Serono has been informed by FDA that approval of its multiple sclerosis therapy Rebif is blocked by the orphan drug exclusivity of both Berlex' Betaseron and Biogen's Avonex, but has not been given a date for when that exclusivity will expire.

In a "complete response" letter to Serono, FDA "stated that Rebif [interferon beta-1a] may not be approved for marketing while orphan exclusivity remains in effect for Avonex or Betaseron," Serono said.

Biogen has interpreted FDA's preliminary ruling to mean that Rebif cannot be approved for marketing until 2003, seven years after the approval of Avonex. An alternative interpretation, however, might be that the exclusivity of both Avonex and Betaseron will expire in 2000, seven years after approval of Betaseron.

FDA apparently has not yet made a final ruling on the issue because there are other matters to be resolved in the Rebif application before it can be approved. Serono indicated that it expects to receive a "tentative approval" letter once it has addressed the remaining issues not related to the Orphan Drug Act.

Serono maintains that Rebif has clinical advantages over the other beta interferon products and thus should be eligible for approval despite their orphan exclusivity. The "complete response" letter to Serono, however, apparently indicates that FDA is going to reject that claim.

The company has also been emphasizing in its discussions with FDA that expiration of Betaseron's exclusivity in 2000 should be the latest possible date for Rebif to be eligible for marketing.

From Serono's perspective, if FDA determines that Rebif cannot be marketed until 2003, the approval of Avonex will have resulted in a three year extension of the orphan exclusivity granted to beta interferon products. The company argues that Rebif should be allowed to come to market after it has waited out Betaseron's seven years of market exclusivity.

Serono points out that if other beta interferon formulations qualify for orphan drug exclusivity and FDA follows the same precedent, Rebif's marketing could be delayed indefinitely.

While not taking a position on whether Rebif should interrupt the orphan exclusivity of either currently marketed product, the National Organization for Rare Disorders is concerned that FDA may set a precedent in which seven year orphan exclusivity periods can be extended indefinitely.

NORD is also concerned about the possibility that FDA will decide that Rebif is the same as two products that the agency previously determined to be different for purposes of the Orphan Drug Act.

In a January response to a letter from NORD, FDA was vague about the length of the orphan exclusivity term granted to Avonex.

"During the development of Betaseron and Avonex, each of the manufacturers was granted orphan designation for its product," FDA noted. "In essence, this meant that the first manufacturer to receive approval would be granted market exclusivity for seven years. Betaseron was licensed first in July 1993."

Avonex was subsequently approved based on data demonstrating an improved safety profile, the agency noted. FDA did not discuss the length of Avonex' exclusivity.

The nearest parallel to the Betaseron/Avonex exclusivity issue is the shared orphan exclusivity of the human growth hormone products Protropin (Genentech) and Humatrope (Lilly). In that situation, however, FDA deemed Humatrope and Protropin to be unique molecules based on a one amino acid difference. The later exclusivity period for Humatrope ended up setting the deadline for new competitors in the market, since products developed by Serono and others were identical to the Lilly molecule.

Serono based the argument for clinical superiority of Rebif on a claim that its studies of a higher dose of beta interferon have demonstrated greater efficacy in sicker patients (those with Expanded Disability Status Scores above 3.5).

NORD's letter to FDA also asked for details about the efficacy of Avonex in more severely ill patients.

FDA verified that Avonex was studied only in patients with EDSS scores from 1-3.5, although the product was approved without restrictions for all relapsing-remitting patients. "FDA believes that limiting usage only to patients with the same range of EDSS scores as those patients that participated in the clinical trial is not appropriate, as safety and efficacy can reasonably be extrapolated to patients with relapsing forms of MS who have somewhat higher EDSS scores."

Serono has sought to line-up support for its position from patient groups and members of Congress, garnering letters of support from Sens. Kerry (D-Mass.), Murray (D-Wash.) and Mikulski (D-Md.). Biogen has also been trying to build support for protecting its orphan exclusivity, and has complained to FDA that Serono's lobbying tactics have amounted to promotion of an unapproved product ("The Pink Sheet" Feb. 1, p. 21).

The National Multiple Sclerosis Society has not taken a position on the approval of Rebif, stating that it will defer to FDA's judgment.

In an April letter to Serono, the National Multiple Sclerosis Society agreed that the Rebif trials "have shown the positive impact and acceptable safety of higher doses of this medication, delivered subcutaneously three times a week," emphasizing that "we particularly note the positive outcomes for a subgroup of more severely disabled individuals."

In a December letter to FDA, Rep. Waxman (D-Calif.) called for a prompt and definitive review of the Rebif application and the issue of orphan exclusivity. Waxman pointed out that the determination should be based on a "fact-intensive" judgment of clinical superiority.

Waxman emphasized the importance of orphan exclusivity as a research incentive, but added that "exclusivity was not intended, however, to be inviolate." Waxman added that "the agency's criteria for clinical superiority are wholly consistent with the goal of maintaining the integrity of market exclusivity as an effective incentive under the Orphan Drug Act."

Serono said that it expects to respond to the other issues raised by the complete response letter "quickly." The issues raised by FDA focus on "clarification of clinical information and data," the company said.

The Rebif BLA was submitted in February 1998 for relapsing-remitting MS and transitional MS based on a single 560-patient pivotal trial. Patients were randomized to thrice-weekly injections of Rebif 22 mcg (6 MIU), 44 mcg (12 MIU) or placebo. Rebif gained marketing approval in Europe in May.

Serono Rebif Blocked By Orphan Exclusivity, FDA Says, But Timing Is Unclear

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