United States: FDA Finalizes Guidance On Biosimilar Interchangeability, Reiterates Case-By-Case Approach To Data Requirements

Last Updated: May 30 2019
Article by Joanne S. Hawana and Elizabeth K. Conti

On May 10, 2019, the Food and Drug Administration issued highly anticipated final guidance that gives drug-makers more clarity on how to demonstrate that a proposed biosimilar product meets the statutory interchangeability standard under the Public Health Service Act (PHS Act or the Act). According to the Act, an interchangeable biosimilar may be substituted for the original biological product without the involvement of a prescriber, similar to the way generic drugs are routinely substituted for brand name drugs at the pharmacy level. The Final Guidance, entitled "Considerations in Demonstrating Interchangeability with a Reference Product," is shorter than the draft version released over two years ago, in response to industry feedback, but generally tracks the original policy positions proposed in the draft, with a few notable exceptions summarized below.

Introduction to Interchangeable Biosimilars

There is no requirement that a new biosimilar product demonstrate itself as "interchangeable" to the reference biological product – that is, the original biological product that the biosimilar sponsor is seeking to rely upon for its own marketing approval. The law contemplates two categories of licensed follow-on biologics, the biosimilar biologic and the interchangeable biosimilar, and this new Final Guidance document does not alter that framework. And although no interchangeable biosimilars have been licensed by FDA since passage of the Biologics Price Competition and Innovation Act (BPCIA), which amended the PHS Act in 2010 to create the legal pathway for biosimilars, at least 45 States have enacted local laws or regulations in order to authorize licensed health care professionals to substitute FDA-approved interchangeable biosimilars if and when they come to market (see our most recent tally of these State laws here).

So what exactly is an interchangeable biosimilar? In addition to meeting the various criteria for being "biosimilar," or highly similar, to the reference biologic as FDA has explained that concept in other industry guidance, the PHS Act requires that the product meet the following two criteria before it can be licensed as interchangeable:

  1. The biosimilar can be expected to produce the same clinical result as the reference biologic in any given patient; and
  2. For a product that will be administered more than once to patients, the "risk in terms of safety or diminished efficacy of alternating or switching between use of the [biosimilar] and the reference product is not greater than the risk of using the reference product without such alternation or switch."

Biologic drugs remain some of the most expensive products on the market due to the complicated nature of making them from living cells and the fact that such products are used to treat serious chronic conditions, such as cancer, multiple sclerosis, and autoimmune disorders. Congress created these heightened interchangeability criteria in an attempt to enhance competition and incentivize the development of cheaper biological product alternatives that would cut costs for patients, governments, and insurance companies in the long run, while at the same time protecting patient safety and ensuring that medical and scientific issues are taken into account during product development and premarket regulatory review. To date, FDA has approved 19 biosimilar products but, as noted previously, none of those have also been approved as interchangeable with the reference biologic. FDA's demanding criteria for this interchangeability designation and the lack of clarity regarding how to achieve or demonstrate that the criteria have been met are cited as contributing factors to the minimal progress in this space over the past several years.

Final Interchangeability Policies Are More Flexible than FDA's First Proposals

The long awaited Final Guidance provides recommendations for the biosimilar industry and introduces more flexibility with respect to the design of the studies required to demonstrate that the interchangeability criteria have been made. In a same-day statement, Acting FDA Commissioner Ned Sharpless summarized the new document this way: "Today's final guidance gives an overview of important scientific considerations in demonstrating interchangeability with a reference product and explains the scientific recommendations for an application or a supplement for a proposed interchangeable product."

More specifically, the final FDA interchangeability guidance goes into the following important scientific topics on which biosimilar sponsors have been seeking greater clarity:

  • What data and information are needed to support a demonstration of interchangeability;
  • Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability;
  • Considerations regarding the comparator product in a switching study or studies; and
  • Considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products (this last topic is covered in abbreviated form, due to the fact that these will be assessed on a case-by-case basis depending on the product).

In comparison to its proposed policies on interchangeability released in January 2017, FDA has not changed its original recommendation that a biosimilar sponsor submit data and information to show that the proposed interchangeable product "can be expected to produce the same clinical result as the reference biologic" (criterion #1, see above) for all of the reference product's licensed conditions of use. Some commenters on the draft guidance had requested this be revised to take into account the fact the a biosimilar – just as a generic drug – can be approved by FDA for fewer indications that the reference product might be approved for, due to patent or exclusivity protections on a subset of indications.

However, one of the most significant changes in FDA's final recommendations is a welcome one for the still-budding U.S. biosimilar industry. The Agency has moved away from language indicating that only FDA-licensed reference biologics could be used to conduct the "switching studies" that will be necessary in most cases to meet the standard set forth in interchangeability criterion #2 (see above). The switching studies should be done in one or more conditions of use, not necessarily all indications for which the reference product is licensed, and the Agency recommends using a condition "that would be adequately sensitive to assess the risk of alternating or switching" and that would support a scientific justification for extrapolating the data to other conditions of use. Further, the biosimilar sponsor will still need to establish a scientific bridge between a non-U.S.-licensed comparator product and the FDA-licensed version in order to justify to the Agency why the switching study is scientifically appropriate and valid:

If a sponsor seeks to use data derived from a switching study or studies comparing a proposed interchangeable product with a non-U.S.-licensed comparator product as part of the demonstration that the proposed interchangeable product meets the standard described in ... the PHS Act, the sponsor should provide adequate data and information to establish a 'bridge' between the non-U.S. licensed comparator and the U.S.-licensed reference product and thereby justify the relevance of the data obtained using the non-U.S. licensed comparator to an evaluation of whether the requirements of [the Act] have been met.

While the design parameters for these switching studies are flexible and FDA encourages sponsors to consult with its Biosimilars Staff about specific design considerations like primary endpoints and statistical analysis, the Agency is still approaching this interchangeability criterion from the position that switching studies will always be required to make the necessary scientific showing under criterion #2. Therefore, any biosimilar sponsor that does not believe a switching study is needed is likely going to bear a heavy burden of convincing FDA to forego such data when the biosimilar product is intended to be administered to patients more than once. On this point, the Final Guidance states that: "If a sponsor of a proposed interchangeable product believes that data from a switching study is not necessary, FDA expects the sponsor to provide a justification for not needing such data as a part of the demonstration of interchangeability." It goes on to note, however, the design of the switching studies can be informed by sponsor's expectations for how the proposed interchangeable biosimilar may be used in clinical practice.

Finally, Dr. Sharpless indicated in his statement accompanying the final guidance that interchangeability designations aim to increase patient and physician confidence in the safety and effectiveness of biosimilars, which is one goal of the Biosimilars Action Plan released in mid-2018. Similarly, the emergence of interchangeable biosimilars on the U.S. market may help to clarify any confusion or disconnects between the payer and health care provider communities when it comes to the appropriate use and coverage of these products.

Interchangeability in the Statute Doesn't Include Exceptions – But Will FDA Create One for Insulin Products?

Next up on FDA's agenda is to focus on the approval of insulin products as biosimilars, following the March 2020 transition of these and certain other drug products from the "drug approval pathway" into the "biologics approval pathway," as mandated by Congress in the BPCIA. Indeed, whether or not the May 10th release of the Interchangeability Guidance was intentionally timed to coincide with this event, the Agency convened a public meeting on May 14, 2019 to hear from stakeholders on the development of biosimilar and interchangeable insulin products.

One of the views expressed during the meeting by multiple presenters was that FDA should not require switching studies before approving an insulin as interchangeable under the BPCIA, given the history of clinical experience with these products and the lack of immunogenicity concerns with this small, simple protein product. (As one public presenter put it: "Insulin is not Humira" – a reference to the fact that monoclonal antibody products are much larger and considerably more complex to characterize than these proteins are). Although the insulin market pressures are unique, and a discussion of the complexities triggered by the March 2020 drug-to-biologic transition is beyond the scope of this blog post, we note this confluence of issues because it will be fascinating to see how the Agency responds to these arguments and what policies it announces for insulin products in particular.

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