Biologics and Biosimilars vs Brands and Generics: Same, Yet Unique

Every brand-name drug can have generics. Every biologic can have biosimilars. They sound like the same idea, but the science, the regulation and the economics behind them are very different.

Drugs vs biologics

A drug is produced by synthetic chemical reactions, combining specific ingredients in an ordered process. Drugs generally have well-defined chemical structures, and the finished product can be analysed to identify all its components.

A biologic is engineered in a living system, such as a microorganism, plant or animal cell, often using recombinant DNA technology. Most biologics are very large, complex molecules or mixtures of molecules. Laboratory methods can make it difficult, if not impossible, to fully characterize them, and some components of a finished biologic may be unknown.

Generics vs biosimilars

A generic is manufactured to be the same as an existing brand-name drug in dosage form, safety, efficacy, route of administration, quality, performance and indications. It is bioequivalent: it works the same way and gives the same clinical benefit. It shares the active ingredient but may differ in inactive characteristics, such as colour or flavour. Because the brand molecule has a well-defined chemical structure, it can be copied exactly.

Biologics are much larger, with primary, secondary, tertiary and possibly quaternary structures. A biosimilar is therefore designed to be highly similar to its reference biologic. It must have the same amino acid sequence and show similar physical, chemical and biological properties, efficacy and safety. Minor differences in clinically inactive components are allowed, but there must be no clinically meaningful differences in safety, purity or potency.

Some describe biosimilars as the “generic version” of biologics. Others avoid the term, because biosimilars are not exact copies of their reference products.

Patents and market entry

A company that develops a new medicine sells it under a brand name, protected by a patent so that only the patent owner can manufacture and market it. Patents let inventors recover the money and time spent creating a new product.

When a patent lapses, regulators such as the FDA approve generics on confirmation of pharmaceutical equivalence and bioequivalence. Because small molecules share the same chemical structure, comparing blood levels of the brand and the generic shows they have the same activity. Competition then lowers prices. The same principle applies to biosimilars, but the economics differ:

Common types of biologics

• Hormones (growth hormone, parathyroid hormone, insulin): substances produced by one tissue and carried in the blood to act on another.
• Interferons: proteins produced by cells in response to viral infection and other stimuli.
• Interleukins: cytokines that direct immune cells to divide and differentiate.
• Growth factors: substances that promote cell growth, such as G-CSF (filgrastim) and erythropoietin.
• Monoclonal antibodies: a single species of immunoglobulin, directed against one epitope of an antigen.
• Polypeptides and proteins: peptides usually have fewer than 50 amino acids, while proteins have more.
• Vaccines: antigens that stimulate the immune system to produce specific antibodies.

How reference biologics are approved

Developers first complete laboratory and animal studies, including repeat-dose toxicity, pharmacokinetics (PK), pharmacodynamics (PD) and adverse events. They then submit an investigational new drug (IND) application to the FDA, or a clinical trial application (CTA) in Europe. Clinical development follows three phases:

1. Phase I: metabolism, pharmacology and safety in humans at single or increasing doses.
2. Phase II: proof of concept, dose finding and initial safety.
3. Phase III: large randomized controlled trials confirming efficacy, outcomes and adverse events.

Characterization studies also describe the structural elements responsible for biological activity, the interactions between active ingredient and excipients, and stability under different formulation, manufacturing and storage conditions.

How biosimilars are approved

The reference product’s manufacturing process is confidential, so biosimilar developers reverse-engineer it, often using newer analytical techniques. This produces extensive comparative data. FDA and EMA requirements are broadly similar, and include:

• Structural and functional assays, and animal toxicology, PK, PD and immunogenicity studies.
• Comparative clinical PK studies, typically on maximum serum concentration (C_max) and the area under the concentration-time curve (AUC).
• Usually at least one randomized trial in an approved indication, showing comparability, not just non-inferiority.
• For an FDA interchangeability designation, historically a switching study.

Two notable differences: the EMA requires a post-marketing surveillance plan, and in Europe individual countries decide on interchangeability or switching.

Examples of US-approved biosimilars (as of December 2022)