+ What Is a Biosimilar?

A biosimilar medicine is a biologic that is approved based on a demonstration that it is highly similar to an FDA-approved biological medicine, known as a reference product. A biosimilar must be determined by the FDA to:

1. be highly similar to the reference product notwithstanding minor differences in clinically inactive components and,
2. have no clinically meaningful differences compared to the reference product in terms of safety, purity, and potency.

Patients and their health care providers can expect that biosimilars approved by the FDA will be just as safe and as effective as their corresponding reference product.

Biosimilars are neither required nor expected to be “identical” to the reference biologic, which itself has some degree of variability because they are produced in living cells. Nonetheless, it is important to know that biosimilars are highly similar to the reference product, and any differences that may exist are expected to not impact safety or effectiveness.

The nature and extent of activities of biological medicines in the body are important. A detailed understanding of how the medicine works (the “mechanism of action”) can help us understand how the structure of the biologic impacts its function in the body, and how changes in the structure of the biologic may affect how it works. A biosimilar and its reference product should have the same mechanism(s) of action for each of the approved indications of use, (e.g. rheumatoid arthritis, Crohn’s disease etc.), to the extent these are known. When the mechanism of action is well understood, a biosimilar can be developed to match its reference product to confirm that it will work in the same way in patients.

Biosimilars must meet the same product and manufacturing quality standards as any FDA-licensed biologic medicine. There are no differences in standards for originator biologics and biosimilars.

Biosimilars must meet the same product and manufacturing quality standards as any FDA-licensed biologic medicine.

The manufacture of biologics is complex and must be precisely controlled to obtain consistent results. Companies that manufacture biologics need to have state-of-the-art tools and techniques to manage sensitivity of product attributes to manufacturing processes like cell culture, protein purification, product fill, and packaging. Because they are made in living organisms, all biologics, (both reference products and their biosimilars) have intrinsic batch-to-batch variability; therefore, critical quality attributes are carefully monitored to ensure they fall within predefined margins.

When changes are made in the manufacturing process of a biologic, the manufacturer must ensure that these changes do not impact the quality, safety and efficacy of the biologic. Further, all such proposed changes are carefully examined by health authorities, including the FDA. Both batch-to-batch variability and manufacturing changes are closely evaluated, regulated, and monitored by the manufacturer and the FDA.

The first U.S. biosimilar was approved in September 2015, and several others have since been approved. There are currently multiple biosimilars under review at the FDA.

Biosimilars have been available and used safely in Europe since 2006. In addition, biosimilars have been approved in other well-regulated regions or countries, including Australia, Canada, Japan, and Korea, thus expanding treatment options and access for health care professionals and patients in those regions.

+ Totality of Evidence

A biosimilar is approved by the FDA based on head-to-head comparisons of the biosimilar and reference product. These comparisons include extensive analytical and functional characterization, as well as animal and human clinical comparisons, that when considered together demonstrate high similarity between the reference product and proposed biosimilar—a concept known as “totality of evidence.” The data must support a conclusion that the biosimilar is highly similar to the reference product, notwithstanding minor differences that may exist in clinically inactive components, and establishing that there are no clinically meaningful differences in safety and efficacy between the biosimilar and the reference product.

In biosimilar development, the foundation of knowledge about the biosimilar begins with the collection and analysis of available public information and experience with the reference product. This includes published scientific studies on the mechanism(s) of action, the structural and functional aspects of the reference product, as well as peer- reviewed clinical trial and post-approval observational data (also known as “real-world evidence”). Published clinical trial and post-approval observational data for the reference product can be important to the design of comparative clinical studies where appropriate. In addition, a biosimilar sponsor will purchase various lots of the reference product over time in order to study the properties of the active ingredient (drug substance) and the formulation. This publicly available information and hands-on testing of purchased material helps biosimilar sponsors understand the relationship between the structure of the molecule and how it functions, which together with an understanding of the mechanism of action enables the design and development of the biosimilar.

Robust analytical and pharmacological data comparing a biosimilar candidate to the reference product is a critical component in establishing the totality of evidence necessary for regulatory approval of a biosimilar. Modern analytical testing and pharmacologic assays are extremely sensitive and are generally more capable of detecting a structural or functional difference between a biosimilar and reference product, should one exist, than are human clinical studies. This is important because highly similar pre-clinical data suggests a lower risk of observing clinical differences between a biosimilar candidate and the reference product.

As part of this totality of evidence approach, a comprehensive analytical comparison of the biosimilar and the reference product has the potential to identify a selective and targeted approach for further clinical development.

Biosimilars are approved using data obtained in a stepwise fashion. The data are evaluated at each step of development to influence subsequent steps, and are used to provide extensive, head-to-head comparisons of the biosimilar and reference product at many levels, which may include:

1. Structural and functional comparisons, which are the foundation of biosimilarity. High similarity must be established at this step before further development can proceed.
2. Testing of toxicity in animals.
3. Human pharmacokinetic comparisons (what happens to a drug in the body).
4. Human pharmacodynamic comparisons (what happens to the body in the presence of a drug). These studies are useful when it is known that pharmacodynamic marker(s) exists that is/are correlated with a meaningful clinical parameter.
5. Comparison of the immunogenicity of the biosimilar and reference product.
6. Human clinical studies (when necessary) to confirm that there are no clinically meaningful differences in safety and efficacy.

Health care providers and their patients can be assured that biosimilars work just as safely and effectively as their reference products.

Studies conducted in humans to support biosimilar approval should directly compare the biosimilar to the reference product in a representative population that is sensitive to detect any potential difference between the products. Generally, the appropriate clinical trial population should be uniform, should be able to clearly detect a treatment response, and when possible, avoid other medications given at the same time that could complicate analysis. of the results. These studies are intended to confirm that the biosimilar works the same in humans as the reference product and to assess immunogenicity, or the comparative human immune response to the biosimilar and reference product. Comparative immunogenicity testing of a biosimilar and reference product should be conducted in healthy volunteers or patients who have functional immune systems to ensure that a difference can be detected should one exist. It is not necessary to study the biosimilar in all patient populations for which the reference product is approved.

It is not necessary to study the biosimilar in all patient populations for which the reference product is approved.

These clinical studies are not designed to independently establish the benefit and risk profiles of either the biosimilar or reference product. Instead, they are intended to reduce any residual uncertainty that may exist from the prior comparative analytical and animal studies in determining that the biosimilar is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and to validate that there are no clinically meaningful differences in safety and efficacy between the biosimilar and the reference product.

When the comparative analytical, animal, human clinical, and immunogenicity data obtained with the biosimilar are added to the knowledge from publicly available information and experience with the reference product, health care providers and their patients can be assured that a biosimilar will work is proven to work just as safely and effectively as its reference product.

+ Stepwise Approach

Biosimilars are approved using data obtained in a stepwise fashion. The data are evaluated at each step of development to influence subsequent steps, and are used to provide extensive, head-to-head comparisons of the biosimilar and reference product at many levels, which may include:

1. Structural and functional comparisons, which are the foundation of biosimilarity. High similarity must be established at this step before further development can proceed.
2. Testing of toxicity in animals.
3. Human pharmacokinetic comparisons (what happens to a drug in the body).
4. Human pharmacodynamic comparisons (what happens to the body in the presence of a drug). These studies are useful when it is known that pharmacodynamic marker(s) exists that is/are correlated with a meaningful clinical parameter.
5. Comparison of the immunogenicity of the biosimilar and reference product.
6. Human clinical studies (when necessary) to confirm that there are no clinically meaningful differences in safety and efficacy.

These data, taken together, form the “totality of evidence” that the FDA examines when considering approval of a biosimilar.

The biosimilar regulatory pathway specifies that a biosimilar can be approved for use in one or more indications of use on the basis of the biosimilar being highly similar to the reference product, notwithstanding minor differences potentially present in clinically inactive components, and that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency.

The stepwise approach begins with comparative analytical testing that is conducted to demonstrate physical, chemical, and functional similarity to the reference biologic. This includes a detailed physicochemical study of the structure of the molecule, functional activities that include binding kinetics, and immunochemical properties; an assessment of impurities that may be present; testing of the finished drug product; and stability of both the biosimilar molecule and the finished medicine product.

The analytical testing is followed by studies in animals to evaluate comparative toxicology of the biosimilar and reference product. Importantly, these non-clinical studies will not only compare the biosimilar and reference product function and activity, but can also evaluate the impact of any analytical differences that may have been observed in the prior step.

The next step is to conduct comparative pharmacokinetic (PK) and pharmacodynamic (PD) or “PK/PD” studies in humans. These studies are often conducted in healthy individuals. A PK study measures what happens to the medicine when it is in the body, including the absorption, concentration, and clearance of the medicine from the body. A PD study evaluates what happens in the body in response to the medicine by testing the effect of a medicine on a physiological function through use of a “marker,” or measurable attribute of activity or function. Comparative PK/PD studies can be conducted in healthy volunteers or patients, and are another level of evidence that helps provide evidence that the biosimilar and reference products are highly similar and that there are no clinically relevant differences in safety and efficacy between the biosimilar as compared to the reference product. Just as in prior steps, comparative PK/PD studies can also be designed so that they help inform the relevance or irrelevance of any differences observed either in structure or function as measured by the prior analytical and animal studies.

The PK/PD studies may then be followed by confirmatory clinical studies that are conducted in patients with the disease being treated. These studies directly compare the biosimilar to the reference product in a patient population that is sensitive to detect any potential difference between the products.

In general, the appropriate clinical trial population should be uniform, should be able to clearly detect a treatment response, and when possible, avoid other medications given at the same time that could complicate analysis. These studies are intended to confirm that the biosimilar works the same in humans as the reference product and to assess immunogenicity, or the comparative human immune response to the biosimilar and reference product.

Comparative immunogenicity testing of a biosimilar and reference product should be conducted in healthy volunteers or patients who have functional immune systems to ensure that a difference can be detected should one exist.

These clinical studies are not designed to re-establish the benefit and risk profiles of either the biosimilar or reference product because that information is already available from studies conducted with the reference product. Instead these studies are conducted to reduce any residual uncertainty in determining that the biosimilar is highly similar to the reference product notwithstanding minor differences that may exist in clinically inactive components, and that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency.

The FDA has the discretion to determine that animal toxicology or a human clinical safety or efficacy study may be unnecessary. Manufacturers are encouraged to discuss the exact nature of the evidence required to establish the totality of evidence.

+ Critical Quality Attributes

Based on the many years of study of the reference product, along with comprehensive public information, biosimilar manufacturers build an understanding of which structural aspects of the reference product can have an impact on clinical safety and effectiveness. The most important of these structural attributes are known as “Critical Quality Attributes.” Biosimilar manufacturers use this knowledge to develop a hierarchy of importance of the many features of the molecular structure and manufacturing process that can be measured.

Numerous sophisticated analytical tests can enable biosimilar manufacturers to carefully measure and compare the structure and biological function of the reference product and biosimilar and to detect foreign or unwanted material from the manufacturing process. However, not all of the items that can be studied and measured are equally important.

The criticality of the quality attributes can be categorized as very high through very low based on their known impact to clinical outcomes. For those that are very high, the biosimilar must match the observed range of the reference product. Statistical analyses are often conducted on important quality attributes to ensure that the assessment of equivalence is rigorous and impartial.

Comparative quality attributes that are low or very low can be conducted in a descriptive manner without statistical analyses. Differences between the biosimilar and reference product that are not critical are permissible, with the caveat that the differences are clearly known not to be clinically important.

+ Biosimilarity

Biosimilarity is established when the totality of evidence supporting a biosimilar is assembled through analysis of all public information, testing of the reference product, and the “stepwise” comparative development of the biosimilar and reference product.

Once satisfied that the totality of evidence is both substantial and sensitive enough to detect potential differences and to address residual uncertainty that may exist, the FDA could approve the biosimilar. The biosimilar regulatory pathway specifies that a biosimilar is approvable for use in one or more indications on the basis of the biosimilar being highly similar to the reference product, notwithstanding minor differences that may exist in clinically inactive components, and that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency.

+ Extrapolation

Extrapolation is the approval of a biosimilar for one or more conditions of use (known as “indications and usage”) for which its reference biological product is licensed but for which there was no clinical study. This approval is based on rigorous scientific evaluation of the existing data from the reference product, as well as the totality of all data (e.g., comparative analytical, functional, PK, PD, immunogenicity, and if conducted, clinical studies) obtained with the biosimilar in direct comparison to the reference product when it is known to the extent possible that the molecule works in the same way in both the studied and extrapolated indication. Manufacturers must also scientifically justify that there are no differences in mechanism of action, toxicity, or immunogenicity across indications that could preclude extrapolation. It is important to appreciate that extrapolation is based on the knowledge of the reference product and the totality of evidence obtained with the biosimilar molecule, and is not based on the clinical similarity of two or more different indications.

Extrapolation is one of the foundations for the abbreviated approval pathway for biosimilars and therefore is critical for the success of biosimilars and their potential benefit to patients.

The FDA examines requests for extrapolation on a case-by-case basis. Every indication for which extrapolation is sought must be scientifically justified by the manufacturer seeking extrapolation for their product. Approval of an additional indication through scientifically valid extrapolation expedites the development of biosimilars and eliminates unnecessary clinical studies, thereby increasing patient access to important therapies.

Extrapolation is one of the foundations for the abbreviated approval pathway for biosimilars and therefore is critical for the success of biosimilars and their potential benefit to patients.

Scientific justification for extrapolation should address, for example, the following issues for the tested and extrapolated conditions of use:

• The mechanism of action(s) in each condition of use for which licensure is sought
• Pharmacokinetics (what happens to the medicine in the body) and pharmacodymanic (what happens in the body in response to the medicine) measures may also provide important information
• The potential immunogenicity of the biosimilar in different patient populations
• Differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to the pharmacological activity of the product or to activities not related to treatment of the disease or condition)
• Any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which licensure is sought

Differences between conditions of use with respect to the factors described above do not necessarily preclude extrapolation. To obtain extrapolation under those conditions, a scientific justification must convincingly address these differences in the context of the totality of the evidence supporting biosimilarity.

+ Interchangeability

The requirements for being designated as “interchangeable” in the U.S. are separate and additional to being designated as “biosimilar.”

According to U.S. law, an interchangeable biologic is a distinct category of biosimilar for which additional data is provided and is not a different product. To obtain an FDA designation of “interchangeability,” the manufacturer of a biosimilar typically must conduct a clinical study with multiple switches back and forth between the biosimilar and reference product. This clinical study must prove that for a product administered to an individual more than once, the risk in terms of safety or diminished efficacy of switching back and forth between the proposed interchangeable biologic and its reference product is not greater than the risk of using the reference product by itself, without switching. The manufacturer of the interchangeable biologic must establish that the interchangeable biologic can be expected to have the same clinical result in all patients and indications for which the reference product is approved.

When applied to biological drugs, the term “interchangeable” or “interchangeability” in the U.S. means that a biosimilar drug may be substituted by a pharmacist for the reference product without first getting permission from the physician who wrote the prescription. This is different from a decision made by a physician to prescribe one drug in place of another, which is a common medical practice.

There is no legal or regulatory requirement that suggests or requires that a biosimilar meet the statutory definition of interchangeability as a prerequisite for a physician to switch a patient from a reference biologic to a biosimilar. Physicians always have the freedom to prescribe whatever drug they believe is appropriate for their patients.

There are no additional quality requirements to establish interchangeability, as the additional data required is clinical in nature. In fact, the interchangeable biologic product is the same biosimilar product that was initially studied, but for which more information is provided to address the specific regulatory requirements.

The requirements for being designated as ‘interchangeable’ in the U.S. are separate and additional to being designated as ‘biosimilar’.

After a product is approved as either a biosimilar or an interchangeable biologic, the FDA will publish this information in an online database called the Purple Book. The Purple Book is updated when the FDA licenses a biological product under section 351(a) (an original new biological drug) or section 351(k) (a biosimilar or interchangeable biologic) of the Public Health Service Act (PHSA). The Purple Book identifies the date of first licensure for biological product under section 351(a) and also specifies if a 351(k) biologic is a biosimilar or an interchangeable biosimilar. Health care professionals can check the Purple Book to see if a product is a biosimilar or an interchangeable biosimilar in a manner comparable to the way that the Orange Book is used to check if the FDA has found a generic drug to be bioequivalent to its reference product.

While the FDA will designate biosimilar interchangeability, U.S. states regulate the practice of pharmacy, including laws describing how and when a pharmacist can substitute one drug for another. Since state substitution laws were originally written based on generic drugs, the laws in each state are being updated to permit pharmacy-level substitution of an interchangeable biosimilar for a reference product.