Biologics are 200 to 1,000 times the size of a small molecule (generic) drug, and far more structurally complex. Additionally, biologics and biosimilars are manufactured in living cells, then extracted and purified, whereas small molecule drugs and generics are manufactured purely via chemical synthesis. These fundamental differences in complexity and large-scale manufacturing are at the core of why biosimilars are not equal to generics.
Biologics and biosimilars are produced in living cells with a multi-step process. Initially, a basic protein structure is “translated” from a DNA sequence and then modifications, including changes and additions, are made to that basic protein structure. These later changes and additions are called post-translational modifications. The impact of post-translational modifications on a product is similar to the impact of a farming environment on growing tomatoes. The look and taste of the same type of tomatoes will vary in different farm environments because of the quality of the soil, use of fertilizers, type of irrigation and weather elements like rain, air, sunlight. Similarly, differences in biological systems (e.g., type of living cell with slightly different cellular environments) used to manufacture biosimilars may cause different types and levels of modifications, which in turn may affect the quality, safety or effectiveness of the product.1 , 2
So, whereas a generic can be identical to a small molecule reference product, biosimilars cannot and are not required to be exactly like the biologic reference product. Given the expected differences, regulatory authorities have outlined robust data requirements to demonstrate similarity. Biosimilar manufacturers will generally need to generate data from lab testing, non-clinical testing and clinical testing to show that the biosimilar they have developed will provide the same therapeutic benefit and risks to patients as the reference product.
Why do the Differences Between Biosimilars and Generics Matter?
Because of the complexity of biosimilars, medical practice with biosimilars will differ from generics in two important ways:
- Pharmacist-led automatic substitution is usually permitted with generic small molecules because they are considered clinically identical to the reference product. However, biosimilars are similar, and not identical, so different regulatory guidelines apply to demonstrate interchangeability, meaning the ability to change back and forth between two different biologic medicines. It is important to have clinical data that proves multiple switches between biosimilars and/or reference product pose no additional risk for patients. A biosimilar designated as “interchangeable” can be changed by a pharmacist without awareness of a physician or patient.
- Some biosimilars may have approval for all, a few, or only one indication of its reference product. Extrapolation to indications not studied for the biosimilar will be evaluated and approved by regulatory authorities on a product-by-product basis.
Biosimilars differ from generics – in complexity, in the manufacturing processes and in the data needed to demonstrate similarity for approval
||4000 to >140,000 Daltons
||Simple and well-defined
||Complex with potential structural variations
||Predictable chemical process to make identical copy
||Specialized biological process to make similar copy
||Easy to fully characterize
||Difficult to characterize due to heterogeneity
||Sensitive to storage and handling conditions
|ADVERSE IMMUNE REACTION
|MANUFACTURING QUALITY TESTS
||Small clinical trials in healthy volunteers
||Large clinical trials in patients
A biosimilar medicine is a biologic medicine that is developed to be similar in terms of quality, safety and efficacy to an already licensed reference biologic medicine. Biosimilars are not the same as generics, which have simpler chemical structures and are considered to be identical to their reference medicines.3 , 4
The chemical structure of the active ingredient is the same for both the generic and the branded drug which can be duplicated via chemical synthesis, in addition to having the same dosage form, route of administration and strength.5