Drug, biologic and biosimilar companies’ comments on US Food and Drug Administration (FDA) draft guidance on biosimilar labeling reveals a major split between those who do and do not want a statement on a biosimilar’s interchangeability status on each new product's label.
The comments come as FDA has still yet to release its guidance on what interchangeability means, and as FDA has not found any biosimilar to be interchangeable with its reference product.
However, that lack of FDA guidance on interchangeability (and the absence of such a designation in the EU, where biosimilars have been used more widely and for a longer period of time, resulting in significant cost savings) has not stopped more than 20 states from enacting legislation that would prohibit pharmacists from switching patients from a biologic to a non-interchangeable biosimilar without a doctor’s consent.
In March, FDA released its long-awaited draft guidance on biosimilar labels, which said the labels will rely heavily on their reference products, though the labels must make certain clarifications about the biosimilar and reference product.
For instance, FDA said that biosimilar labels should not include a description of a clinical study that merely supports a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference product for the approved indications.
But the label may include information specific to the biosimilar necessary to inform safe and effective use of the product, which could include differences such as administration, preparation, storage or safety information that do not otherwise preclude a demonstration of biosimilarity, FDA says.
“In cases where the biosimilar product applicant is not seeking approval for all the indications for which the reference product is licensed, the combined data described in the reference product labeling should be included in the biosimilar product labeling in a manner that is not indication-specific. However, any text that refers to an indication for which licensure has not been sought by the biosimilar product applicant and is included to ensure safe use of the biosimilar product should be revised to avoid an implication that the biosimilar has been approved for that indication(s),” FDA says.
And as far as interchangeable biosimilars, FDA was as coy in the draft guidance as it has been about when it will release its draft guidance on interchangeability (FDA’s biosimilar lead Leah Christl continues to suggest the guidance will be released some time in 2016).
“FDA continues to consider the types of data and information that would support a demonstration that a biological product is interchangeable with a reference product,” the draft says. “Any specific recommendations for labeling for interchangeable biological products, including any interchangeability statement similar to the biosimilarity statement described in section IV.C.1.b of this guidance, will be provided in future guidance.”
In their comments on the draft guidance, most of which were released this week, pharmaceutical, biologic and biosimilar companies were much more forthcoming on their opinions on whether to include a statement on interchangeability in a biosimilar’s label.
Amgen – which is developing what is likely to be the first biosimilar for AbbVie’s blockbuster Humira (adalimumab), but which is also attempting to thwart biosimilar competition for its blockbuster Enbrel (etanercept) – makes clear that it supports both an interchangeability statement on biosimilar labels and a statement on biosimilarity.
“FDA has recognized that only biosimilars that have met the additional approval standard of interchangeability are evaluated by FDA and affirmatively found to be safe for substitution with the reference product at the pharmacy without the intervention of the prescribing physician,” Amgen says in its comment dated 2 August.
Amgen says it also believes a biosimilar label should include a summary of the clinical data, including immunogenicity data, used to demonstrate biosimilarity or interchangeability to “help provide health care practitioners with the evidence necessary to make important individualized treatment decisions for their patients.”
Sanofi, Janssen, and AbbVie also took sides with Amgen (which is consistent with the views of the trade groups BIO and PhRMA) noting that biosimilar labels can be improved by including a statement about the interchangeability status of a biosimilar and including in the biosimilar label the relevant clinical study data that supported its approval.
Similarly, Pfizer said in its comments that biosimilars should not be labeled “as though they were small molecule generic drugs” and that it “recommends that biosimilar labeling include a statement reflecting whether interchangeability has been assessed.” Pfizer also said it “has substantive concerns about the Agency’s approach to biosimilar data in biosimilar labeling as well as the Agency’s characterization of such data as a general matter.”
“The draft guidance suggests that biosimilar data ‘are not likely to be relevant’ or ‘useful’ to health care practitioners and ‘may cause confusion, resulting in an inaccurate understanding of the risk-benefit profile of the product.’ This language and the related discussion should be struck from final guidance,” Lisa Skeens, VP of global regulatory affairs, writes.
Against an Interchangeability Statement
In the opposite corner of the fight is Merck & Co., which in comments posted Wednesday, says “that a single blanket approach applicable to all biosimilar products (e.g., inclusion of a statement on all biosimilar labels that a biosimilar [is] [is not] interchangeable with its reference) is not appropriate, and may cause unnecessary confusion among stakeholders.”
Merck recommends that rather than using such blanket statements, FDA take a risk-based approach for each biosimilar “when determining if a recommendation is necessary ‘to inform safe and effective use by a health care practitioner.’
“As a fundamental point, any policy approach to interchangeability labeling is premature without first defining the regulatory standards of an ‘interchangeable biologic,’” Andrew Robertson, director of global regulatory policy at Merck, writes.
Similarly, Boehringer Ingelheim says that it “does not agree that a biosimilar label needs to include a ‘biosimilarity statement,’ i.e., a statement that the product is a biosimilar. Such information is not ‘essential scientific information needed by health care practitioners for the safe and effective use of a drug.’ It is nonetheless available in the Purple Book, and not in any manner hidden.”
Boehringer also seeks to clarify that separating the definition of a biosimilar (in a footnote) from the rest of the “biosimilarity statement” in the text of the label “greatly increases the risk that a prescriber (or patient) reading the label will ignore the footnote and may rely on an inaccurate assumption of what is meant by the term ‘biosimilar’ in the text.”
In addition, Boehringer says that "characterizing a biosimilar as biosimilar to the reference product for the indications listed risks confusing providers and patients. BI fears that the phrase ‘for the indications listed’ could be read to imply, inaccurately, that the biosimilar has been found not to be biosimilar to reference product indications absent from the biosimilar label. For example, when a reference product is licensed for an indication covered by unexpired orphan exclusivity that indication would not appear on the biosimilar’s label, but that does not necessarily mean that the biosimilar is not biosimilar to the reference product for that indication. To avoid this misinterpretation, BI recommends any biosimilarity statement leave out such a phrase or suggestion."
Novartis’ generic division Sandoz, meanwhile, says in its comment: “It is self-evident that the very act of highlighting the indications that are extrapolated is being proposed by some groups in order to raise doubts as to the safety and efficacy of the biosimilar for those indications, and perhaps to also imply inferiority of biosimilars across the board. We believe that these are the true purposes of requests that the PI highlight the extrapolated indications for biosimilars, and in the future for interchangeable biologics. The FDA should not accept imputations that the Agency has approved biologics, in the form of biosimilars, that are any less safe and effective than the originator products to which they refer."