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In March the FDA published a new draft guidance for industry on Labeling for Biosimilar Products.

This has been issued by FDA to aid companies in developing labeling for submission to FDA in applications for marketing approval. As with all guidances, this is not a “legally enforceable” set of requirements, but rather recommendations that are suggested by FDA but are not obligatory.  However, as with most guidances, it is a good idea to follow them (or at least propose a reasonable alternative). Also note that this is a draft and not the final guidance. Comments are being sought by the FDA.

It is important to note that the definitions established for biologics’ “biosimilarity” and “interchangeability” are not the same as definitions in place for generic versions of drug products.



Biosimilarity is defined as “the biological product is highly similar to the 
reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”

Comment: This definition fails in one grammatical aspect.  It is a “circular definition” in the term being defined is “used as a part of the definition or assumes a prior understanding of the term being defined” –Wikipedia.

That is, biosimilarity is defined as being highly similar. This presumes one knows what similar means in this context. This is somewhat ameliorated by the subsequent sentence which notes that there are “no meaningful differences…” It is still not totally clear what “meaningful differences” means. Nonetheless, this is a useable working definition with FDA defining, in effect, biosimilarity on a product by product basis.



Interchangeability is defined as biosimilarity and “the demonstration that the product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the 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.”

Comment: Interesting to note that the product “can be expected to produce the same clinical result.” Not that it has already been demonstrated to produce the same clinical result. Let the buyer beware (caveat emptor).


General Labeling Principles

The FDA then discusses general principles to be used for the labeling. We will examine here primarily those areas that touch on safety.

FDA notes that a biosimilar product has no clinically meaningful differences with the reference product in regard to safety, purity and potency. The FDA approved labeling for the approved reference product can be “relied upon” (that is, “used”) by the practitioner to make prescribing decisions. The biosimilar product should include relevant data from the reference product labeling with appropriate product-specific changes.

The labeling for the biosimilar should include a description of the clinical data that supports the safety and efficacy of the reference product though detailed clinical trial data does not necessarily need to be included.

There are several sections devoted to how the names of the reference product and the biosimilar should be handled in the labeling. Please refer to the draft guidance for these details. This is a rather complex area.

Another complexity revolves around what to include in the biosimilar labeling when the biosimilar is not approved for all of the indications or conditions of use that the reference product is approved for. In this case, information related to the unapproved indication should not be included. This can become tricky when information has to be removed from Boxed Warnings, Contraindications, Warnings and Precautions, Adverse Reactions, Drug Interactions and Use in Specific Populations.

Comment: The obvious danger here is that a less than well-informed reader might infer that the biosimilar does not have the safety issues that appear in the reference product and is therefore (possibly) safer! This can be tricky and medical, legal and regulatory should all input into these decisions. Obviously, FDA will have the final word.


Clinical Trials

FDA also discusses what details of clinical trials should be included in the biosimilar’s labeling.  They note that some of the trials may have been done with the reference product in different patient populations or indications or with different conditions of use. Thus not all of this data is relevant or applicable to the biosimilar’s patient population and use. FDA then states that it believes that including data from such studies would not be useful for health care practitioners.

Comment: This is obviously a tricky area. If the company leaves out information which may in fact be, or turn out to be, relevant it may lead to exposing patients to risks and harm that might have been avoided. This could, of course, lead to litigation and other problems. Careful thought and analysis, with input from experts, FDA and others should be gotten.

In regard to Adverse Reactions, FDA specifically addresses the issue of immunogenicity with protein products. There should be a subsection in the Adverse Reactions section labeled Immunogenicity with a paragraph that states (using these words or similar ones):

“As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. 
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to [reference 
product’s proper name] in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.”

FDA also discusses updating the safety information for the product over the course of the product’s lifespan. FDA reminds the application holder that they must promptly review all adverse drug experience information gotten from any source (including marketing, postmarketing trials and surveillance, epidemiologic studies, literature reports and unpublished papers) and comply with the safety reporting requirements including expedited reports, periodic reports etc. (21CFR600.80).

No surprises here.

The application holder must change the labeling to ensure that the new information is incorporated such that the labeling is no longer “inaccurate.” The company must be sure the labeling is accurate and up to date. If not, the product can be deemed to be “misbranded.” This can, as you know, lead to all sorts of problems and penalties.

For full details on FDA requirements for labeling, including safety, please refer to 21 CFR201.56(d) and 201.57 as well as the Guidance from 2013 on labeling.



We are seeing the beginnings of the evolution of biosimilar labeling. Since this whole area is fairly new, the FDA, the applicants and, of course, the health care practitioners and patients are working to find the best way to communicate the appropriate information.  How and whether reference product safety data from indications that are not approved in the biosimilar should be included in the biosimilar labeling will likely evolve over time.

A similar issue was seen decades ago when drugs and biologics were approved for limited indications in the US but wider indications ex-US.  In this situation, documented and important safety data was obtained for unapproved indications from abroad. There was much debate as to whether this data should be included in the labeling of complex drugs used in very ill patients (who often had multiple concurrent diseases). These issues were resolved on a case by case basis.  Often such safety data was included in the US labeling even though the data was obtained in patients who were receiving the drug for unapproved US indications.

Similarly safety labeling for generic vs reference drugs is a much debated issues. This whole area is evolving and it will change over time. Stay tuned.


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