Drug Shortage Dilemma: Trying New Tactics in a Tough Arena

Fresh strategies for grappling with the chronic, and at times critical, shortages of cancer drugs that have frustrated the oncology community for the past decade are likely to help alleviate supply problems, oncology and pharmaceutical leaders say. Yet they predict that forging significant and lasting improvements will be difficult due to the complexity of the issues underlying the shortages.

Bolstered by new legislation that takes effect in October, the FDA will gain resources to evaluate generic drug candidates and more clout to monitor supplies. The American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) have endorsed the changes.

Nevertheless, the Food and Drug Administration Safety and Innovation Act was enacted amid much disagreement among government officials, oncology leaders, pharmaceutical executives, and political figures about the causes for shortages.

Figure 1. National Drug Shortages

January 2001 to June 30, 2012

Each column represents the number of new shortages identified during that year.

University of Utah Drug Information Service. Reprinted with permission.

Reasons variously cited in the oncology sphere include manufacturing problems, quality issues, Medicare pricing rules, regulatory logjams, and the overall economic dynamic of producing cancer drugs, particularly sterile injectables.

Whatever the causes, however, experts agree that the shortages have spawned problems in cancer care: insufficient supplies for treating patients, a deficit of materials for clinical trials, borrowing and hoarding among medical institutions, the sale of counterfeit drugs, and a gray market for medications in limited supply.

Defining a Dangerous Quandary

While shortages of prescription drugs have posed problems for more than a decade, the numbers grew substantially from 2007 through 2011, according to the University of Utah Drug Information Service (Figure 1). These shortages have affected various therapeutic areas (Figure 2), but the US Government Accountability Office noted that the number of oncology drugs experiencing supply deficits has risen significantly since 2009.¹

Michael P. Link, MD

As of early June, 22 cancer therapies had been in short supply during the previous two years, including preservative-free methotrexate, which has contributed to a 90% cure rate in children with acute lymphoblastic leukemia (ALL), said Michael P. Link, MD, service chief of Pediatric Hematology- Oncology at the Lucile Packard Children’s Hospital at Stanford in Palo Alto, California. The immediate past president of ASCO spoke during a press conference about drug shortages during the organization’s 48th Annual Meeting.

“The crisis has been particularly bad in cancer care,” agreed Richard L. Schilsky, MD, professor of Medicine and Hematology/Oncology section chief at the University of Chicago in Illinois, and chairman of the ASCO Government Relations Committee, during the June press conference. “It creates uncertainty, anxiety, and higher out-of-pocket costs for patients, and difficulty in planning for physicians.”

Link added that the crisis has hit community oncologists especially hard since they usually don’t have pharmacy staff to help them secure drugs that are in scarce supply.

Richard L. Schilsky, MD

At the height of the drug shortage at the University of Chicago, Schilsky recalls receiving a weekly e-mail asking doctors to make “painful” decisions about which patients should receive certain chemotherapy treatments.

Similarly, one nurse observed the severity of a drug shortage when a stem cell transplant for a child with ALL was delayed for the second time due to a lack of busulfan, according to the nonprofit Institute for Safe Medication Practices (ISMP). After completing an evening shift, ISMP stated, the nurse drove three hours to another state to borrow the doses her hospital could not find closer to home.

Beyond simply frustrating, the problem can be dangerous.

There are no alternatives for some cancer drugs, noted Rear Admiral Sandra Kweder, MD, deputy director of the FDA’s Office of New Drugs, in a statement before the Committee on Health, Education, Labor and Pensions of the US Senate in late 2011.² When there are substitutes, ISMP has reported, other problems can arise, including severe side effects. In the organization’s recent survey of nearly 100 hospital pharmacy staff members, 27% said they were aware of mistakes made in the formulations or strengths of drugs given as alternatives for medications in short supply.³

Sandra Kweder, MD

In one case, the summary stated, methohexital was used as a substitute for propofol, and practitioner “unfamiliarity… resulted in a serious dilution error during reconstitution of the powder. The patient ultimately received a massive overdose of the drug and died despite resuscitation efforts.”

In a survey of 204 US oncologists, some also reported dangerous or deadly results of drug shortages, according to National Analysts Worldwide, with 48% of respondents noting tumor recurrence and 40% saying they had seen patients die sooner.⁴

In addition to their impact on individuals, drug shortages are slowing cancer research, noted Kweder and Schilsky. Because of a lack of certain drugs, trials and patient enrollment have been delayed or stopped; in other cases, trial protocols have been violated or data have been confounded by the use of alternative treatment regimens, they stated.

Manufacturing Issues Blamed

According to Kweder, the shortages are primarily the result of manufacturing and quality problems.

“With large manufacturers of sterile injectable drugs,” which are more complex to manufacture than many other treatment types, “shortages are often due to a single facility closing due to quality issues,” she said during the ASCO press conference.

Figure 2. Common Drug Classes in Short Supply*

*Through June 30, 2012

CNS indicates central nervous system; EENT, eye, ear, nose, and throat; GI, gastrointestinal. University of Utah Drug Information Service. Reprinted with permission.

In her statement before the Senate committee, Kweder noted that, of 127 drug shortages tracked by the FDA from January 1, 2010 to August 26, 2011, 80% involved sterile injectables, 50% generic or unapproved therapies, and 28% oncology drugs (Figure 3).² Fifty-four percent of the sterile injectable shortages, she said, were “due to product quality issues such as particulates, microbial contamination, impurities, and stability changes resulting in crystallization.”

In such cases, Kweder said, a manufacturer may temporarily close a plant, or the FDA might order it closed. “If one company makes 30 products and they have a problem, 30 products are at risk of a shortage,” she told the Senate committee.

Kweder also blamed industry consolidation, contending that, in 2010, the top five generic drug manufacturers were responsible for 80% of all sterile injectables, by volume, being sold in the United States. If one firm were to stop production, she said, the others might not be able to pick up the slack.

Some manufacturers have contributed to shortages by reducing the size of their inventories to minimize loss of drugs that expire quickly, Kweder told the Senate committee. She added that shortages can be caused by increases in demand, decisions by companies to stop making medications, and a lack of access to active pharmaceutical ingredients.

Figure 3. A Portrait of the Drug Shortage Problem

Based on 127 drug shortages from January 1, 2010, to August 26, 2011

Shortages by Route of Administration

Shortages by Drug Class

Shortages by Primary Reason for Disruption in Production and Supply

API indicates active pharmaceutical ingredient.

The three panels of this figure provide an FDA analysis of drug shortages that occurred over a nearly 20-month period.

US Food and Drug Administration. A review of FDA’s approach to medical product shortages. www.fda.gov/DrugShortageReport.

Published October 31, 2011. Accessed July 26, 2012.

Hagop M. Kantarjian, MD

Drug Pricing Rules and Practices Cited

Just as important in explaining drug shortages are economic factors, an expert said during a panel discussion on drug shortages at the ASCO meeting. Hagop M. Kantarjian, MD, a professor and chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, said a drug pricing rule that became effective in 2005 has prevented the generic market from flourishing and producing the amount of products patients need.

Meant to control costs, the rule established under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 allows healthcare providers— who typically buy cancer drugs and sell them directly to patients—to charge the average sale price for those medications, plus 6% for their services (ASP plus 6%).

In the past, with more generic drug companies in the marketplace, the prices of generic chemotherapy medicines were driven down from hundreds of dollars to as little as $10 or $20, Kantarjian said. Now, he said, the few remaining companies in the market can’t raise their prices to meet demand; if the prices of their generics increase more than 6% every six months, Medicare won’t reimburse oncologists for the difference under the ASP plus 6% rule.

Some experts argue that oncologists, who rely on profits from the sale of chemotherapy drugs, contribute to shortages by choosing to prescribe more expensive name-brand drugs. While Kantarjian called that view “cynical,” he did suggest that “healthier” prices would make generics more attractive to both industry and private practice.

In an October 2011 report, the Assistant Secretary for Planning and Evaluation (ASPE), an office that conducts research and advises the US Department of Health and Human Services, agreed that shortages occur because generic drug prices cannot respond to the forces of supply and demand.⁵

But ASPE emphasized the increased number of oncology drugs going off patent as a factor; that trend, the report said, has induced generic companies to manufacture more products without immediately expanding capacity, forcing them to make profit-based choices about how much of each drug to produce.

Kantarjian said that another troubling development has been the growth of a gray market, in which wholesalers buy up drugs in short supply and resell them at inflated prices.

“There are drug distributors that foresee an opportunity of profit upon rumors or knowledge of possible drug shortages, so they order a drug and then they sell it at 600% to 3000% profit,” said Kantarjian, who suggested that such activity, while rare in the United States, should be made illegal. “That’s much bigger than you can get even on Wall Street or selling illegal drugs, so we have to keep an eye on this activity.”

FDA’s Role Lauded and Criticized

According to Kweder, the number of drug shortages has decreased since October 2011, when President Barack Obama issued an executive order directing the FDA and the US Department of Justice to take more preventive actions. A central recommendation was that the agencies encourage companies to report anticipated shortages, which the FDA did in a letter to industry.

The FDA also responded by working to double its number of employees dedicated to drug-shortage prevention and mitigation, activities that can include expediting new drug applications and other “submissions from manufacturers that may alleviate the drug shortage,” such as the extension of drug expiration dates, increases in manufacturing capacity, or ingredient changes, Kweder told the Senate committee.

In the 10 months before Obama’s order, the agency received about 10 notifications each month about potential disruptions in drug manufacturing. In the four weeks afterward, Kweder said, the FDA received 61 notifications, a sixfold increase. In large part as a result, she said, 150 shortfalls were averted between October 2011 and June 2012, including 50 this year, and the number of new shortages decreased slightly during that period. In all of 2011, Kweder said, the FDA prevented 195 shortages due to manufacturer notifications.

When the FDA knows a shortage is on the horizon, Kweder said, it can help companies inspect their drugs for safety; work with the drug makers—or other companies that produce the same medications—to ramp up production; or import similar drugs from overseas. To address a doxorubicin injection shortage, she said during the ASCO press conference, the FDA enlisted Pfizer’s help to relaunch different sterile injectable oncology drugs to be used as substitutes.

Another strategy is to allow a company to continue marketing a medically necessary drug if the firm can resolve a quality issue before the medicine reaches patients. An example, Kweder said in her Senate testimony, was when a manufacturing change led to dangerous crystal formation in vials of sterile injectable cytarabine, used to treat some leukemias. After learning that warming the vials dissolved the crystals, the FDA allowed the shipment of the medicine with a letter of instruction to healthcare professionals.

Despite that example and others, the US House of Representatives Committee on Oversight and Government Reform contends the FDA has been too aggressive in its enforcement efforts since 2009, encouraging generic injectable drug makers to shut down simultaneously for remediation—regardless of whether their products posed a danger to patients, and without considering how the closures might affect drug availability. As a result, the committee wrote in a June 2012 report, America’s makers of generic injectables are operating, collectively, at 70% of their previous manufacturing capacity.⁶

The FDA told OncologyLive that its enforcement efforts are “not the root cause of the drug shortage problem,” and that the agency “balances the risks posed to patients by a shortage against the risk posed by (problems with) product quality or safety.”

According to the FDA, the four plant shutdowns mentioned in the House committee’s report were voluntary on the part of drug makers and the result of “extremely serious quality problems that could put patients at risk. These risks included: endotoxin contamination, which may cause severe fever and death; the presence of metal particles in drugs, which can cause injury to patients when injected; and overfill of vials of liquid morphine, which could result in caregivers administering an accidental overdose to patients.”

Ralph G. Neas

In each case, the FDA said it “worked with manufacturers to try to assess and address quality concerns, and try to avoid a shortage.”

Pledging to support the FDA’s efforts is a private-sector group, the Generic Pharmaceutical Association (GPhA). Through its industry-funded Accelerated Recovery Initiative (ARI), the group wants to facilitate the collection of drug-supply data from generic companies, the analysis of the data using computer modeling, and the opportunity for the FDA to use that information to mitigate and prevent drug shortages, said Ralph G. Neas, president and CEO of the GPhA, during the ASCO panel discussion.

The GPhA has worked closely with the FDA on the initiative, and as of late July was awaiting an advisory opinion from the Federal Trade Commission.

Financial Incentives Proposed

Kantarjian acknowledges that the FDA’s efforts have helped to decrease the number of chemotherapy drug shortages by half, but he still believes it’s essential to strengthen the generic market through financial incentives.

In a paper published this year in the Journal of Clinical Oncology, Kantarjian and colleagues suggested that, rather than a Medicare formula of ASP plus 6%, generic drugs should be priced between ASP plus 10% and ASP plus 20%.⁷ Another tactic, the authors wrote, would be to set generic pricing at 5% to 10% of comparable brand-drug prices. In European countries, where name-brand and generic drugs are closer to each other in price, there are fewer shortages, Kantarjian pointed out.

Oncology Drugs on FDA's Current Drug Shortages List*

The FDA defines a drug shortage as "a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the patient level." While reporting anticipated shortages to the FDA currently is voluntary on the part of drug makers, it will become mandatory under the recently signed Food and Drug Administration Safety and Innovation Act (SIA), which will take effect on October 1, 2012.

Generic Name

Tumor Type/Oncology Use

Asparaginase injection

Acute lymphoblastic leukemia

Daunorubicin hydrochloride solution solution for injection

Acute lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia

Denileukin diftitox injection

Cutaneous T-cell lymphoma

Dexrazoxane for injection

Cardioprotective agent for doxorubicin and other anthracyclines

Doxorubicin lypholized powder and liposomal injection

Varied neoplastic conditions, including hematologic malignancies, and breast, ovarian, and bladder

Gallium nitrate injection

Cancer-related hypercalcemia

Leucovorin calcium lyophilized powder for injection

Methotrexate rescue in osteogenic sarcoma; reduce toxicity in other settings

Leuprolide acetate injection

Advanced prostate palliative treatment Mechlorethamine HCI injection Hodgkin disease, hematologic malignancies, bronchogeniccarcinoma

Methoxsalen

Cutaneous T-cell lymphoma palliative treatment regimen

Methotrexate injection

Breast, head and neck, leukemia, lymphomas, lung

Metoclopramide injection

Chemotherapy-induced nausea and vomiting

Mitomycin powder for injection

Adenocarcinoma of stomach or pancreas in combination therapy

Ondansetron injection

Chemotherapy-induced nausea and vomiting

Pentostatin for injection

Hairy cell leukemia

Prochlorperazine Injection

Chemotherapy-induced nausea and vomiting

Thiotepa for injection

Bladder, breast, ovarian, lymphomas

Thyrotropin alfa injection

Thyroid adjunctive diagnostic and treatment

Vinblastine sulfate injection

Hematologic malignancies, testicular carcinoma

*List reflects information posted as of August 20, 2012.

Sources

Current drug shortages index. US Food and Drug Administration website http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm.

Updated August 20, 2012. Accessed August 20, 2012.

Drug Information Online. Drugs.com website. http://www.drugs.com.

Since generic drug prices constitute just 2% of the cost of cancer care in the United States, Kantarjian said during ASCO’s meeting, the challenge would be to avoid overwhelming inflation. An adjustment that struck the right balance, though, could save $200 million to $425 million a year in shortage-related costs and provide physicians with always-available substitutes for expensive name-brand drugs, he said.

ASCO, too, has called for economic adjustments— specifically, financial rewards for companies that draft drug-shortage contingency plans and remain in the market for low-cost medications.

And ASPE has recommended that private organizations that buy drugs and sell them to healthcare providers, such as insurers or group purchasing organizations (GPOs), strengthen their failure-to-supply requirements. That means the GPOs would pay more for generic medications, but require manufacturers to pay a fee if they failed to provide promised drugs.

“Such contract changes are likely to lead manufacturers to invest in extra capacity of both production lines and active pharmaceutical ingredients,” ASPE’s October 2011 report stated.⁵

Still another strategy would be to no longer pay oncology practices based on chemotherapy sales, but instead for relying on certain first-line, mostly generic drug combinations and sequences to treat specific diseases. That approach would be cheaper, and at least as effective for patients, as the formula in place now, suggested Mandy L. Gatesman, PharmD, and Thomas J. Smith, MD, in a 2011 paper in The New England Journal of Medicine.⁸

New Law Signed in July

The Food and Drug Administration Safety and Innovation Act, which Obama signed into law on July 9, requires manufacturers to alert the FDA six months in advance about market withdrawals or drug-supply interruptions—although it doesn’t include penalties for noncompliance, as ASCO had wanted.⁹

The legislation also requires generic drug makers, for the first time, to pay user fees that will increase the FDA’s resources for reviewing new generic-drug applications. That change is expected to help the FDA plow through a backlog of more than 2500 applications by shortening the per-application review time from 31 months to 10 months. From 2013 through 2017, the fees contributed by the industry are expected to total $299 million a year, or about half of 1% of all generic drug sales, according to the FDA.¹⁰

If a specific drug shortage seems imminent, the law will allow the FDA to try to avert the problem by expediting related drug applications or inspections of manufacturing facilities.

Under the act, the FDA will undertake new measures to consider, in advance, the ramifications of regulatory actions on drug supply or clinical trials. If a regulatory action does disrupt drug supply, the FDA will be required to consider working with another drug maker to increase production.

Finally, the act will allow individual health systems to repackage leftover doses of drugs in shortage, as a means of extending their own supply.

To Neas, those updates signal the commitment of stakeholders to ending drug shortages.

“I think 2012 is going to be looked upon by us all as a line of demarcation,” he said, “when we started collaborating in a meaningful way to get the job done.”

References

1. US Government Accountability Office. Drug shortages: FDA’s ability to respond should be strengthened. http://www.gao.gov. Published November 21, 2011. Accessed July 30, 2012.
2. Kweder S. Prescription drug shortages: examining a public health concern and potential solutions [testimony]. US Food and Drug Administration website. http://www.fda.gov. Published December 15, 2011. Accessed July 17, 2012.
3. A shortage of everything except errors: harm associated with drug shortages. ISMP Medication Safety Alert. Institute for Safe Medication Practices website. http://www.ismp.org. Published April 19, 2012. Accessed July 17, 2012.
4. Independent survey of US oncologists by National Analysts Worldwide finds drug shortages and escalating costs result in grave health consequences [news release]. Philadelphia, PA: EON: Enhanced Online News; February 1, 2012. http://eon.businesswire.com. Accessed July 17, 2012.
5. Office of the Assistant Secretary for Planning and Evaluation. ASPE Issue Brief: economic analysis of the causes of drug shortages. http:// aspe.hhs.gov. Published October 2011. Accessed July 17, 2012.
6. US House of Representatives Committee on Oversight and Government Reform. FDA’s contribution to the drug shortage crisis [staff report]. http://oversight.house.gov. Published June 15, 2012. Accessed July 17, 2012.
7. Link MP, Hagerty K, Kantarjian HM. Chemotherapy drug shortages in the United States: genesis and potential solutions [published online ahead of print January 30, 2012]. J Clin Oncol. 2012;30(7):692-694. doi: 10.1200/JCO.2011.41.0936.
8. Gatesman ML, Smith TJ. The shortage of essential chemotherapy drugs in the United States [published online ahead of print October 31, 2011. Updated November 2, 2011]. N Engl J Med. 2011; 365(18):1653-1655.
9. US Congress. Food and Drug Administration Safety and Innovation Act. United States Government Printing Office website. http://www.gpo.gov. Accessed July 17, 2012.
10. US Food and Drug Administration. Fact Sheet: new user fees for generic drugs will enhance Americans’ access to less expensive drugs and generate major cost savings. www.fda.gov. Updated July 16, 2012. Accessed July 17, 2012.