Special Report

Workshop Examines Causes, Potential Remedies for Drug Shortages

Worsening shortages of many drugs are increasingly affecting patient care, according to numerous participants at a Food and Drug Administration (FDA)-sponsored workshop held last week. Drugs in short supply include antibiotics, anesthesia drugs, and intravenous nutrition. Cancer drugs, however, make up the largest proportion of drugs in short supply, and the impact of the shortages on cancer care was a focus of discussion at the daylong meeting.

The workshop came only days after Department of Health and Human Services Assistant Secretary for Health Dr. Howard Koh told attendees of a congressional hearing that shortages of cancer drugs—primarily of older chemotherapy agents that are the backbone of treatments for a number of cancers—have delayed or halted enrollment in many NCI-sponsored clinical trials.

The September 26 workshop brought together key stakeholders—including physician and hospital group representatives, patient advocates, and drug industry representatives—in an effort to better understand the reason for the shortages and to discuss potential solutions to what have been the largest and, for some of these drugs, the longest-lasting shortages on record.

Although numerous participants reported that the shortages are affecting growing numbers of patients, the FDA also had some good news to report. Working closely with drug manufacturers, the agency said, it has been able to prevent 99 new shortages this year.

The Cancer Impact

Drug shortages began occurring regularly more than a decade ago, but they have worsened in recent years. According to the FDA, the number of drugs in short supply has tripled since 2005. In 2010, 178 drugs were in short supply, said Dr. Edward Cox, coordinator of FDA’s Drug Shortage Program. And, he continued, 2011 “is expected to be worse.”

The chemotherapy drugs currently in short supply include decades-old drugs such as 5-FU, vincristine, daunorubicin, cytarabine, and leucovorin, which have long been part of standard treatments for leukemia and for testicular and colorectal cancers. Almost all of the drugs are sterile injectables and available as generics. In fact, in many cases, the brand-name versions of the drugs are no longer manufactured, said Dr. Ralph Neas, president of the Generic Pharmaceutical Association.

When effective chemotherapy drugs have been unavailable, oncologists have had to turn to alternatives that may be less effective and are often more toxic, said Dr. Lawrence Solberg of the Mayo Clinic Jacksonville. As a result, he continued, patients “are experiencing increased suffering.”

Diane Hamlin and her 16-year-old daughter, Abagale, put a human face on just what the shortage can mean for some patients. Abagale was diagnosed with acute myeloid leukemia in March 2011. One of the drugs that is highly effective against AML, daunorubicin, was not available. So Abagale’s physicians had to use doxorubicin instead. (Doxorubicin, however, is also in short supply.)

The mucositis in her mouth, throat, and stomach caused by the drug was so severe that Abagale was in constant pain, had to receive heavy doses of painkillers, and had to be fed through an IV tube. The ordeal, which lasted nearly a month, “was a very dark time for me,” Abagale said.

Causes and Side Effects

Economic forces and regulatory and manufacturing problems, among other issues, have all contributed to the shortages, said Dr. Douglas Throckmorton, deputy director of FDA’s Center for Drug Evaluation and Research. The largest contributor—accounting for roughly 54 percent of the shortfall—has been product quality and manufacturing issues, such as failure to comply with good manufacturing practices and issues with particulate matter in drug vials.

Other key factors have been product discontinuations, industry consolidation (just seven companies now produce most of the sterile injectables that are in short supply), and a lack of alternate sources of raw materials used to make the drugs and in manufacturing capacity.

For example, Johnson & Johnson reported September 23 on its website that supplies of Doxil, a form of doxorubicin encapsulated in a liposome, or lipid shell, would be limited over the next few months because the company is transitioning to a new contract manufacturer after its current manufacturer “indicated its intentions to transition out of the contract manufacturing services business over the next several years.”

At the workshop last week, Dr. Neas and other manufacturing representatives disputed whether consolidation in the drug manufacturing industry has had an appreciable impact on the shortages. Jonathan Kafer of Teva Pharmaceuticals, one of the largest manufacturers of sterile injectable drugs, noted that the spike in shortages over the past 2 years has coincided with manufacturing issues at several different companies.

And even after manufacturing problems have been addressed, the product is not immediately available, Kafer stressed. Sterile injectables, which are complex to manufacture, can take several months to become broadly available after production resumes, he said.

A particularly troubling outcome of the shortages, numerous participants said, has been the growth of so-called gray markets: secondary distributors of drugs that are not part of the mainstream distribution process. The safety and reliability of drugs obtained from these distributors is questionable, several participants cautioned, and such distributors often charge outrageous markups.

Bryant Mangum of Premier healthcare alliance reported that in a survey of 42 of Premier’s acute-care hospitals, 18 gray-market vendors made nearly 1,750 offers of back-ordered or unavailable drugs. The average markup for the drugs was 650 percent; the highest markup (for a blood pressure drug) was 4,533 percent, with markups for cytarabine (3,980 percent) and leucovorin (3,170 percent) not far behind.

FDA staff and other participants cautioned hospitals and community physicians not to purchase drugs from gray-market distributors and to report suspect distributors to their state pharmacy boards, to FDA’s MedWatch program, and to state and local authorities.

Searching for Solutions

Following a November 2010 summit on the drug shortages, a stakeholder working group was convened to develop recommendations on how to address current shortages and how to prevent or mitigate future shortages.

Included among the working group’s recommendations was more robust and earlier communication among FDA, industry, hospitals, and clinicians about potential shortages. The group also recommended establishing criteria for identifying drugs that are vulnerable to shortages and processes for ensuring that alternate sources of supply are in place for such drugs. Other recommendations raised at last week’s meeting included the creation of a national stockpile of critical drugs, similar to a system used by the Centers for Disease Control and Prevention for pediatric vaccines.

Many participants praised FDA for its work in averting nearly 100 drug shortages this year alone. The manufacturers played a big role in the process, said Capt. Valerie Jensen, associate director of the FDA’s Drug Shortage Program, by giving the agency early warning of production issues and requesting expedited regulatory review when it was needed to ensure an adequate supply of a critical drug.

Early notification of production interruptions or product discontinuations would be required under the Preserving Access to Life-Saving Medications Act, a bill that has been introduced in the House and Senate, said Joseph Hill of the American Society of Health-System Pharmacists.

Alleviating the shortages will take collaboration and changes in numerous areas, said Dr. Erin Fox of the University of Utah’s Drug Information Service. “There’s no one solution that can fix this problem,” she said. “It’s too complex.”

—Carmen Phillips

Further reading: “Continued Shortage of Chemotherapy Drugs Causing Concern”