WASHINGTON – Flexing its regulatory discretion, the FDA curbed two critical cancer drug shortages by speeding approval of a new source for preservative-free methotrexate and allowing the temporary importation of Lipodox as an alternative to Doxil.

Because of the methotrexate shortage, the agency expedited its review of APP Pharmaceuticals Inc., of Schaumburg, Ill., as a supplier of preservative-free methotrexate, used in spinal injections to treat children with acute lymphoplastic leukemia.

Although it currently makes methotrexate with preservatives, APP stopped making the preservative-free formulation several years ago, FDA Commissioner Margaret Hamburg said at a media briefing. Use of preservatives in spinal injections could cause paralysis.

The preservative-free formulation has been in short supply since Ben Venue, a division of Boehringer Ingelheim GmbH, of Ingelheim, Germany, shut down its Bedford, Ohio, facility for an extended period in November 2011 due to manufacturing problems. (See BioWorld Today, Feb. 14, 2012.)

The FDA began working with other suppliers of methotrexate to ramp up production before the Ben Venue plant shut down, Hamburg said.

But supplies were running dangerously low, and there were fears that the drug would not be available within a week or so.

The crisis has been averted. Even though APP doesn't expect to have its preservative-free version available for four weeks to six weeks, Hamburg said Ben Venue will release some supplies, and Hospira Inc. ramped up its production and had a new batch available Tuesday, a few weeks earlier than expected. Other approved suppliers also are stepping up production.

At this point, Hamburg anticipates the available supply of preservative-free methotrexate will be enough to meet the needs of patients.

To alleviate the shortage of Johnson & Johnson's Doxil, which also stemmed from the shutdown of the Ben Venue facility, the FDA is allowing the temporary importation of Sun Pharma Global FZE's Lipodox (doxorubicin hydrochloride liposome injection), which is not approved for use in the U.S. (See BioWorld Today, Dec. 14, 2011, and Jan. 20, 2012.)

Temporary importation of an unapproved drug is a rarely used tool in the FDA's discretionary arsenal. If possible, the agency prefers to work with a manufacturer that's already approved to produce the drug, Sandra Kweder, deputy director of the FDA's Office of New Drugs, said at Tuesday's briefing.

Several oncologists speaking at the briefing expressed relief that the shortages had been curbed. "But it's not the end of the story," Peter Adamson, of the Children's Oncology Group, said. "There are potential future shortages waiting to happen."

He noted that the Preserving Access to Life-Saving Medications Act, S. 296, which would require early notification to help address shortages before they occur, has been sitting in Congress for more than a year.

Passing legislation can be difficult, Adamson acknowledged, adding that it is no more difficult than treating a child with cancer.

He challenged Congress to pass the bill within the next four weeks. The bill's sponsors, equally tired of the wait, are trying to get it passed as an amendment to an unrelated transportation bill. (See BioWorld Today, Feb. 16, 2012.)

Hamburg noted that early notification helped the FDA avert 195 shortages last year and 114 since Oct. 31, 2011, when President Barack Obama issued an executive order that directed the FDA to broaden reporting of potential shortages of certain drugs. Voluntary reporting has increased sixfold since October, she added.

To clarify the how, what, when and why that drugmakers need to provide when reporting a potential shortage, the FDA issued a draft guidance Tuesday that covers both mandatory and voluntary reporting.

Supreme Court Passes on Janssen

While Abbott is likely breathing a sigh of relief that the Supreme Court has decided not to hear Janssen Biotech Inc.'s appeal of a case involving its blockbuster Humira (adalimumab), many biotechs are disappointed that the court passed on providing much-needed clarification on what's required in the written description for a biologic patent.

The U.S. Court of Appeals for the Federal Circuit has been raising the bar on written descriptions since the 1990s. But in Janssen Biotech Inc. v. Abbott Laboratories, it took the bar to a whole new level, basically requiring a company to reduce its claim to practice, said Li Westerlund, vice president for global intellectual property for Bavarian Nordic Group.

Bavarian Nordic had submitted an amicus brief, urging the Supreme Court to grant cert in the case, which involves Janssen's claims for recombinant antibodies that bind to the human tumor necrosis factor-alpha protein.

The high bar the Federal Circuit has set "is an important issue for the biotech industry," Westerlund told BioWorld Today, noting that biotech is the only sector subject to that heightened standard for written descriptions.

"This standard needs to be looked at," she said. From a practical perspective, it's not possible to require a biotech to invest resources in creating a product only to support patents.

With the switch of the U.S. patent system to first to file and the need for biotech to patent early upstream, such a standard doesn't work, she added.

Mary Webster, a patent attorney with Nixon Peabody, agreed. The thought in biotech has been that "you don't know what your patent means until the Federal Circuit tells you what it means," she told BioWorld Today. But now, companies won't know if the written descriptions in their patent claims are adequate until the Federal Circuit says they're adequate, she added.

Meanwhile, rather than deciding whether to grant cert in The Association for Molecular Pathology v. Myriad Genetics Inc., the Supreme Court put a hold on the case. (See BioWorld Today, Feb. 16, 2012.)

Forest Faces Class Risk

An unresolved cardiovascular safety issue hanging over inhaled anticholinergics as a class could be a factor when Forest Laboratories Inc. argues its case for aclidinium bromide before the Pulmonary-Allergy Drugs Advisory Committee Thursday.

New York-based Forest developed aclidinium, a new molecular entity in the class, with Almirall SA, of Barcelona, Spain, to treat chronic obstructive pulmonary disease (COPD).

The long-acting antimuscarinic agent was tested in Phase III trials in a fixed-dose combination with formoterol fumarate.

While the FDA didn't assert a definitive drug-related cardiovascular concern with aclidinium in the briefing documents for the advisory committee meeting, it noted the inability to eliminate that risk because of limited long-term safety data for the drug, Jefferies analyst Corey Davis said.

The agency recognized that the small imbalance for cardiovascular deaths in both the placebo-controlled trials and long-term trials did not rise to the "level of a clear safety signal." And it found the overall long-term safety database for aclidinium relatively modest compared with other COPD development programs.

The cardiovascular risk "is of particular importance given the concern for possible increased mortality that has been raised with other inhalational anticholinergic agents," the FDA said.

Because of aclidinium's extremely low event rates, a large and long safety trial would be needed to completely eliminate the risk, Jefferies' Davis said in a note.

Citing the four-year, 6,000-patient UPLIFT safety study required for Spiriva (tiotropium, Boehringer Ingelheim GmbH), he said he wouldn't expect the FDA would "require every drug in the class to duplicate such an effort – particularly after UPLIFT came back clean."

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