Infrastructure Issues in the US Drug Supply: Where Did the Drugs Go?

North America is facing a shortage of certain drugs, and you do not have to be a pharmacist buyer tasked with procurement to realize our drug supply is under pressure. Governmental and professional groups—including the US Food and Drug Administration (FDA), American Society of Clinical Oncology (ASCO), Institute for Safe Medication Practices (ISMP), Association of Community Cancer Center, and American Pharmacists Associ ation, among others—have been stating that this is a serious problem that may not be resolved anytime soon. Pharmacists and physicians are spending significant resources on managing the shortage instead of treating patients. “Whatever the cause, drug shortages have become a key patientsafety concern in health care today,” according to a report issued by the ISMP this past summer.¹ Michael P. Link, MD, incoming ASCO president, has said, “We’ve heard a crescendo of complaints and concerns…it’s the worst shortage we’ve experienced in three decades. In terms of scope, it’s huge.”²

The drug supply infrastructure is weak or failing in several key areas, ranging from recalls of already manufactured items to shortages for supplier or manufacturing reasons to manufacturers exiting the marketplace due to lack of incentive. There are even suggestions that all reasons put forth to date do not fully account for what is happening. Regardless of the reason, sourcing drugs has become challenging in general, and acutely so with regard to parenterals used in a hematology/oncology practice. This article seeks to evaluate the known causes for the drug shortage and provide a clearer picture of the current state of the crisis.

Recalls
Many drugs appear to be recalled as a preventive measure or on cautionary advice. There are also recalls for egregious reasons, such as misbranding, gross contamination, and adulteration. Those who remember the Tylenol scare of 1982 will probably be unable to find anything today that compares. At that time, the fear and apprehension generated by the recall were palpable; the recall was on everyone’s mind, in daily conversations, and blanketed the nightly news. When Johnson & Johnson launched the recall, it affected as many as 21 million drug packages in circulation.³

North America had had few recalls of over-the-counter products or of any kind that received much attention. Johnson & Johnson’s reaction set the bar for the future. It spared no expense to protect the public from what turned out to be a small number of tainted products, which were intentionally adulterated and not the result of manufacturing error. Still, the scarcity of recalls made it seem grandiose.³

By contrast, recalls are commonplace today. In fact, in early 2011, Johnson & Johnson issued a large voluntary recall for a suite of Tylenol products for problems such as lax cleaning procedures and poor documentation. After further investigation, one product was found to have incorrect labeling.⁴ In 2008, a slightly different situation occurred when the sourcing of raw materials caused Baxter to recall its heparin, which was manufactured in China. In that case, the animal source (pig intestine) had been laced with oversulfated chondroitin, resulting in the manufacture of tainted heparin.⁵

Regardless of the reasons, if the final by-product harms patients or has great potential to harm patients, the recall system is designed to remove them, and the number of recalls is climbing. A cursory review of the FDA website and the drug tracking site managed by the University of Utah indicates that there were about 30 drug recalls in 2010.⁶

A recall is when a product is removed from the market or a correction is made to the product because it is defective or has the potential to cause untoward harm. The FDA is tasked with oversight of drug safety, as well as recalls. However, only some recalls stem from an FDA concern about the product. Others occur when a company discovers a problem on its own. Regardless of the cause, recalls should not be confused with a market withdrawal or a stock recovery.⁷

Although the current number of recalls is high, they account for only a small portion of the disruptions that clinicians and patients face. For example, of the approximately 3500 items published on a wholesaler (AmerisourceBergen) website as backordered from a top-three drug wholesaler, only 16 were unavailable because of an active recall.⁸ This equates to less than 0.5%. Still, at the time of publication, the number of items unavailable is large. That number, however, includes a few medical supplies and is not entirely (but mostly) comprised of medications.⁸

The recall of Procrit in late 2010 because of lamellae, glass flakes, or protein clusters in the glass vials had a dramatic impact on hospitals, clinics, and practices using that growth factor, and it affected a large number of patients. That recall led to a shortage of the medication, and that, in turn, strained the availability of Aranesp, the only other product approved for chemotherapyinduced anemia. When one agent is recalled, the ripple effects can impact the availability of other agents used as alternatives and replacements. In addition, stockpiling or hoarding mentality can take hold.

Shortages
Backordered medications and shortages are becoming an almost daily occurrence in health-system pharmacies and physician offices. The scope is broad enough to be hitting all areas of patient care, but it is impacting the oncology marketplace at levels that are difficult to absorb, particularly with high-use medications, including emergency and pain medications, anesthetic agents, and oncologics.⁹

The FDA and the American Society of Health- System Pharmacists (ASHP) maintain lists of drugs in short supply or unavailable. At press time, the FDA was tracking 48 shortages 10 and the ASHP listed 145 items that are either on shortage or backorder.⁶ The ASHP list can be characterized as a more comprehensive resource because the FDA lists only those shortages of medically necessary products that have a significant impact on public health and safety. By definition, a drug is considered medically necessary if it is used to treat/prevent a serious disease or condition, with no other source immediately available and no medically acceptable alternative.

Table 1

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The increase of shortages, from a low of 58 in 2004 to a high of about 200 in 2010, has continued with an almost unbroken trajectory upward, according to a report by Erin Fox, PharmD, manager of drug information services for the University of Utah, at the Drug Shortages Summit in November 2010.¹¹ Data from the FDA indicate that in 2010, injectables accounted for more than three-fourths of all shortages. In addition, two-fifths of all shortages were the direct result of quality issues, such as microbial contamination, impurities, or particulates.¹² Regardless of the reasons (and they are many and multifactorial), the shortage situation is impacting patient care. According to drug wholesaler AmerisourceBergen, at the time of publication there remain 3460 items on backorder from the manufacturers. This information is provided by manufacturers to facilitate understanding regarding the nature of the problem. At present, more than 80% of the items fall into one of four categories (Table 1).⁸

Of the 15 categories used to explain why a drug is unavailable, 11 account for just more than 14%.⁸ Most drugs are unavailable because of production and demand issues,8 resulting in ongoing frustration among providers. And because there is no advance warning, crisis management in trying to source desperately needed agents perpetuates stress.

Particularly acute in the oncologic arena is the knowledge that certain regimens can cure disease and withholding them in those settings could be a death sentence to patients. Recently, it was my unpleasant duty to explain to a patient with testicular cancer why no cancer center in the country would be able to provide bleomycin as part of his treatment regimen. Similar situations have occurred in the past year with mitomycin and doxorubicin. To label this as “distasteful” is a gross understatement.

“We are clearly facing one of the worst drug shortages of the past 30 years, particularly of life-saving medications, including chemotherapy products,” said Mike Cunningham, PharmD, vice president and general manager, GPO & Information Services, McKesson Specialty Care Solutions (e-mail communication, January 17, 2011). “The current shortages are leading to shortages of alternative products, thus perpetuating the cycle. Through work with the Healthcare Distribution Management Association [HDMA], McKesson Specialty Care Solutions is actively engaged in a collaborative advocacy effort with other professional associations working closely with the FDA to discuss causes and trends of drug shortages, and explore possible strategies to manage and mitigate shortages.”

The comments from the wholesaler community are echoed in the physician office practice setting. “The shortage of critical life-saving chemotherapy drugs during 2010, and continuing in 2011, is unprecedented and unacceptable. These shortages have created operational hardships for oncologists and other healthcare providers, but more importantly, have compromised appropriate levels and timing of critical patient treatments,” noted Roy Beveridge, MD, medical director, US Oncology, in a response to queries about how the crisis is impacting the largest oncology physician practice in North America (e-mail communication, January 17, 2011). “While we have collaborated with other professional colleagues, drug manufacturers, and professional organizations to obtain products, the routine supply of many agents is still in question, and sufficient supplies of several critical drugs cannot be assured. We believe that the FDA should engage in all efforts to assist US healthcare providers in their ability to provide curative treatments to cancer patients.”

William Guss, PharmD, MBA, FCSHP, vice president of pharmacy services for Aptium Oncology, Inc, provided an even graver summary of the shortages (e-mail communication, January 14, 2011). “We have taken the drug supply chain for granted because it is so efficient, but that is changing. Aptium manages hospital-based cancer centers, and each has a pharmacy with a small staff dedicated to that site. Our pharmacists wear many hats, one of which is to manage purchasing and inventory. They keep inventory carrying cost low, while maintaining enough so that no patient is ever turned away, but their biggest value in being in the center is having the ability to focus on the clinical and safety aspects of treatment. However, recalls, shortages, backorders, and specialty distribution channels that require drop shipments for REMS [risk evaluation and mitigation strategies] multitudes of separate agents, and special programs like REMS are imposing greater time and administrative burdens on our staff. Just stocking more of everything as insurance is not the answer, nor even plausible. These issues raise cost and reduce efficiency, but of most concern, increase the potential risk to patients.”

To address the shortage issues, professional societies (American Society of Anesthesiologists, ASCO, ASHP, and ISMP) joined with pharmaceutical manufacturers, wholesalers/distributors, and the regulatory community (including the FDA) and convened the Drug Shortages Summit.¹¹ The summit’s summary report identifies common causes for the shortages, which include manufacturing difficulties, natural disasters, reductions in the supply of raw materials (80% of which derive from outside the United States), unanticipated surges in demand, increases in voluntary recalls, enforcement activity by the FDA, and artificial shortages due to stockpiling/hoarding and manufacturer business decisions.¹¹

Businesses have often discontinued older products that are not as profitable as newer ones. This challenge, however, is now coupled with a new one—the ever-increasing complexity of modern-day drug manufacturing makes manufacture a more resource-intensive process than in the past. Older products with low profit margins take lower precedent in the production lineup. The free-market system ensures that, as their scarcity increases, the price clinicians are willing to pay also increases such that companies will shift resources back to the production of items that have increased profit margin.

Today, drug manufacturers can no longer just move a few pieces of equipment and twirl a few valves for a quick production run. Manufacturing interruptions can lead to significant ripple effects, because each production line is often used for multiple drugs, and the drug runs are done in amounts that will just satisfy projected/forecasted needs. This means that the system has very minimal slack and, if problems arise or batches do not pass regulatory scrutiny, shortages are inevitable. In addition, in today’s high-tech manufacturing plants, production runs and their scheduling are coordinated with the care and scrutiny of a space launch.

The lead time needed to make switches between products may be significant—time that is affecting patients’ access to medications. For their part, manufacturers want the freedom to make decisions that uphold their fiduciary responsibility to shareholders, but they also want to provide for their customers. Many manufacturers are lobbying for the reduction, not the addition, of red tape.

Table 2

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As stated earlier, the FDA tracks drugs that are in short supply and fall into what it deems medically necessary or urgent need. By mid-February 2011, the FDA was tracking just under 60 drug irregularities.¹³ Most of the drugs in short supply are injectables, including sedating agents such as propofol, heparin, and hard-hitting chemotherapy drugs (Table 2).¹³ The FDA approved only 21 new drugs in 2010—the fewest since 2007. The FDA has recently shown more of a willingness to delay or reject medicines with potential safety risks. There were 25 approvals in 2009 and 24 approvals in 2008, according to the FDA’s website.¹⁴ Only 19 new drugs were given the green light in 2007, the fewest approved in a single year for 24 years.¹⁵

Taking Action
The FDA, an agency within the Department of Health and Human Services, is charged with protecting the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biologic products. In addition, it regulates medical devices, the US food supply, cosmetics, dietary supplements, and products that give off radiation.¹⁶

Some Americans are calling for more governmental control, including the power to dictate to companies what to produce and when. More bureaucracy, however, is hardly a prescription for success. A simpler solution may be for a manufacturer to send an early warning of its removal of a product from production or confidential notification of a production problem. This would help the FDA to fulfill its existing role of ensuring access to essential medications for patients. The FDA has, in this role, worked with industry to accelerate approvals and approve the extension of expiration dates where data can corroborate the validity of doing so. The FDA also has allowed drug importation outside of normal channels. One recent example was when it assisted California’s access to sodium thiopental for capital punishment.¹⁷ Ideally, this power would be used to facilitate pharmacists’ access to imported live-saving medications, not life-ending ones. The salient point is that, when needed, the FDA can streamline the bureaucratic red tape to respond to a crisis. Pharmacists are the ideal conduit to partner with the FDA in trying times like these.

Pharmacists are the drug experts, and their profession is expected to handle drug shortages. This appears to be true outside of the United States as well. The Canadian Pharmacists Association (CPhA) released a report in December 2010 that surveyed their membership (in October 2010) about whether they were unable to fill any prescriptions during their most recent shifts.¹⁸ Of the 427 pharmacists who responded online, 81% had problems locating a drug during their most recent shift, and 93% could not find at least one drug in the previous week. Most (89%) pharmacists also said that drug shortages have greatly increased over the past 12 months, and 70% said the shortages were affecting their patients’ health, with 91% stating patients were inconvenienced.¹⁸

One positive thing to come out of the current drug crisis in Canada is reflected in a statement by CPhA Executive Director Jeff Poston, PhD. Dr Poston calls for governments to increase the scope of practice for pharmacists to better use their skills and training to help patients deal with a shortage when it arises.¹⁹ Valerie Jensen, RPh, Associate Director of the Center for Drug Evaluation and Research–Drug Shortage Program at the FDA, is quoted to have said that “fewer and fewer firms are making these [generics]. It’s a complex manufacturing process compared to oral drugs and other drugs. These are not products that are really profitable.”²⁰

Although there is no single overarching reason for the shortages, the potential for customers clamoring for scarce agents and not being particularly price sensitive is sending a loud message to the generic pharmaceutical manufacturers. “[We] are taking steps to address the shortages and expect the situation will improve significantly over the coming weeks and months,” said Jim Keon, president of the Canadian Generic Pharmaceutical Association.²¹ The association listed shortages of active pharmaceutical ingredients, changes to regulations, production issues, and changes to processes and equipment as possible reasons for the shortages.

There have been several shortages as a result of microbial contamination, such as in the Genzyme plant that produced Cerezyme and Fabrazyme. Despite being manufactured by three corporations, during the height of the shortage in the summer of 2010, propofol was only available from one corporation because of microbial contamination with one of the manufacturers and an exit from the marketplace by the other. Surgeries and procedures were being postponed or canceled, but the FDA was able to assist in the temporary importation of the drug from a European supplier.²⁰

As reported by Jensen and Rappaport in August 2010, data demonstrate the rising acuity of the situation.²² Of the 110 drug shortages existing in 2008, only 35% involved sterile injectables. In 2009, that proportion rose to 46% of 157 drug shortages.²² Although many reasons have been discussed, these authors provide nuance. They suggest that even though generic formulations of many agents have been on the market for some time, only a limited number of companies can successfully produce them, because of the complex and long manufacturing lead times.²² In addition, because companies’ production lines often are used for several product lines, any interruption in manufacturing process can impact multiple drugs. Just-in-time manufacture also ups the risk for any sudden change in supply or demand causing significant consequences for patients and clinicians.

Lack of available medically acceptable alternatives to drugs that are backordered or on shortage adds to the crisis. This problem can become compounded if the medically appropriate substitutes or alternatives are not reimbursed by insurance companies. Frustrations only grow when the efforts to source a product or alternative results in product procurement, but we are still unable to fully solve the problem due to financial constraints.

In May 2009, the Hematology Oncology Pharmacy Association (HOPA) conducted a survey of its membership, and found that only four drug shortages were having significant impact on patient care.²³ That number would assuredly be higher if it were repeated today. In fact, most HOPA members recommended that the association lobby the FDA for allowance of emergency importing of drugs to deal with unanticipated shortages.²³

Changes to laws or regulations are now being evaluated. In February 2011, Senators Amy Klobuchar (DMinn) and Bob Casey (D-Penn) introduced legislation that would require drug manufacturers to notify the FDA when a drug shortage may occur because of certain incidents, such as manufacturing problems, trouble obtaining raw materials used to manufacture the product, or business decisions, including ceasing manufacture of a drug. The legislation would also require the FDA to provide up-to-date public notifications of a shortage, as well as the agency’s plans to address such a shortage.²⁴ In the same vein, ASHP’s Bona Benjamin, director of Medication-Use Quality Improvement, posits the idea for a governmental incentive program similar to that incentivizing the adoptions of electronic health records or the inducements to develop orphan drugs.²⁵

Conclusion
Particulates, lamellae, source problems, toxic by-products, microbial contamination, failed quality checks, adulteration, manufacture scheduling problems, and falling profit margins—whatever it is, these interruptions in drug supply endanger the access of patients to medication in the United States and beyond. Whether you support the new healthcare law or not, there is clear and present danger to the drug supply in North America and, although no immediately obvious solutions are available, perhaps the one constant in all of this is the pharmacist. Will our pharmacy leaders stand up and take charge?

Will we as a profession promote ourselves as the caring professionals that have been operating for some time under stressful and draining conditions, doing our utmost to ensure that patients get the best treatment we can provide? Because this crisis appears not to be waning but accelerating, we need to look at ourselves and become the pharmacists we were meant to be.

Disclosure
Dr Tyler is on the Speakers’ Bureau of Bristol-Myers Squibb and Eisai Pharmaceuticals.

References

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Reprinted with permission from the Journal of Hematology Oncology Pharmacy™.