How To Label A Biosimilar? Copy The Reference Product, FDA Told Sandoz

But agency had to weigh how presentation differences between Sandoz’s Zarxio and Amgen’s Neupogen, as well as Neupogen-specific safety information, should be reflected in the biosimilar’s labeling.

FDA had to weigh whether and how differences in the presentations of Sandoz Inc.’s Zarxio (filgrastim-sndz) and its reference product, Amgen Inc.’s Neupogen (filgrastim), should be reflected in biosimilar labeling that was otherwise highly “generic-like” in approach.

Review documents show the agency advocated early on for the Neupogen label to serve as the model for Zarxio’s prescribing information and that adjustments had to be made to the biosimilar’s proposed labeling after Neupogen’s prescribing information was converted into a new format.

Neupogen labeling was converted to the Physician Labeling Rule format just one month before Zarxio’s approval.

With the exception of a Zarxio labeling recommendation against direct administration of less than 0.3 mL, FDA reviewers concluded that differences in presentation between Zarxio and Neupogen did not pose medication error risks or quality issues that warranted dramatically different labeling between the products (see box for related stories).

FDA approved Zarxio March 6 for all five of the indications that were on the Neupogen label at that time (Also see "Sandoz Biosimilar Approval Answers Questions On Labeling But Not Naming" - Pink Sheet, 9 Mar, 2015.).

Zarxio labeling is a near mirror-image of that for Neupogen, reflecting only the clinical data for the innovator biologic and not the biosimilar. Labeling also does not identify Zarxio as a biosimilar or mention the reference product by name.

More Stories About Zarxio’s Review

This issue of “The Pink Sheet” includes extensive coverage of FDA's evaluation of the first, and so far only, biosimilar the agency has approved:

• (Also see "Zarxio Syringe’s Limitations May Delay Decision On Neupogen Interchangeability" - Pink Sheet, 15 Jun, 2015.)
• (Also see "Sandoz’s Biosimilar Data-Bridging Plans For Zarxio Faced FDA Doubts" - Pink Sheet, 15 Jun, 2015.)
• (Also see "FDA’s Inaugural Biosimilar Review Bumpier Than First Appeared" - Pink Sheet, 15 Jun, 2015.)
• (Also see "Sorry, Wrong Email: FDA’s ‘Oops’ Moment In The Zarxio Review" - Pink Sheet, 15 Jun, 2015.)
• (Also see "Zarxio Reviewers" - Pink Sheet, 15 Jun, 2015.)
• (Also see "Zarxio Clinical Development Timeline" - Pink Sheet, 15 Jun, 2015.)

FDA has said it looked to the model of ANDA and 505(b)(2) products in deciding how biosimilar labeling should be written. However, biosimilar sponsors have complained that such an approach, which relies entirely on the innovator’s data, restricts their ability to discuss the quality data and clinical information upon which the biosimilarity determination was made (Also see "Biosimilars’ Generic-style Labeling Limits Data Promotion, Companies Say" - Pink Sheet, 25 May, 2015.).

The agency’s generic-centric approach to biosimilar labeling took some stakeholders by surprise due, in part, to draft guidance in existence at the time of Zarxio’s approval.

The guidance stated that biosimilar labeling should include a “clear statement” advising that the product is approved as a biosimilar to a reference product, and whether the product has or has not been deemed interchangeable.

Such language was removed from the final version of the guidance issued almost two months after Zarxio’s approval (Also see "Biosimilar Guidances: Broader Populations Permitted; More Immunogenicity Requested" - Pink Sheet, 18 May, 2015.).

Neupogen Labeling As A Template

The redacted Zarxio review documents reflect little of FDA’s internal policy discussions around the product’s labeling. Still, they suggest FDA had its eye on a generic-centric labeling model as early as November 2013, when agency staff and Sandoz had a biosimilar product development meeting pursuant to the biosimilar user fee program.

While labeling was not specifically discussed at that meeting, FDA provided preliminary written responses to Sandoz five days earlier on potential discussion questions, including labeling. FDA suggested that modeling Zarxio labeling after that of Neupogen would be a “reasonable starting point” (see box).

FDA’s Early Thoughts On Labeling

In written questions and responses leading up to the Nov. 19, 2013 biosimilar product development meeting, Sandoz and FDA discussed how the sponsor should approach proposed labeling for its biosimilar, EP2006.

• Sandoz: “Does the agency agree that the biosimilar prescribing information for EP2006 should be essentially the same as the prescribing information of the U.S. reference listed biologic Neupogen?”
• FDA response: “Your proposed approach to draft proposed labeling is a reasonable starting point for submission of your proposed 351(k) BLA. Submit your draft proposed labeling for EP2006 in the PLR format. We request that your annotated labeling identify, with adequate specificity, the source of all data and information presented. We will provide additional comments on draft proposed labeling during review of your 351(k) BLA.”

Sandoz’s BLA submission on May 8, 2014 included draft labeling; the company submitted revised labeling on Jan. 22, 2015.

Notably, during the course of FDA’s review of Zarxio, Neupogen labeling underwent a dramatic change.

Neupogen was first approved in 1991. On Feb. 6, 2015, just one month before Zarxio’s approval, the Amgen product’s labeling was converted into the format required under the 2006 Physician Labeling Rule (PLR).

FDA has previously declined to comment on the timing of the Neupogen labeling PLR conversion. However, it stands to reason the agency would have wanted labeling for both the reference product and its biosimilar to be in the same format.

On the same day FDA approved the new Neupogen labeling, the agency sent a “general advice” letter to Sandoz. The letter, signed by Division of Hematology Products Director Ann Farrell, contained comments on Sandoz’s Jan. 22 draft labeling and included a copy of the Neupogen labeling in PLR format.

“We recommend that you incorporate relevant data and information from the reference product labeling, with appropriate product-specific modifications, in your draft proposed labeling,” Farrell said. ”You may use this PLR format labeling as a template to facilitate a consistent approach to your draft proposed PLR format labeling.”

“Submit to your BLA annotated labeling that describes the areas where your proposed labeling differs from the approved Neupogen labeling,” Farrell told Sandoz. “Please also submit your proposed labeling in tracked changes where the areas that differ are noted.”

Zarxio Syringes Can Be Used For Dilution

One area of difference with labeling implications was in product presentation. Neupogen is available in single-dose vials and prefilled syringes, while Zarxio is only approved in prefilled syringes (Also see "Biosimilar But Different: Zarxio, Neupogen Diverge On Syringes, Vials" - Pink Sheet, 16 Mar, 2015.).

In a March 4 memo, Office of Biotechnology Products labeling reviewing Jibril Abdus-Samad noted that Neupogen labeling includes a section on “Administration Instructions for Dilution (Vial Only).” This language “may imply only the vial container closure should be used to prepare dilution solutions.”

The administration and dilution instructions were revised when Neupogen labeling was converted to PLR format, in part, to improve the organization of certain information. “Because Neupogen is supplied in both vials and PFS [prefilled syringes], the revision also aimed to encourage practitioners to use the vial for preparation of diluted solutions and the prefilled syringe for direct injections,” Abdus-Samad said. “This revision was not due to any safety concerns with using prefilled syringes to prepare diluted solutions.”

The review notes that Sandoz proposed prefilled syringes as the only container closure system for Zarxio. “From a product quality perspective, OBP does not have any concerns with practitioners using the Zarxio PFS for preparing diluted solutions of Zarxio,” Abdus-Samad said.

OBP consulted with the Division of Medication Error Prevention and Analysis on the potential for medication errors. “From a medication perspective standpoint, there are no known safety issues related to using Zarxio prefilled syringe to prepare a diluted Zarxio injection for administration to a patient,” DMEPA said, according to Abdus-Samad’s review.

However, OBP recommended the Zarxio dilution instructions be more consistent with those found on the Neupogen label, “taking into account the differences in container closure system.”

Neupogen Safety Risks ‘Relevant To Zarxio’

The Office of Prescription Drug Promotion also consulted on the Zarxio draft labeling and sought to ensure that safety-related information derived from the experience with Neupogen did not downplay the potential risks posed by the biosimilar.

In a Feb. 15 memo, OPDP Regulatory Review Officer Adam George recommended revisions “to adequately convey that the relevant data (i.e., risk information) are also relevant to Zarxio.”

In Zarxio labeling, language regarding warnings, precautions and adverse events makes frequent reference to “filgrastim” or “filgrastim products,” but no specific references to Neupogen.