Disappearing Drugs
By Crystal Conde Texas Medicine May 2012

Shortage Worries Physicians, Federal Officials 

Public Health Feature – May 2012 

 Tex Med. 2012;108(5):29-33. 

By Crystal Conde 
Associate Editor 

Austin oncologist Debra Patt, MD, MPH, recalls one of the scariest moments in her career. In December 2010, she discovered an Austin hospital had run out of the cytarabine she needed for a patient with acute myelogenous leukemia, a fast-progressing cancer that typically takes a patient's life within three months if he or she is not treated quickly and properly. 

"I was really concerned because this particular drug has no alternative," said Dr. Patt, chair of the Texas Medical Association's Committee on Cancer. 

Dr. Patt practices at Texas Oncology, a group she says constantly examines drug inventory to help anticipate and head off shortages. The practice also can contact other Texas Oncology pharmacies and area hospitals to find needed drugs.  

"Luckily, Texas Oncology was able to acquire cytarabine and give it to the hospital. That was a close call that would have compromised patient care. It made me and other doctors nervous," she said. 

According to the U.S. Food and Drug Administration (FDA), the shortage of cytarabine has been resolved since October 2011, with two U.S. manufacturers reporting adequate supply and anticipating no further supply problems. Unfortunately, many drugs linger on the FDA's drug shortage list. 

Oncology is one of many specialties hard hit by a nationwide drug shortage that began in 2006. (See “Drug Shortage," October 2011 Texas Medicine, pages 23-29.) In fact, since then, the number of drugs in short supply rose dramatically, more than quadrupling over five years to a record 267 in 2011, according to the University of Utah Drug Information Service, which tracks national drug shortages. 

A Whitehouse.gov fact sheet says 43 percent of these shortages were due to product quality concerns. Quality problems during manufacturing ranged from finding glass shards and metal filings in drugs to discovering fungal or other contamination in injectable products. Additional leading reasons for the reported shortages were delays in manufacturing or shipping (15 percent) and active pharmaceutical ingredient shortages (10 percent).  

A Review of FDA's Approach to Medical Product Shortages, published in October, says sterile injectables accounted for the majority (80 percent) of the 127 studied drug shortages from 2010 to 2011. Sterile injectables include oncology drugs, anesthetics, intravenous nutrition drugs, and many drugs used in emergency departments.

Surgical oncologist R.Y. Declan Fleming, MD, president of the Travis County Medical Society and a member of the TMA Committee on Cancer, doesn't administer drugs to patients but he's noticed the limited supply of some of the drugs patients receive following surgery.  

"When a shortage occurs, patients often receive older or less desirable drugs that may have worse side-effect profiles. It's a real pity that this is a far too frequent part of patients' experiences now," he said. 

TMA President-Elect Michael Speer, MD, a faculty member in the Neonatology Section of Baylor College of Medicine, says drug shortages are frustrating because "the best medication for the patient's condition is no longer available." He adds that physicians have no choice but to make drug substitutions that may not be in the patient's best interest.  

Bob Stuifbergen, pharmacy manager for Texas Oncology-Austin Midtown, says many effective, tried-and-true drugs are generic and manufactured by only a handful of companies.  

"When one quits producing the drug, there isn't enough time for the other manufacturer to ramp up production to accommodate for the volume. It is more profitable for drug manufacturers to produce the new, high-cost agents rather than the lower-cost alternatives," he said. 

Dr. Patt says a shortage of Doxil, used to treat ovarian cancer, forces her to use an alternative drug. She notes, however, that not all alternative drugs are as effective as the preferred drug, and some can pose different side effects for patients.  

Doxil has been missing from the U.S. marketplace for more than a year because the company that makes the drug for Johnson & Johnson had to shut down production due to quality concerns. FDA acted earlier this year to replace Doxil, temporarily allowing importation of the drug Lipodox from India. The agency also approved a new supplier for a preservative-free version of methotrexate, a drug for children with acute lymphoblastic leukemia, for lymphomas, and for osteosarcoma. 

Dr. Patt applauds the FDA's actions to bring effective, lifesaving drugs onto the market. 

"Allowing similar drugs into the market will benefit many patients. These are tools we need to effectively treat them," she said, adding that she hopes the federal government will take more measures to reduce the impact of the nationwide drug shortage. 

In the meantime, physicians can report a drug shortage to FDA and request a current list of drug shortages.  

FDA isn't the only agency to take heed of the drug shortage and its effect on patients and physicians. The Texas Medical Board (TMB) is taking drug shortages and drug storage into account as mitigating factors in investigations of physicians who use expired drugs. 

TMB spokesperson Leigh Hopper says the board recently heard from a physician about a case in which doctors had to use expired emergency drugs to resuscitate a patient, thus raising the question of whether the board would consider the use of expired drugs a violation of the standard of care. 

"The short answer is, if TMB investigates a complaint involving expired drugs, it will consider the drug shortage as well as storage conditions in making a determination," Ms. Hopper said in an email. 

Ms. Hopper says an FDA study the military requested produced most of the information about drug expiration dates.  

"With a large and expensive stockpile of drugs, the military faced tossing out and replacing its drugs every few years. What they found from the study is many of the drugs, both prescription and over-the-counter medications, were good to use years after the expiration date. But the key was proper storage," she wrote.  

She added the board has no plans to amend its rules, which don't specifically address the use of expired drugs. The issue would arise only if someone files a complaint against a physician. TMB would then investigate to determine "if the expired drug was used as a result of a documented shortage, and if so, was it stored properly," Ms. Hopper said. Potential penalties for use of expired drugs range from a fine and required continuing medical education to revocation of a physician's medical license, depending on the circumstances of the case, according to Ms. Hopper. 

Dr. Patt doesn't know if the use of expired drugs has increased since the drug shortage began but says if things get bad enough, "we could see an increase in expired drug use. My practice has a strict policy against administering expired drugs," she said.   

White House, FDA Act 

In the wake of a shortage, FDA works with manufacturers to address low-risk (wrong expiration date on package) and high-risk (particulate in product or sterility issues) quality and safety problems. FDA may use its regulatory discretion to address shortages to mitigate any significant risk to patients.  

FDA can encourage remaining firms to ramp up supply. When a company needs a new manufacturing site or new raw material supplier, FDA can expedite the review of these changes. For products in shortage or at risk for shortage, FDA can expedite the review of new manufacturers interested in producing the product.  

In rare cases, the agency can temporarily import drugs from other countries or unapproved sources. While FDA can exercise some regulatory discretion in extreme circumstances, the agency can't force a manufacturer to produce a product or impose a penalty on a manufacturer for not notifying FDA of a discontinuation.  

By law, manufacturers don't have to report plans to discontinue producing a product unless they are the sole manufacturers of a drug that is life supporting, life sustaining, or intended for use in the prevention of a debilitating disease or condition.  

In October, the White House directed FDA to do more to curb drug shortages. Specifically, it ordered FDA to:  

• Use its existing authority to require sole-source drug manufacturers to notify FDA in advance of issues that could lead to shortages of certain critical drugs; and 
• Expedite its regulatory reviews of new drug suppliers, manufacturing sites, and manufacturing changes to help avoid or mitigate an existing or potential drug shortage.  

FDA immediately reminded all pharmaceutical manufacturers of their responsibility to report the discontinuation of certain drugs to the agency. It also encouraged manufacturers to voluntarily tell FDA about potential prescription drug shortages in cases where law currently doesn't require disclosure. 

In December, in response to the executive order, FDA began requiring manufacturers that are the only producers of certain drug products to report to FDA all interruptions in manufacturing of products that are life supporting, life sustaining, or intended for use in the prevention of a debilitating disease or condition.  

An HHS fact sheet reports that since the October executive order, FDA has prevented shortages of 96 drugs (86 from one firm). Before the executive order, the number of shortages prevented since January 2010 was 137, bringing the total number of shortages prevented in the past two years to 233. 

It's critical that TMA and the American Medical Association examine the drug shortage problem "because it affects patient safety and welfare," says Dr. Speer.  

Health organizations are collaborating with stakeholders to develop recommendations to prevent shortages and to improve communication about impending drug discontinuations and limited supplies.  

The TMA House of Delegates adopted a recommendation on drug shortages and physician communication made by the TMA Committee on Infectious Diseases at TexMed 2011. The committee said "better tracking of drug shortages and more effective communication are certainly warranted to make health care professionals aware of shortages and allow them to plan accordingly."  

The report directs the association to "work with the American Medical Association and appropriate federal agencies to increase federal monitoring of potential drug shortages and enhance communications with physicians regarding drug shortages and alternative treatments."  

At its 2011 Interim Meeting, the AMA House of Delegates backed the recommendations formed at the 2010 American Society of Anesthesiologists Drug Shortages Summit.  

Those recommendations include:     

• Exploring the expansion of FDA authority to require manufacturer notification of market withdrawals;   
• Defining and implementing evidence-based and other criteria for identifying critical drug therapies that are vulnerable to drug shortages;   
• Considering incentives to manufacturers that produce critical drug products or that upgrade manufacturing plants to meet or exceed good manufacturing practices in exchange for guarantee of continued production of these therapies; and   
• Establishing improved processes to extend product stability for products in short supply.    

Delegates also directed AMA to advocate that FDA or Congress require drug makers to establish a continuity plan for supplying vital and life-sustaining medications and vaccines.  

The house asked the AMA Council on Science and Public Health to report at the June 2012 Annual Meeting on progress in preventing drug shortages, especially in oncology. 

Drug Prices Skyrocket 

The U.S. Food and Drug Administration (FDA) is working with the U.S. Department of Justice (DOJ) to address stockpiling and exorbitant pricing of scarce drugs.  

"Buyer Beware: Drug Shortages and the Gray Market" is an analysis conducted by North Carolina-based Premier Healthcare Alliance, which operates a health care purchasing network and consists of more than 2,500 U.S. hospitals. The analysis defines the gray market as "a supply channel that is unofficial, unauthorized, or unintended by the original manufacturer." In the face of a product shortage, gray market vendors may sell the item at an exorbitant price. 

The analysis found the average markup for drugs in shortage was 650 percent. Ten drugs in short supply offered at the highest markups are:  

• Labetalol (cardiology): 4,533 percent; 
• Cytarabine (oncology): 3,980 percent; 
• Dexamethasone 4 mg injectable (oncology and rheumatology): 3,857 percent; 
• Leucovorin (oncology): 3,170 percent; 
• Propofol (critical care sedation and surgery): 3,161 percent; 
• Papavarine (critical care): 2,979 percent; 
• Protamine (critical care): 2,752 percent; 
• Levophed (critical care): 2,642 percent; 
• Sodium chloride concentrate (critical care): 2,350 percent; and 
• Furosemide injectable (critical care): 1,721 percent. 

Health care professionals concerned about drug price gouging due to shortages can contact FDA's Office of Criminal Investigations. 

In addition, late last year, U.S. Sen. Charles Schumer (D-N.Y.) filed legislation to make purchasing life-sustaining drugs and selling them at huge markups a federal crime. The bill gives the DOJ the authority to prosecute price gougers and to take action against unprincipled drug distributors.  

Crystal Conde can be reach by telephone at (800) 880-1300, ext. 1385, or (512) 370-1385; by fax at (512) 370-1629; or by email.  

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