Biosimilars and Interchangeability
Biosimilars are highly similar to approved reference biologics, offer substantial cost savings, and — once designated interchangeable — can be substituted by a pharmacist without prescriber intervention. This guide explains how they work, how they are approved, and what the evidence shows about switching.
What is a biological medicine?
Unlike conventional small-molecule drugs (aspirin, metformin, lisinopril), biological medicines are derived from living cells — bacteria, yeast, mammalian cells, or other biological systems. They include monoclonal antibodies, fusion proteins, hormones, enzymes, and cell therapies. Because they are produced by complex living systems, they are inherently larger, more structurally complex, and more variable than small molecules.
Key examples include: adalimumab (Humira — anti-TNF for rheumatoid arthritis, IBD), trastuzumab (Herceptin — anti-HER2 for breast cancer), insulin analogues, and erythropoietin (for anaemia in CKD). The FDA biologics approval pathway (BLA) ↗ differs from the standard NDA pathway used for small molecules. The NCBI overview of biologics regulation ↗ provides academic background.
How biosimilars are approved
In the US, biosimilars are approved under section 351(k) of the Public Health Service Act via the BPCI Act ↗. The approval standard is a totality of evidence that the proposed biosimilar is highly similar to the reference product with no clinically meaningful differences in safety, purity, or potency.
Evidence typically includes:
- Analytical studies — structural and functional characterisation comparing primary sequence, higher-order structure, post-translational modifications (glycosylation), and biological activity
- Preclinical studies — animal toxicology and pharmacokinetic/pharmacodynamic comparisons
- Human PK/PD studies — comparative pharmacokinetics in healthy volunteers or patients
- Clinical immunogenicity assessment — anti-drug antibody formation rates
- Clinical efficacy/safety data — may be required for residual uncertainty, but can be reduced with robust analytical evidence
The EU pathway through EMA ↗ uses a similar totality-of-evidence approach. Current EMA overarching guideline: EMEA/CHMP/437/04 Rev 1 ↗.
Interchangeability — the US-specific standard
In the US, FDA can designate a biosimilar as interchangeable with the reference product if it meets an additional standard: it produces the same clinical result in any given patient, and switching produces no greater risk than continued use of the reference product.
Once designated interchangeable, the biosimilar can be substituted at the pharmacy level without prescriber involvement — subject to state pharmacy practice laws that permit automatic substitution (currently most states). This mirrors the dispensing model for small-molecule generic drugs. See the FDA interchangeable biosimilars list ↗ for all currently designated products.
In October 2026, FDA finalised guidance eliminating the requirement for dedicated switching studies for most biosimilars, relying on totality-of-evidence from existing data — significantly accelerating the interchangeability pathway. Details: our FDA biosimilar interchangeability news item.
| Designation | Standard | Pharmacist substitution? |
|---|---|---|
| Biosimilar | Highly similar, no clinically meaningful differences | No — requires prescriber authorisation in most states |
| Interchangeable biosimilar | Same clinical result in any patient; switch safety established | Yes — in states permitting automatic substitution |
| Generic drug | Identical small molecule; bioequivalent AUC/Cmax | Yes — in virtually all states |
FDA Purple Book, bioequivalence, and biosimilar approvals
The FDA Purple Book ↗ is the official database listing all FDA-licensed biological products, including biosimilars and interchangeable biosimilars. It serves a similar function for biologics as the Orange Book serves for small-molecule generic drugs. Each entry includes the reference product, biosimilarity determination, and interchangeability status. The Purple Book is the definitive source for confirming whether a biosimilar has been approved and whether it is designated interchangeable.
It is important to distinguish bioequivalent drugs from biosimilars. Bioequivalence is the regulatory standard for small-molecule generic drug approval — two formulations are bioequivalent if they have the same rate and extent of absorption (within 80–125% confidence intervals for AUC and Cmax). Biosimilars, by contrast, undergo a different approval pathway because large-molecule biologics cannot be exactly replicated. The totality-of-evidence approach for biosimilars includes analytical similarity, functional assays, and clinical comparison — a more comprehensive but conceptually different standard than bioequivalence. For full details on bioequivalence methodology, see our bioequivalence glossary entry and generic vs brand-name drugs guide.
As of late 2026, the FDA has approved over 45 biosimilar products in the United States, with interchangeability designations now available for multiple adalimumab, insulin, and pegfilgrastim biosimilars. The streamlined interchangeability pathway finalised in October 2026 is expected to further accelerate approvals. For the most current listing, consult the FDA biosimilar product information page ↗.
Cost savings and market uptake
The US biosimilar market grew significantly after 2023 adalimumab biosimilar launches. Humira had been the world's best-selling drug for years, with annual US sales exceeding $20 billion. Multiple interchangeable biosimilars have reduced list prices by 60–80%. Analysis by KFF ↗ and the IQVIA Institute ↗ track market share and savings estimates. CMS has issued Part D formulary incentives ↗ favouring biosimilar placement on preferred tiers.
Globally, the WHO biotherapeutics guidelines ↗ and the EMA biosimilar framework ↗ have enabled European biosimilar markets to achieve higher uptake rates than the US, driven by national tender and switching programmes.