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Final Rule Draws Line Between Orphan Status and Exclusivity

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By Mari Serebrov
Washington Editor

The FDA etched a distinct line between orphan drug designation and exclusivity in a final rule released Wednesday, making it clear that getting the designation doesn't guarantee seven years of market exclusivity.

A hypothesis of superiority is enough to get the designation when another drug has already been approved for the same orphan indication, but evidence of clinical superiority is needed for exclusivity, according to the rule, which amends the regulations issued in 1992 to implement the Orphan Drug Act.

Drawing the line was necessary to avoid possible misinterpretations of the existing rule, according to the agency. The new language makes it clear that "sponsors may have to demonstrate clinical superiority to obtain orphan-drug exclusivity even if they did not have to submit a plausible hypothesis of clinical superiority to obtain [the] designation," the FDA said.

For instance, if a drug hasn't been approved yet for a specific orphan indication, a candidate could be granted orphan drug status without a superiority hypothesis. After that designation is granted, another drug could be approved for the indication, which would then require the candidate to demonstrate superiority to that approved drug to get exclusivity.

The rule also makes it clear that if a candidate is awarded an orphan drug designation based on a superiority hypothesis, it doesn't have to prove that specific hypothesis to get the exclusivity, but it still has to demonstrate superiority, either in safety or efficacy, to the approved drug.

The final rule, which goes into effect Aug. 12, formalizes the agency's thinking that led to it rescinding orphan exclusivity for Octapharma USA Inc.'s Wilate (von Willebrand Factor/Coagulation Factor VIII Complex) last year. (See BioWorld Today, Aug. 10, 2012.)

Although Wilate was the same drug as CSL Behring LLC's Humate-P, which was approved in 1999 and enjoyed seven years of orphan exclusivity, the FDA designated the follow-on as an orphan drug based on Octopharma's plausible hypothesis for superior safety in that the manufacturing of Wilate involved two viral inactivation processes whereas the Humate manufacturing entailed only one.

The agency re-evaluated the exclusivity granted to Wilate in response to a citizen petition filed by Behring. As a result of that re-evaluation, the FDA decided that the available data didn't "support a conclusion that Wilate has been demonstrated 'to provide a significant therapeutic advantage over and above that provided' by Humate."

The final rule, published in Wednesday's Federal Register, also closes a loophole that let drugmakers game the orphan drug process by creating arbitrary, but "medically plausible," subsets of patients with a nonrare disease, the FDA said. Under the existing regulations, sponsors were required to demonstrate that a subset of fewer than 200,000 U.S. patients was medically plausible. Since that term wasn't defined, some drugmakers attempted to create artificial subsets to take advantage of orphan drug incentives such as tax credits and market exclusivity.

The agency received four comments on the change, which was included in a proposed rule issued in 2011. All of the commenters urged the FDA to retain "medically plausible" in the definition of an orphan subset. But the agency stuck to its proposal, saying the term caused too much confusion and would continue to allow artificial orphan populations, which would divert resources from R&D of drugs for true orphan diseases and conditions. (See BioWorld Today, Oct. 19, 2011.)

At-Risk Launch to Cost $2.15B

An at-risk launch of generic Protonix tablets will cost Teva Pharmaceutical Industries Ltd. and Sun Pharmaceutical Industries Ltd. $2.15 billion in a settlement reached with Pfizer Inc., of New York, and Nycomed A/S, now part of Takeda Pharmaceutical Co. Ltd., of Osaka, Japan.

Jerusalem-based Teva's share of the tab is $1.6 billion, half of which will be paid this year and the remainder in 2014. Sun, of Mumbai, will pay $550 million. Pfizer and Takeda will divide the proceeds, with Pfizer getting 64 percent.

The settlement ends a 10-year patent infringement battle that culminated in Teva's launch of 20 mg and 40 mg generic Protonix (pantoprazole sodium) in December 2007 – three years ahead of the patent expiry for pantoprazole.

The generic acid reflux drug was launched a few months after a federal district court denied Wyeth's (now part of Pfizer) motion for a preliminary injunction. A federal jury upheld the validity of the Wyeth patent in 2010.

FDA Creates GAIN List

Taking the next step in a battle against superbugs, the FDA proposed a rule creating a list of pathogens that qualify as targets for antibacterial and antifungal drugs being developed under the Generating Antibiotic Incentives Now (GAIN) provision of the FDA Safety and Innovation Act.

Qualifying drugs are eligible for designation as a fast-track product and an additional five years of exclusivity.

The proposed list, published in Wednesday's Federal Register, includes Acinetobacter species, Aspergillus species, Burkholderia cepacia complex, Campylobacter species, Candida species, Clostridium difficile, Enterobacteriaceae, Enterococcus species, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, N. meningitidis, nontuberculous mycobacteria species, Pseudomonas species, Staphylococcus aureus, Streptococcus agalactiae, S. pneumoniae, S. pyogenes and Vibrio cholerae.

Comments on the list and proposed rule are due by Aug. 12.