FDA Denies Millennium Petition on Generic VELCADE and . . . Yada, Yada, Yada . . . Permits ANDA Labeling “Carve-in”/“Carve-up”

By Kurt R. Karst

Last week, FDA did something unprecedented (although not unexpected, at least by this blogger)! And based on the absence of any reporting in the trade press or online chatter, nobody seems to have taken note of FDA’s decision. In a November 6, 2017 response to a June 9, 2017 Citizen Petition (Docket No. FDA-2017-P-3672) submitted by Millennium Pharmaceuticals, Inc. (“Millennium”) concerning the company’s drug product VELCADE (bortezomib) for Injection, 3.5 mg/vial (NDA 021602), FDA – apparently for the first time ever – ruled that the Agency will allow a generic drug manufacturer to “carve-up” brand-name labeling and “carve-in” to generic drug labeling a condition of use that no longer appears in brand-name labeling.

We won’t go page-by-page through Millennium’s 31-page Citizen Petition and various requests, or FDA’s 21-page Petition Decision. Instead, like Seinfeld’s Elaine Benes, we’re going to “yada, yada, yada” over most of the content of those documents and just get to the endgame. But first, a little background. . . .

In March 2017, we put up a post, titled “Orphan Drugs: The Current Firestorm, a Real Evergreening Issue, and a Possible Solution” We described the “Real Evergreening Issue” alluded to in the title of the post as follows:

[T]here may be a real evergreening issue that’s probably been overlooked by most folks. In some cases, a single orphan drug designation can result in multiple periods of orphan drug exclusivity. . . .

In most instances, multiple and staggered periods of orphan drug exclusivity stemming from the same designation do not stymie generic competition. For example, if FDA grants an orphan drug designation for Drug X for Disease Y and the sponsor first obtains approval of the drug for use in adults with Disease Y and then later for the same drug for use in children with Disease Y, FDA would grant two separate periods of orphan drug exclusivity – one for each approval. An ANDA applicant may obtain approval of the drug for the adult population indication once the initial period of orphan drug exclusivity expires, and then later for the pediatric population indication once that second period of orphan drug exclusivity expires.

But not all cases are as easy as the one above. You see, indications, like Pokémon, can evolve into something new. There appear to be a growing number of cases where FDA has granted multiple periods of orphan drug exclusivity based on the same original orphan drug designation, and where the drug’s indication evolves into something new, shedding and subsuming the previous indication statement. This could occur, for example, as different disease stages or different lines of therapy are approved. (Some possible examples of this might be in the cases of Ibrutinib, Cinacalcet, Bortezomib, and Bevacizumab.) As the old labeling is shed, the new labeling may not allow for an ANDA (or biosimilar) applicant to easily (if at all) omit information protected by a new 7-year period of orphan drug exclusivity.

But is the solution to what may be a real evergreening problem opening up the Orphan Drug Act? This blogger thinks that there could be a better solution. . . . [One] possible remedy is for [the Office of Generic Drugs] to take a broader view of permissible labeling changes. That is, considering so-called labeling “carve-ins” that clarify the omission of other labeling information (and effectively return an indication to its previous state). It’s a topic FDA raised a few years back (see our previous post here), but that the Agency ultimately decided not to address.

Curiously, Millennium’s Citizen Petition was submitted to FDA just a few weeks later and raised, among other things, the precise issue we described in our March blog post. Specifically, Millennium requested that FDA:

  • Refrain from approving any ANDA or 505(b)(2) bortezomib product for any mantle cell lymphoma indication with labeling that omits information regarding the safe and effective conditions of use for treatment in previously untreated patients or labeling that adds new language to modify Velcade's current mantle cell lymphoma indication.
  • Seek public comment if FDA is considering allowing an ANDA applicant to revise Velcade's current mantle cell lymphoma indication by adding new language, consistent with FDA's prior action in a similar situation.

. . . and yada, yada, yada . . . FDA says in the Agency’s November Petition Decision that the Agency will, in fact, permit ANDA applicants to “carve-in” and “carve-up” brand-name labeling. Here are the important parts to note from FDA’s Petition Response (pages 12-15):

Velcade was approved as a second-line treatment for mantle cell lymphoma in 2006. The indication was changed in 2014 to include previously untreated patients (i.e., first-line treatment), resulting in a revised indication “for the treatment of mantle cell lymphoma.” The Petition states that the “approval of the revised mantle cell lymphoma indication resulted in multiple exclusivity periods, including orphan drug exclusivity.” The Petition notes the following:

VELCADE was awarded orphan exclusivity in 2006 for “Treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.” With regard to the current orphan exclusivity, FDA's orphan database describes the “approved labeled indication” as “Treatment of patients with mantle cell lymphoma who have not received at least 1 prior therapy.” That set of patients was incorporated into the labeling through the revised indication statement, which states that “VELCADE is indicated for the treatment of patients with mantle cell lymphoma.”

The Petition states that FDA may not approve “any bortezomib product for the treatment of patients who have not received at least 1 prior therapy” until the expiration of the orphan drug exclusivity period on April 8, 2022 and further states “[b]ecause VELCADE has only one broad mantle cell lymphoma indication, . . . FDA may not approve any ANDA or 505(b)(2) ‘for the treatment of mantle cell lymphoma.’”

The Petition argues that FDA should not allow ANDA applicants to carve out the protected first-line indication and to seek approval for the non-protected aspects of the treatment of mantle cell lymphoma indication. The Petition states that “FDA’s carve-out authority and precedent make clear that the agency will permit only omissions and minor attendant changes” to approved labeling. According to the Petition, “[i]t is not possible to omit words from the current mantle cell lymphoma indication and/or to make de mininus changes to arrive at an indication that does not disclose the exclusivity-protected use for first-line mantle cell lymphoma.” The Petition states that an ANDA applicant “would have to add language to create a new indication for second-line treatment that is not part of VELCADE’s current labeling.” In other words, because Velcade’s current labeling contains a broad indication “for the treatment of mantle cell lymphoma,” the Petition contends that applicants may not carve out the protected first-line indication without impermissibly changing the language of the indication or referencing a discontinued version of Velcade’s labeling. The Petition asserts, however, that FDA lacks the authority to approve of such a change. . . .

FDA disagrees with the Petition’s assertion that FDA may not approve ANDAs or 505(b)(2) applications for bortezomib drug products that rely on Velcade and that propose to carve out Velcade’s protected first-line information regarding mantle cell lymphoma (i.e., the indication for “treatment of patients with mantle cell lymphoma who have not received at least one prior therapy”). Prior to the approval of supplement 040 to NDA 021602, the labeling for Velcade included the following second-line treatment indication: “VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.” The second-line treatment indication for mantle cell lymphoma currently is not protected by exclusivity. Upon approval of supplement 040, the Indications and Usage section was revised to include a new patient population for mantle cell lymphoma, patients who have not received at least one prior therapy. Thus, the revised indication included both patients who have received at least one prior therapy (the second-line treatment indication that is unprotected by exclusivity) and patients who have not received at least one prior therapy (the first-line treatment that is protected by exclusivity). The current approved indication provides that “VELCADE is indicated for the treatment of patients with mantle cell lymphoma.” It would be appropriate, in FDA’s view, to omit the exclusivity-protected information and retain the non-protected indication for the “treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.” . . .

In this situation, FDA may omit the first-line mantle cell lymphoma indication. However, because of the way the indication is currently worded, the only way to omit the protected indication is to add words. FDA could have approached the labeling for Velcade differently. As described above, when the indication for “treatment of patients with mantle cell lymphoma who have not received at least one prior therapy” was granted exclusivity under the Orphan Drug Act, the indications for both first- and second-line treatment of mantle cell lymphoma were written as “treatment of patients with mantle cell lymphoma,” which FDA believes to be clear and concise. We note that the mantle cell lymphoma indications could have been written as “treatment of patients with mantle cell lymphoma who have received at least one prior therapy and treatment of patients with mantle cell lymphoma who have not received at least one prior therapy.” If the indications had been written as such, then omission of the words describing the protected indication would result in “treatment of patients with mantle cell lymphoma who have received at least one prior therapy” and would presumably be allowable under the Petition’s “only omissions” standard. We do not believe it would be appropriate for the scope of exclusivity for Velcade to be broadened due to the writing of labeling in a clear and concise manner. Further, we think this is consistent with our past practice. FDA does not believe there is a need to solicit public comment on this change in labeling.

Based on some recent patent infringement litigation, it does not appear that FDA will be approving generic VELCADE any time soon. As such, we are unlikely to see Millennium sue FDA with respect to the Petition Decision discussed above. But the “carve-in”/“carve-up” issue is likely to come up again soon (perhaps in the coming months) in the context of another drug we identified in our previous post on the topic. We’ll leave it to our readers to ponder what drug that might be.