A biosimilar is a “highly similar” copy of a biologic drug, but it is not a generic. This definition understandably causes confusion among oncology patients and providers alike, but it is an important distinction, according to Jim Koeller, MS, professor at The University of Texas at Austin.
At the AONN+ 2020 Midyear Conference, Mr Koeller provided the (virtual) audience of navigators with an in-depth look at the exhaustive processes behind the development and approval of oncology biosimilars, emphasizing the fact that just because a biosimilar is approved by the FDA does not mean that it is available for use.
Koeller’s First Law: Biosimilars Are Not Generics
Biologics are defined as “a wide range of products derived from cell lines from living organisms, such as vaccines, blood and blood components, and recombinant therapeutic proteins that prevent, treat, or cure a disease.” Examples include therapeutic proteins like granulocyte colony-stimulating factor and monoclonal antibodies like rituximab and trastuzumab.
The FDA defines a biosimilar as “a biological product that (a) ...is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “(b) there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.”
“Biosimilars must demonstrate safety, purity, and potency,” said Mr Koeller. “That’s the key.”
The category of biosimilars was not created to repeat the entire developmental program of the biologic. Rather, a separate process of robust analytical testing is used to establish high similarity to the reference product.
The “Only Reason” to Use Biosimilars
According to Mr Koeller, there is only one reason to use biosimilars, and that is to save money.
“If the companies making these biosimilars had to repeat the entire developmental sequence of the originator, the cost wouldn’t be much different. All they have to do is demonstrate no clinically meaningful differences,” he said. “Remember, the originator has already gone through multiple large phase 3 studies to prove where the drug is effective.”
Manufacturers carefully control biologic variability to help assure batch consistency, but the product’s quality attributes (usually 30 or more) have to remain within a prespecified range. In addition, manufacturing processes of biologics undergo changes over time after their approval (infliximab has had over 30 manufacturing changes in its life cycle). Subsequent to these changes, or biologic “drift,” the biologic must then undergo in-depth comparability studies to assess the potential impact of these differences on the biologic’s safety profile or efficacy, and to make sure it still falls within the standard variability allowed for that product.
The statement that “biosimilar and biological reference medicines are similar but not identical” is perhaps one of the most frequently misunderstood sentences when it comes to biosimilars, he said.
Mr Koeller stressed that biosimilars are not exact copies of biologics—they are only highly similar—as there are batch-to-batch differences of every biologic made due to inherent variability in the manufacturing of biologics. So if the originator biologic has to allow for variability in its production, making a copy of it must also allow for variability.
A biosimilar is not trying to prove its efficacy, and it is not trying to be superior to the reference biologic; it is only trying to prove equivalence, or noninferiority. However, he noted that analytic comparisons for a biosimilar are likely to be even more extensive and comprehensive than those made for reference biologics after a manufacturing change.
Interchangeability versus Substitution
To date, no biosimilar approved in the United States has been granted the “interchangeable” designation by the FDA; this designation means that the biologic reference product may be substituted by a biosimilar without intervention from the prescribing provider. But at the state level, the rules vary. According to Mr Koeller, states have been busy putting laws into effect that create standards for pharmacy substitution of biosimilars for biologics, and most states now have their own biosimilar laws on the books. He urges providers to check on the laws regarding the substitution of these products in their respective states.
“But the only way a product gets into an institution, hospital, or health system is through the Pharmacy and Therapeutics [P&T] Committee,” Mr Koeller emphasized. “That is the doorway all products must pass through to get on the formulary.” Ultimately, medical staff and the P&T Committee (composed of physicians, pharmacists, nurses, finance, legal, administrators, and others) will decide on the clinical use of a biosimilar within their institutions based on efficacy, safety, and financial considerations. “Remember, the only reason you want to bring in this biosimilar is to save money; to save cost to the health system, to save cost to your drug budget, and to save the cost of copays to patients,” he added.
However, the biosimilar approval and implementation processes are still fraught with hurdles. Major issues include customer nonfamiliarity with the biosimilar company, companies trying to sell expensive biosimilars with a “generic product mentality,” lengthy P&T approval times, reference companies countering with disinformation and misinformation, and physician pushback on “therapeutic” products (highlighting the need for more extensive education around biosimilars).
So Where Does the United States Stand on Oncology Biosimilars?
Remember “Koeller’s 2nd Rule: Just because it is FDA approved does not mean it is commercially available,” he said.
When a typical pharmaceutical receives FDA approval, companies rush to get the product out quickly so they can sell their new drug and make money. But for a biosimilar, it’s not so simple. Mr Koeller explained that biologic products are now surrounded by secondary patents, making it difficult or impossible for biosimilars to enter the market.
For example, a drug like Humira (adalimumab) has more than 160 secondary patents that surround it. Adding these protective patents prevents the developers of biosimilars from launching their products.
“Humira has 3 biosimilars approved, but the first one won’t be available until the beginning of 2023 because of the patent protections that surround that $19 billion drug,” he said. “So just because you hear something got FDA approved, don’t get too excited that it may be available.”
However, several more biosimilar products are slated to become commercially available by the end of the year, he said, adding that the FDA is behind these drugs having a place in the oncology drug market because they save money to government-funded programs like Medicare and Medicaid.
“So be patient,” said Mr Koeller. “More biosimilars are on the way.”
