Biosimilar Labeling Variation From Reference Product OK, FDA Says

FDA appears open to more variation between the labels of a biosimilar product and its reference biologic than may have been evident in its first approval under the 351(k) pathway.

Although biosimilar labeling should incorporate relevant data and information from the reference product's labeling, there are situations in which the biosimilar labeling may be different from that of the reference product, FDA states in a new draft guidance.

However, the agency also envisions situations in which a biosimilar that is not licensed for all of the indications on a reference product's label may still need to include some information about that off-label indication to ensure safe use.

FDA's draft guidance, "Labeling for Biosimilar Products," released March 31, largely reflects the principles the agency followed in labeling the first (and to date only) approved biosimilar product, Sandoz Inc.'s Zarxio (filgrastim-sndz), which references Amgen Inc.'s Neupogen (filgrastim).

However, it also suggests there may be more leeway for biosimilar labeling to look different from its reference product than was the case with Zarxio.

For one thing, the guidance calls for inclusion of a "biosimilarity statement" and identification of the reference product in the biosimilar's label. Zarxio labeling does not identify the Sandoz product as a biosimilar or mention Neupogen by name.

Labeling That Is Similar, Not Necessarily Identical

FDA approved Zarxio in March 2015 with labeling that was almost identical to that of Neupogen and which reflected only the clinical data for the Amgen product. (Also see "Sandoz Biosimilar Approval Answers Questions On Labeling But Not Naming – UPDATED" - Pink Sheet, 6 Mar, 2015.).

FDA said it looked to the model of ANDA and 505(b)(2) products in deciding how Zarxio's labeling should be written (Also see "Biosimilar Labeling Dissected: Sandoz’s Zarxio Uses Amgen’s Neupogen Text" - Pink Sheet, 9 Mar, 2015.).

In the draft guidance, FDA sticks to the view that generally only the clinical data relevant to the reference product should appear in the biosimilar's labeling (Also see "Biosimilar Labeling: FDA Says Leave Comparability Data Out" - Pink Sheet, 31 Mar, 2016.).

"FDA’s finding of safety and effectiveness for the reference product, as reflected in its FDA-approved prescribing information, may be relied upon to provide health care practitioners with the essential scientific information needed to facilitate prescribing decisions for the proposed biosimilar product’s labeled conditions of use," the guidance states. "Accordingly, FDA recommends that in the biosimilar product labeling, applicants incorporate relevant data and information from the reference product labeling, with appropriate product-specific modifications."

However, the relevant reference product data that should be incorporated in the biosimilar's labeling will depend on whether the 351(k) applicant is seeking approval for some or all of the reference biologic's approved indications and dosing regimens, the guidance adds.

In sections of the biosimilar's labeling that are based on reference product labeling, FDA anticipates that the text will be similar.

However, "text based on the reference product labeling need not be identical and should reflect currently available information necessary for the safe and effective use of the biosimilar product," FDA said. "Certain differences between the biosimilar and reference product labeling may be appropriate."

For example, biosimilar labeling must conform to the Physician Labeling Rule (PLR) and the Pregnancy and Lactation Labeling Final Rule (PLLR) and, therefore, may differ from the reference product if the latter was not required to meet such requirements at the time of the biosimilar's licensure.

In Zarxio's case, the Neupogen label was converted to the PLR format one month before the biosimilar was approved.

"In addition, biosimilar product labeling may include information specific to the biosimilar product 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," the guidance states.

Zarxio's availability in only a prefilled syringe, and some limitations inherent with that presentation, led to some product-specific differences in the label compared to that of Neupogen, which is available in both syringes and vials (Also see "How To Label A Biosimilar? Copy The Reference Product, FDA Told Sandoz" - Pink Sheet, 15 Jun, 2015.).

Off-Label Indications

Sandoz sought and received approval for all of the indications on the Neupogen label at the time of the biosimilar's licensure, although Amgen subsequently added an orphan indication to the reference product's labeling (Also see "Neupogen Claim’s Orphan Protection May Keep Zarxio At Bay" - Pink Sheet, 27 Apr, 2015.).

When a biosimilar applicant obtains licensure for fewer than all indications and dosing regimens for which the reference product is licensed, "certain text in the reference product labeling related to conditions of use for the reference product that are not approved for the biosimilar product would generally not be included in the biosimilar product labeling," the guidance states.

However, FDA says that in certain circumstances it may be necessary to include information in the biosimilar's labeling about an indication for which the 351(k) applicant is not seeking licensure "in order to help ensure safe use (e.g., when safety information in the reference product labeling is related to use of the product and is not specific to a particular approved indication(s) or when information specific to only the biosimilar product’s indication(s) cannot be easily extracted)."

"Such text should be written in a manner that does not imply that the biosimilar product is approved for a reference product indication(s) or use(s) that has not been approved for the biosimilar product," the guidance states.

Specific labeling sections that could be affected in such circumstances include the boxed warning, contraindications, warnings and precautions, adverse reactions, drug interactions, and use in specific populations.

The guidance includes an example of how this might look in practice.

In the warnings and precautions and adverse reactions sections, "the reference product labeling may group the events by type from all the reference product clinical trials for all the indications for which the reference product is licensed."

"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," FDA said.

"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)."

The guidance's provisions regarding discussion of off-label uses on a biosimilar's labeling could draw some strong comments from industry.

The innovator industry may be loath to see any discussion of an unapproved use on a biosimilar's label. On the other hand, a labeling statement that a biosimilar is not approved for a particular indication could help bolster an innovator's efforts to retain market share in the face of biosimilar competition.

Product Identification

The guidance also discusses approaches to product identification, specifically, when to use the biosimilar product name, the reference product name, the core name and more than one name.

If a biosimilar has a proprietary name, it should be used in labeling text that is specific to the biosimilar or refers only to that product. If a proprietary name is not available, the biosimilar's proper name should be used in such circumstances.

The guidance's nomenclature examples reflect the approach described in the agency's August 2015 draft guidance on nonproprietary names for biologics and biosimilars, with a product's proper name comprising a core name that is attached by a hyphen to a designated suffix consisting of four lower-case letters (Also see "FDA Biosimilar Naming Policy Takes Middle-Of-The-Road Approach" - Pink Sheet, 27 Aug, 2015.).

FDA's proposal that the four-letter suffix be meaningless has drawn strong opposition (Also see "FDA's Biologics Naming Plan: Industry Wants 'Memorable' Suffixes" - Pink Sheet, 9 Nov, 2015.).

Revising Biosimilar Labeling

One question that arose in the wake of the Zarxio approval, with its near-identical label to Neupogen, was whether biosimilar sponsors would be able to make safety-related changes to labeling on their own initiative (Also see "FDA's Biosimilar Labeling Stance Spurs Preemption Questions" - Pink Sheet, 12 Oct, 2015.).

FDA's guidance appears to answer that question in the affirmative.

"As with any biological product, a biosimilar product application holder must promptly review all adverse drug experience information obtained or otherwise received from any source, foreign or domestic, including information derived from commercial marketing experience, post-marketing clinical investigations, post-marketing epidemiological studies/post-marketing adverse event surveillance, reports in the scientific literature, and unpublished scientific papers," the guidance states.

"When new information becomes available that causes information in labeling to be inaccurate, the application holder must take steps to change the content of its product labeling," FDA said.

However, the guidance does not state whether a biosimilar labeling change would necessitate a change in the reference product's labeling, and vice versa.

Zarxio recently underwent its first labeling change.

On March 3, FDA approved a "changes being effected" supplement to include glomerulonephritis in the label's warnings and precautions and post-marketing experience sections. These changes mirrored revisions to the Neupogen label that were approved in July.

However, the Zarxio labeling supplement also corrected an inconsistency between the information related to injection sites in the prescribing information and the Instructions for Use, FDA's approval letter said.

Open For Comments

Stakeholders have 60 days to submit comments on the guidance.

In a March 31 statement, Patients for Biologics Safety and Access said the group was pleased to see the provision requiring products be clearly labeled as biosimilars.

However, "we believe the final guidance must take other important steps, including a requirement that biosimilar labels specify which indications were approved based on extrapolation of data rather than clinical testing," the group said. "We also believe final labeling guidance should require the inclusion of pertinent clinical data and adverse events specific to the biosimilar as well as a statement declaring whether or not the product has been approved as interchangeable."

FDA said specific labeling recommendations for interchangeable products will be provided in a future guidance.