Drug Industry Daily - Dec. 3, 2010 Issue

Vol. 9 No. 234

Advisory Panel Favors AstraZeneca’s Thyroid Cancer Drug Zictifa

An FDA advisory committee has given its support to AstraZeneca’s thyroid cancer treatment Zictifa, saying agency concerns about the drug’s safety were not enough to justify limiting its indication.

While FDA drug reviewers had focused on Zictifa’s (vandetanib) “substantial toxicity profile,” members of the agency’s Oncologic Drugs Advisory Committee told the FDA Thursday that physicians would be able to determine the appropriate use of the drug for their patients.

“This is a drug that appears to work and appears to work pretty well,” said Mikkael Sekeres, an oncologist at the Cleveland Clinic. “I would favor leaving the criteria broad —most oncologists would have the good sense to give this appropriately.”

AstraZeneca is seeking to have Zictifa approved to treat patients with unresectable locally advanced or metastatic medullary thyroid cancer. However, the FDA had questioned whether the drug’s indication should be narrowed to patients with progressive, symptomatic medullary thyroid cancer (DID, Dec. 1).

Among the FDA’s concerns was a Phase III trial of Zictifa involving 331 patients, in which about 31 percent of patients taking the drug experienced a serious adverse event compared with 13 percent who took a placebo.

The advisory committee did not hold a direct vote on whether the drug should be approved, but a majority of the panel members expressed their support for the treatment.

“I think the patients who need the drug will get the drug under [AstraZeneca’s] proposed [indication],” said Margaret Tempero, deputy director of the University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center.

“The company should be given great credit for doing a study in a very rare disease,” added Patrick Loehrer, interim director of Indiana University’s Melvin and Bren Simon Cancer Center.

The panel did weigh in on potential postmarketing requirements for Zictifa though, voting unanimously that if the drug is approved by the FDA, additional doses should be explored by AstraZeneca in postmarket trials to determine its optimal dose.

Zictifa was originally developed by AstraZeneca as a treatment for advanced non-small cell lung cancer. However, the company was forced to withdraw its regulatory submissions for the drug, then known as Zactima, after an updated analysis showed adding the drug to chemotherapy resulted in no overall survival advantage (DID, Oct. 29, 2009). — David Belian


GSK and Valeant Receive Complete Response Letter for Ezogabine

The FDA has issued a complete response letter for ezogabine, GlaxoSmithKline (GSK) and Valeant Pharmaceuticals’ investigational anti-epileptic drug.

According to the companies, the FDA cited nonclinical reasons for the letter. GSK and Valeant are reviewing the letter and are working toward a response, which they hope to submit to the FDA as soon as possible in 2011.

When pressed for details by DID, a GSK spokeswoman would not identify what information the FDA cited or a goal date for the companies’ response.

Ezogabine’s NDA for adjunctive treatment of adults with partial-onset seizures was submitted to the FDA in October 2009.

In August, the drug was endorsed by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee based on its efficacy as an add-on seizure treatment (DID, Aug. 12).

However, in September, the FDA delayed the user fee action goal date to Nov. 30 to review a risk evaluation and mitigation strategy submitted by GSK and Valeant at the end of August (DID, Sept. 1). — Molly Cohen


J&J, Merck Recall 12 Million Bottles of Mylanta Over Labeling

Johnson & Johnson–Merck Consumer Pharmaceuticals (JJMCP) is recalling bottles of two OTC heartburn products, including Mylanta, to correct a labeling issue.

The recalls involve 12 varieties of Mylanta liquid products totaling 12,344,928 bottles and one AlternaGEL liquid product accounting for 84,744 bottles, Johnson & Johnson (J&J) spokesman Marc Boston told DID.

An internal review of the products, which are being recalled in the U.S. and Puerto Rico, discovered information about a small amount of alcohol used in flavoring agents was missing from the packaging.

Because the recalls are not due to adverse events, consumers can continue to use the products, the company says.

Mylanta and AlternaGEL are manufactured at JJMCP’s Lancaster, Pa., plant, according to Boston, but some of J&J’s other facilities have recently had similar problems.

J&J subsidiary McNeil Consumer Healthcare last month recalled three Tylenol liquid products due to mislabeling of the presence of alcohol in flavoring agents. While the information was noted on the package, it was absent from the bottles’ front panel (DID, Nov. 29).

In early November, McNeil received a Form 483 after its Las Piedras, Puerto Rico, production facility failed to follow written and approved procedures. The rash of McNeil  manufacturing issues and recalls increases the risk that J&J may face further FDA enforcement, ranging from additional warning letters to more severe actions such as a potential hold on future manufacturing or shipments via consent decree or seizure, Wells Fargo analyst Larry Biegelsen writes in a Nov. 30 note (DID, Dec. 1). — Molly Cohen


Momenta Files Suit Against Teva as Generic Lovenox Competition Looms

With Teva Pharmaceutical Industries believed to be on the verge of gaining FDA approval for its generic version of Lovenox, Momenta Pharmaceuticals — the only company with a generic version of Sanofi-Aventis’ blood-thinner currently on the market — has filed suit against Teva claiming patent infringement.

In a complaint filed Thursday in the U.S. District Court for the District of Massachusetts, Momenta argues that in order to develop a generic version of Lovenox (enoxaparin sodium), Teva would have to use methods developed and patented by Momenta.

The company is asking the court to issue an injunction preventing Teva from marketing its generic Lovenox should it gain FDA approval, as well as monetary damages.

The FDA approved Momenta and Sandoz’s generic version of Lovenox earlier this year and, to the chagrin of Sanofi and other generic-drug makers, did not require clinical trials for the complex molecule (DID, July 27).

If successful, the suit would further extend Momenta’s exclusivity on the drug, which has brought in huge sales for the company, earning nearly $300 million in its first nine weeks on the market (DID, Nov. 2).

Momenta’s legal strategy is also one that is likely to become more common as companies move into developing generic versions of complex molecules and biologics, Chad Landmon, an attorney with Axinn, Veltrop & Harkrider, told DID.

“I think we’re going to see more and more of this [with generic biologics] where the manufacturing method really is the way to identify the product,” Landmon said. “I think you’re going to see innovators and follow-on companies asserting this a lot in the biologic space.”

For its part, Momenta defended the suit, saying that it is a standard industry practice.

“If a branded company can patent their process, particularly in the case of a biologic, I would think the same could be done by a company using its expertise to produce a similar or equivalent version,” Richard Shea, Momenta’s chief financial officer, told DID.

Teva says that its generic Lovenox does not infringe any patents and Momenta’s lawsuit is without merit, adding it will seek reimbursement of all legal fees.

Besides the Israeli generic-drug maker, other companies, including Amphastar Pharmaceuticals and Hospira, are known to be developing generic versions of enoxaparin as well (DID, Aug. 6). — David Belian


FDA Wants Crackdown on Adventitious Viruses in Biologics

The FDA is expecting biologics manufacturers to work harder to reduce the possibility of adventitious virus contamination at contract manufacturers, as well as their own sites, after recent significant and preventable contaminations, an FDA official says.

For example, using multiple methods for viral clearance could have prevented some contamination issues seen at companies, Rick Friedman, director of CDER’s Division of Manufacturing and Product Quality, told DID Thursday.

The agency is also finding “too many significant issues” between manufacturers and their contractors, such as quality assurance ethics that are not compatible with each other, Friedman said at the PDA/FDA Adventitious Viruses in Biologics workshop in Bethesda, Md. He noted the FDA has issued warning letters to both sponsors and contract manufacturers.

Friedman recommended meaningful audits and proper change notification provisions in quality agreements as important steps toward minimizing the risk of contamination.

Contamination prevention and control are “particularly tough when there’s so much biological sourced material and biological systems involved,” he added. 

Areas manufacturers should scrutinize include cell banks, raw materials (particularly animal-derived), processes, facilities, material segregation and containment, and controls over storage and handling.

“Raw material choices are big,” Friedman emphasized. “It’s something we’re going to be looking at in [good manufacturing practice] inspections a lot.” The FDA will be assessing companies’ treatment of incoming raw materials, and disinfection of supplies brought into the processing area is critical, he said.

Inspectors will also determine how well a manufacturer or contractor can close systems off to personnel and the environment, as well as cleaning and sterilization of equipment.

Biologics manufacturers also should assess their production processes’ ability to inactivate and remove infectious viruses. Friedman recommended using different methods of virus inactivation or removal in the same production process to achieve maximum viral clearance. However, some legacy processes do not include multiple viral clearance techniques, he told DID.

But companies’ evaluation of their processes should not stop with one-time studies, he warned, adding manufacturers must monitor their processes every day and look for signals of process drift, or opportunities for improving production processes.

Process drift also needs to be monitored at contract manufacturers, Friedman said Wednesday during the PQRI-FDA workshop on process drift.

A shift in product characteristics may be caused by a new batch of raw materials or a new supplier, and a company’s panel of incoming product testing should be able to detect if a batch is different. Testing also should be conducted during significant manufacturing stages.

These issues can also pose problems for companies preapproval, Jay Elterman, director of CBER’s division of manufacturing and product quality, said Thursday at the workshop.

Adventitious agents have been cited in clinical hold letters, and the FDA has noted issues with materials sources, lack of information on viral strain history, or lack of information on the identity and purity of source materials. Companies also have neglected to provide the agency with their description and results of their adventitious agent testing.

“Lack of documentation has certainly been raised during the [preapproval reviews] and would certainly lead into the next couple of questions,” Elterman noted. — April Hollis

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