FDA's treatment of an orphan-protected Remicade indication in the labeling for Celltrion Inc.'s biosimilar Inflectra may stir some controversy.

While Inflectra's approved labeling does not include an indication for pediatric ulcerative colitis, an orphan-protected use on the labeling of Janssen Biotech Inc.'s Remicade (infliximab), it nevertheless contains language suggesting the biosimilar is safe and effective for this other pediatric use.

The labeling language may spur complaints from rare disease advocates concerned that any reference to an orphan-protected, off-label indication in biosimilar labeling undercuts the marketing incentives designed to spur research and development of rare disease treatments.

The approach also may draw the ire of innovators unhappy about mention of their protected claims in a competitor's labeling.

FDA approved Inflectra (infliximab-dyyb) April 5 as the second biosimilar in the US, 13 months after Sandoz Inc.'s Zarxio (filgrastim-sndz) became the first product licensed under the 351(k) pathway (see related story,[A#14160405006]).

Inflectra received approval for all but one of the indications on the label of Remicade, the reference product. Indications common to both products' labels are: adult and pediatric Crohn's disease, adult ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis.

The lone indication not copied over from the Remicade label is pediatric ulcerative colitis. This claim on the Remicade label is protected by orphan product exclusivity until September 2018 ([A#14150209003]).

While the orphan-protected claim is not mentioned in Inflectra labeling's Indications and Usage section, it does not go entirely without mention in the biosimilar's labeling.

Addressing Pediatric Use

The Pediatric Use section of Inflectra labeling states: "The safety and effectiveness of infliximab products have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn’s disease. However, infliximab products have not been studied in children with Crohn’s disease or ulcerative colitis <6 years="" of="">

This language mirrors that found in the Remicade label, although the brand name "Remicade" is replaced with "infliximab products" in the biosimilar's labeling.

Additional language specific to pediatric Crohn's disease is also largely carried over from the Remicade label.

However, immediately following the pediatric Crohn's disease language in the biosimilar's label is the following statement: "A pediatric assessment for Inflectra demonstrates that Inflectra is safe and effective in another pediatric indication. However, Inflectra is not approved for such indication due to marketing exclusivity for Remicade (infliximab)."

In contrast, the Remicade label contains information on the TNF-inhibitor's safety and effectiveness for reducing the signs and symptoms, and inducing and maintaining clinical remission, in patients ages six years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.

FDA's decision to describe Inflectra as safe and effective in another pediatric indication may irritate orphan disease advocates. At a February advisory committee review of the Celltrion product, a representative from the National Organization for Rare Disorders blasted the agency's request for panel discussion on whether there was sufficient scientific justification to extrapolate data to support a determination of biosimilarity for pediatric UC ([A#00160215009]).

The agency invited discussion on this topic even though it said it could not license Inflectra for pediatric UC until the orphan protection expired.

FDA's draft guidance on biosimilar product labeling, released March 31, did not specifically discuss how pediatric data should be reflected in labeling. The guidance states that biosimilar labeling generally should describe the clinical efficacy and safety data for the reference product, but not the clinical data a 351(k) sponsor used to gain approval ([A#14160331004]).

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 ([A#00160404011]).

Inflectra Label Not Exactly Silent On Remicade's Orphan-Protected Claim

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