Biosimilars FAQs
Here are answers to some of the most common questions people have about biosimilars and how they’ll be used and regulated in the U.S. If you don’t find the information you are seeking, please contact us.
Biological medicines, also known as biological therapies or “biologics,” are medicines that are produced by living organisms, including human, animal, or microorganism cells. Today, they are commonly produced through biotechnology. Biologics are very large, complex molecules or mixtures of molecules and can be proteins, sugars, and nucleic acids, as well as living entities such as cells and tissues.
Biologics are different than most drugs used today because most drugs are made by synthetic chemical processes and are much smaller molecules than biologics.
Biologics work within a patient’s body by supplementing or interrupting natural pathways, processes, and signals in order to treat a specific disease or disorder.
All biological medicines vary to a degree from one batch to the next even when the same manufacturing process is used. This is normal and expected. Strong manufacturing controls are put in place to ensure that all variability stays within pre-specified and pre-approved ranges.
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:
- Structural and functional comparisons, which are the foundation of biosimilarity. High similarity must be established at this step before further development can proceed.
- Testing of toxicity in animals.
- Human pharmacokinetic comparisons (what happens to a drug in the body).
- 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.
- Comparison of the immunogenicity of the biosimilar and reference product.
- 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.
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:
- Structural and functional comparisons, which are the foundation of biosimilarity. High similarity must be established at this step before further development can proceed.
- Testing of toxicity in animals.
- Human pharmacokinetic comparisons (what happens to a drug in the body).
- 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.
- Comparison of the immunogenicity of the biosimilar and reference product.
- 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.
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 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 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.
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.
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:
- be highly similar to the reference product notwithstanding minor differences in clinically inactive components and,
- 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.
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 will have the same safety and effectiveness as the corresponding reference product.
Biosimilars are neither required nor expected to be “identical” to the reference biologic, which itself has some degree of inherent 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 have an impact on safety or effectiveness.
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.
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 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 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.
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.
When applied to biological drugs, the term “interchangeable” or “interchangeability,” means that a biosimilar drug may be substituted by a pharmacist for the reference product without first getting permission from the health care provider who wrote the prescription. This is different from substitution by the health care provider, which is a common medical process whereby that provider can write a prescription for one drug in place of another.
According to U.S. law, an interchangeable biologic is a distinct category of biosimilar and is not a different product. To obtain an FDA designation of “interchangeability,” the sponsor 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 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.
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 molecule is exactly the same as the biosimilar that was initially approved from that sponsor, — the difference being that additional clinical data was provided in order to gain the interchangeability designation from the FDA. This clinical data is used to support the requirement that an interchangeable biologic can be expected to produce the same clinical effect in any given patient for which the reference product is approved and that there is no additional risk as a result of switching repeatedly between the reference product and the interchangeable biosimilar.
While the FDA will designate biologic interchangeability nationally, individual 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 biologic for a reference product. Many states have either passed or are considering legislation, but the enabling legislation is not yet in place in all states. The status of state-by-state substitution laws can be located here.
Some of the most difficult-to-treat diseases, such as cancer, anemia, and autoimmune disorders (e.g., multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease) may be treated or managed with biologics. Some biologic treatments are delivered in a health care setting in the form of an injectable or a solution to be administered intravenously. While biologics make up a small percentage of the total number of drugs on the market, they can be very expensive to the patients who rely on them, and are a significant cost to the U.S. health care system. Since their origins in the 1980s, biologics have grown to be a $179 billion market in 2014 (EvaluatePharma World Preview 2015, Outlook to 2020. 8th Edition – June 2015), and the overall market for biologics is expected to continue growing due to the number of new biologic drugs currently under development. The RAND Corporation has projected that the introduction and growth of biosimilar medicines in the U.S. will reduce direct spending on biologics by $44.2 billion from 2014 to 2024.
The introduction of biosimilars is anticipated to help lower the cost burden of biologics on the U.S. health care system, and may help expand access to biological medicines. Expiring patents for several biological medicines in the coming years will create an opportunity to develop biosimilars to these products.
The availability of biosimilars introduces competition, which provides more treatment options and may help to bring down prices. The availability of affordable biosimilars may improve access, and enable more patients to be treated with these therapies. Data have shown that in some indications for which biologics may be used, the use of biologics earlier in a treatment regimen (e.g. by lessening or eliminating step therapy) may improve individual patient outcomes when compared to patients not treated with biologics until later in the treatment cycle.
The introduction of biosimilars on the market means more treatment options and increased competition. This competition may lead to high-value therapies at reduced prices. Industry experts have suggested the savings obtained with biosimilars could free up health care funding for coverage of new medicines or other societal needs.
Yes. There are no clinically meaningful differences in terms of safety, purity, and potency between an FDA-approved biosimilar and its reference product. A biosimilar must have the same mechanism(s) of action as its reference product to the extent they are known, which means it will work in the same way. The FDA will only approve a biosimilar if:
- Convincing data is provided to demonstrate that it is highly similar to the reference product.
- It utilizes the same mechanism(s) of action for the condition or conditions of use prescribed (to the extent they are known for the reference product).
- Condition(s) of use have been previously approved for the reference product. Route of administration, dosage form, and the strength of the biological product are the same as those of the reference product.
- The facility in which the biosimilar is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
Biosimilars work in the same way as their biological reference product; biosimilars have no clinically meaningful differences in safety and efficacy compared to their reference products.
A biosimilar may be prescribed by a physician for patients newly diagnosed with a disease, or at the discretion of the physician, for patients who may already have been treated with the reference product. A provider must write the specific name of the biosimilar on the prescription or order. A pharmacist must dispense the biologic specified, or must obtain permission in advance from the prescribing physician to dispense a different biologic in place of the product identified on the prescription order.
Once a biosimilar is approved by the FDA as an interchangeable biologic it may be substituted by a pharmacist for the prescribed reference product without first getting permission from of the prescribing physician, subject to the appropriate state laws governing the practice of pharmacy.
No. Biosimilars are not like generic drugs because most generic drugs are chemically synthesized while biosimilars are manufactured using living systems. Generic drugs are identical copies of brand-name drugs, and sponsors must demonstrate that generic drug levels in the body are the same over time as their respective reference drugs. This means they have the same active ingredient and are identical in terms of dose form, safety, strength, administration, quality, performance characteristics, and intended use.
In contrast to generics, biosimilars are derived from living systems and are commonly more complex than generic drugs. Biosimilars are highly similar to their respective reference product, notwithstanding minor differences in clinically inactive components. Manufacturers must demonstrate that there are no clinically meaningful differences between a biosimilar and reference product in terms of safety, purity, and potency.
Biosimilars are approved by the FDA using a new regulatory pathway that focuses heavily on structural analysis, although some clinical studies are often required. The heavy focus on structural and analytical testing is appropriate because analytics are often more sensitive and have a greater capability to detect differences than would be apparent in a clinical study.
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:
- Structural and functional comparisons, which are the foundation of biosimilarity. High similarity must be established at this step before further development can proceed.
- Testing of toxicity in animals.
- Human pharmacokinetic comparisons (what happens to a drug in the body).
- Human pharmacodynamic comparisons (what happens to the body in the presence of a drug), where a relevant pharmacodynamic marker exists.
- Human clinical studies to confirm that there are no clinically meaningful differences in safety and efficacy.
- Comparison of the immunogenicity of the biosimilar and reference product.
These data, taken together, form the “totality of evidence” that the FDA examines when considering approval of a biosimilar, although the FDA has the discretion to decide that certain types data may not be needed for a particular biosimilar.
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 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 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.
A biosimilar may be approved 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 head-to-head clinical comparison. This approval is based on extrapolating the totality of evidence obtained with the biosimilar in direct comparison to the reference product when we know (to the extent possible) that the molecule works in the same way in both the studied and extrapolated indication (known as the “mechanism of action”).
The FDA examines requests for extrapolation on a case-by-case and indication-by- indication basis. Every indication for which extrapolation is sought must be scientifically justified by the company 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.
“Non-medical switching” or “non-medical substitution” are terms that refer to formulary-driven changes between drug options that are thought to be therapeutically equivalent, but that are very different in structure. In contrast, biosimilars and interchangeable biologics are proven to be highly similar in both structure and function to their reference products. Because a transition from a reference product to a biosimilar is between two highly similar products that the FDA has explicitly found to have no clinically meaningful differences, the Forum believes that the concept and terms of “non-medical switching” and “non-medical substitution” do not apply to biosimilar or interchangeable biologic products.
The Biosimilars Forum opposes any legislative efforts that limit biosimilar utilization via a prohibition on non-medical switching from one medicine to another that the FDA has approved as a biosimilar to the original medicine.