Expectation of drug shortages has become ‘new norm’ for cancer care

More than 230 drugs appeared on the American Society of Health-System Pharmacists’ drug shortage list as of mid-January.

The list — primarily comprised of generic, sterile injectables — included six oncology drugs and two hematology drugs.

The undersupply of one agent — doxorubicin liposomal (Doxil Janssen), an anthracycline chemotherapy used to treat metastatic ovarian cancer, Kaposi’s sarcoma and multiple myeloma — has been particularly troublesome.

“When we have patients with diseases such as ovarian cancer that require a specific drug that is no longer available, it impacts patients, physicians and anyone who is involved in the caregiving process,” J. Leonard Lichtenfeld, MD, MACP, deputy chief medical officer for the American Cancer Society, told HemOnc Today. “These issues create unneeded anxieties for patients, and barriers to physicians and hospitals caring for patients.”

In February 2012, the FDA allowed for a foreign supplier to augment the stock of Doxil. A year later, the agency approved a generic version of the agent to try to alleviate the shortage.

“There were alternatives, but they were not preferred alternatives,” Lichtenfeld said. “There were concerns as to whether the biological effect was equivalent. Being a cancer patient is difficult enough, and this just adds another layer of burden, whether it happens in a small practice, large practice or anywhere in between.”

Drug shortages peaked in 2011, when 267 agents were in short supply. Since then, the FDA created its own drug shortage database, expedited generic approvals and began marketing foreign-manufactured drugs in hopes of minimizing the problem. Still, shortages of many agents continue, including some that have persisted for years.

HemOnc Today spoke with several key opinion leaders about how they have dealt with and tried to address oncology shortages, the extent to which the FDA’s actions have helped, and what else must be done ensure sufficient supplies of critical therapeutic agents.

A lingering issue

A survey conducted by Goldsack and colleagues — published in 2014 in the American Journal of Health-System Pharmacy — showed 98% of pharmacy directors dealt with at least one injectable oncology shortage in the prior 12 months. Seventy percent of respondents said they had an insufficient supply to treat patients, and 63% reported running out of at least one injectable.

“Every time I speak, I ask everybody who is in the room to raise their hands if they have been impacted by drug shortages, and every hand goes up,” Ted Okon, executive director of the Community Oncology Alliance, told HemOnc Today. “This is especially important in the cancer realm, where when one regimen fails, oncologists move on to the next thing.”

The problem extends beyond injectable oncology drugs, according to R. Brian Mitchell, MD, president of the Virginia Cancer Institute.

“The drug shortage problem is hitting us again, and one of the biggest shortages having an impact right now is saline,” Mitchell said in an interview. “Plain old salt water is going to run out soon, and other IV fluids are close behind. We have to address this issue all the time by asking, ‘Can we use alternative fluids in certain situations? Can we use different size bags? Can we substitute injections or oral medication so that it does not have to be mixed in saline?’”

Goldsack and colleagues found clinicians employed several strategies to deal with drug shortages. Nearly two-thirds (62%) of respondents used alternative regimens, 46% altered dosages, 43% delayed treatments and 21% referred patients to other facilities.

One method of addressing shortages is to identify alternative medications that can be used. Unfortunately, determining that the alternative drug is equally effective and safe is not always clear-cut.

“During the shortage of mechlorethamine, we and others made a protocol change to substitute cyclophosphamide for mechlorethamine,” William L. Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, told HemOnc Today. “Unfortunately, we later determined that the outcomes from treatment were not equivalent to what we had seen with mechlorethamine. In cancer, where dose intensity is such a critical part of outcomes, if you are not able to attain the amount necessary of the drug in shortage, you risk impairing the outcome goals.”

Practice management often is impacted by the shortages.

“We spend a lot more time trying to procure the different drugs in shortage or to find substitutions as opposed to time we should be using for face-to-face patient care and quality assurance,” Thomas A. Gallo, executive director of the Virginia Cancer Institute and treasurer of the Association of Community Cancer Centers, said in an interview. “This creates a huge administrative burden, and the required staffing has increased our costs significantly. Many independent practices don’t employ pharmacists, so the physicians and nursing staff directly have to deal with these issues.”

These burdens have direct consequences on quality of care, Lichtenfeld said.

“Anything that makes a cancer patient’s care more difficult — whether for the physician who is concerned about how they can obtain a drug or the patient who is concerned about whether their treatment date will change — takes away from what should be the core focus: the patient,” Lichtenfeld said.

Manufacturing issues

Manufacturing issues caused more than 50% of drug shortages in 2013, whereas 5% to 10% stemmed from active ingredient shortages, according to the FDA.

“Not all shortages can be prevented … since, in some cases, serious quality problems may preclude the safe use of a drug for patients such as particles of glass, metal or other materials found in drugs meant for injection into patients,” Stephen King, spokesman for the FDA’s Center for Drug Evaluation and Research, told HemOnc Today. “In other cases, firms may make a business decision to discontinue a drug, and FDA does not have the authority to require a firm to manufacture a drug or to make a specific amount. In all cases, FDA uses every tool available to work with manufacturers to meet patient needs and to resolve shortages as quickly as possible.”

Drug supplies hinge on how facilities are run.

“It is the responsibility of the drug manufacturers to maintain quality manufacturing so that the drugs they make work the way they are supposed to and are safe for patients,” King said.

Manufacturing issues prompted the closure of Ben Venue Laboratories, the previous manufacturer of Doxil. Hikma, which purchased the facility, announced in August 2014 that it had no plans to reopen it.

“A significant contributing cause of drug shortages is simply that we have aging facilities,” Greene said. “Whether an inspection recognizes that there is a production issue or the factory is closed for maintenance, those changes can have dramatic impacts on the market because we have relatively few suppliers of important drugs.”

The Food and Drug Administration Safety and Innovation Act, signed into law in July 2012, requires manufacturers to notify the FDA 6 months prior to potential supply disruptions.

“The legislation has had a successful outcome because the notifications … allow FDA time in many cases to coordinate with manufacturers to prevent or mitigate shortages,” King said. “FDA determines how best to address each shortage situation based on its cause and the public health risk associated with the shortage.”

The FDA takes several steps to manage manufacturing or quality problems.

“FDA … works with other firms making the drugs that are in shortage to help them ramp up production if they are willing and able to do so,” King said. “Often, they need new production lines approved or need new raw material sources approved by FDA to help increase manufacturing. FDA can — and does — expedite review of these to help resolve shortages of medically necessary drugs, such as oncology drugs.”

These actions have helped reduce the number of new shortages, which peaked at 250 in 2011, declined to 117 in 2012, and fell to 44 in 2013.

“Although there are a number of oncology drugs that continue to show up on shortage lists, we are not seeing as much difficulty obtaining oncology products,” Greene said. “The problem is the number of shortages that have persisted.”

Yet is unrealistic to expect this legislation or other voluntary efforts — such as the Generic Pharmaceutical Association’s Accelerated Recovery Initiative (ARI) — to eradicate the problem, experts said.

According to Lichtenfeld, in the case of the ARI — which uses a third party to monitor generic drugs and potential shortages then notify the FDA of the problem — there must be multiple manufacturers of the drug in question before the surveillance is active.

“A lot of generics do not have three manufacturers, so this is an issue,” Lichtenfeld said.

The 6-month warning may not always be feasible, either, Okon said.

“If there is a sudden case where a production line goes down and they hadn’t anticipated a shortage, it may be hard to give a warning,” he said. “It is unrealistic to always expect that.”

In some cases, the attempts to provide advanced notice of potential shortages have compounded the problem, Okon said.

“When a shortage is announced, we’ve seen hoarding on the part of fly-by-night wholesalers that buy out inventory of drugs,” Okon said. “When you announce there’s going to be a shortage, you’re going to exacerbate the shortage.”

In order to prevent stockpiling, major distributors allot drugs to practices according to prior usage.

“There has been this concern that large purchasing groups, such as large hospitals, get preferential treatment,” Lichtenfeld said. “They get a substantial amount of the market, and there is little leftover for everyone else.”

A shortage of generics

The production of generics also has contributed to drug shortages.

“Even though people want to talk about this being a quality problem, it is a financial problem,” Okon said. “When was the last time we heard of a shortage of big-name drugs made by one manufacturer, like Avastin? Why aren’t there ‘quality’ problems there? The problem is the margins on generics are so small, and they are made worse by the increasing number of government discount and rebate programs.”

The lack of profit on generics often is attributed to Medicare reimbursements.

“Medicare has limited payments for these drugs and, because the payments are low and can’t respond to market forces, we can’t increase the payments,” Lichtenfeld said. “We live in a competitive market, and if there was an easy solution, we would have it.”

Gallo also referenced Medicare reimbursement.

“The current average sales price mechanism of reimbursement for many of these drugs has caused the actual reimbursements to be pennies — often times under a dollar — per unit of the drug,” Gallo said. “I’m not sure that is a sustainable system for these publicly traded manufacturers.”

The 340B Drug Pricing Program — which makes life-saving treatments available to low-income, uninsured and underinsured patients at extreme discounts — also drives down margins.

“We are in 100% denial that this is an economic program that is tied to vital, critical access programs such as 340B,” Okon said. “We are fooling ourselves if we think that forcing lower prices with increasing rebates and discounts is not going to have an impact on our generic manufacturing.”

The Generic Drug User Fee Act (GDUFA) 2012 amendments — designed to expedite generic drug approval — have improved the drug shortage situation, according to David Gaugh, RPh, senior vice president of sciences and regulatory affairs of the Generic Pharmaceutical Association.

“[The association] and its members enthusiastically support the full implementation of actions that can be provided by generic industry-generated fees from GDUFA, which total nearly $300 million annually,” Gaugh told HemOnc Today. “This includes expediting the approval process, completing site inspections, reducing the Abbreviated New Drug Application backlog and other critical functions of the FDA, each of which play a role in getting generics to patients as quickly and safely as possible.”

There are more than 3,000 generic products in that backlog, Gaugh said.

“Shortages are complex and multi-faceted, and different therapies face different circumstances,” Gaugh said. “Some therapies in shortage are only made by one or two manufacturers. Others are the result of unplanned disruptions in manufacturing for any variety of reasons. There is no single cause and no single solution. Still, the FDA and stakeholders at all levels of the supply chain are working tirelessly to make sure that treatments are within reach for millions of patients.”

No simple fix

Surveys of clinicians’ experiences with drug shortages may not portray a true picture of the situation, experts said.

The survey by Goldsack and colleagues showed 98% of pharmacy directors reported dealing with at least one injectable oncology shortage within the prior 12 months, a figure that remained unchanged from 2011.

“This suggests that neither the reauthorization of the Prescription Drug User Fee Act nor the … GDUFA — or any other measures of the FDA Safety and Innovation Act signed into law by the president on July 9, 2012 — have had a significant impact on the shortages of injectable oncology drugs in practice,” they concluded.

Greene disagreed.

“I’m personally aware that the drug shortages group at the FDA has been very effective at mitigating a number of shortages that could have had a major impact on the country,” Greene said. “We do not often see the details behind that.”

The fact that drug shortages are avoided may not be apparent in the 98% rate, Lichtenfeld said.

“That a shortage may exist … is one metric and it is an important one,” he said. “But the question of effectiveness of a policy really has to focus on whether they have been able to reverse the number of shortages and the duration of shortages over any given period of time.”

Despite its efforts and intentions, it has become clear that it will take much more than FDA action to eradicate drug shortages, Mitchell said.

“I’m flabbergasted by anyone who thinks the FDA is going to solve this problem,” Mitchell said. “They are not a drug company and they have no manufacturing capability. Reimbursement for generics needs to have a floor so that these drugs have a profit, or else, who is going to make them? You wouldn’t do it, I wouldn’t do it and our government wouldn’t do it if there wasn’t some modest profit in it.”

Physicians can do their part, King said.

“If a hospital or a practitioner is experiencing a shortage that is not found on the FDA website, there is a reporting mailbox where the public can report shortages (drugshortages@fda.hhs.gov),” King said. “Early notification of supply disruptions is extremely important so that FDA can begin to work on the problem with manufacturers as soon as possible.”

Government incentives to generic manufacturers has been proposed, but it is not necessarily a solution, Okon said.

“Incentives may give a short-term lift, but they would just further distort the market,” Okon said. “We have to do a realistic analysis — which no one wants to do — of how these programs that are extracting more discounted rebates are impacting our underlying generic marketplace.”

The gray market — which sells versions of extremely marked-up drugs in shortage — might be another target. The Gray Market Drug Reform and Transparency Act — designed to prevent unscrupulous pharmacies from purchasing as many supplies of a drug in shortage as possible, then selling them at exorbitant prices — was introduced in the House of Representatives in May 2013 and referred to the Subcommittee on Health, but no action was taken.

“The gray market is dangerous, but it exists because people are simply willing to pay the money for these drugs,” Greene said. “The issues with the gray market would not exist if people would not purchase from it.”

A solution might take the effort of many parties.

“Rather than trying to keep putting Band-Aids on this system, we need to have a real, honest discussion and study the root economic cause for what is drying up our generics,” Okon said.

That may be easier said than done, Lichtenfeld said.

“There is no easy solution,” he said. “If there was, we would have it.”

Life with shortages

Practices have developed many strategies to minimize the effects of drug shortages.

One such practice — informal networks and alliances among hospitals and independent practices — has become widespread across the United States.

“There has definitely been collaboration in the community to make sure that patients’ needs are met,” Gallo said. “However, this is becoming more and more difficult with the increasing number of these issues.”

Although this system is helpful, it is not perfect.

“We have loaned or bartered with hospitals for drugs in many situations. When they did not have [one particular drug], we would send them the drug and they would pay us back with different medications,” Mitchell said. “This still takes up a lot of time with the pharmacist, as well as the doctors and management making those decisions.”

Despite how common drug shortages are, a survey conducted by Emanuel and colleagues — presented at the ASCO Annual Meeting in 2013 — indicated 70% of cancer centers lacked formal guidance for allocation decisions.

“We should have enough of an infrastructure to be able to provide these services to all the patients who need them,” Gallo said. “It is unfortunate we even need to think about these things.”

However, umbrella-statement guidelines may not be realistic.

“The question of defining what is ethical and what is not without knowing a specific situation of a case is very challenging,” Greene said. “That is probably why many organizations have not defined formal ethical guidelines.”

The fact the problem has persisted for so long has prompted some to question whether drug shortages are the new norm.

“I have repeatedly heard stories about patients waiting for treatments that I never want to hear again,” Okon said. “Unfortunately, horrible events are going to have to occur before we really tackle this and look at what we’re doing to our ability to provide these critical drugs and how we’re harming the system.”

Open discussions will be crucial, Lichtenfeld said.

“It has become the new norm to expect drug shortages,” he said. “It is no longer getting a lot of public attention, although maintaining public awareness is critical to getting the problem solved. If we don’t constantly revisit this and make people aware of it, then this will become the status quo. For patients who face life-threatening illnesses, this should not be the status quo.” — by Alexandra Todak

References:

American Society of Health-System Pharmacists. Drug shortages resource center. Available at: www.ashp.org/menu/DrugShortages. Accessed Jan. 9, 2015.

Emanuel E. Abstract #CRA6510. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.

Goldsack JC. Am J Health-Syst Pharm. 2014;71:e24-e31.

U.S. Food and Drug Administration. Drug Shortages. Available at: www.accessdata.fda.gov/scripts/drugshortages/default.cfm. Accessed Jan. 9, 2015.

For more information:

Thomas A. Gallo can be reached at Virginia Cancer Institute, 7202 Glen Forest Drive, Suite 200, Henrico, VA 23226.

David Gaugh, RPh, can be reached at email: media@gphaonline.org.

William L. Greene, PharmD, can be reached at william.greene@stjude.org.

Stephen King can be reached at cdertradepress@fda.hhs.gov.

J. Leonard Lichtenfeld, MD, MACP, can be reached at the American Cancer Society, 250 Williams St. NW, Atlanta, GA 30303.

R. Brian Mitchell, MD, can be reached at Virginia Cancer Institute Reynolds Crossing, 6605 West Broad St., Suite A, Richmond, VA 23230.

Ted Okon can be reached at Community Oncology Alliance, 1101 Pennsylvania Ave NW, Suite 700, Washington, DC 20004.

Disclosure: King receives a salary from the FDA. Gallo, Gaugh, Greene, Lichtenfeld, Mitchell and Okon report no relevant financial disclosures.

Would adoption of European drug pricing practices resolve the issue of drug shortages in the United States?

Yes. European drug pricing practices would increase the cost and profitability of generics, the primary source of drug shortages.

Analyses have identified many underlying causes for drug shortages, including production issues, FDA overregulation and a short supply of raw materials. However, a majority of drugs in shortage are generics, for which there are meager profit margins. Patented drugs with large profit margins are rarely in shortage. Since passage of the Medicare Modernization Act of 2003, Medicare reimbursement for physician-administered drugs was capped at 6% of the average sales price (ASP). Prior to that year, oncologists bought drugs at 66% to 88% of the ASP, and they made 20% to 50% profit margins on the drugs by selling them at higher costs. Those profits encouraged oncologists to practice in rural areas and made care more accessible throughout the country.

The 6% margin scarcely covers pharmacy costs incurred by receiving, inspecting, storing and dispensing the generic agents. Further, manufacturers are unable to increase generic drug costs much higher than 6% in any 6-month period. Chemotherapy drug shortages started having an impact by 2006 — the year after the Medicare Modernization Act was implemented — and have largely escalated thereafter. On the other hand, the price of patented drugs consistently increases by 10% to 12% annually.

Drug shortages exist throughout the world but are felt most acutely in the United States. In Europe, Medicare and the ASP plus 6% rule do not exist, thereby allowing the cost of generic chemotherapy agents to be higher and the profit from these agents to be greater. Therefore, more companies viably manufacture generic agents and shortages occur less frequently. The costs of brand drugs in Europe also tend to be lower due to agreements between the drug companies and governments.

An amendment of the ASP plus 6% rule to reflect European practices might improve market forces. By keeping ASP plus 6% for brand drugs but increasing the formula to ASP plus 10% to 20% for generic agents, generics would become more profitable and their manufacture more competitive. Another alternative would be to set a minimum price for generics, perhaps at 3% to 5% of the comparable patented drug price.

Drug shortages have been estimated to cost $200 million to $300 million annually. Although this calls for an increase in prices, it would enable oncologist access to well-priced generics and extend the treatment of life-saving medications to the patients who need it.

Hagop M. Kantarjian, MD, is chair of the department of leukemia at The University of Texas MD Anderson Cancer Center. He can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: hkantarjian@mdanderson.com. Disclosure: Kantarjian reports no relevant financial disclosures. 

There is no need to look to Europe for the solution to what is now a global crisis. It was “made in the USA” and must be fixed here.

The US generic drug shortages have had a domino effect. Many of the drugs in short supply here also are scarce in Europe and elsewhere around the world.

This market has been broken by the anticompetitive contracting and pricing practices, self-dealing and kickbacks of giant hospital group purchasing organizations (GPOs), which control the purchasing of upwards of $300 billion annually in drugs, devices and other supplies for about 5,000 American hospitals.

This public health emergency originated with a misbegotten 1987 statute called the Medicare anti-kickback “safe harbor,” which exempted GPOs from criminal prosecution for taking kickbacks from vendors. It gave rise to a “pay-to-play” scheme in which drug makers and other suppliers pay exorbitant fees in return for contracts that give them exclusive access to GPO-member facilities.

This statute defeated the original and sole purpose of GPOs: saving hospitals money. For more than 80 years, until the safe harbor took effect in 1991, they had succeeded. Since then, overwhelming evidence shows that they actually inflate health care supplies costs by at least 30%.

Today, these cartels are in the business of selling market share to the highest bidder. They are nothing more than extraneous middlemen with a computer and a cash register. They are not subject to meaningful oversight, regulation or disclosure requirements. No one outside this secretive system seems to know where the billions in fees are going.

That’s why there are only one or two US suppliers for a given drug, or even none at all. Because of these fees, even drug makers that enjoy monopoly or oligopoly positions often cannot afford to properly maintain or upgrade plants and equipment, leading to adverse FDA inspections and even plant shutdowns. Although GPOs claim that their fees don’t exceed the 3% statutory limit, documents tell a different story. They show that these fees have sometimes exceeded half of a drug maker’s revenue for a single drug!

In February 2014, the Government Accountability Office released a drug shortage report — mandated by Congress — that cited GPOs as a “potential underlying cause.” However, a more focused GAO investigation — requested in November 2012 by six senior House members — on the role of GPOs in causing the shortages and the deadly 2012 fungal meningitis outbreak was shut down by the powerful GPO cabal. The GPOs knew that they could not survive a thorough, honest investigation.

To end the shortages, we must restore market competition and integrity to the health care supply chain by repealing the safe harbor. To accomplish that, health care practitioners and other stakeholders must make themselves heard in Washington.

Phillip L. Zweig, MBA, is executive director of Physicians Against Drug Shortages, a patient advocacy group created to restore competition to the generic prescription drug and hospital group purchasing industries (www.physiciansagainstdrugshortages.com). He can be reached at plzweig@aol.com. Robert A. Campbell, MD, is chairman of Physicians Against Drug Shortages and president of the Pennsylvania Society of Anesthesiologists. Disclosure: Zweig and Campbell report no relevant financial disclosures.