Because biosimilars are produced from living organisms, biological products generally have more variability than traditional chemical drugs. In fact, biologic medicines of all kinds have some variability between lots, even when manufactured by a single company.
Therefore, the goal in creating a biosimilar is to make a safe and effective therapy that treats a disease the same way as the original biologic medicine, while also falling within the same variability limits as batches of the originator biologic medicine. To achieve this, the FDA requires biosimilars to meet a rigorous scientific standard of similarity and be deemed “highly similar” before they are made available to patients.
Biosimilar manufacturers use a reverse engineering process to produce a biosimilar; in that, they do not always have access to the original cell line used to produce the originator biologic medicine, but must fall within the originator’s batch variability limits for regulatory approval.
Biosimilar manufacturers conduct batch analyses of multiple batches of the originator biologic medicine, perform analytical and functional characterizations, and upstream and downstream manufacturing processes developed based on previously defined quality attributes. Similarity is achieved and verified through a scientific process that confirms there is no clinically meaningful difference between the biosimilar and the original product, even if there are slight differences in clinically inactive components. The same approach is used when manufacturing process changes are instituted by the originator biologic company.
According to the FDA, that means patients and healthcare professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.
Unlike with new medicines, the goal of the scientific testing for a biosimilar therapy is to confirm that the medicine is highly similar to the original, not to re-establish safety and efficacy for the biologic medicine. Those determinations have already been made with the original medicine. Similarity testing occurs multiple times across multiple batches of the originator medicine throughout the product development process.
These tests cover scientific quality, nonclinical and clinical parameters. This analysis can also include a wide variety of other techniques beyond costly clinical trials. Newly developed analytical tools allow biosimilar developers to characterize molecules with greater precision than ever before, which will help to expedite these approvals down the road.
The Biosimilar Development Process
Because the development of a biosimilar is based on what is known and proven through the originator biologic medicine clinical trials with the reference product rather than reproving the same point, the steps for creating a biosimilar focus on establishing that a biosimilar is structurally and functionally highly similar to the reference product. The concept is simple: molecules that have essentially similar structure will generally produce the same reaction in the body.
The biosimilar development process occurs in three major stages:
characterization of the target reference product and perfecting the manufacturing process,
confirmation of biosimilarity (and, where sought, interchangeability), and
Step 1: characterization of the target reference product and perfecting the manufacturing process
The first step in development is a thorough understanding of the reference biologic, accomplished through an examination, known as characterization, of structure and function.
Once this information is obtained, the next phase is the development of the manufacturing process, which delivers the highly similar therapy. The fundamental principle for demonstrating biosimilarity is that the biologic active substance a biosimilar contains is established as indistinguishable from that contained within the originator biologic medicine. State-of-the-art biological development technologies and highly sensitive analytical tools are used to systematically engineer a biosimilar molecule to match the medicine’s quality attributes that were identified in the characterization stage. This is an iterative process where each part of the manufacturing procedure is optimized in repeating steps. This continues until the manufacturing process consistently produces a highly similar molecular structure to the original medicine. In many cases, this part of the process—creating a highly similar molecule —takes significantly longer than developing a manufacturing process for a novel biologic.
There are two regulatory designations in the U.S.: a biosimilar medicine and an interchangeable biologic. For scientists seeking regulatory designation of their medicine as an interchangeable biologic, additional testing must be performed to demonstrate that a medicine meets the supplementary requirements to earn that classification. The FDA requires that a product with a designation as interchangeable can be expected to produce the same clinical result as the originator biologic product in any given patient, and for a biologic that is administered more than once, that the risk of switching is not greater than the risk of maintaining the patient on the originator biologic.
Step 2: confirmation of biosimilarity (and, where sought, interchangeability),
Once high similarity has been established between the biosimilar and the original biologic medicine through analysis and testing the FDA reviews all the information and determines the additional non-clinical and clinical studies, if any, that will be required to confirm biosimilarity and interchangeability. These analytical and clinical analyses allow FDA to extrapolate multiple indications for the biosimilar without requiring the extensive clinical efficacy trials required for brand biologic approval.
Clinical trials are generally required for biosimilar approval in highly regulated markets, such as the E.U., United States, Japan, Canada and Australia. However, the scope and requirements for biosimilar clinical trials depends on the data submitted. Biosimilar products in the same class may provide clinical trials of different designs and conceivably, clinical trials may not be required at all. Where there is robust and convincing analytical data, for example, and additional data is required, a more tailored clinical trial program may provide a more effective way to demonstrate biosimilarity and interchangeability.
Step 3: Approval
In the early stages of development, biosimilar manufacturers meet with the FDA to discuss a product development plan and approaches to providing adequate scientific justifications throughout the review process. Before approving any product for patient use, the FDA looks at the totality of evidence and conducts a rigorous review of all the data to determine whether the applicable scientific standards have been successfully met. Once a biosimilar is approved, it can be produced and distributed in the United States.