Biological medicines now treat many serious and long-term conditions, but many are expensive. As the exclusivity of these medicines ends, biosimilars are reaching more therapeutic areas. Because biological medicines cannot be copied exactly, biosimilars are developed and approved differently from both new biologics and small-molecule generics.
This article explains what biosimilars are, what they’re used for and why they matter. It then covers how similarity is demonstrated, how interchangeability works and what risks need to be managed.
A biosimilar is a biological medicine that’s highly similar to an approved reference product, with no clinically meaningful differences.
A biosimilar is a biological medicine that’s highly similar to another biological medicine already approved, known as the reference product. The European Medicines Agency (EMA) defines this similarity in terms of structure, biological activity, efficacy, safety and immunogenicity profile. Immunogenicity is a medicine’s ability to provoke an immune response.
The core test is that there are no clinically meaningful differences between the biosimilar and its reference product. In the EU, a biosimilar contains a version of the active substance of an already authorised biological medicine, and its similarity is established through a comprehensive comparability exercise. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) licenses biosimilars based on a detailed head-to-head comparison with the reference product.
In the US, the Biologics Price Competition and Innovation Act of 2009 created a route to support access to lower-cost biologics. Biosimilars are licensed through the abbreviated 351(k) Biologics License Application pathway.
Biosimilars are approved to the same standards of quality, safety and efficacy as any other biological medicine. Although the regulatory routes can often differ, they apply the same underlying principle that approval ultimately depends on the strength of the comparative evidence rather than repeating the reference product’s full development programme.
Most conventional medicines are small molecules made by chemical synthesis. Their structure is fixed, so a generic can be identical to the original and is typically approved on the strength of a bioequivalence study.
Biological medicines, by contrast, are made in or derived from living systems, such as bacterial, yeast or mammalian cells, usually using recombinant DNA technology.
With biologics, ‘the process is the product’. Even small changes to manufacturing can alter the final medicine, so the process has to be tightly designed and controlled. Every biological medicine shows some variability, including between batches of the same reference product, so that variability is monitored to keep it within approved limits.
A biosimilar developer uses its own cell line and manufacturing process, so it can’t reproduce the reference product’s molecular micro-heterogeneity exactly. Quality attributes such as three-dimensional structure, charge variants and glycosylation (the sugar groups attached to a protein after it’s made) can differ slightly. That’s why a biosimilar is described as highly similar rather than identical, and why it’s regulated through its own pathway rather than as a generic.
Biosimilars are used for the same conditions as their reference biologics, across many serious and long-term diseases. These include cancers, diabetes, neutropenia, growth disorders, enzyme or hormone deficiencies, and inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease.
Some of the most established examples in the NHS are in oncology and immunology. Trastuzumab, a targeted treatment for breast and stomach cancer, has biosimilars including Herzuma, Ontruzant and Trazimera. Rituximab, used in chronic lymphocytic leukaemia and some types of non-Hodgkin lymphoma, has biosimilars including Truxima, Ruxience and Rixathon. Adalimumab, used for arthritis, Crohn’s disease and ulcerative colitis, also has several biosimilars, including Amgevita, Hyrimoz and Imraldi.
Biosimilars are important because they bring price competition once a reference product’s protection ends. NHS England’s position is that this lets more patients access treatment sooner and frees funding for other treatments and improvements to care pathways.
An original biologic has to establish its own safety and efficacy through a full development programme. A biosimilar doesn’t repeat that work. Instead, the developer uses comprehensive comparability studies to show that the product is highly similar to the reference product, despite the natural variability of biologics. The reference product’s established safety and efficacy can then be relied on, avoiding unnecessary repetition of clinical trials.
The evidence is built in steps. It starts with an extensive analytical comparison of physicochemical and biological properties, often called the analytical comparability exercise. Non-clinical in vitro and in vivo data follow. The clinical part compares pharmacokinetics (PK, how the body handles the drug), pharmacodynamics (PD, the drug’s effect on the body), safety and immunogenicity. Regulators then assess the totality of this evidence rather than any single study.
Where the analytical, PK and PD data are sound, comparative efficacy trials are often not required. Any immunogenicity assessment should show that the biosimilar produces no higher immune response than the reference product.
This reliance on comparability is well established. Regulators use the same approach to assess manufacturing changes to any biological medicine, including reference products, to confirm a change hasn’t affected quality, safety or efficacy.
For some molecules, PK similarity alone may be enough to support an application. For others, such as erythropoietin, PK data or model-based analysis may be needed because PK alone may not show that the two products are highly similar.
FDA guidance encourages sponsors to characterise exposure and exposure-response relationships and sets out what to weigh when choosing a PD biomarker. The factors include how soon the biomarker changes after dosing and whether it returns to baseline once dosing stops. Other factors are its dynamic range across the product’s exposure range, its sensitivity to differences between the proposed biosimilar and the reference product, and its relevance to the drug’s mechanism of action, where that’s known. The analytical validity of the biomarker assay matters too.
One published analysis, for example, compared the duration of severe neutropenia with the area under the effect curve for absolute neutrophil count, and found that absolute neutrophil count was a predictive safety biomarker.
Equivalence margins are another area of judgement. Regulatory guidance has suggested bioequivalence-based bounds of 80–125% for the confidence interval, but such tight thresholds aren’t always needed for PD endpoints. Health authorities have indicated that wider bounds can be acceptable where they’re justified, and model-based arguments built on PD principles can support similarity.
Many biologics are licensed for several indications. Extrapolation is the principle that when a biosimilar has been shown to be similar to its reference product in one indication, its safety and efficacy can be extended to the reference product’s other indications, provided the mechanism of action is shared.
Where the comparative evidence supports extrapolation, all of the reference product’s indications can be claimed. Once the MHRA has authorised the product, prescribers should consider it therapeutically equivalent in those indications.
Extrapolation can still prompt questions, particularly where the reference product treats quite different diseases and the biosimilar’s clinical data come from a single indication. For that reason, the scientific justification for extrapolation should be supported by preclinical studies or other relevant tests.
Three related terms often get blurred. Interchangeability is the position that one product can be used in place of another with the same expected clinical effect. Switching is a prescriber’s decision to move a patient from one product to another. Substitution is dispensing one product in place of another at pharmacy level without consulting the prescriber.
In the EU, EMA and the Heads of Medicines Agencies (HMA) issued a joint statement in 2022 that biosimilars approved in the EU are interchangeable from a scientific viewpoint. A biosimilar can be used instead of its reference product, or vice versa, and in place of another biosimilar of the same reference product. Member states still decide whether pharmacies can substitute them automatically, and national approaches have varied considerably.
In England, NHS guidance treats an authorised biosimilar as interchangeable with its reference product and with other biosimilars of the same reference product. Before a switch, clinicians should consider whether the patient is clinically stable and whether the product suits them, including its delivery device. Pharmacy-level substitution isn’t permitted for any biological medicine in England.
The US treats interchangeability as a separate designation. An interchangeable biosimilar must be expected to produce the same clinical result as the reference product in any patient, and moving between the two must not add risk compared with staying on the reference product. A product that meets these criteria can be substituted for the reference product without the prescriber’s involvement.
Immunogenicity is a central scientific concern. The small quality differences described earlier can affect a biological medicine’s effects and side effects, including immune reactions. Monitoring continues once the product is on the market.
A biosimilar can also differ from its reference product in ways that don’t involve the active substance but still matter in practice. Its formulation or delivery device may be different, and its licensed indications may not match the reference product exactly. These differences need to be checked against the product information when choosing a product or planning a switch.
Traceability is a further risk. Biosimilars often share the same international non-proprietary name (INN) as their reference product, so an adverse event reported by INN alone can’t be linked to a specific product. UK guidance calls for biological medicines to be prescribed by brand name, and patients should be told which brand they’re receiving. The brand and batch should also be recorded on adverse event reports so that they can be attributed correctly.
Every biosimilar should have a risk management plan, which sets out how potential risks will be identified and tracked, including through post-marketing pharmacovigilance and immunogenicity studies.
A separate risk sits outside established biosimilar pathways. Some countries have licensed biological products on data that wouldn’t meet EU or US regulatory expectations, under labels such as ‘similar biologics’, ‘biocomparables’ or ‘biogenerics’. Where these products are on the market alongside true biosimilars, the regulatory route behind a product matters as much as its label.
Since a biologic can’t be copied exactly, a biosimilar has to show through stepwise comparability that it’s highly similar to its reference product, with no clinically meaningful differences. That evidence, led by analytics and supported by targeted PK, PD and immunogenicity data, is what allows the reference product’s established safety efficacy to be relied on.
Quanticate’s statistical consultancy team supports biosimilar sponsors with statistical planning, analysis and interpretation across comparative development programmes. Our statisticians can help assess PK and PD study designs, equivalence margins and the assumptions behind them, so the comparative evidence is set up to support a case for similarity. Request a consultation to discuss your requirements.