Washington Editor

The record number of drug shortages in the U.S. could be a glass half-full/half-empty proposition for biotechs.

Last year, 178 different drugs hit the FDA's list of drugs in short supply. "That was a record year for shortages," Valerie Jensen, associate director for the agency's drug shortage program, told BioWorld Today. That number was up more than 13 percent from the 157 listed in 2009.

While there are biologics that can't keep up with demand, the majority of the 67 drugs currently listed by the FDA as being in short supply are older pharmaceuticals, Jensen said.

What that means for biotechs on the glass half-full side is opportunity. To meet the need in a shortage situation, the FDA will consider other drugs approved for the same indication, off-label uses of other drugs and investigational products, FDA spokeswoman Shelly Burgess said.

But on the half-empty side, a biotech could have clinical trials delayed if a comparator drug or part of a drug combination isn't readily available.

While it is the sponsor's responsibility to ensure there is an adequate supply of all the drugs needed in a trial, the FDA will make companies aware of shortages it knows about. "There are situations when clinical trials were delayed or put on hold due to a shortage of the drug used in the study," Burgess told BioWorld Today.

Sometimes those shortages are unpredictable. Genentech Inc.'s Xeloda (capecitabine), for instance, hit the shortage list this year when the Roche Group subsidiary recalled 13 lots of bottled 500-mg tablets due to the presence of low levels of naphthalene and 1, 4 – dichlorobenzene. The chemotherapy agent, used in a number of trials with biologics, remains in short supply and is being offered in alternative packaging while the South San Francisco-based company corrects the problem.

One of the current trials using capecitabine is Aeterna Zentaris Inc.'s Phase III perifosine trial for colorectal cancer. The study compares a combination of perifosine and capecitabine with placebo plus capecitabine. (See BioWorld Today, March 10, 2011.)

In this case, Aeterna, of Quebec City, has been lucky. The Xeloda shortage has not affected its trials, company spokesman Paul Burroughs told BioWorld Today.

Three-fourths of the drug shortages reported last year involved sterile injectables, Jensen said. And most of the shortages could be traced to three basic problems:

manufacturing quality issues, especially at larger factories;

delays in getting product needed to make a drug;

a company's discontinuation of a drug.

With older drugs, several companies often share the market for a specific product. If one of the companies experiences a problem, its competitors may not have the capacity to step in and fill the increased demand, Jensen said.

That's the case with cisplatin, another chemotherapy agent that may be used in combination with biologics or as a comparator arm in some biologic trials. Shortages of cisplatin injection 1 mg/mL solution have been ongoing since last year.

Teva Pharmaceutical Industries Ltd., of Petach Tikva, Israel, and Bedford Laboratories, of Bedford, Ohio – two of the three companies that make cisplatin – have experienced manufacturing delays. With the Bedford product on back order and Teva releasing it as it becomes available, APP Pharmaceuticals Inc., of Schaumburg, Ill., finds itself with more demand than it can meet.

Since such shortages likely are temporary, other companies that make the drug may be reluctant to invest in expanding their capacity, Jensen said.

Capacity generally isn't an issue with sole-source drugs, including most biologics, Jensen said. Companies that are the only ones making a drug consider the demand when planning their capacity.

During a shortage, the FDA works with companies to resolve quality issues and meets with other firms to discuss steps they can take to fill the void. Except with orphan drugs, the agency doesn't have the authority to consider a company's capacity when granting exclusivity or new indications, Jensen said.

Thus, Spectrum Pharmaceuticals Inc. recently received FDA approval for the use of Fusilev (levoleucovorin) in combination with 5-fluorouracil to treat patients with advanced metastatic colorectal cancer, despite a shortage of levoleucovorin that began in March.

Since levoleucovorin can be used in place of leucovorin, that shortage has been exacerbated by manufacturing delays of leucovorin calcium lyophilized powder at both Teva and Bedford.

When Fusilev was first approved in 2008, it had a narrow indication – to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdose of folic acid antagonists, Spectrum spokesman Paul Arndt told BioWorld Today. The manufacturing capacity was ample for that indication.

"We have been working diligently in preparation for the approval" of the expanded indication, Arndt said. Those preparations included ramping up manufacturing to meet the increased demand.

Although Spectrum should have adequate supply now, the FDA used its enforcement discretion to permit the Irvine, Calif., company to import levoleucovorin powder to address the shortages for both levoleucovorin and leucovorin.

The FDA will resort to imports, on a temporary basis, when shortages are ongoing, Jensen said, adding that the imported products are thoroughly evaluated.

For example, as a result of an ongoing supply disruption of Genzyme Corp.'s Fabrazyme (agalsidase beta), the FDA permitted Basingstoke, UK-based Shire plc to provide its ERT Replagal (agalsidase alfa) to U.S. patients with Fabry disease under an early access program. Replagal is approved in 45 countries, but it has yet to be approved in the U.S. (See BioWorld Today, Aug. 4, 2010.)

The Cambridge, Mass.-based Genzyme, now part of the Sanofi-Aventis Group, is the only company with an FDA-approved treatment for Fabry disease.

Continuing manufacturing problems with Fabrazyme have led to repeated patient petitions asking the Department of Health and Human Services to exercise its so-called "march-in" rights under the Bayh-Dole Act to grant an open license for other drugmakers to use Genzyme's patents.

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