CLEVELAND, Ohio -- Pharmacists donned white suits in a sterile chamber then entered a "clean room" on a recent Tuesday at the Cleveland Clinic's main campus, ready to make a medication needed for patients.

The team mixed 60 batches of Bupivacaine 0.1 percent + Fentanyl 2mcg/ml -- an epidural anesthetic used during surgery. They make this anesthetic once, at times twice, a week in addition to other drugs Clinic doctors need for patients.

A nationwide shortage of medications continues to worsen at an alarming rate with no solution in sight, forcing medical systems in Northeast Ohio to take steps like this to avoid going without sometimes basic drugs.

Currently, 213 medications are in scarce supply in the United States. Most of them are sterile injectables -- which include older drugs used for cancer treatment, anesthetics for surgery, antibiotics for infections, "crash cart" drugs used in emergency rooms and electrolytes for patients on intravenous-nutrition feeding tubes.

In 2005, just 61 drugs were on the shortage list, according to the Food and Drug Administration. Last year, 178 drugs were on the limited-supply list -- 132 of them given in hospitals by injection or intravenously.

Shortages could cost hospitals across the nation at least $415 million a year, according to Premier Healthcare Alliance (pdf), a national watchdog group.

Shortages are a problem nationwide



The shortages stem from several things. The FDA will temporarily halt production at plants when quality-control and sterility issues are detected. Manufacturers periodically face a lack of raw materials, and some companies choose to stop production of older, low-profit medicines once patents expire in favor of newer, high-cost drugs.

"If there's a production line with quality-control problems, it may affect five or six drugs," said Dr. Mandy Leonard, system director of drug-use policy and formulary management in the Cleveland Clinic's pharmacy department.

"With expansion in the global market, countries like China and India are making drugs and competing for raw materials," Leonard said. This could make components harder to obtain and more expensive for U.S. manufacturers.

Nationwide concern over this complex issue continues to build.

Last month, President Barack Obama signed an executive order instructing the FDA to take quick action in three areas: widening the reporting of potential shortages, alerting the Justice Department to suspected price-gouging by third-party vendors, and finding quick solutions when drug producers have quality-control issues.

Making sterile injectable drugs is a complex process that involves numerous steps, said Carl H. Lufter Jr., director of pharmacy services at University Hospitals Case Medical Center. "They have to use different types of manufacturing practices to ensure sterility of the product. That's when they may run into quality-control problems with the FDA."

Pharmacists at the Clinic, UH and other area medical centers devote a large portion of each day tracking the FDA's shortage list and keeping doctors apprised of scarce drugs as they map out treatment plans for patients.

"When we're aware of a shortage, we look at whether we use the drug, how much we have in inventory and when the shortage is expected to be over," Leonard said.

Sometimes, there are alternatives on the pharmacy shelves. "There could be another option that still has data making it an acceptable alternative for treatment," she said. Oral medication, in some situations, may be acceptable for some patients instead of injectables.

Pharmacists look at conservation as well. Surgeons, for example, may routinely discard portions of a medication used in the operating room if the sterile vial from the manufacturer contains a larger dose than needed. Pharmacists can stretch the medication on hand by going into the clean room and repackaging drugs into smaller doses, she said.

In some instances, pharmacists mix a needed drug if they can get the raw components. "It's going back to what we went to pharmacy school for. We don't like to do this unless we have to, though," Leonard said.

By law, hospitals are allowed to mix a compound for their own use but are prohibited from selling it to another institution, Leonard said.

While manufacturers are not required to announce shortages, the reasons for them or the anticipated duration, the FDA works with companies to get the information so it can be posted on the government website, said Shelly L. Burgess, FDA public affairs specialist.

Companies are, however, required to tell the government six months in advance about discontinuations of sole sources and medically necessary drugs.

"This limited requirement is not sufficient to address the drug-shortage problems," Burgess said.

This year, 99 shortages were avoided because companies voluntarily notified FDA officials, who worked with manufacturers to overcome production difficulties.

One of the drugs that concerned Northeast Ohio doctors this year was cytarabine, an anti-leukemia medication that has no alternative. The production holdup stemmed from an active ingredient that was crystallizing. To avert a shortage, the FDA permitted the drug to be sold but with instructions on how to dissolve the crystals before administering it to patients.

Burgess said that when a critical drug supply is in jeopardy, the FDA searches for overseas companies that are willing and able to temporarily export the drug. The FDA evaluates the foreign drug to ensure that it is of adequate quality and risk free.

"Information about the imported drug and how patients can access supplies is posted on the FDA drug-shortage website, along with the 'Dear Healthcare Professional' letter from the company that is [exporting] the drug," she said. Medical centers, by law, are not allowed to purchase drugs from foreign companies unless they are approved by the FDA.

Right now, all of the drugs listed on the FDA's drug-shortage website (tinyurl.com/drugshort) are considered medically necessary, she said.

But the FDA cannot force U.S. companies to manufacturer specific drugs, even if the need is critical.

Problem contributes to gray market



Some doctors want the government to compel companies to give advanced notice of manufacturing holdups because treatment delays may interfere with recovery.

But some people think that too much advance notice could create yet another problem: hoarding and price gouging by companies that buy up and resell drugs on what has become known as the gray market.

UH's Lufter said medical centers that get solicitations from unfamiliar distributors sometimes have no guarantee of where the drug was initially purchased, its pedigree or whether it was stored properly.

During congressional hearings last month, Premier Healthcare Alliance officials testified that the average markup of gray-market drugs was 650 percent and in extreme cases 1,000 percent.

An ongoing congressional investigation, which began in October, found that several nonmanufacturing companies were selling drugs at extremely high prices. One company offered cytarabine for $990 per vial, which officials said is more than 80 times the typical contract price of $12 per vial.

A survey by the Institute for Safe Medicine Practices, a nonprofit watchdog group, found that 56 percent of purchasing agents and pharmacists at 549 hospitals reported receiving daily solicitations -- by telephone, email or fax -- from as many as 10 gray-market vendors.

But not all secondary distributors should be lumped into the "gray market" designation, said Pat Earl, CEO of Secure Pharma Distributor Network. Some misconceptions come from not understanding how distribution pricing works, she said.

Earl explained that a group purchasing organization, or GPO, typically represents a number of hospitals. The GPO negotiates a discounted contract price off the wholesale acquisition price, or WAC, with drug manufacturers.

Larger wholesalers then buy at the WAC price, sell the drugs to hospitals at the GPO rates and immediately recover the price differential from the manufacturers.

A secondary distributor that is not part of the GPO-authorized network would initially pay the WAC price or higher for a drug; adding expenses such as storage and shipping would increase the cost to the next buyer, she explained.

She used propofol, a surgical anesthetic, as an example. Propofol has a wholesale acquisition cost of around $5.60 per 20 milliliter vial. Its GPO price can be as low as 48 cents per vial, which is a 91 percent discount. When a secondary distributor buys the drug at the WAC price or higher and then sells it, adding expenses, the end price tag could be 1,000 percent over the negotiated GPO price.

In the meantime, Northeast Ohio medical centers are trying to keep pace with the mounting shortages and maintain care for patients.

"We try to make this seamless for the patients and physicians and try to make sure it doesn't affect patients," the Clinic's Leonard said.