The current state of biosimilars in practice

By Naveed Saleh, MD, MS
Published February 15, 2022

Key Takeaways

  • The safety and efficacy of biosimilar and interchangeable products are rigorously investigated by the FDA.

  • Interchangeable products go through additional FDA vetting vs biosimilars.

  • Real-world evidence for multiple switches between biosimilars and reference products is lacking.

Physicians interested in prescribing biosimilars are faced with a multitude of questions. Should biosimilars be switched with reference products? What is the data on making this switch, and what are the benefits of switching? Although there is a common misconception that biosimilars are simply “generic” drugs, the answer is more complex because the drugs are more complex.

Owing to the manufacturing process and the natural variability between manufactured biologic drug batches, biologic products are highly similar to reference products but not exactly the same. Fortunately, the testing involved in the approval of a biosimilar is just as rigorous—and in some cases, even more rigorous—than it is for other drugs.

Regulatory process

In terms of FDA approval, reference products and biosimilars undergo similar thorough testing. The reference product is a single biological product that has already been approved by the FDA, and the biosimilar product is sized up with relation to this reference product. 

Reference products are evaluated in a “standalone” application, which consists of all the data and information needed to prove safety and efficacy, such as clinical trial data and disease indications.

Manufacturers of biosimilar products must prove that the product has no clinically meaningful differences in safety, purity, and effectiveness from the FDA-approved reference product. To this end, the manufacturer of the biosimilar provides data that starts with detailed structural and functional characteristics and transitions to animal/human trials as necessary. 

Animal studies look at toxicity, whereas clinical studies examine potency of the product with respect to one or more reference product indications, as well as analysis of immunogenicity, pharmacokinetics, and pharmacodynamics. Clinical trials may also include head-to-head comparisons with the reference product.

Biosimilars may be approved for all or a subset of indications of the reference product. Sometimes, the reference drug can have unexpired exclusivity for an indication that precludes other manufacturers from infringing. As such, prescribers should review the labeling of biosimilars to determine indications. 

The maker of a biosimilar only needs to support biosimilarity, so it is unnecessary to conduct expensive and lengthy clinical trials, which translates to faster access to products, increased treatment alternatives, and cost savings passed down to the patient. 

Indeed, the potential cost savings of using biosimilars in lieu of reference products could be substantial, according to the results of a study published in Rand Health Quarterly. The authors estimated that between 2017 and 2026, the use of biosimilars will decrease direct spending on biologics by $54 billion, which translates to 3% of total expenditures on biologics. 

The authors noted, however, that this figure could range between $24 billion to $150 billion, with real-world savings depending on industry/regulatory decisions, as well as policy changes that bolster the biosimilar industry. 

Abbreviated approval pathway

Through the Biologics Price Competition and Innovation Act (BPCIA), an abbreviated approval pathway was established to offer greater access to safe and effective biologics. This pathway allows for more treatment options and decreases healthcare costs via competition.

The abbreviated licensure pathway does not mean that standards are lowered for biosimilars or for interchangeable products. It simply permits the biosimilar applications to draw from extant scientific knowledge about the reference product. This step cuts drug-development costs.

Related: These 4 meds were fast-tracked by the FDA in 2021

Interchangeable products

An interchangeable product is a biosimilar that meets further requirements delineated by the BPCIA. The product is expected to produce the same clinical result as the reference product in all patients. For products administered to patients more than once, the risks involved in safety or reduced efficacy and the risks involved in switching between the reference product and the interchangeable product are also evaluated.

Importantly, interchangeable products can be substituted for the reference product without prescriber participation.

“High standards for approval should assure health care providers that they can be confident in the safety and effectiveness of an interchangeable product, just as they would be for an FDA-approved reference product,” according to the FDA.

Related: Adverse effects of 4 drugs approved in 2021

Information for the prescriber

When the FDA approves a biosimilar, substitution for a reference product at the pharmacy level is not determined. This step is considered outside the purview of the FDA. Some states do permit such exchange by the pharmacist, which is a practice referred to as “pharmacy-level exchange.” More information on this state-specific practice is available through state pharmacy boards.

The FDA assures that their rigorous evaluations ensure there are no clinically meaningful differences between a reference product and biosimilar when used as intended. The same holds true of interchangeable products, which meet even more rigorous standards.

Although the FDA supports the use of biosimilars and interchangeable products, real-world evidence is limited. 

The authors of a systematic review involving the TNF antagonist infliximab wrote, “While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios.”

To illustrate the point, the authors pointed out a paucity of data supporting multiple switches, and suggested that post-marketing pharmacovigilance is needed via registries and long-term observational studies regarding safety and efficacy of multiple switches.

What this means for you

The safety and efficacy of biosimilar and interchangeable products are supported by FDA testing. Nevertheless, physicians may want to examine extant literature and pharmacovigilance/registry data with regard to specific products—especially in the context of multiple switches.


  1. Biosimilar and Interchangeable Products. FDA.

  2. Feagan BG. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Alimentary Pharmacology and Therapeutics. 

  3. Mulcahy AW. Biosimilar Cost Savings in the United States. Rand Health Quarterly.

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