The door isn't fully closed on the acute oncology drug shortages of 4 years ago, observers say, though the FDA has established rules for greater disclosure by manufacturers and continues to tweak guidelines that would require far more information about manufacturing processes and production issues.
Dan Zuckerman, MD
The door isn’t fully closed on the acute oncology drug shortages of 4 years ago, observers say, though the FDA has established rules for greater disclosure by manufacturers and continues to tweak guidelines that would require far more information about manufacturing processes and production issues.
The FDA sought feedback on its draft quality metrics guidance through an open comment period that continued through the end of September. The changes would require manufacturers to provide more information about drug quality and aid the FDA in heading off potential drug shortages.1 Details such as the success and failure of attempts to produce quantities of particular drugs would be required information as well as details on product quality complaints. Also, the FDA has suggested in the draft guidance that it be notified of corrective actions taken and be informed about any involvement by senior management in product reviews. In response, members of the International Society for Pharmaceutical Engineering (ISPE) have advocated for a phased introduction, with just a few of the requirements applying to higher-risk facilities, and with voluntary reporting, initially, to limit the administrative burden on manufacturing companies.
The director of the Drug Information Service at University of Utah Health Care, Erin Fox, says a lack of transparency in manufacturing and product supply has been a key issue in drug shortages of recent years, and in efforts to understand the quality and origin of drugs on the United States market. For this reason, she says the FDA’s quality metrics effort is “a really good step,” though its value to the physician community is limited in that the data provided by manufacturers will not be made publicly available.
“You can go to the store and buy a pack of raspberries and see if they’re from California or from Mexico, but you can’t know that about the medicine, and that’s what’s really frustrating,” she says.
Fox praises a requirement that drug companies notify the FDA of pending shortages, a rule enacted through the FDA Safety and Innovation Act of 2012. “Overall, we have a picture of improvement—significant improvement—especially if you think back to where we were in 2010 and 2011, when patients were being turned away from chemotherapy,” she says.
aShortages for 2015 reflect first 6 months of year only.
Source: University of Utah Drug Information Service
Even so, now is not the time to ease the pressure on the FDA, says Dan Zuckerman, MD, executive medical director of St. Luke’s Mountain States Tumor Institute in Idaho, a group of 5 treatment centers grappling with ongoing shortages of key drugs.
“What I wouldn’t want to see is a sense that the issue is solved, that we can forget about it for now,” says Zuckerman. “I think that for the foreseeable future it may need to stay on both our radar and the FDA’s radar.”
Zuckerman participated in an ASCO lobbying effort in the early part of this decade to raise the profile of the drug shortage problem so that the FDA would take ownership and spearhead a meaningful reform effort. “We’re pleased to see that steps have been taken to address this through the FDA, through the lobbying efforts by ASCO, and by having more visibility on the congressional side.”
Although the drug shortages were acute, a key culprit was Teva’s Irvine, California, manufacturing plant, which was the source of up to 55 products and came to a lengthy standstill after it failed an FDA inspection.
Zuckerman recalls the crisis too vividly to believe that it couldn’t happen again without ongoing vigilance.
“We were really becoming concerned, on too routine a basis, that patients weren’t getting the care they needed, particularly for pediatric drugs,” he says. Obtaining supplies of needed drugs was not always possible, and the pharmacy at St. Luke’s often had to juggle priorities and call around to outside facilities in search of fresh supplies, finding in many cases that those facilities were going through exactly the same difficulty.
The liposomal doxorubicin was in very short supply during that period, Zuckerman recalls. “We sometimes had to delay patients or cancel patients and, frankly, sometimes even use alternative chemotherapies that we had concerns were just not quite effective or were a little more toxic.” At one point St. Luke’s considered importing the drug, but practice managers eventually decided against doing that because they could not be certain about the quality of potential imports. That’s not to say that other practices didn’t make the decision to buy imported drugs, Zuckerman says. Indeed, enabling imports has been one of the FDA’s tools for making scarce drugs available in a crisis, says Fox. Over the past few years, the FDA has granted various foreign-based manufacturers the right to import saline to deal with shortages here. An ongoing shortage of chemotherapy drug thiotepa could not be alleviated the same way because manufacturers were not willing to produce for this market, and so the FDA allowed hospitals here to purchase the product directly from Italy, Fox says. That created a new problem for clinics here, Fox explains. “It’s hard to explain to your purchasing department that you have to arrange for a wire transfer to a Swiss bank.”
aActive shortages as of June 30, 2015.
bSedatives and tranquilizers
Source: University of Utah Drug Information Service
The shortages that peaked in 2011 have abated, but the problem continues. In the case of doxorubicin, supplies still tend to run low. “It’s not as frequent or acute, but it still is happening,” says Zuckerman. “We’re counting milligram doses and vials while we’re waiting for the next shipments. Our pharmacy managers are still wringing their hands over it.”
University of Utah Drug Information Service data show that new drug shortages climbed from a low of 58 in 2004 to 268 at the height of the problem, in 2011. New shortages reached 185 last year and numbered 68 in the first half of this year. In the second quarter of this year, there were 215 ongoing shortages (Figures 1,2).
One sector of oncology care that is highly sensitive to the impact of drug shortages is pediatrics, says Susan Weiner, founder of Children’s Cause for Cancer Advocacy. “If a company manufactures a drug and has developed and gotten approval for another drug that costs more, there is every reason to stop producing the older, cheaper drug. Because the backbone regimen of treating these kids consists of older drugs, which have become either low price or generic, the threat of shortage is serious, and the effect can be life-altering for kids,” Weiner says.
An example of this is the relatively cheap drug methotrexate. Used in the treatment of cancer and autoimmune diseases and considered one of the world’s most essential medications by the World Health Organization, methotrexate has been around for more than 60 years and yet, owing to manufacturer discontinuance and other issues, the drug has been in short supply.
Among 4 different manufacturers of methotrexate, Sandoz and West Ward Pharmaceuticals have discontinued production of some forms of the drug and Teva has it on back order, according to the American Society of Health-System Pharmacists (ASHP).
Because there are only about 15,000 childhood cancer patients a year, manufacturers have little interest in producing specialized drugs for such a limited market. Precision medicine has yet to penetrate childhood oncology to the extent that it has for adults, Weiner says. “There really are only 3 drugs that were approved first for use in pediatrics. The rest are developed typically for adults first, and then if it may be a useful treatment for children, it is introduced into pediatric clinical trials.”
Drug availability also influences whether clinical trials can be conducted successfully. Childhood cancer patients are vulnerable to variations in protocols because a large percentage of children are treated in National Cancer Institute or institutional clinical trials, Weiner says.
Weiner supports efforts by the FDA to get stricter with manufacturers to ensure the production of high quality drugs. “What worries me is that some ofthese key drugs will disappear. There is no incentive and no requirement for companies to continue to make these small market, off-patent drugs,” she says.
In 2012, 35% of drug shortages were due to quality issues that required facility remediation efforts, whereas 31% were the result of quality issues stemming from problems with product manufacturing; 14% were related to the discontinuation of product; and 8% were due to shortages of key materials. Only 6% were the result of an increase in demand, according to the FDA. 2
In some cases, shortages are related to federal drug policy, such as the Centers for Medicare & Medicaid Services’ practice of reimbursing average sales price plus 6% on medications and controlling the rate at which those payments can be increased. Critics say that lowers the incentive for manufacturers to enter the market for a drug when a shortage develops.
At the end of the day, drug manufacturing is a business, and the FDA does not have the authority to force a company to make a product, no matter how critical it may be. Many manufacturers are running their production lines at full capacity and don’t have the reserve space to institute production of a drug that is in short supply. The problem of incentivizing manufacturers to produce has therefore been forefront in many discussions about drug shortages. “Ultimately, manufacturers are responsible for ensuring sustainable production of quality drugs,” the FDA said in a recent statement.3 “FDA continues to encourage pharmaceutical companies interested in making drugs in short supply to submit applications so that there are multiple manufacturers making these drugs. Spreading the production of a drug over a variety of manufacturers reduces the potential for an over-reliance on one or few manufacturers.”
Meanwhile, manufacturers continue to make market decisions that protect their own interests. An example of a marketplace football right now is carboplatin, an almost all-purpose oncological drug that has been around for decades and which is in short supply. Of 7 manufacturers that produce the drug, 2 have decided not to continue production and others are struggling to meet demand, according to ASHP.
“Carboplatin’s not going to go away. It’s a heavy lifter—for ovarian cancer, for lung cancer—maybe even in a subset of breast cancer,” says Zuckerman. “Even though it’s an old drug, we’re discovering new uses for it, so I think all of us oncologists are aware that the shortage is not manufacturing failure or that they can’t get a certain chemical, but that it could be a conscious choice by pharma that ‘We’re just not going to invest a lot in that.’”
The threat of such action has the potential to keep doctors awake at night. “That’s scary,” Zuckerman says. “We’ve seen that happen a lot with antibiotic development. That’s a parallel story where we know that for the last 10-15 years, there’s been very little put in, because pharma doesn’t see it as a wise financial investment for health, for country, or for all of us. Yet we still need those things.”