What is the FDA biosimilar approval pathway?
7. What is a switching study?

What is a Biologic?

A biologic is a medication created from living organisms such as animal cells, yeast, or bacteria. The following are key points about biologics:

• Types of biologics include monoclonal antibodies, vaccines, gene therapy, etc.
• Treat various diseases, including cancer, rheumatoid arthritis, psoriasis, diabetes, etc.
• Have a large molecular weight
• Administered by infusion or injection
• Variability exists between lots since biologics are created with living organisms.

The FDA approved the first biologic, an insulin medication made from E.coli cells, in 1982. By 2014, 93% of net drug spending at a global level was on biologics.3 In response to the high cost of biologics, the concept of reference products and biosimilars was born.

What is a Reference Product?

According to the FDA, a reference product is “the single biological product, already approved by FDA, against which a proposed biosimilar product is compared.” A biosimilar must prove it is “highly similar” to the reference product and can produce similar clinical results to gain approval by the FDA.

What is a Biosimilar?

A biosimilar is also a biological product created from living organisms and defined by the following characteristics:

• Biosimilar manufacturers must demonstrate that the biosimilar is “highly similar” to the reference product,
• No clinically meaningful differences exist between the biosimilar and the reference product in terms of the safety, purity, and potency of the product (i.e., safety and effectiveness).

Biosimilars are a new class of drugs. The U.S. government recognized the rising prices of biologics and passed the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) on March 23, 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be biosimilar or interchangeable with an FDA-licensed reference product.5Following the passage of the BPCI Act, the first biosimilar, Zarxio®, was approved by the FDA on March 15, 2015.2 The major difference between generic drugs and biosimilars is generics must demonstrate bioequivalence, while biosimilars do not. Interchangeable biosimilars are more similar to generics because pharmacists can substitute a biologic for a biosimilar without the prescriber's approval.1

What is an Interchangeable Biosimilar?

Interchangeable biosimilars and interchangeable products are synonymous. The concept of interchangeability has created some confusion amongst HCPs.6 The following characteristics define interchangeable biosimilars:

• Produce the same clinical result in patients as the reference product.
• Have similar safety and efficacy as the reference product when alternated with the reference product.
• Can be substituted without the intervention of a medical prescriber, subject to state laws and approval of FDA.

Interchangeability is unique to the U.S. and an FDA designation that provides the basis for one-to-one substitution by a pharmacist (pharmacy-level substitution) without notification of the prescriber.7 Manufacturers can decide to pursue this optional designation, but it requires additional trials.7Semglee®, an insulin product for diabetics, is the first biosimilar to receive an interchangeable designation by the FDA in July 2021.4

Following the approval of Semglee®, the FDA approved Cyltezo (adalimumab-adbm), the first interchangeable biosimilar to Humira® (adalimumab), in October of 2021. Source:https://www.fda.gov/media/151094/download

What is Pharmacy-Level Substitution?

Pharmacy-level substitutions or auto-substitutions can occur when a biosimilar obtains “interchangeability” status.1Figure 1 depicts pharmacy-level substitution. When a provider prescribes the reference product, the pharmacist can dispense an interchangeable biosimilar rather than the reference product without notifying the prescriber.

What is the FDA Biosimilar Approval Pathway?

The BPCI Act created an abbreviated approval pathway for biosimilars under section 351(k) of the Public Health Service Act (PHS Act). The following studies are required to support biosimilarity:

• Analytic studies (establish similarity)
• Animal studies (establish toxicity)
• Human pharmacokinetic/pharmacodynamic studies (establish clinical meaningfulness)
• Immunogenicity assessments (establish clinical meaningfulness)

The FDA reviews the totality of evidence when reviewing biosimilars for approval, and there is “no one pivotal study demonstrating biosimilarity.”

What is a Switching Study?

When a biosimilar wants to achieve interchangeability status, switching studies are necessary to prove patients can switch between the reference product and biosimilar without experiencing side effects or loss of efficacy. The data required to demonstrate interchangeability depends on the complexity of the biosimilar.The ACMA will offer the Board Certified Biologics and Biosimilars Specialist (BCBBS) program, the first-ever accredited board certification program for healthcare professionals focused on biologics, in November 2022.