Joseph Park, PhD, is the senior manager of regulatory strategy and policy at Samsung Bioepis. Park obtained his PhD from the Korea Advanced Institute of Science and Technology.


Joseph Park, PhD

With numerous adalimumab biosimilars launched in the United States in 2023, the impact of an FDA interchangeability designation has been extensively discussed with much speculation, but its commercial significance is yet to be determined. FDA is the only regulator in the world that has the legal authority to designate a biosimilar as interchangeable with its reference product, and this is stated on the biosimilar label. The FDA authority to designate biologics as “interchangeable” was created by the Biologics Price Competition and Innovation Act of 2009 enacted on March 23, 2010.

According to the definition in that law, an interchangeable biologic is a biosimilar biological product that can be expected to produce the same clinical result as the reference product in any given patient. Additionally, the law requires the sponsor to show that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch” for a biological product that is administered more than once to an individual.

Once a biosimilar product is designated as an interchangeable biologic by the FDA, the biosimilar product may be substituted for the reference product by a pharmacist other than the health care provider who wrote the original prescription (albeit subject to state law).

Image credit: Aliaksandr Marko | stock.adobe.com

The FDA interchangeability designation can only apply to products that the agency has determined to be biosimilar to a standalone originator reference biologic already licensed by the FDA at least 12 years prior. Consequently, an originator biologic can never be designated as interchangeable, and a biosimilar that is designated as an interchangeable biologic remains the same product. Namely, a subsequent interchangeability designation does not change the safety, efficacy, and quality of a biosimilar already licensed by the agency nor any other aspect of that product.

 The FDA determination of interchangeability can be subsequent to the licensure and launch of a biosimilar, or it can occur concurrently with the initial approval as biosimilar.

Although a separate designation is given, the interchangeable product does not denote a higher quality standard than for a biosimilar product. There are no differences in quality between a biosimilar and an interchangeable biologic as no further modifications are made prior to the showing of interchangeability, and the same “highly similar” standards apply to both biosimilar and interchangeable products. The only difference between the biosimilar and interchangeable products is the amount of clinical data that might have been collected and that the designation has been requested by the product’s sponsor. In some cases, no additional studies were necessary, and the FDA accepted well-reasoned scientific justifications alone.

 Further, it is important that all stakeholders be aware that a biosimilar with the interchangeability designation is not a better biosimilar.

Few biologics are self-administrated or not administrated by the physician who prescribed them. The interchangeability designation is a legal distinction that allows a pharmacist, where they are involved, to substitute an interchangeable biologic for its reference product at their discretion (subject to state law). Such substitution will most likely be based upon a cost-saving for a key decision maker, such as payer or patient.

Consequently, the interchangeability designation is only relevant to dispensing and not prescribing.6 Namely, it is only relevant to those self-administered biologic products dispensed at the pharmacies, such as insulin, adalimumab, and etanercept. Prescribing of most biologics remains the authority of the physician, and a physician can prescribe an approved medicine for any indication (and indeed can preclude substitution for any drug or biologic). As such, the FDA interchangeability designation is not relevant to physicians, and physicians should never await the designation for biosimilars that are already available to their patients.

Misunderstanding Surrounding the Interchangeable Designation

However, there is also the common usage of the term 

, which signifies that 2 products can be exchanged with each other with no change in clinical result. This is already true of biosimilars absent the FDA’s formal 

 designation, and indeed FDA has said that all biosimilars are already interchangeable for the purposes of physicians’ prescribing.

 However, the legal and common uses of interchangeability continue to be conflated. The resulting confusion has created the misperception by a few less informed audiences that biosimilars without such an FDA interchangeability designation cannot be switched with the reference product (or indeed with any other biosimilar product to the same reference product). This is incorrect. It is important that all stakeholders realize that the FDA interchangeability designation is a legal one and does not change the clinical benefit for the patient.

Meanwhile, real-world evidence for biosimilars has been accumulating in Europe and other highly regulated markets and is extensive. Multiple biosimilars for many conditions have been proven to behave exactly as would be expected in both single switch and multiple switch studies, as well as during routine care as shown through reliable pharmacovigilance. This real-world evidence can provide stakeholders in the United States with additional confidence in biosimilars given the same clinical results in both naïve and established patients because the biosimilars becoming available in the country are the same products as are already used elsewhere.

European health authorities, as represented by the Heads of Medicines Agencies (HMA), have concluded that European Union (EU)–licensed biosimilars should be viewed as “interchangeable,” in that they can be exchanged for the reference product and provide the same clinical effect, and that transitioning between a reference biologic and its biosimilar will neither induce nor enhance immunogenicity.

 These conclusions are supported by post-approval safety data of biosimilars published in systematic reviews carried out in 2017 and in 2021 on the safety, immunogenicity, and interchangeability of biosimilar monoclonal antibodies and fusion proteins, respectively.

In a more recent review published in 2022, the authors performed a systematic review on multiple transitions between biosimilars to the same reference biologics and found no clinically meaningful reduction in efficacy or increase in adverse events in the biosimilar-to-biosimilar studies performed to date.

All Biosimilars Are Interchangeable as a Scientific and Clinical Matter

As a scientific and clinical matter, all biosimilars are considered “interchangeable” with their reference product. Those regulatory authorities with the most extensive experience with biosimilars, including European Medicines Agency (EMA) and UK Medicines and Healthcare products Regulatory Agency (MHRA), in addition to FDA, have reached the same conclusion.7 They have made their conclusions public as a formal statement along with the HMA to help mitigate the confusion created by the English language, not biosimilars.11,14-15

In the joint EMA-HMA statement, the EMA Biosimilar Medicinal Products Working Party (BMWP) and HMA Working Group of Biosimilars experts clarified that additional systematic switch studies are not required to support interchangeability at the prescriber level when approval for a biosimilar is granted in the EU.

 Following the publication of the joint statement, the EMA-HMA further clarified in their “Q&A on the statement on the scientific rationale supporting interchangeability of biosimilar medicines in the EU” that their statement on the interchangeability of biosimilars also covers situations where multiple switches are taking place within the group of products that share the same reference product, or indeed between the reference product and any of its biosimilars. This is independent of frequency of switches and number of products involved.

Similarly, MHRA has explicitly stated that “a biosimilar product is considered to be interchangeable with their [reference product (RP)], which means a prescriber can choose the biosimilar medicine over the RP (or vice versa) and expect to achieve the same therapeutic effect” and that likewise “a biosimilar product is considered to be interchangeable with another biosimilar to the same RP” in the guidance on the licensing of biosimilar products updated in November 2022.

Although the US interchangeability designation was intended to facilitate the ease of use of biosimilars, it has created a level of confusion that risks having the opposite effect, which could hamper uptake and decrease patient access to life-changing medicines. It is essential that practitioners, regulators, and payers around the world understand that the current US interchangeability designation is a purely legal designation and carries no implication of greater quality.

With growing experience in biosimilars across the highly regulated market, it is becoming evident that all biosimilars are interchangeable as a scientific and clinical matter and that switches between them carry little or no additional risk. Indeed, that risk is hypothetical and unsupported by evidence.

All stakeholders can have the same confidence in any FDA-licensed biologic—both biosimilars and the originator reference, independent of an interchangeability designation or the regulatory pathway by which they are approved. Further, when physicians and their patients show confidence by treating biosimilars and their reference products with the same clinical expectations, a more competitive market for biosimilars can emerge in the United States. This facilitates access and will allow manufacturers to better support greater surety of supply.

1. FDA. Implementation of the Biosimilars Price Competition and Innovation Act of 2009. Accessed Aug 22, 2023. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/implementation-biologics-price-competition-and-innovation-act-2009

2. FDA. Interchangeable biological products. Accessed August 22, 2023. https://www.fda.gov/media/151094/download

3. FDA. Approval letter for Semglee. FDA. Accessed August 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/210605Orig1s000Approv.pdf

4. FDA. Approval letter for Cimerli. FDA. Accessed August 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761165Orig1s000Approv.pdf

5. FDA. Approval package for Rezvoglar. FDA. Accessed August 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761215Orig2s000Approv.pdf

6. Park JP, Jung B, Park HK, et al. Interchangeability biologics is a legal distinction in the USA, not a clinical one. 

. 2022;36(4):431-436. doi:10.1007/s40259-022-00538-6

7. Kirkner RM. FDA’s Gottlieb Aims to End Biosimilars Groundhog Day. 

. January 2019. Accessed August 22, 2023. https://lscpagepro.mydigitalpublication.com/publication/index.php?m=38924&i=562686&p=6&ver=html5

8. Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of biosimilars: a European perspective. 

. 2017;31:83-91. doi:10.1007/s40259-017-0210-0

9. Kurki P, Barry S, Bourges I, Tsantili P, Wolff-Holz E. Safety, immunogenicity and interchangeability of biosimilar monoclonal antibodies and fusion proteins: a regulatory perspective. 

. 2021;81:1881-96. doi:10.1007/s40265-021-01601-2

10. Cohen HP, Blauvelt A, Rifkin RM, et al. Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. 

. 2018;78:463-478. doi:10.1007/s40265-018-0881-y

11. European Medicines Agency/Head of Medicines’ Agency. Statement on the scientific rationale supporting interchangeability of bio similar medicines in the EU. European Medicines Agency/Head of Medicines’ Agency. April 21, 2023. Accessed August 22, 2023. https://www.ema.europa.eu/documents/public-statement/statement-scientific-rationale-supporting-interchangeability-biosimilar-medicines-eu_en.pdf

12. Cohen HP, Hachaichi S, Bodenmueller W, et al. Switching from one biosimilar to another biosimilar of the same reference biologic: a systematic review of studies. 

. 2022;36:625-637. doi:10.1007/s40259-022-00546-6

13. Gros B, Plevris N, Constantine-Cooke N, et al. Multiple inflixim ab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort. 

 2023;11(2):179-188. doi:10.1002/ueg2.12357

14. European Medicines Agency/Head of Medicines’ Agency. Q&A on the statement on the scientific rationale supporting interchange ability of biosimilar medicines in the EU. European Medicines Agency/Head of Medicines’ Agency. 2023. Accessed August 22, 2023. https://www.ema.europa.eu/documents/other/qa-statement-scientific-rationale-supporting-interchangeability-biosimilar-medicines-eu_en.pdf

15. UK Medicines and Healthcare products Regulatory Agency. Guidance on the licensing of biosimilar products. European Medicines Agency/Head of Medicines’ Agency. Accessed August 22, 2023. https://www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products

 is the senior manager, regulatory strategy and policy at Samsung Bioepis.

 is the head of regulatory strategy and policy at Samsung Bioepis.

Articles

The legal and common uses of “interchangeability” continue to be conflated.

Confusion Persists Around the Interchangeability Designation for Biosimilars

In July 2021, Semglee (insulin glargine-yfgn) was approved by the US FDA as the first interchangeable biologic in the United States. In October 2021, Cyltezo (adalimumab-adbm) was approved as the first interchangeable monoclonal antibody. In less than 6 months, the first adalimumab biosimilar is expected to launch in the United States, followed by 6 to 9 more launching in the second half of 2023.

Will the FDA designation of interchangeability matter commercially? No one knows, but it is important to clarify what interchangeability means from a clinical and regulatory perspective. This is especially the case as biosimilars are introduced to a wider pool of health care professionals in diverse specialties who may have less familiarity with what biosimilars are and the benefits they offer to their patients.

Biosimilars and Interchangeable Biologics from Legal Perspective

, or elsewhere when the biologic product is approved by the governing regulatory agency as a “biosimilar,” they are already “interchangeable” with their reference biologic as a clinical matter.

 Many countries, including the United States, have created mechanisms to transition patients to biosimilars to provide greater and earlier access to these medicines.

In the United States, interchangeability is a legal distinction, and the term “interchangeability” is defined under section 351(k) of the Public Health 24 Service Act (PHS Act). The law enables the interchangeable biologic product to “be substituted for the reference product without the involvement of the prescriber.” This concept of interchangeability for biologics corresponds to automatic substitution for generic small molecule drugs.

In Europe, the law is silent on interchangeability because approvals are centralized, whereas how the medicines are purchased, distributed, and prescribed is made separately by each country’s health authority.

Interchangeability for Biologics is a Legal Distinction in the USA, Not a Clinical One

, an FDA designation of interchangeability is only relevant to dispensing decisions and not prescribing ones, and hence not applicable to physician-administered biologics.

 of “interchangeable biologic” to create the generic-like opportunity

 for biologics that are dispensed in retail or specialty pharmacies. The states govern substitution of medicines by other than the prescriber through their practice of pharmacy laws. The interchangeability designation was expected to act like FDA’s designation of therapeutic equivalence for generic small molecule drugs and offer opportunities for greater market competition and wider access to biologics for patients.

The existence of a legal statute and an additional regulatory designation for interchangeability seems to have triggered misunderstanding around interchangeable biologics as representing a "higher" standard. This is not the case—biosimilars and interchangeable biologics are approved under the same biologics license application (BLA) and both are safe, pure and potent just like every other FDA approved biologic. The same 

 that apply to the original biologic also apply to the interchangeable biologic and the biosimilar.

Biosimilars and Interchangeable Biologics from Clinical Perspective

 is based on the well-established regulatory concept of comparability.

 Comparability has been used successfully for several decades to ensure consistency between biological products before and after a manufacturing change. Both biosimilarity and comparability are grounded on the scientific fact that biologically active parts of the molecule, “critical quality attributes,” having consistent composition and conformation will govern the clinical outcome. If critical quality attributes are shown to be comparable then the same clinical results can be expected. This has been shown to be true in practice with both originator and biosimilar products, and hence as a scientific matter, comparability and biosimilarity apply the same principles.

Interchangeable biologics are the very same biosimilars upon which additional studies may have been done, to satisfy the statutory requirements for an interchangeable biologic to demonstrate “the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.”

Decades of experience with manufacturing changes to marketed reference products are useful for assessing the potential clinical implications of “switching” between reference products and biosimilars, especially potential risks associated with immunogenicity. No reasons for concern have been seen, and the observation and surveillance with the marketed products have been extensive and intense, especially since biosimilars became possible.

Since the approval of the first biosimilar in Europe in 2006, multiple biosimilars have become available, and their use is widespread. Biosimilars are now available in more than 100 countries around the world, and the accumulated patient treatment experience with biosimilars is over 

 of treatment through 2020 in Europe alone.

 Because many countries use centralized or regional tender systems, large-scale transitions of treatment have occurred over many years, including switching from the reference product to a biosimilar, vice versa, and multiple switches between biosimilars. Despite diverse cases of transitions occurring frequently, patients’ treatment experience has remained consistent because the active moieties in each product give the same clinical results—that is what the regulators expected upon their approval and that is what has been shown to be the case in practice.

And to further confirm expectations, European Public Assessment Reports (EPARs) and European Medicines Agency post-marketing surveillance reports of approved biosimilars, along with real-world studies conducted by third-party investigators, show that the accumulated experience with biosimilars do not result in unexpected outcomes compared to using the reference product alone.

This is consistent with what has been observed with reference products going through manufacturing changes. Science is a universal language and the same science is applied around the world, irrespective of a given sponsors business model. This can be a further source of great confidence for all biologics.

As biosimilars become more widely used in the market, they become more familiar and so more accepted. We have seen this with oncology biosimilars—trastuzumab, bevacizumab, and rituximab—and they are now having 

 of the market share by volume in the US.

 Understanding biosimilars and experience with them, especially by health care providers and their patients is the key.

Health care providers and their patients must be confident that biosimilars are approved to the same quality standards as every other biologic, and know that the FDA is confident that they will perform clinically in the same manner as their reference product. Otherwise, they would not have been approved. And it is imperative that health care professionals involved in the prescription and dispensing of biologics have adequate and accurate information about the product’s clinical profile as well as logistical and supply chain considerations in order to guide their patients’ choices. As adalimumab biosimilars start to become dispensed in pharmacies, pharmacists can play an important role in providing information and addressing questions about the equivalence of quality, efficacy, and safety of biosimilars and especially regarding interchangeability.

Consequently, it is increasingly urgent that semantic games cease, and in particular the implication that interchangeable biologics are better biosimilars be dismissed. We need to reduce barriers to patient access to these life-changing treatments, and work together to improve medical care for many chronic and acute diseases through affordability and accessibility to all biologics, including originator biologics, biosimilars and interchangeable biologics. That way everyone can benefit.

Gillian Woollett, MA, DPhil, is the the vice president and head of regulatory strategy and policy at Samsung Bioepis. Prior to her work at Samsung Bioepis, she served as Avalere Health's senior vice president for over 10 years.

Joseph Park, PhD, is the senior manager of regulatory strategy and policy at Samsung Bioepis. Park obtained his PhD from the Korea Advanced Institute of Science and Technology.

 Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of biosimilars: a European perspective. 

 FDA’s Gottlieb aims to end Groundhog Day. Managed Care Magazine. January 2019. Accessed June 2022. 

https://lscpagepro.mydigitalpublication.com/publication/index.php?m=38924&i=562686&p=6&ver=html5

https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/hatch-waxman-letters

 US FDA. Biosimilar and interchangeable biologics: more treatment choices. 

https://www.fda.gov/consumers/consumer-updates/biosimilar-and-interchangeable-biologics-more-treatment-choices

 Webster CJ, George KL, Woollett GR. Comparability of biologics: global principles, evidentiary consistency and unrealized reliance. 

. 2021;35:379-87. doi:10.1007/s40259-021-00488-5

 Biosimilar use in Europe. Medicines for Europe. Accessed June 2022. 

https://www.medicinesforeurope.com/wp-content/uploads/2020/12/BIOS5.pdf

 The US Is Entering Round 2 of Biosimilar Activity, Says Cardinal Health’s Oskouei. The Center for Biosimilars. May 2022. Accessed June 2022. 

https://www.centerforbiosimilars.com/view/the-us-is-entering-round-2-of-biosimilar-activity-says-cardinal-health-s-oskouei

As more biosimilars are granted interchangeability status, 2 representatives from Samsung Bioepis stop misinformation in its tracks by clarifying that the designation will primarily impact pharmacy dispensing instead of prescription habits.

Joseph Park, PhD

Confusion Persists Around the Interchangeability Designation for Biosimilars

Contributor: Interchangeability Is a Dispensing Issue, Not a Prescribing One