FDA asks stakeholders to weigh in on solutions
The drug shortage crisis is not over yet. Although the number of new drugs in short supply decreased in 2012 from an all-time high of 267 in 2011, health systems are still experiencing high numbers of shortages, many of them due to unresolved shortages from previous years.
By the end of the fourth quarter of 2011, the University of Utah Drug Information Service had identified 273 active shortages. A year later, active shortages hit an all-time high of 299. In the first quarter of this year, there were 295 active drug shortages.
Those shortages added up to a national problem for health-system physicians, pharmacists, and their patients, according to Erin Fox, PharmD, a clinical pharmacist and manager of the university’s Drug Information Service, Salt Lake City, Utah. Her organization tracks national drug shortages, researches alternative agents, and shares that information with the American Society of Health-System Pharmacists (ASHP) to post at its website (http://www.ashp.org/shortages).
“There is no single reason for drug shortages, but the problem has escalated to the level of a public health crisis as patients and clinicians are impacted daily,” said Fox, who provided comments in April to the FDA Drug Shortages Task Force, which is working to develop a strategic plan to address and prevent drug shortages.
The most common drug classes in short supply last year included antibiotics, central nervous system drugs, electrolytes, and nutrients with trace elements of zinc. These shortages have had an impact on patient care.
In mid-December 2012, three premature infants in a hospital neonatal intensive care unit (NICU) developed severe dermatitis on their hands and feet, around their mouths, and in the diaper area. The infants all had severe cholestasis. They all had been treated with parenteral nutrition, and after infections, drug reactions, and new adhesives were ruled out, the focus turned to the parenteral nutrition.
It was discovered that the hospital pharmacy had reported a shortage of injectable zinc the month before. The result of that shortage, according to a report from the Centers for Disease Control and Prevention (CDC), was zinc deficiency dermatitis in the three newborns. The CDC warned other NICUs of the need to monitor zinc levels in premature infants to avoid this condition.
One of the two manufacturers of injectable zinc, Hospira, expects to release its product (zinc chloride 1 mg/mL 10 mL vial) this month, according to the ASHP website.
Shortages of electrolytes have also been at crisis levels for hospitals, Fox told Drug Topics. When a facility does not have enough calcium chloride, dextrose solution, and phosphates, it can be extremely disruptive to provision of medical care.
“You have to scramble on a daily basis to try to make ends meet at your facility when you are out of your basics,” Fox said. “At our facility, we have had to switch back and forth in providing a different dialysis solution for patients, depending on if we have enough calcium chloride or calcium gluconate. There is high potential for medication errors when switching back and forth like that with different products and different doses,” she added.
Chemotherapy drug shortages also were critical in 2010 and 2011. However, by last year, the severity of these shortages had decreased significantly. But the shortage of chemotherapy drugs had significant impact on patient care during that time, through delays in chemotherapy administration, changes in treatment dose or regimen, increased costs, and reimbursement challenges, said James M. Hoffman, PharmD, medication outcomes and safety officer, pharmaceutical services, St. Jude Children’s Research Hospital, Memphis, Tenn.
In a report about oncology drug shortages that was published in the April issue of the American Journal of Health-System Pharmacy, Hoffman and his colleagues found that of 243 oncology pharmacists who responded to a national survey on drug shortages, 239 reported at least one drug shortage at their institutions in the 12 months previous to the September 2011 survey, and 235 reported that compared to the situation in 2010, drug shortages associated with oncology treatments had increased. Most of the respondents worked for community hospitals and academic medical centers.
Chemotherapy delays or changes in treatment regimens were reported by 227 of these institutions, Hoffman said. Treatment delays resulting from drug shortages were felt acutely by patients with ovarian cancer, colorectal cancer, breast cancer, and acute myeloid leukemia. The oncology medications that were hard to obtain during this period were liposomal doxorubicin, fluorouracil, leucovorin, paclitaxel, cytarabine, doxorubicin, daunorubicin, and bleomycin.
When leucovorin - a rescue drug - was running low at Hoffman’s hospital, oncology pharmacists promoted oral use when it was appropriate. They also had to substitute levoleucovorin, which is similar to leucovorin, except for its price.
“Levoleucovorin is a much more expensive drug - about 60 times - than leucovorin,” said Hoffman. “So drug shortages have had an impact on healthcare costs.”
Besides cost, the potential for medication errors weigh on pharmacy staffs when another drug must be substituted. As do other cancer centers, St. Jude Children’s Research Hospital works to avoid medication errors resulting from incorrect conversions when it is necessary to switch to a substitute drug, but sometimes errors do happen.
“We work hard once we know about a drug shortage. We educate our pharmacists and all clinical staff about the conversions. We update this information twice a week,” said Hoffman. This practice is critical, as drug shortages can occur abruptly.
In 2009, a shortage of the drug mechlorethamine, used for the treatment of patients with intermediate- and high-risk Hodgkin lymphoma, was associated with a higher rate of relapse in children, teens, and young adults, said Hoffman.
St. Jude Children’s Hospital researchers led a study examining the two-year cancer-free survival of patients who received the drug substitute cyclophosphamide instead of mechlorethamine for treatment of Hodgkin lymphoma. The retrospective analysis found that patients who received the substitute of cyclophosphamide had a higher rate of relapse, with the estimated 2-year cancer-free survival dropping from 88% to 75%.
“We can think of no credible explanation for this dramatic difference in event-free survival other than the drug substitution, since careful analysis of our data demonstrated that patients in the cyclophosphamide cohort did not have more unfavorable clinical features than those in the mechlorethamine cohort,” said Monica L. Metzger, MD, one of the study’s principal investigators. The article was published in the December 27, 2012 issue of the New England Journal of Medicine.
“Our results demonstrate that, for many chemotherapy drugs, there are no adequate substitute drugs available,” Metzger said in “Drug shortage linked to greater risk of relapse in young Hodgkin lymphoma patients,” an article published at the hospital’s website (www.stjude.org).
The drug shortage crisis has forced health systems to become proactive when dealing with these daily challenges. Management of shortages in drug products has required pharmacists to take on the important role of tracking these shortages. This costs them more time, and most health-systems have not added more resources, according to Hoffman.
“Pharmacists are taking hold of this new role to support patient care,” Hoffman said. “Unfortunately, this is the ‘new normal’ with drug shortages not going away.”
More expansive than the list of critically necessary products made public by FDA is ASHP’s online drug shortage bulletin, which includes all drugs in short supply (www.ashp.org/DrugShortages/Current/). In addition, using information supplied by the University of Utah Drug Information Service, ASHP provides a list of alternative agents for management of drug shortages and compares the drugs in terms of dosing at the onset of action (minutes) and the clinical duration after clinical dosing (minutes).
Other strategies that help with management of drug shortages within health systems include centralization within the pharmacy of drugs in short supply, education of physicians and other healthcare professionals about alternative agents for use, and sharing of repackaged sterile injectables for use within the same health system.
Bona Benjamin, PharmD, director of Medication-Use Quality Improvement at ASHP, corresponds with ASHP members on a regular basis about the management of drug shortages.
“What some pharmacists have told me that has worked well is to make the pharmacist who participates in patient care the expert on shortages,” Benjamin said. “While the healthcare team is rounding and making decisions, the pharmacist can inform them what drugs are available and what drugs are in short supply.”
Last July, the Food and Drug Administration Safety and Innovation Act of 2012, legislation designed to help alleviate the drug shortage crisis, was signed into law by President Obama.
ASHP has been a strong advocate of this law, which includes an early notification system requiring drug manufacturers to inform FDA of any production issues at their facilities or of plans to discontinue a drug.
Manufacturers must notify FDA six months before a product is discontinued and as soon as possible in the case of production problems. FDA is responsible for notifying the Drug Enforcement Administration (DEA) within 30 days if the drug in question is a controlled substance.
In addition, the new law requires FDA to create an updated list of critically needed drugs in short supply, to be maintained at the FDA website for easy public access. (http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm.) The list includes the names of the drugs, their manufacturers, the reasons for the shortages, and the estimated duration of each shortage.
The legislation also allows hospitals to repackage drugs that were in short supply into smaller volume doses for use within their own health systems.
FDA has made progress over the last two years in preventing shortages. According to Valerie Jensen, a pharmacist who is associate director at FDA’s Center for Drug Evaluation and Research (CDER), FDA prevented 195 shortages in 2011 and 282 in 2012. However, she said, more work needs to be done.
ASHP’s Benjamin echoed those sentiments when she spoke with Drug Topics last December.
“Even though there are fewer new drug shortages, pharmacists are still coping with the same intensity of shortages,” Benjamin said. “FDA has been able to prevent shortages with earlier notification, but there is a lot of remediation to be done to get drug supplies back to where they need to be. The year 2011 was a very intense year for shortages.”
In February this year, FDA formed an internal Drug Shortages Task Force and called for stakeholders to provide suggestions for a strategic plan to enhance efforts to address and prevent drug shortages, Jensen wrote in her column for “FDA Voice.”
In April, Fox, at the University of Utah Drug Information Service, suggested that FDA work with manufacturers of drugs in short supply to identify incentives that would help manufacturers produce quality products and respond quickly in the event of a drug shortage.
Fox also suggested that FDA consider offering manufacturers incentives to produce unit-of-use dosage forms needed in contemporary pharmacy practice.
“Few suppliers have responded to the need to supply medications in the appropriate concentration or dosage form for clinicians,” she said. “Hospitals need prefilled syringes that are stable at room temperature and bar-code ready. Hospitals need patient-controlled anesthesia syringes for their pumps.”
It would help mitigate drug waste if manufacturers supplied common doses and dosage forms necessary for patient care, Fox said.
The Generic Pharmaceutical Association (GPhA) also submitted comments to the task force, emphasizing that the association and the generic drug industry had been working to resolve these shortages and would continue in their efforts.
“A significant number of the reported shortages have been attributed to difficulties associated with the manufacturing and release of generic sterile injectable products. The manufacturing community has been responsive to this issue and has been extremely active in working with all stakeholders, and especially the FDA, to find suitable solutions that accelerate the availability of critical drugs in short supply,” wrote David R. Gaugh, RPh, senior vice president for sciences and regulatory affairs, GPhA, in his comments to FDA Drug Shortages Task Force.
He said that GPhA, the FDA Drug Shortages Team, and IMS Health were working to develop and implement a pilot program to help alleviate potential shortages, known as the Accelerated Recovery Initiative.
In addition, Gaugh suggested a number of incentives for the task force to consider, such as tax credits to offset investments in manufacturing capacity, reduced filing fees for building redundancy into the manufacturing plan, accelerated approval for filings at alternative sites, issuance of expedited review vouchers and accelerated approvals for manufacturers investing in building redundancy into their submissions, and a streamlined regulatory approval process for new manufacturing facilities and for products already approved in another facility that are then transferred to new facilities.
Until manufacturing facilities are improved, drug shortages that affect patient care will continue for the next few years, Fox said.
Hopefully, economic incentives for drug manufacturers will help to replenish drug supplies, Hoffman concluded.
Reasons for drug shortages
Generic sterile injectables have been at the center of the drug shortage crisis for some time because of economic and technological factors, according to Janet Woodcock, MD, director of the FDA’s CDER, and Marta Wosinska, director of the Economics Staff at FDA’s CDER.
“The current shortage crisis with generic sterile injectable drugs follows directly from contamination problems at multiple facilities - problems that have required correction through upgrades of systems and/or production processes,” said Woodcock and Wosinska, in an article published in the February issue of Clinical Pharmacology & Therapeutics.
They explained that these drug shortages were the result of contamination of sterile products by bacteria, endotoxins, or mold, and in some cases by the presence of glass shards and metal found in vials.
“Some of the quality issues have been with particles, such as glass shards and shavings,” said Erin Fox, PharmD, a clinical pharmacist and manager of the university’s Drug Information Service, Salt Lake City, Utah. “In some cases to prevent a severe shortage from happening, FDA has allowed those products to continue to be marketed with a required filter, so the safety issues have been addressed. Other manufacturing glitches have been sterility issues of bacterial or fungal contamination. These are pretty serious manufacturing issues and are serious to fix.”
The manufacturing problems are linked to poor maintenance of facilities and equipment, antiquated and inadequate aseptic operations, and suboptimal quality control and oversight, according to FDA. In some cases, manufacturing had to be halted completely to address these problems; in other instances, remediation was possible without a complete shutdown of the production process.
Woodcock and Wosinska attribute the shortages of generic sterile injectables to the fact that there is little economic reward because the generic manufacturers are competing on price, not quality. They stated in their article that hospitals and clinics view generic products as interchangeable and are not aware of any differences in the quality of production.
In addition to economic forces, FDA attributes the lack of quality investments to “aging facilities, new production opportunities, contracting practices, economic downturn, and a possible increase in price competition,” Woodcock and Wosinska noted.