The recent shortages of certain chemotherapy agents needed by cancer patients as well as other key drugs used for anesthesia and fighting infections raise questions about who's minding the national drug supply and how to ensure that effective medications are available when there's limited financial incentive to produce or distribute them and no mandate that manufacturers notify the Food and Drug Administration about most upcoming shortages.
The drug shortage has increased steadily for the last decade, noted Cynthia Reilly, Director of the American Society of Health-Systems Pharmacists' (ASHP) Practice Development Division.
All of the chemotherapy drugs and most of the others affected are classified as sterile injectables that have been linked to either quality or production issues and are more difficult to switch over to other manufacturers—that is, if manufacturers were interested in producing generic drugs with smaller profit margins than other newer, more lucrative drug lines have.
“Unfortunately, the issue of drug shortages isn't new, but what is new is the dramatic increase in the number of drugs and the duration of the shortages,” Ms. Reilly said during a telephone interview. “The case with chemotherapy makes it crystal clear how important this is.”
She cited annual increases from 70 drugs in 2006, to 129 in 2007, 149 in 2008, 166 in 2009, and 211 in 2010, and the expectation, she said, is that this will continue and is not just a blip. Certain oncology drugs are among those most in demand, and about a dozen oncology drugs are listed on ASHP's constantly updated Drug Shortages Resource Center website (www.ashp.org/drugshortages).
The cancer drugs that seem to be in the greatest demand are leucovorin, etoposide, doxorubicin, epirubicin, daunorubicin, and cisplatin.
Anesthetics on the list include propofol, morphine, and epinephrine, and antibiotics include colistimethate, erythromycin, TMP/SMZ, foscarnet, and amikacin.
Drug Shortages Summit
To stem the tide of shortages, four organizations convened a Drug Shortages Summit last November in Bethesda that included representatives from health professional organizations and pharmaceutical manufacturers and distributors, as well as from the FDA and the Centers for Disease Control and Prevention, who attended portions of the conference as observers.
Organized by ASHP, ASCO, the American Society of Anesthesiologists, and the Institute for Safe Medication Practices (ISMP), the summit addressed the scope and causes of the shortages, including:
* Harm to patients and the potential need for changes in public policy and stakeholder practices to prevent that harm.
* The need to develop an action plan reflecting the recommendations and intent of stakeholders.
* How to work together to stop patient harm and disruptions in patient care caused by drug shortages.
The recommendations (www.ashp.org/drugshortages/summitreport) were released in January, and key among them were continued collaboration to explore strategies to improve communication among those in the pharmaceutical supply chain and health care providers, and to remove barriers faced by FDA and drug manufacturers to minimize the impact of the shortages.
OT spoke with a number of meeting participants representing various perspectives on the issue.
All agreed that better communications was critical and more transparency was needed, and a few cited anecdotal accounts of patient deaths due to shortages to underscore the urgency, as well as examples of hoarding and price increases by certain distributors capitalizing on the situation.
But for some, “communication” also seemed to be code for increasing FDA's authority to mandate that manufacturers comply with advance notice about upcoming shortages or intentions to stop producing drugs.
In fact ASHP's Reilly said that when manufacturers were surveyed about reasons for their shortages, 47% said the reasons weren't known or they didn't provide any information.
Captain Valerie Jensen, RPh, Associate Director of the FDA's Center for Drug Evaluation and Research's Drug Shortages Program, said that FDA has been doing everything it can within its current regulatory authority to address drug shortages when they occur, including working with manufacturers to restore supplies, and keeping information updated on its website (http://www.fda.gov/Drugs/DrugSafety/DrugShortages).
But that often occurs only after shortages are severe because of the agency's limited authority, a situation that some of the summit participants had been trying to remedy by meeting with legislative aides from US Senator Amy Klobuchar's (D-Minn.) office.
Newly Introduced: Preserving Access to Life-Saving Medications Act
On February 7, Sen. Klobuchar and Sen. Bob Casey (D-Pa.) introduced the Preserving Access to Life-Saving Medications Act requiring drug manufacturers to provide the FDA with early notification of any incident that might result in a drug shortage.
As the senators noted in a statement, these incidents may include changes made to raw material supplies, adjustments to manufacturer production capabilities, and certain business decisions such as mergers, withdrawals, or changes in output.
The bill also directs the FDA to provide up-to-date public notification of any shortage situation and the actions the agency would take to address them.
Other reasons for drug shortages are:
* Quality problems.
* The fact that fewer firms are making some of the older sterile injectables, which are generally not economically attractive.
* The complexity of manufacturing sterile injectables, making it difficult to increase production suddenly.
* The limited capacity of many of these manufacturers to ramp up and produce drugs when other companies have manufacturing problems.
For example, leucovorin is manufactured only by two companies—Teva and BenVenue—and when Teva voluntarily halted production to upgrade its processes and systems, it resulted in a shortage, and BenVenue was not able to meet the extra demand.
The FDA has since reported that Teva should be bringing the drug back to market by April.
Worst in Several Decades
ASCO President-elect Michael P. Link, MD, told OT that he thinks we are now facing the worst drug shortage in several decades since recordkeeping began.
The pediatric oncologist from Stanford University School of Medicine said he began to notice the shortage several months ago after being contacted by oncologists in his area, and he alerted ASCO about the situation. The society was most concerned about how the shortage would affect general patient care and clinical trials, he said.
“Our immediate concern is treating patients in the clinic. Adriamycin [doxorubicin] is a major hitter and the best available therapy and it's incredibly frustrating to tell patients they can't have it. We can find some workarounds, but they are not always as effective, and sometimes when workarounds are used off-label insurance companies are often slow to reimburse for them.”
When asked about the methotrexate shortage several years ago that affected many pediatric oncology patients and others (OT, 4/25/05), Dr. Link said that it isn't just business issues that are affecting the current situation and that the shortages are the result of a perfect storm or confluence of factors.
For example, if manufacturing a certain drug has limited financial incentives then there may only be a few companies making it, and if production problems affected one company then it could mean an instant 50% shortage.
This could then be compounded by distribution problems if distributors starve up the available supply, and that could be further exacerbated if big cancer centers with large contracts with big suppliers or with multiple suppliers can get the drug, then possibly making smaller community practices that order as needed much more vulnerable—“And in cancer, the majority of adult patients are taken care of in community practices, so that's where the pain feels the worse,” he said.
Other discussions at the summit included determining what are considered “medically necessary” drugs, increasing expiration dates on some drugs after undergoing batch testing, and dealing with those grandfathered drugs, mostly anesthetics, that never underwent FDA scrutiny because they were in use before passage of the Food, Drug, and Cosmetic Act of 1938.
Arnold Berry, MD, MPH, the American Society of Anesthesiologists' Vice President of Scientific Affairs, said that ASA became aware of the shortage of certain anesthetics in fall 2009 when some of its members began calling in about the problem.
Dr. Berry, Professor of Anesthesiology at Emory University School of Medicine, said the shortages of propofol and epinephrine were fairly random around the nation, affecting both large institutions and smaller practices.
“We've been impacted by the shortage in a slightly different way than oncologists have been,” he explained. “We take care of patients in acute settings where things happen quickly and we need to rely on availability right away.”
The shortages have affected how patients are cared for during surgery, and in some cases elective surgery has been canceled to ensure that supplies are available for required procedures, he added.
“Over the past 30 years anesthesiology has become much safer, and mortality rates have gone down, and patients expect safe and effective anesthesia. When propofol was in very short supply, the ASA began working with FDA, which began working with another manufacturer in Europe that made a drug with a slightly different formulation and was able to get it imported here, alleviating the shortage.”
He said the summit allowed everyone involved in the issue to get together and explain things from their perspectives and called it an enlightening experience that helped him understand a number of things he either took for granted or hadn't thought about before.
Michael R. Cohen, RPh, MS, ScD, President of the Institute for Safe Medication Practices, said that when ISMP surveyed 1,800 health care professionals last September the results showed that the risk of medical errors increased as health care institutions coped with dosing or frequency of administration issues when shortages forced use of alternative drugs.
More than a third surveyed responded that the shortage led to medical errors that could have been harmful to patients, including fatal errors.
“This is a serious issue. There is no hammer to make manufacturers notify the FDA,” he said noting the big effort to work with Senator Klobuchar on her bill, which was supported by ISMP, ASCO, the Minnesota Hospital Association, the American Hospital Association, and, Fairview Hospital in Minnesota, where the senator had previously held discussions about the proposed legislation.
Dr. Cohen also noted the recent decision by Hospira, the sole manufacturer of sodium thiopental, to stop producing the anesthetic agent because of pressure from Italy—where Hospira's plant is located—to promise that the drug would not be used in lethal injections.
Sodium thiopental is still considered a first-line anesthetic for certain procedures involving geriatric, neurologic, cardiovascular, and obstetric patients, and the side effects from other medications could lead to serious complications, according to a statement issued by ASA.
The FDA's Captain Jensen said that even with its current limitations, the agency was able to prevent 38 additional drug shortages last year.
“But [many times] the information that firms give us is proprietary and we need their permission to post it. What we hope is that firms understand it is important to notify us early on.”
No ‘Easy Button’
Gordon Johnston, Vice President of Regulatory Sciences for the Generic Pharmaceutical Association (GPhA), also attended the summit. Former deputy director of the FDA's Office of Generic Drugs, he told OT that sometimes drug shortages are totally unexpected with things that can come up suddenly that can affect the global supply chain.
He agreed that communications among all stakeholders is necessary and cited communications between the manufacturers and FDA, the FDA and health care practitioners, and within the whole supply network as areas for improvement.
“Within the wholesalers network it's not a highly organized process to find out what residual supplies are available, so they could be triaged within the supply chain to the most important uses,” he said.
“We need to look at and improve the entire communications chain from manufacturers though end users, and legislation is an area that would bring about additional communications.”
Mr. Johnston said mergers and acquisitions have also had an impact on capacity, and that while emergency room products are pretty stable, oncology demands can change with changes in protocols.
He also mentioned that when trade associations get together there are always antitrust issues that can be raised.
“It would be great if there were some ‘easy button’ we could push to help with supply and demand, but it's complicated and there is no easy button.”
And he said that GPhA has had discussions about the issues, “but we haven't developed any particular policies, or strategies, or recommendations coming out of the summit.”