United States: FDA Finalizes Guidance Documents On Biosimilars

Six years after legislation was adopted creating a new pathway for the approval of biological products that are biosimilar to existing FDA-approved biologics, the Food and Drug Administration (FDA) continues to issue guidance to clarify its interpretation of the law.

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure pathway within the Public Health Service Act (PHS Act) for biological products that are biosimilar to or interchangeable with an FDA-licensed biological product. The BPCI Act essentially created a pathway similar to an Abbreviated New Drug Application, which is used to approve generic drugs, that applies to biologics.

In a series of three final guidance documents issued in late April 2015, the FDA seeks to explain its interpretation of assorted issues concerning the BPCI Act. Those issues include scientific considerations of establishing biosimilarity, quality considerations demonstrating biosimilarity of a therapeutic protein product, and other issues concerning biosimilarity, and requirements for submitting a biologic license application (BLA). Draft versions of these guidance documents were issued in February 2012. The FDA has been seeking input on the BPCI Act since shortly after its enactment; in November 2010, the FDA held a public hearing and established a public docket to solicit input on issues related to implementing the BPCI Act.

Interested persons may submit comments regarding these guidance documents either at http://www.regulations.gov or to the Division of Dockets Management.

Scientific Considerations

The guidance document titled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Guidance for Industry intends to assist sponsors in demonstrating biosimilarity between a therapeutic protein product (i.e., the proposed product) and a reference product through the abbreviated licensure pathway created under Section 351(k) of the PHS Act. As an initial matter, the guidance points out that sponsors should be aware of the complexities of protein products and take this into consideration when designing a development program to demonstrate biosimilarity. The guidance then addresses an approach to demonstrating biosimilarity and how the FDA will evaluate that demonstration.

The FDA recommends a stepwise approach to obtain the data and information necessary to support the demonstration of biosimilarity. Using the stepwise approach will allow a sponsor to evaluate uncertainties about the biosimilarity of the proposed product and identify additional steps necessary to address that uncertainty. The FDA lays out a model of the stepwise approach starting with extensive structural and functional characterization which should serve as the foundation for the development program. The guidance also recommends that sponsors consider animal studies, their role in assessing toxicity, and in some cases bolstering support for the biosimilarity demonstration. The guidance also provides information on generic scientific principles for demonstrating biosimilarity, including structural analysis, functional assays, animal data, and clinical studies.

The guidance indicates that when the FDA evaluates the sponsor's demonstration, it will use the totality-of-the-evidence approach when considering the information submitted in the biosimilar application. The FDA will consider the proposed product's characterization, nonclinical evaluation, immunogenicity data, comparative clinical study data, etc. The FDA plans to use a risk-based approach in its evaluation, which will allow for minor structural or formula differences in the proposed product and the reference but still lead to a finding of biosimilarity.

Finally, the guidance addresses post-marketing safety considerations. The guidance indicates that post-marketing safety monitoring should focus on any particular safety or effectiveness issues associated with the reference product or the proposed product. Monitoring should also be designed to differentiate between adverse events associated with the reference product and the proposed product. The FDA may require post-marketing safety studies to evaluate certain safety risks. Because of the complexity and uniqueness of these products, the guidance encourages consultation with the FDA throughout the development process.

Quality Considerations

The guidance document titled Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product deals with the technical aspects of "chemistry, manufacturing, and controls" (CMC) information for a proposed biosimilar application. This guidance intends to provide sponsors with an overview of analytical factors that are relevant to determining whether a proposed product and the reference product are highly similar for the purpose of submitting a marketing application through the abbreviated licensure pathway under section 351(k) of the PHS Act. While the 351(k) pathway applies generally to biological products, this guidance focuses specifically on therapeutic protein products.

This guidance finalizes the draft guidance issued by the FDA in February 2012. In response to comments made on the draft guidance, the final guidance provides further clarification on general principles on topics including the use of comparative analytical data to provide the foundation for a biosimilar development program, the timing of submission of analytical similarity data, the appropriate number of lots needed, and the type of bridging data needed when sponsors use a non-U.S.-licensed comparator product in certain studies.

Additionally, this guidance describes key factors for consideration when assessing whether a proposed product and the reference product are highly similar, including (1) Expression System; (2) Manufacturing Process; (3) Assessment of Physiochemical Properties; (4) Functional Activities; (5) Receptor Binding and Immunochemical Properties; (6) Impurities; (7) Reference Product and Reference Standards; (8) Finished Drug Product; and (9) Stability.


The guidance document titled Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, Guidance for Industry answers questions posed to the FDA about the FDA's interpretation of certain statutory requirements added by the BPCI Act. The questions reflect comments submitted to the public docket, and the FDA used the question and answer format in an effort to promote transparency. The FDA plans to update the guidance document to include additional questions and answers in the future.

The questions and answers cover three broad categories: (1) biosimilarity and interchangeability; (2) provisions related to the requirement to submit a BLA for a biological product; and (3) exclusivity.

The bulk of the guidance addresses issues concerning biosimilarity and interchangeability. It clarifies that a biosimilar's application need not exactly mirror all aspects of the reference product. For example, a biosimilar product can have a formulation and a delivery device or container closure system different from the reference product. The application must demonstrate the product is highly similar to the reference product, and that the differing delivery device or container closure system is compatible for use with the final formulation. The FDA also states that a biosimilar product can obtain a license for fewer than all presentations (e.g., strengths or delivery devices or container closure systems) for which the reference product is licensed. An applicant also need not seek a license for all the conditions of use for which the reference product is licensed.

On the issue of demonstrating that a proposed injectable biosimilar product has the same "strength" as the reference product, the FDA explains that the biosimilar product generally must have the same total content and concentration of drug substance as the reference product. However, "for certain complex biological products, a modified approach may be needed."

The BPCI Act amends the definition of "biological product" to include a "protein (except any chemically synthesized polypeptide)," and the guidance document answers the question of how the FDA interprets this definition. The FDA provides a definition for both "protein" – any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size – and "chemically synthesized polypeptide" – any alpha amino acid polymer that is made entirely by chemical synthesis and is less than 100 amino acids in size.

Finally, the guidance addresses issues of exclusivity. The BPCI Act provides various exclusivity periods, including for reference products and for the first product determined to be interchangeable with a reference product. The FDA answered the question of how a prospective biosimilar applicant can determine if there is unexpired orphan exclusivity for an indication for which the reference product is licensed. The guidance points to the FDA's website, which contains a searchable database for orphan designated and/or approved products and indications. The FDA clarifies that it will not approve a subsequent application for the "same drug" for the indication during the seven-year period of orphan exclusivity, except as otherwise provided in the Federal Food, Drug, and Cosmetic Act, and 21 C.F.R. part 316.

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.

In association with
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Check to state you have read and
agree to our Terms and Conditions

Terms & Conditions and Privacy Statement

Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

Use of www.mondaq.com

You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). 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 & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.


Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd 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 or performance of information available from this server.

The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.


Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.

Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

If you do not want us to provide your name and email address you may opt out by clicking here .

If you do not wish to receive any future announcements of products and services offered by Mondaq by clicking here .

Information Collection and Use

We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

Mondaq News Alerts

In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.


A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

Log Files

We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.


This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

Surveys & Contests

From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.


If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.


From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

*** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .


This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

Correcting/Updating Personal Information

If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

Notification of Changes

If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

How to contact Mondaq

You can contact us with comments or queries at enquiries@mondaq.com.

If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.