United States: FDA Issues Final Guidance On "Considerations In Demonstrating Interchangeability With A Reference Product"


On May 10, 2019, the Food and Drug Administration (FDA) issued final guidance on “Considerations in Demonstrating Interchangeability With a Reference Product,” which describes the agency's current thinking related to demonstrating interchangeability of biosimilar therapeutic protein products under the Public Health Service Act (PHS Act).1 In his announcement on the final guidance, Acting Commissioner Ned Sharpless described it as “a significant action that will help promote competition in the biologic market” and indicated that such competition would increase access to lower cost biosimilar and interchangeable products. The guidance is the final version of the draft guidance document issued on January 17, 2017, as previously reported by Ropes & Gray. 

Although the recommendations in the final guidance for demonstrating interchangeability are largely in line with those provided in the draft guidance, the final guidance contains a few notable changes as described below. Overall, the guidance includes recommendations to provide clarity to developers of proposed interchangeable products and explains that development plans and data requirements will ultimately be decided on a case-by-case basis. Sponsors are encouraged to meet with FDA early on in the development program to discuss what information will be required in an interchangeability submission.

General Principles

An interchangeable biological product is one that may be substituted by a pharmacist for a reference product without the intervention of the prescribing health care provider.2 Under the PHS Act, an application for an interchangeable product must demonstrate that: (i) the product candidate is biosimilar to the reference product, (ii) the product candidate can be expected to produce the same clinical results as the reference product in any given patient, and (iii) for a biological product that is administered more than once to an individual, the risk in terms of safety and diminished efficacy of alternating or switching between the product candidate and the reference product is not greater than the risk of using the reference product without alternation or switching.

In the guidance, FDA explains that it will consider the totality of evidence when assessing a sponsor’s application for interchangeability. Although the biosimilar pathway is generally applicable to all products that meet the definition of a “biological product” under the PHS Act,3 the guidance is confined in scope to therapeutic protein products.

Data Necessary to Support an Interchangeability Determination

In general, FDA believes that the following factors will be relevant in assessing interchangeability:

  • Identification and analysis of the critical quality attributes;
  • Identification of analytical differences between the reference product and the proposed product, as well as the potential clinical impact of the differences;
  • Analysis of the mechanism(s) of action in each condition of use for which the reference product is licensed;
  • Analysis of any differences in the expected pharmacokinetics and biodistribution of the product in different patient populations for which the reference product is licensed;
  • Analysis of any differences in the expected immunogenicity risk of the product in different patient populations for which the reference product is licensed;
  • Analysis of any differences in the expected differences in expected toxicities in each condition of use and patient population for which the reference product is licensed; and
  • Information on any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed.

These factors are largely unchanged from those described in the draft guidance. To the extent that data required to support an interchangeability determination has been previously submitted by the applicant to support a demonstration of biosimilarity, the applicant should consult with FDA about how to reference or re-submit these data when seeking licensure for the proposed interchangeable product. For any differences that exist between the reference product and the proposed interchangeable product, FDA recommends that the sponsor provide data and information justifying why those variances still allow for the two products to generate the same clinical result in any given patient. A sponsor may seek licensure for a proposed product with fewer conditions of use than the reference product, but FDA recommends that, when possible, the proposed interchangeable product align with the reference product’s license for conditions of use. 

In addition to the data and information necessary to demonstrate biosimilarity, as described in FDA guidance on biosimilarity, a determination of interchangeability depends on, among other factors, the proposed product’s:

  • Complexity and the extent of comparative and functional characterization. As part of the biosimilarity analysis, FDA must determine that the proposed product is “highly similar to the reference product notwithstanding minor differences in clinically inactive components.”4 FDA acknowledges that there is a range of comparative analytical data that may be submitted to support licensure as a biosimilar or interchangeable product, and that the product’s degree of structural and functional complexity may influence the extent of clinical data needed to support a demonstration of interchangeability. 
  • Immunogenicity risk. The clinical experience with the reference product, as well as complete risk assessments of the proposed and referenced product, may inform the type and amount of data appropriate for an interchangeability determination. For example, if a product has an extensive clinical history demonstrating that immunogenicity does not affect clinical outcomes, less data may be needed to support a demonstration of interchangeability, as compared to a product with a documented history of inducing adverse immune responses.

FDA believes that postmarket data collected from products licensed as biosimilars, without corresponding data from prospective and adequately designed studies, generally would not be sufficient to support a demonstration of interchangeability. However, FDA may consider postmarket data on a licensed biosimilar product to determine what additional data are necessary to support an interchangeability determination.

Further, if the proposed product is determined to be interchangeable with respect to a particular condition of use of the reference product, the sponsor would need to provide sufficient scientific justification for extrapolating data sufficient to support an interchangeability for each additional condition of use covered by the application.

Switching Studies

FDA generally recommends that sponsors conduct “switching studies” to assess risks associated with switching from the reference product to the proposed interchangeable product. The design of a switching study may be informed by how the proposed product will be used in clinical practice and should consider, among other things, when alternating or switching might cause the most clinical concern. The final guidance outlines a flexible approach with respect to the design of a switching study that FDA determines is necessary to support interchangeability. Additionally, the guidance now more clearly states that a switching study may not be necessary, even for a biological product that is administered more than once to an individual, if the sponsor provides a justification for not needing such data.

The key design issues addressed in the final guidance are:

  • Study endpoints. FDA recommends that the primary endpoint of a switching study assess the effects of switching on clinical pharmacokinetics (PK) and pharmacodynamics (PD) between the switching arm and non-switching arm following the final switch. These metrics, as distinguished from clinical efficacy endpoints, are more likely to be sensitive to changes in immunogenicity and/or exposure resulting from switching. Where PK and/or PD are not adequately sensitive endpoints, FDA expects sponsors to propose and justify other selected endpoints.
  • Study design. FDA recommends a switching study with a lead-in period of treatment with the reference product, followed by a randomized two-arm period (one arm incorporating switching and the other arm receiving only the reference product). The final guidance provides a new illustrative example of a switching study design, and makes recommendations on calculating sample size, determining the number and duration of switches, and other aspects of the study design. The final guidance also includes detailed recommendations on proposed integrated study designs that can be used to support both a biosimilarity and interchangeability determination. FDA explains that an integrated study has to be adequately powered to (i) evaluate the appropriate endpoint(s) to support a biosimilarity demonstration of no clinically meaningful differences for biosimilarity and (ii) evaluate PK and PD following the last switch to support a demonstration of interchangeability.
  • Study population. FDA recommends that the study population for switching studies be adequately sensitive for detection of differences that are a result of switching between the reference product and the proposed product. FDA notes, however, that healthy subjects or a patient population that is different from that used to support licensure of the reference product may be used so long as adequate scientific justification is provided. 

Use of a Non-U.S.-licensed Comparator in Switching Studies

The final guidance contemplates use of a non-U.S.-licensed comparator in switching studies, at least in some circumstances, so long as the sponsor establishes an adequate bridge between the non-U.S.-licensed comparator and the U.S. reference product. In the draft version, FDA had said that using a non-U.S.-licensed comparator “generally would not be appropriate in a switching study” and recommended that sponsors of proposed products rely on a U.S.-licensed reference product in a switching study. 

The guidance describes considerations for the type and extent of data needed to establish an adequate bridge to justify use of a non-U.S.-licensed comparator. FDA explains that, because in a switching study the comparator product is used in both the switching arm and the control non-switching arm, the bridging data needed to justify use of a non-U.S.-licensed comparator in a switching study may be different or more extensive than is needed in other contexts in which a non-U.S.-licensed comparator is used. For example, subtle differences in levels of specific structural features may not preclude use of a non-U.S.-licensed comparator in studies to support a demonstration of biosimilarity, where the comparator is being used as a control. In contrast, in a switching study, multiple exposures to the reference product and the proposed interchangeable product may potentially prime the immune system to recognize the subtle differences in structural features and the overall immune response could be increased. FDA encourages sponsors to discuss with the agency the design of a switching study early in the product development process. 

Presentations for Interchangeable Products

The draft guidance set forth a detailed framework on the types of data and information that sponsors should submit related to the proposed presentation (i.e., container closure system or delivery device). The final guidance omits the previous framework in favor of high-level recommendations, and FDA has indicated that it intends to provide more detailed recommendations in a separate guidance.5 FDA makes clear in the final guidance, however, that a sponsor not seek licensure for a presentation for which the reference product is not licensed, and that the presentation should be shown to be compatible for use with the final formulation of the proposed product through sufficient testing. FDA encourages sponsors to contact the agency early during product development to discuss the proposed presentation and specific considerations related to the licensure of the proposed product as an interchangeable product.

Next Steps

Although no interchangeable products have been approved to date, 19 biosimilars have been licensed since the creation of the abbreviated licensure pathways for biologics, with a majority of those being licensed within the past two years. The agency has signaled in its public announcements a priority of enhancing competition in this space by facilitating patient access to biosimilar and interchangeable products. This guidance provides recommendations that manufacturers of reference biological products as well as companies seeking to demonstrate interchangeability should understand as they consider the regulatory and commercial hurdles associated with pursuing this route to market. In particular, stakeholders should note the agency’s shift in position on use of a non-U.S.-licensed comparator in switching studies to support a demonstration of interchangeability, which may contribute to an earlier entrance to the market of interchangeable products than had been anticipated before issuance of this final guidance. For example, if a product is first approved as interchangeable in an ex-U.S. jurisdiction, the manufacturer may be able to obtain approval of that product as an interchangeable in the U.S. without conducting a new switching study, so long as the manufacturer provides bridging data to demonstrate that use of the ex-U.S. switching study was appropriate


1. 42 U.S.C. § 262(k).

2. Id. at 262(i)(3).

3. Id. at 262(i)(1).

4. Id. at 262(i)(2)(A).

5. 84 Fed. Reg. 21342, 21344 (May 14, 2019).

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Similar Articles
Relevancy Powered by MondaqAI
Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
In association with
Related Topics
Similar Articles
Relevancy Powered by MondaqAI
Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
Related Articles
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Mondaq Free Registration
Gain access to Mondaq global archive of over 375,000 articles covering 200 countries with a personalised News Alert and automatic login on this device.
Mondaq News Alert (some suggested topics and region)
Select Topics
Registration (please scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.


The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.


Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions