In 2009, the U.S. Congress passed the Biologics Price Competition and Innovation Act. This legislation created a new way for biologic products to be approved by the U.S. Food and Drug Administration (FDA). Understanding the implications first requires an understanding of some basic definitions:
• Biological product: A specific categorization that includes a variety of medications that are generally made of large, complex molecules. Many times these products are produced in unique ways using microorganisms or cells of plants or animals. Because these products contain such complex molecules, there can be slight differences between products when manufactured that are considered normal and expected.
• Reference product: A product approved through a full safety and effectiveness review by the FDA. This is the product to which the proposed biosimilar product will be compared.
• Biosimilar product: A biological product that is highly similar to and is considered to have no clinically meaningful difference to the reference product.
• Generic drug product: A drug product that has an active drug ingredient identical to the previously FDA-approved brand-name product.
FDA approval process
Biosimilar manufacturers must demonstrate to the FDA that the product is comparable to the reference product in purity, chemical identity and bioactivity. Additionally, there must be pharmacokinetic and pharmacodynamic studies to demonstrate no clinically meaningful difference in safety and effectiveness.
While biosimilars may be thought of as “generics” of their reference products, this is not technically true. Both generic drugs and biosimilar products go through a shortened pathway to approval with the FDA; however, generic drugs approved by the FDA are required to have the same active ingredients and bioequivalency (no difference in the rate and extent at which the product releases and become available at the site of action) to their brand-name counterparts. Biosimilar products must prove to be highly similar and have no clinically meaningful differences in safety and effectiveness to the reference products. Approval applications for biosimilar products can also request to be considered interchangeable by including data demonstrating the same clinical result if given to a patient and that if a patient switches between products, there are no differences in effectiveness or an increased safety risk.1
The FDA maintains the Purple Book: Lists of Licensed Biological Products that includes all products approved through the biologic approval pathway. This resource includes biosimilars and information about interchangeability. For generic drugs, information about interchangeability is found in the Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations.
Biosimilar insulin in the U.S.
In other parts of the world, including Europe and Asia, insulins have been approved through the biosimilar pathway. However, in the U.S., these products have gone through the FDA approval process through a different pathway and are called a “follow-on product.” This is because the original approval of insulins was through the drug approval process versus approval as a biological product. Because the Biologics Price Competition and Innovation Act applies only to products licensed as biological products, it is not technically possible to have a biosimilar insulin in the U.S. It is also impossible to have a generic insulin in the U.S. due to the fact that insulin is a more complex molecule than chemically synthesized drugs. Instead, the pathway that insulin has taken has been different, with manufacturers developing similar products to those that have been previously approved and being licensed as follow-on biologics by the FDA. There are rule changes scheduled to take place in early 2020 that will make these differences less confusing by merging the two processes so that a biological product approved as a drug will be classified the same as other licensed biological products.5,6
As discussed, no insulins are currently approved by the FDA through the biosimilar pathway in the U.S., and this is not expected to change until 2020. There are currently two follow-on insulin products available for use in the U.S. The first product was a basal insulin, Eli Lilly and Company’s Basaglar® insulin glargine injection, with the reference product being Sanofi-Aventis’ Lantus® insulin glargine injection. Basaglar® gained approval by the FDA in December of 2015, with availability the following year. Additional insulin glargine injection products have either received tentative approval from the FDA or have been approved and distributed in other countries but are not currently available in the U.S. In December of 2017, the FDA approved the first rapid-acting follow-on insulin product, Sanofi-Aventis’ Admelog® insulin lispro injection, reference product Eli Lilly’s Humalog® insulin lispro injection. Admelog became available in the U.S. in 2018. Recently Eli Lilly announced they will be offering a lower priced authorized generic of their rapid acting insulin Humalog. This is different than a biosimilar product in that there will be no difference in the insulin molecule since it will be available from the same manufacturer.
Both patients and health care providers should expect that there should be no clinical difference between taking a biosimilar or its reference product. Biosimilar and follow-on products must be approved by meeting FDA standards that support both the safety and effectiveness being similar to the reference product. If a patient has been treated previously with the reference product, there should be no clinical difference in outcomes with the biosimilar product. If a product is approved as an interchangeable biosimilar product, then additional testing has been done to demonstrate patients were successfully switched back and forth between the biosimilar and reference product without increased risk of adverse outcomes or decreased risk of effectiveness. Due to small differences in the manufacturing process, rare but serious immunogenicity reactions may occur when switching to a biosimilar or follow-on product.
Whether a pharmacy is able to substitute a biosimilar for its reference product without contacting the prescriber is dependent upon pharmacy practice laws in each state. As of 2018, 45 states and Puerto Rico have laws regarding biosimilar substitution, though specifics of each state law do vary. In general, each state legislation will address key concepts, including how the products are FDA approved, if a prescriber decision is necessary for substitution, if a prescriber must be communicated with or notified, how the patient is notified, what records must be kept, and if cost or pricing affects the decision.5
The high and increasing cost of prescription medications has been well established in the past few years. One of the major contributors to increasing costs has been biologic products, including insulin, cancer medications and monoclonal antibodies. The increasing cost of insulin has been realized by the health care system, insurance payors and patients with out-of-pocket costs also increasing.13
Similar to generic drugs, biosimilar products may allow for patients to access treatment at lower costs. The decreased cost is primarily due to the decrease in clinical trials costs, though biosimilar products require higher clinical trial costs than routine generic drugs due to the requirements described above.1 Additionally, having biosimilar products available should promote competition between manufacturers, which may drive price decreases and, as a result, increase patient access to the product. Other countries have seen decreased treatment costs by up to 40 percent due to biosimilar products. Because biologic products have higher production costs and due to the evolving FDA regulations, it is still unknown if the biosimilar pathway will reduce costs of insulin in the U.S.12 However, a recent evaluation by the RAND Corporation has estimated that biosimilar products, including insulins, will decrease direct spending on biologic drugs by $54 billion between 2017 and 2026 in the U.S.13
The Biologics Price Competition and Innovation Act has created the opportunity for biosimilar products to enter the drug market in the U.S. These products are not the same as a generic drug but do offer similar benefits in terms of potential decreased cost and increased access to medications. The rigorous process for approval of biosimilar or follow-on products gives clinicians and their patients assurance of the safety and effectiveness of these products but does still incur significant costs for manufacturers. The future impact on the on the insulin market and diabetes management is still to be determined, but potential benefits for patients and the healthcare system are promising.
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About our expert
Kristina Naseman, PharmD, MPH, MLDE, BCACP, CDE
Doctor of Pharmacy and master licensed diabetes educator at University of Kentucky HealthCare for the inpatient diabetes service team, Barnstable Brown Diabetes Center and Maternal-Fetal Medicine