Editor

As the last line of defense against killer bugs, ViroPharma Inc.'s generics-threatened Vancocin (vancomycin) is "particularly ill-suited to being the test case" for an FDA plan to change the standards for bioequivalence testing of nonsystemically absorbed drugs. So wrote Michel de Rosen, CEO of ViroPharma, in a letter to the agency.

That was more than three years ago - and now things are starting to move. Draft guidance from the FDA lays out the terms under which a generic form of vancomycin could win approval, and those requirements no longer include human tests - i.e., no clinical trials. An advisory committee takes up the matter Aug. 4.

Waiting in the wings with its generic vancomycin is Mylan Inc., of Pittsburgh, which already has filed an abbreviated new drug application. Vancocin, approved for antibiotic-associated pseudomembranous colitis caused by Clostridium difficile (CDI) and enterocolitis caused by Staphylococcus aureus, including C. difficile-associated disease, sold $232.2 million for ViroPharma last year.

In late 2004, when the company bought rights to Vancocin from Indianapolis-based Eli Lilly and Co. for $116 million, the drug already was off patent. But ViroPharma had cause to feel secure, since there was no delineated pathway for approval of a generic version of the locally acting therapy. The FDA - with its mandate to make health care cheaper (a goal accomplished partly by making life easier for generic drug makers) - wants to change this.

ViroPharma has argued that its product is not "highly soluble": It doesn't dissolve by 85 percent in 30 minutes under various pH conditions. Generic versions meet that standard, so they are not bioequivalent to Vancocin, insists ViroPharma.

The FDA's way around this argument, explained JPM Securities analyst Liisa Bayko, is to change the definition of "highly soluble" somewhat, so that Vancocin and generics fall within the parameters, and then to allow in vitro dissolution testing to determine equivalence. That's the gist of briefing paperwork released June 30 related to the upcoming panel meeting.

"Obviously, it's going to be ViroPharma's job to put doubt in peoples' minds" as to the validity of the dissolution test, Bayko said.

"I can't think of another case in which the FDA has done this," said Kurt R. Karst, attorney with the Washington firm of Hyman, Phelps & McNamara, speaking of the backward approach to altering the regulations so that generics can reach the market earlier. As pressures mount to make health care cheaper, such tactics could become more common if the agency succeeds this time around.

Regulators have tackled the question of bioequivalence for systemic vs. locally acting drugs before. During a July 23 advisory meeting, consultant Dale N. Gerding from the Loyola University department of medicine, pointed out that no in vitro way had been devised to test for C. difficile infection in the gastrointestinal tract, and since Vancocin is the preferred treatment for life-threatening CDI, any generic version should undergo human experiments to determine if they work.

On the other side of the issue was a spokesperson for generic drug maker Akorn Inc., of Buffalo Grove, Ill., who used graphs to show that the dissolution rates of Vancocin and other versions of vancomycin may be accurately proven identical that way.

Nothing got resolved at the July meeting. At the August session, the FDA will be trying to make advisors accept the idea that regulators' own previous guidance - under which Vancocin does not meet the "highly soluble" criteria - is too conservative. Vancocin, they will say, comes close enough. And the FDA has a somewhat trickier chore ahead: convincing panelists that the slight difference does not matter in CDI.

Interestingly, the approval itself of Vancocin in 1986 (when still in the hands of Lilly) was based only on data related to dissolution rates, with no trials evaluating efficacy or safety, although this may not have any importance in the current debate.

Complicating the scenario still further: In 2005, a generic drug maker submitted data claiming to prove that Vancocin is, in fact, fast-dissolving by the FDA's measures. Exton, Pa.-based ViroPharma said no, and the FDA ran its own tests, ultimately siding with the company.

It all points to a wide variation in the solubility tests themselves - which could cause advisory committee members to swing toward demanding human trials, though the FDA is arguing that trials with generic versions would not be able to pinpoint differences between forms of vancomycin, since Vancocin is used at the higher doses for CDI.

Lazard Capital Markets and JMP Securities expect the FDA to clear generic versions of Vancocin, and fairly soon. As far back as 2006, when the FDA's Office of Generic Drugs first made known the bioequivalence guidelines, Lazard saw the handwriting on the wall. That year, Lazard began modeling for a launch of generic vancomycin in 2010. Estimates of revenues by the firm show a steady slide for Vancocin: $253 million next year, $139 million in 2010, $98 million in 2011, and $44.5 million in 2012.

ViroPharma has had its ups and downs. In February, shares took a hit of more than 50 percent after the antiviral maribavir failed to meet its primary endpoint of preventing cytomegalovirus disease in a Phase III trial in patients undergoing stem cell transplant. (See BioWorld Today, Feb. 10, 2009.)

In October, though, Lev Pharmaceuticals Inc.'s Cinryze won approval for hereditary angioedema, gaining FDA clearance as a prophylactic treatment for patients with the rare genetic disorder. ViroPharma merged with New York-based Lev and brought Cinryze on board. The C1 inhibitor later faltered when the FDA, in a complete response letter, asked for another trial before clearing the drug for treating acute HAE attacks. (See BioWorld Today, May 5, 2008.)

HAE is hard to diagnose, and a number of other players are coming up fast in the space, making ViroPharma ripe, or almost so, for acquisition by a bigger firm with more sales oomph and a complementary product. Those who might be interested include Bristol-Myers Squibb Co., Cephalon Inc. and Genzyme Corp.

Meanwhile, ViroPharma already has sued the FDA - not over the bioequivalence issue per se, but over access to internal documents related to the dispute. If the agency changes the rules and a generic version of vancomycin reaches the market, Karst said, ViroPharma would almost certainly litigate directly against the FDA over that, too.

Obviously, the last thing any biotech firm needs is the FDA as an enemy, and ViroPharma would probably lose anyway. But, especially absent a partner (or owner), it would have to try saving what it can of Vancocin. As the clamor for cheaper health care rises and reforms take hold, the FDA is likely to carry out more rule tweaks to let generics in, and a victory in the Vancocin scenario would only add fuel.

The deck is stacked against ViroPharma. "It's very hard [to win] when you're talking about bioequivalence," Karst said. Judges and juries alike have some difficulty understanding scientific matters. Often, they figuratively throw up their hands and let the FDA tell them what's what.

Karst cites a pending case that, although far afield from ViroPharma and Vancocin, involves a bioequivalence dispute and probably will have similar outcome.

Aliso Viejo, Calif.-based Valeant Pharmaceuticals Inc.'s Efudex (fluorouracil) topical cream, approved almost 40 years ago for actinic or solar keratoses, won clearance in 1976 for superficial basal-cell carcinomas. A generic challenger arose in 2004, and Valeant put forth a citizen petition asking that the FDA not allow the product without trials in BCC. Last year, the FDA denied the petition and approved an abbreviated new drug application from Spear Pharmaceuticals Inc., of New York.

Valeant sued the FDA two weeks later. The dispute is still winding its way through the court system, Karst said, and predicted the outcome will favor Spear's generic. "Courts are going to look at these cases and say: 'Agency discretion. [The FDA officials] are experts in this field, and we're going to defer to them.'"