Biosimilars and originator biologics: what the difference is and what to specify

What a biological medicine is

A biological medicine, or biologic, is a medicine whose active substance is produced by living cells rather than by chemical synthesis. Monoclonal antibodies such as adalimumab, infliximab and bevacizumab, insulins and other therapeutic proteins all belong to this group. Because they are large, complex molecules made by a biological process, no two batches are perfectly identical even from the same manufacturer, and the manufacturing process itself is part of what defines the product.

What a biosimilar is, and why it is not a generic

A generic medicine is an exact chemical copy of a small-molecule medicine such as metformin: the active substance is identical atom for atom, and approval rests mainly on showing that the generic is absorbed in the same way.

A biosimilar is different. It is a biological medicine that is highly similar to an already approved reference product, the originator, in structure, biological activity, safety and efficacy. Because a biologic cannot be copied exactly, the biosimilar’s manufacturer must demonstrate, through an extensive comparability exercise, that any differences between the two products have no clinically meaningful effect. That exercise includes detailed analytical characterisation, functional assays, pharmacokinetic and pharmacodynamic studies and, usually, a comparative clinical trial in a sensitive indication.

How the EMA approves a biosimilar

In the European Union, biosimilars are assessed centrally by the European Medicines Agency. The evaluation is built on comparison: the question is not whether the medicine works in absolute terms, which the reference product has already established, but whether the biosimilar matches it closely enough that the existing evidence for the reference product applies. Where similarity is demonstrated, the biosimilar can be approved for the indications of the reference product, including indications that were not studied in its own clinical trial. This is called extrapolation and is justified by the shared mechanism of action.

The first biosimilar was approved in the EU in 2006. Since then, biosimilars of adalimumab, infliximab, bevacizumab, trastuzumab, rituximab, insulins and several other biologics have been approved, and the safety record of the class over that period is what underpins the interchangeability statement described below.

Interchangeability and substitution

Two words are often mixed up. Interchangeability is a scientific judgement that one product can be used in place of another with the same clinical effect, including switching a patient from one to the other. Substitution is the practice of a pharmacist dispensing a different product from the one named on the prescription.

In September 2022 the EMA and the Heads of Medicines Agencies published a joint statement that biosimilars approved in the EU are interchangeable with their reference product and with other biosimilars of the same reference product. Whether pharmacists may substitute one for another automatically remains a national decision: some countries allow it, some require the prescriber’s agreement, and rules outside the EU differ again. Prescriptions for biologics are therefore often written by brand name, and changing between products is a decision for the prescriber.

Naming: INN plus brand

Every biologic carries an international non-proprietary name, the INN, which identifies the active substance: adalimumab, infliximab, bevacizumab, insulin lispro. The originator and each biosimilar share this name. Each product also carries its own brand name and, for injectables, its own pen or syringe. A request that names only the INN is ambiguous; a request that names the brand identifies the exact product.

Examples from the catalogue

Adalimumab. The originator is Humira (AbbVie). Biosimilars approved in the EU or the US include Amgevita/Amjevita (Amgen), Cyltezo (Boehringer Ingelheim), Hyrimoz (Sandoz), Hulio and Idacio (Fresenius Kabi), Hadlima and Imraldi (Samsung Bioepis), Yuflyma (Celltrion), Abrilada (Pfizer), Simlandi (Alvotech) and Yusimry (Coherus). They differ in device, concentration and the presence of citrate buffer, which some patients find painful, so the presentation matters as much as the name.

Infliximab. The originator is Remicade (Janssen). Biosimilars include Inflectra/Remsima (Celltrion), Flixabi/Renflexis (Samsung Bioepis), Zessly (Sandoz) and Avsola (Amgen). Infliximab is given as an intravenous infusion in a clinic; a subcutaneous formulation of Remsima also exists.

Bevacizumab. The originator is Avastin (Roche). A number of biosimilars are approved, among them Mvasi, Zirabev, Aybintio, Alymsys, Abevmy, Oyavas and Vegzelma.

Insulin lispro. The originator is Humalog (Eli Lilly). Admelog (Sanofi) is a biosimilar insulin lispro; Lyumjev is a faster-acting formulation from the originator and is not a biosimilar.

What to specify when you request a biologic

To receive exactly the product intended by the prescriber, a request should state:

1. the active substance (INN) and the brand name;
2. the strength and the presentation, for example a 40 mg pre-filled pen or a 100 mg vial;
3. the quantity and the intended treatment period;
4. the destination country, because the products authorised there and the rules on substitution differ.

A valid prescription is required for every biologic in our catalogue, and the destination country’s prescription and import rules are verified before anything is shipped. All of these products are cold-chain medicines; the storage temperature and the room-temperature allowance of each one are on its medication page.