Ribavirin ANDAs Await ICN Petition; FDA Generic Rule Takes Effect

The delay in approval for generic versions of Schering-Plough's Rebetol (ribavirin) illustrates one limitation of FDA's revised Waxman/Hatch regulations.

Three Rivers, Teva and Geneva are awaiting a final decision by FDA regarding a labeling "carve out" for ribavirin ANDAs.

The dispute over protected labeling is an example of the types of issues that will still cause unpredictability in the exact timing of generic launches, even under FDA's new Waxman/Hatch rules.

The regulations clarify the types of patents that can be listed in FDA's "Orange Book" and limit patent holders to a single 30-month stay of approval on ANDAs. FDA published the final rule June 18, with an effective date of Aug. 18 (¹ , p. 13).

However, the rules do not address the process for "carving out" protected brand labeling from generic products, nor do they address eleventh-hour citizen petitions.

On July 14, Three Rivers, Teva and Geneva won a summary judgment ruling against ICN in patent litigation involving three ribavirin method-of-use patents (² (Also see "Generic Ribavirin Labels Will Carve Out Rebetol/PEG-Intron Indication" - Pink Sheet, 21 Jul, 2003.), p. 12).

However, the ANDAs have not yet been approved by FDA while the agency considers issues raised by ICN regarding protected labeling for Rebetol.

Rebetol is approved for use in combination with Schering's Intron-A and the newer PEG-Intron formulation. Labeling referring to use with pegylated interferon is still protected by Waxman/Hatch exclusivity, and ICN argues that FDA cannot approve a generic application that "carves out" the protected use.

FDA considers labeling carve outs on a case-by-case basis. Generic companies maintain that the decision-making process can be cumbersome, since it involves input from the Office of Generic Drugs, the relevant new drug review group, the Office of Pediatrics and the Office of the Chief Counsel.

The matter had already been considered by FDA at the time of the summary judgment ruling. The court decision referred to a June 27 letter from the agency stating that the protected labeling could be carved out of generic labeling.

ICN, however, filed a citizen's petition prepared by Hogan & Hartson Partner David Fox on July 16 spelling out its case that generics cannot be approved without violating the company's labeling exclusivity.

The petition argues that, because Rebetol is not approved as stand-alone monotherapy, its labeling must be considered in conjunction with the labeling for interferon products.

"The labeling for Rebetol and the labeling for PEG-Intron were approved as a mutually conforming unit," the petition says. "The two products are intended to be used together and, as such, the labeling for each product is designed to ensure complete consistency."

Therefore, while it may be possible to craft labeling for ribavirin that excises any reference to PEG-Intron, generic companies "cannot escape the fact that PEG-Intron continues to bear labeling on the use of PEG-Intron with ribavirin."

"The removal of information from one component of an FDA-approved combination regarding use with the other component effectively renders the individual products, as well as the combination, misbranded and unapproved within the meaning" of the FD&C Act, the petition asserts.

Schering-Plough originally marketed Rebetol only in a bundled package with Intron-A (under the trade name Rebetron ). Hepatitis C patient advocacy groups complained about the bundling of the products - and Schering's pricing for the combination (³ (Also see "Bristol Seeking Two NDAs For UFT Combos In Response To Rebetron Debate" - Pink Sheet, 30 Aug, 1999.), p. 7).

Schering ultimately agreed to market Rebetol separately, but priced it at virtually the same amount as the Rebetron combination package (⁴ (Also see "Schering Rebetol Costs $1,650 Per Month, 3% Less Than Combo Rebetron" - Pink Sheet, 15 Oct, 2001.), p. 15).

The Hepatitis C Action & Advocacy Coalition submitted comments to FDA July 29 urging the agency to reject the ICN petition out of hand.

"The petition contradicts actual law, and has nothing to do with the safety, efficacy or even valid labeling of the drug," HAAC argues. "It is simply a last ditch delay tactic."

Hogan & Hartson supplemented the petition on July 29, arguing that the terms of Schering-Plough's sublicensing agreement with the three generic companies support ICN's argument.

Schering settled its litigation against the generic firms in February, granting the companies a license to Schering's patents in exchange for a royalty on generics. The settlement took Schering out of the litigation at a time when the company is focusing on turning around its operations and resolving multiple investigations of its activities.

ICN maintains that the terms of the settlement, as outlined in Schering's SEC filings, demonstrate that coadministration of ribavirin with PEG-Intron is an "intended use" of the generic products.

Schering's description of the settlement states that it covers "all of Schering-Plough's U.S. patents relating to ribavirin and its use in treating hepatitis C, including its use in combination with interferon or peginterferon."

"By entering into these agreements, the generic sponsors cannot separate themselves from labeling and marketing of PEG-Intron," ICN asserts.

Three Rivers submitted its own comments on July 25, prepared by GrayCary attorney David Rosen. "This citizen petition is merely another tactical maneuver by a brand name pharmaceutical company after losing a summary judgment ruling, in a last minute, desperate effort to delay generic competition."

During its review of Waxman/Hatch rules, FDA considered possible approaches to limiting the use of citizen petitions.

In 1999, FDA issued a proposed rule that would have prohibited petitions that focus solely on approval standards for a specific generic product. However, FDA withdrew the proposed rule in April (⁵ (Also see "Citizen Petition Proposed Rule Withdrawn; FDA Cites Improved Response Rate" - Pink Sheet, 7 Apr, 2003.), p. 28).

FDA Chief Counsel Dan Troy concluded that the agency could not dismiss last-minute petitions out of hand, but said that sponsors should expect a skeptical hearing on eleventh-hour issues (⁶ (Also see "Waxman/Hatch Reform Should Await Pending Supreme Court Decision – Hatch" - Pink Sheet, 22 Apr, 2002.), p. 12).

The petition appears to have delayed generic approvals by at least two weeks. Par, which will market Three Rivers' version of ribavirin, originally expected resolution of the labeling issues by Aug. 1 (⁷ (Also see "Ribavirin ANDAs Await Decision By FDA; Par, Roche Expect Launch In August" - Pink Sheet, 28 Jul, 2003.), p. 8).

Ribavirin was first approved for marketing (in injectable form) in 1985. Rebetol/Rebetron was approved in June 1998.