Coming up short: Low supplies of key drugs force physicians to scramble

On Feb. 21, the FDA took the unusual step of allowing temporary overseas importation of methotrexate and liposomal doxorubicin.

Supply of those two drugs was running dangerously low. Some hospitals reported that their stock of methotrexate, used to treat acute lymphoblastic lymphoma, was down to 2 weeks, and quantities of liposomal doxorubicin, used to treat ovarian cancer and sarcoma, had been non-existent for months.

Max J. Coppes, MD, PhD, MBA, senior vice president of the Center for Cancer and Blood Disorders at Children’s National Medical Center in Washington, D.C., supported the move at the time but said the FDA would need to make systemic changes to prevent further shortages.

“It’s a laudable decision by the FDA based on the current shortages of drugs,” said Coppes, also a HemOnc Today Editorial Board member. “I would assume this is a one-time decision, and I hope this will generate the discussion as to whether a process needs to exist that would allow importation to happen in other circumstances where a critical shortage of chemotherapy drugs develops.”

Jack Muckstadt, PhD, professor of engineering at Cornell University, has studied drug shortages for almost a decade. Manufacturers’ profit margins and infrastructure costs are key contributors to the problem, he said. Photo courtesy of Cornell University reprinted with permission

Drug shortages are not new. Physicians who treat cancer said certain drugs were getting harder to find 2 years ago, and between 230 and 270 drugs went into shortage last year. Some are calling the current shortage the worst in 30 years, prompting fears that such scarcity may be permanent.

In a survey of 204 oncologists conducted in January by National Analysts Worldwide, about 80% of respondents reported that they had been “unable to provide some patients with appropriate or timely treatment due to drug shortages.” Almost 50% reported observing tumor recurrence and 40% reported observing early death among their patients due to shortages. Moreover, 61% said patients would be less likely to receive timely treatment in the next 12 months due to shortages and 54% expected that patients would be less likely to receive optimal therapy.

“We haven’t been able, in a short time frame, to take full measure of the implications and consequences of the inability to provide to patients in a timely basis proven drug therapies,” said Susan Schwartz McDonald, PhD, CEO of National Analysts Worldwide. “These are therapies that have earned their stripes. There are years of data to verify their impact on patients and patient outcomes, so we shouldn’t be surprised that distortions in the supply chain would have clinical consequences.”

Cash is king

Several factors, including manufacturing problems and a lack of raw materials, contribute to drug shortages, but the problem is especially acute for sterile injectables. A January article published in Cancer said sterile injectables accounted for upward of 80% of all reported drug shortages in 2010 and 2011.

The FDA, which did not respond to requests to speak with HemOnc Today for this article, has strict quality control standards for manufacturers of IV drugs. Quality control problems forced Ben Venue Laboratories of Bedford, Ohio — a leading manufacturer of methotrexate and several other drugs — to voluntarily suspend operations in November. Many shortages can be traced to closures at Ben Venue.

The article in Cancer said problems at manufacturing facilities accounted for 43% of shortages, whereas delays in manufacturing or shipping were responsible for 15% of shortages and a lack of basic ingredients caused another 10%.

The problem comes down to money, said Jack Muckstadt, PhD, professor of engineering at Cornell University and former director of the university’s School of Operations Research and Industrial Engineering.

“Ultimately, in order to have products, the manufacturer has to make a profit,” he said. “Profits can only be made if you charge reasonable prices. I’m not defending the price of pharmaceuticals, but at some point, if you squeeze too hard, you will eventually end up with no profit.

“Over time, for a variety of reasons, the margins for certain drugs, particularly generics, have gotten so small that the number of manufacturers in the US has dwindled,” Muckstadt said. “Compounding that, the infrastructure required to provide safety in manufacturing costs a lot of money, and the desire to improve safety over time requires incremental and sometimes substantial investments.”

Muckstadt, a member of Cornell’s Institute for Disease and Disaster Preparedness and a member of the Board of Scientific Counselors of the Centers for Disease Control and Prevention, began studying the problem of drug shortages about 8 years ago after a series of conversations with professors at Weill Cornell Medical College.

Because manufacturers are in business to make a profit, these shortages are predictable and likely permanent, barring major changes in the way pharmaceuticals, especially generics, are produced in the United States, Muckstadt said.

“This is a never-ending problem, and the number of drugs that we’re going to find in short supply will continue to rise over time,” he said. “At one level, we’re trying to keep the costs down. On another level, if you squeeze hard enough, eventually manufacturers will cry uncle and turn their productive capacity to drugs for which they have patents and for which they’re going to get reasonable returns for their investors.”

Increasing financial incentives or providing price supports for manufacturers could increase medical costs at precisely the moment the nation is fixated on reducing them, but the expense of shortages already is in the system, said Darcy Malard Johnson, PharmD, oncology pharmacy program manager with Fairview Pharmacy Services in Minneapolis.

“As a health care system, we need to ensure we can produce these products to treat patients,” Malard Johnson said. “An incentive program to encourage companies to produce these critical drugs, for which we don’t have alternatives, might be something we need to explore.”

Fairview is trying to track the amount of time staffers spend managing drug shortages.

Max J. Coppes

“There are a lot of indirect costs we’re absorbing in terms of time and staffing resources to try to limit the impact to patient care,” Malard Johnson said.

A controversial editorial published by The New England Journal of Medicine in November suggested that oncologists have a profit incentive to sell more expensive name-brand drugs, which cuts into the market for lower-priced generics. Oncologists are only allowed to charge a 6% markup on medication, according to Medicare rules.

“Why use paclitaxel (and receive 6% of $312) when you can use Abraxane (for 6% of $5,824)?” Mandy L. Gatesman, PharmD, and Thomas J. Smith, MD, wrote in their editorial.

Malard Johnson had never seen a physician take the increased reimbursement of a brand product into account when designing a treatment plan, she said, adding that a physician may be more inclined to use the less expensive drugs to reduce the financial burden on a patient.

“A patient may be a self-paying patient or underinsured and have to pay substantial costs for chemotherapy out of their own pockets. Sometimes, in those situations, the patient cannot afford the expensive brand-name product, which may have proven most efficacious for their therapy and a clinician will need to switch to another regimen that the patient can afford,” Malard Johnson said. “If a cancer center follows such practice of utilizing expensive brand drugs for the financial incentive, it should raise ethical questions.”

Scrambling for treatments

The lack of availability of certain medications has forced clinicians to spend considerable time developing contingency treatment plans.

Steve Fijalka, PharmD, director of operations for pharmacy services at the University of Washington Medical Center/Seattle Cancer Care Alliance and associate professor with the UW School of Pharmacy, participates in a weekly phone conference with colleagues at other institutions in the alliance. If a certain drug is in short supply, the alliance members coordinate efforts for using therapeutic alternatives, acquiring generic drugs and staying in contact with manufacturers to know when new supplies may become available.

“It takes a lot of communication, a lot of planning and a lot of time,” Fijalka said. “I probably spend an hour a day on drug shortages. … We’ve been somewhat fortunate because larger organizations have been able to work with their institutions to make sure we can maintain supply, but we are by no means immune to shortages.”

Malard Johnson has participated in regular conference calls with pharmacy staff at the four hospitals and five outpatient clinics in the Fairview system for about 9 months. Staffers discuss current shortages and try to identify others that may occur soon.

Fairview also has begun working with its ethics board to develop a plan in the event the system is forced to turn away patients or ration drugs if there is no therapeutic alternative.

“We’ve created these mental models already,” Malard Johnson said. “Clinics and health care facilities need to begin thinking about and deciding, proactively, how they will address those situations. It is not something you want to make a quick decision about.”

Physicians at Duke Cancer Institute in Durham, N.C., are taking similar steps to stay on top of shortages, according to David A. Rizzieri, MD, associate professor of medicine in the cellular therapy division. They decide as a group which patients are at greatest need for a particular medication, such as those who need drugs for curative purposes as opposed to palliative care, and which patients can be switched safely to alternative drugs.

David A. Rizzieri

Shortages go beyond anticancer agents, Rizzieri said.

“Last year, there were some antiviral medicines that were not available. I do know of patients who progressed with bad viral illnesses who did not have alternative medicines available that may or may not have been able to save their lives,” he said. “It’s not limited to just chemotherapy. These shortages affect other lifesaving drugs.”

Government efforts

Three pending pieces of legislation in Congress focus on drug shortages.

Senate bill S. 296, the Preserving Access to Life-Saving Medications Act, would require a prescription drug manufacturer to provide 6 months notice of any discontinuance or interruption in the manufacturing of a drug that likely would result in a shortage. The measure also would require the manufacturer to provide notice “as soon as practicable” after becoming aware of an interruption. That bill currently is in committee, and there is a companion bill, H.R. 2245, in the House of Representatives.

H.R. 3839, the Drug Shortage Prevention Act of 2012, also is in committee. That bill would require the FDA to produce a national critical drug list and a national critical drug shortage list. The FDA would be tasked with expediting review of new drug applications or abbreviated new drug applications for so-called critical drugs, as well as any request by the sponsor of a critical drug to approve a change to the manufacturing process, approve a change to the manufacturing facility or add an alternate active pharmaceutical ingredient supplier.

Further, the bill would require the Department of Health and Human Services to study the feasibility of creating a national contingency plan to address critical drug shortages, including the possible creation of a federal stockpile of critical drugs.

Even if such legislation is approved, it may not make much difference, said Margaret R. O’Donnell, MD, professor and associate clinical director in the department of hematology and hematopoietic cell transplantation at City of Hope in Duarte, Calif.

“It’s been the reality for the past 2 years that we are constantly trying to piece together drug supplies or alternative dosing schedules or alternative regimens to compensate for what’s not available,” she said. “I don’t see what the proposed measures in Congress are going to do to fix that problem. Notifying us there is going to be a shortage drives up drug prices but doesn’t necessarily prevent the shortage.”

Rizzieri said he was a bit more hopeful.

“It will ensure heightened communication,” he said. “The key will be ensuring that the government acts in an efficient way to help us overcome these impending shortages.”

A formal system in Canada lets physicians petition the government to allow foreign importation when a shortage is expected. Canada currently is importing cotrimoxazole, an antibiotic used to prevent infection in patients undergoing chemotherapy, from the United States.

Coppes, who serves as an adviser to Health Canada, roughly the equivalent to the FDA, said he would like to see the United States adopt a similar approach.

“There’s a formal request reviewed by Health Canada, and they can allow import of that drug from a different country,” he said. “If drugs cannot be made in this country, patients should have access to lifesaving drugs made elsewhere with the same standards we’re used to in the United States.”

Margaret R. O’Donnell

The ‘gray market’

The FDA can alleviate shortages by looking for foreign suppliers, as it did with methotrexate and liposomal doxorubicin. In some cases, physicians take pre-emptive measures. Fijalka and Malard Johnson said they have increased their stocks when they know a drug is at-risk for going into shortage.

Physicians dislike acknowledging the existence of a so-called “gray market,” through which drugs available for those willing to take the risk. Speculators procure drugs of sometimes unknown origin and offer them to medical centers in need, usually at huge cost. An editorial in The New England Journal of Medicine estimated that the markup on the gray market can be as high as 3,000%.

Some physicians and pharmacists, including Malard Johnson, said they have received calls from non-contract distributors offering drugs in short supply. Pursuing such offers can be dangerous because the drugs may be stolen and there is no way to know how they were manufactured or maintained.

“If a health system decides to purchase something from a non-contract distributor, they may not be able to obtain the pedigree of the drug,” Malard Johnson said. “Recently, there have been reports of counterfeit Avastin making it into the US market. That is one worry about purchasing from a non-contract distributor. The drugs might have changed hands a half-dozen times.”

The FDA released the warning about counterfeit bevacizumab (Avastin, Genentech) on Feb. 14. The agency also sent letters to 19 medical practices across the country alerting them that they purchased unapproved cancer medications — possibly including the counterfeit bevacizumab — from Quality Specialty Products, a foreign supplier that also uses the name Montana Health Care Solutions.

“It’s risky buying off the gray market. You never know where those drugs come from, and it’s expensive,” Fijalka said. “We don’t buy off that market, but others have had to.”

Fear of the unknown

President Barack Obama issued an executive order last fall that directs the FDA to accelerate reviews of new applications for marketing of generic drugs and also establishes tougher requirements for reporting potential drug shortages.

The effort is a step in the right direction, but it remains unclear what effect it will have on supply, Bruce A. Chabner, MD, director of clinical research at Massachusetts General Hospital Cancer Center, wrote in an editorial in The New England Journal of Medicine.

“It will be up to the community of cancer doctors, patients and concerned citizens to demand further action at the federal level and by the private sector to ensure access to lifesaving and life-extending drugs,” Chabner wrote.

Meantime, the ramifications of current drug shortages may never be known.

Despite the responses to the National Analysts Worldwide survey, experts said it is difficult to draw a direct connection to the absence of a particular drug and a poor patient outcome. Few cancers have a 100% cure rate, and patients can relapse or progress on treatment for a variety of reasons.

Still, even a slight possibility that patients might get sick or die because physicians could not acquire the drug that may have saved their lives causes doctors to worry.

“It’s going to be hard to know a year from now whether the child who relapses does so because he didn’t get the methotrexate dose in the proper sequence, because it got frame shifted by 6 months and other drugs were substituted in the interim,” O’Donnell said. “We don’t know if there were more relapses due to last year’s cytarabine shortage. There will always be people who recur, and we don’t know if it was because of their natural disease biology or because they got less-than-optimal dosing.” – by Jason Harris

Are drug shortages the ‘new normal’ for cancer care?

Nicholas J. Petrelli

I absolutely do not see drug shortages as the new norm.

Americans are more than capable of finding a solution to this problem. This country has been through a lot in the past decade and always comes out on top.

Physicians, patients and patients’ families have been aware of drug shortages because they have to deal with them. The general public, however, has not been made aware of the problem until recently. They are being made aware of the problem now, and one of the great things about this country is that when there is a public outcry, we will get change and find a solution.

There needs to be some incentive for companies to produce generic drugs that do not generate revenue, some sort of formula that makes it reasonably profitable to produce these necessary drugs. We are seeing fewer and fewer companies that are willing to produce generics, and we can’t depend on just a handful of manufacturers.

Maybe we need a pricing floor for generic drugs. Maybe we need mandatory reporting of potential shortages, as proposed by the Drug Shortage Prevention Act sponsored by Rep. John Carney, D-Del., and Rep. Larry Bucshon, R-Ind., who also is a heart surgeon.

Let’s not wait until we have a shortage and then manage by crisis. Let’s get mandatory reporting so that if a company has to be shut down, we can start to work on a solution right away.

There are about 2,000 backlogged approval applications for generic medications, with a median time to approval of about 30 months. That is an obvious target for reform.

Price supports will add cost, but that is better than a 3,000% markup in price that clinics are paying now in the gray market from scalpers. Medical costs are skyrocketing, but that’s due to a lot of factors beyond drug prices.

These drug shortages, to me, are unfair to patients in this country. Despite skyrocketing costs in medical care, this is still the country where I want to get my treatment. But we can’t allow drug shortages to continue to occur and, at the same time, we must control medical costs.

Dale Shepard

Chemotherapy drug shortages are likely to continue, and they are likely to get worse before they get better.

The number of chemotherapeutic agents on the shortage list is increasing, and most are generic medications. The shortage of chemotherapy, naturally, has led to an outcry from patients, their families, professional organizations and advocacy groups.

What is the solution? President Obama signed an executive order last year to encourage manufacturers to report impending shortages, hasten the review process for generic drugs and investigate price gouging. Unfortunately, this does little to address the causes of the problem.

These shortages are primarily due to discontinuation of production at the manufacturer level, and they usually are driven by economic considerations. Would knowing about an impending shortage of a particular chemotherapy drug 3 months earlier prevent a shortage that affects our treatment of patients? Not likely. If a drug manufacturer is discontinuing production of a generic chemotherapy due to economic concerns — usually a low profit margin — it seems unlikely another generic manufacturer will start making this drug. The low profit margins have led to manufacturing problems for some agents due to inattention to quality control and maintenance of equipment.

The problems aren’t entirely caused by the manufacturers, however. Because revenue from administering chemotherapy is linked to the price of the medication, there is more incentive for oncologists to use more expensive medications. This decreases the demand for the cheaper generic medications and hastens discontinued production.

Shortages of chemotherapy have created a tremendous burden on oncology practices. These practices must now dedicate considerable resources to obtaining any available supplies of certain drugs, seeking alternate suppliers and developing alternative treatment regimens.

The solutions to shortages of chemotherapy agents are not likely to be quick or easy. ASCO has proposed possible solutions, including decreasing administrative barriers for manufacturers of generic medications, adjusting Medicare payment levels for generic drugs, increasing FDA authority for management of shortages, offering incentives for producers of generic drugs and creating a national stockpile program. These will not be quick fixes, nor should they be. Patients with cancer deserve a long-term solution that ensures the optimum efficacy and safety of their treatment.

References:

• Chabner BA. N Engl J Med. 2011;365:2147-2149.
• Gatesman ML. N Engl J Med. 2011;365:1653-1655.
• Gehrett BK. JAMA. 2012;307:153-154.
• Jenks S. J Natl Cancer Inst. 2011;103:914-915.
• Jensen V. N Engl J Med. 2010;363:806-807.
• Larkin H. H&HN. Drug shortage may be worst in 30 years.
• Link MP. J Clin Oncol. 2012:30;692-694.
• Mitka M. JAMA. 2011;306:1069-1070.
• Printz C. Cancer. 2012;doi:10.1002/cncr.27386.
• Rosenthal ET. J Natl Cancer Inst. 2012;104:168-170.
• Rosenthal ET. J Natl Cancer Inst. 2012;104:264-267.

For more information:

• Nicholas J. Petrelli, MD, is medical director of the Helen F. Graham Cancer Center in Newark, Del. Disclosure: Dr. Petrelli reports no relevant financial disclosures.
• Dale Shepard, MD, PhD, is an associate staff physician in solid tumor oncology at the Taussig Cancer Institute at Cleveland Clinic. Disclosure: Dr. Shepard reports no relevant financial disclosures.

Disclosures:

• Dr. Rizzieri reports receiving speaking fees from Allos, Celgene, GlaxoSmithKline, Incyte, Novartis, Seattle Genetics, Spectrum and Teva. Drs. Coppes, Fijalka, Malard Johnson, Muckstadt, McDonald and O’Donnell all reported no relevant financial disclosures.