Tag: cancer treatment

Last November, FDA inspectors found almost farcical conditions when they inspected an Indian manufacturing plant that supplies medical drugs to the United States. The plant, owned by Intas Pharmaceuticals, had hardly any working systems for ensuring the purity or sterility of its products. And its employees were trying to conceal evidence of these problems by shredding and hiding documents or, as one quality-control officer admitted, dousing them in acid.

Intas provided America with a lot of frontline chemotherapy drugs—half of the country’s supply in some cases—that are used to treat more than a dozen types of cancer. When the disastrous inspection led the company to halt production, other manufacturers couldn’t make up the difference. Hospitals are now reeling: In a recent survey, 93 percent of U.S. cancer centers said they were experiencing a shortage of the drug carboplatin, while 70 percent were low on another, cisplatin.

Even short delays in cancer treatment can increase a patient’s odds of death, and substitute medications may be less effective or more toxic, if they exist at all. Chemo drugs often run dry—“I can’t think of a year in the past 10 or 12 where we didn’t face some kind of shortage,” Yoram Unguru, a pediatric oncologist at the Herman & Walter Samuelson Children’s Hospital at Sinai, told me—but the current crisis is unprecedented in scale, for reasons that go beyond Intas’s woes. Fourteen cancer drugs are currently scarce, jeopardizing the care of hundreds of thousands of Americans. “I’ve been doing this forever, and this is absolute lunacy,” Patrick Timmins III, a gynecologic oncologist at Women’s Cancer Care Associates, told me.

By delivering drugs at lower doses or over longer intervals, most oncologists are still managing to treat most of their patients—but barely. “Patients often say to us, I just need a plan,” Eleonora Teplinsky, an oncologist at Valley Health System, told me, and the shortages riddle every plan with question marks. Some institutes have already been forced to ration care. Timmins no longer has enough cisplatin and carboplatin to treat patients with recurrent tumors, even though those drugs can improve one’s quality of life or offer decent odds of another remission. “A lot of people are going to be hurt,” he told me. “Lives will be shortened.” Such tragedies are especially galling because the drugs in shortage aren’t expensive, state-of-the-art treatments that patients might struggle to access anyway, but cheap ones that have existed for decades. “It’s just unfathomable that a patient wouldn’t be able to receive them,” Amanda Fader, a gynecologic oncologist at Johns Hopkins, told me.

Intas screwed up, but how could one manufacturer’s downfall trigger such widespread problems? The coronavirus pandemic made plain how reliant the U.S. is on brittle international supply chains, but this much-discussed fragility doesn’t explain the current shortages: Cancer drugs are not scarce for the same reasons that yeast, toilet paper, or couches were. They’re scarce because the market for some of our most important medicines—the ones that should be most accessible—is utterly dysfunctional, in a way that is both very hard to fix but also entirely fixable.

Many recent supply-chain problems were caused by an external force—a pandemic, a hurricane, a stuck ship—that throttled a product’s availability, leading to surging demand and dwindling stocks. But most cancer-drug shortages are caused by internally generated problems, created within the market because of its structure. In other words, “they’re self-inflicted wounds,” Marta Wosińska, a health-care economist at the Brookings Institution, told me.

Generic drugs such as cisplatin are sold at extremely low prices, which overall have fallen by more than 50 percent since 2016. These ever-tightening margins have forced many manufacturers to tap out of the market; for example, the U.S. gets all its vincristine, an anti-leukemia drug, from just one company.

Such drugs are also hard to make. Because they’re injected into the bloodstream, often of severely ill people, they must be manufactured to the highest possible standards, free of microbes and other contaminants. But quality costs money, and generic drugs are so unprofitable that manufacturers can rarely afford to upgrade machinery or train employees. If anything, they’re compelled to cut corners, which makes them vulnerable to spontaneous manufacturing problems or disastrous inspections. And because they usually run at full capacity, any disruption to production has severe consequences. The affected manufacturer might fail to financially recover and leave the market too. Its competitors might struggle to ramp up production without triggering their own cascading shortages. And the drugs, which were never profitable enough to manufacture in surplus, quickly run out.

These principles apply not only to cancer drugs but to generics as a whole, dozens or hundreds of which have been in shortage at any given time for the past decade. The markets that produce them are frail and shrinking. And even when a drug is manufactured by many companies, they might all rely on the same few suppliers for their active pharmaceutical ingredients (APIs)—the chemicals at the core of their medicines. Mariana Socal, a pharmaceutical-market expert at Johns Hopkins, has shown that a third of the APIs in America’s generic-drug supply are made in just two or three (mostly overseas) facilities, and another third are made in just one.

The supply chains that link these chemicals to finished drugs are also frustratingly opaque. Consider fludarabine, one of the cancer drugs that’s currently in shortage. The FDA has approved 12 companies to make it, but only five actually market it; only because of a Senate-committee inquiry is it publically known that of those five, only one makes the drug itself; two others get theirs from Europe, and one of those used to supply the final two. Meanwhile, six facilities are registered to make fludarabine’s API, but it’s again unclear which ones really do, or which manufacturers they supply, or even, for one of them, which country it is in. The fludarabine market is clearly weaker than it first appears, but how weak is hard to gauge. The same goes for cisplatin and carboplatin, Socal told me: She and other experts thought their markets looked resilient, until the Intas shutdown dispelled the illusion.

This opacity masks not only the market’s weaknesses but also its strengths. Erin Fox, a drug-shortage expert at the University of Utah Health, oversees a drug budget of more than $500 million, and would love to spend it on manufacturers that make the most reliable medicines, even if their products cost a little more. But “we just don’t know which products are higher-quality than others,” she told me. The FDA has an internal scoring system that it uses to decide which facilities to inspect, Fox said, but because those data aren’t publicly available, manufacturers can distinguish themselves only through price. “We get a race to the bottom where companies undercut each other to get the lowest price, and then quit either because their manufacturing is so poor, or they can’t afford to make medicines anymore,” Fox said. As Wosińska and Janet Woodcock of the FDA identified in 2013, “The fundamental problem … is the inability of the market to observe and reward quality.”

The average generic-drug shortage lasts for about a year and a half. Many people I spoke with hoped that the current wave could abate more quickly if other manufacturers slowly ramp up. The FDA is also looking to import scarce drugs from international suppliers, and has temporarily allowed a Chinese company to sell its cisplatin in the U.S. But ultimately, “it’s very hard to solve a shortage after it started,” Allen Coukell, of the nonprofit Civica Rx, told me. They need to be prevented from happening at all.

Some commonly suggested preventive measures might not work very well, because they misdiagnose the problem. Politicians often focus on bolstering domestic manufacturing, but Wosińska, Fox, and others told me that many drug shortages have been caused by manufacturing problems in American facilities. Because American drugmakers are subject to the same flawed markets as foreign ones, moving the problem inshore doesn’t actually solve it. Nor does stockpiling generic drugs, though a worthwhile idea. These strategies work well against an external shock like a pandemic, Wosińska said: When faced with unpredictable external forces, it pays to build a large buffer. But because the shocks that cause drug shortages arise from predictable forces inherent to the market, the best bet is to reimagine the market itself—a “very difficult problem but a solvable one,” Stephen Colvill, the executive director and a co-founder of the nonprofit RISCS, told me.

A few new initiatives show how this could be done. Civica Rx, which was launched in 2018, sources generic drugs from manufacturers that it vets for quality; it then builds up rolling six-month inventories of those drugs, which it supplies to hospitals through long-term contracts. (Civica is also building its own generics-manufacturing facility in Virginia.) RISCS, founded in 2019, uses confidential data from manufacturers to rate generic-drug products according to the robustness of their supply chains. The FDA has also been developing its own rating system—the “quality management maturity” (QMM) program—that assesses a manufacturer’s quality-control practices; the program successfully completed two pilots but is still being developed and has no firm launch date, an FDA spokesperson said.

In theory, these initiatives should allow hospitals to make better purchasing decisions, and shift the market toward drug companies that are least likely to be responsible for shortages. In practice, Wosińska thinks that hospitals need to be pulled into such a culture shift. For example, she and her colleague Richard G. Frank argue that Medicare could reward hospitals for proactively choosing reliable vendors or participating in programs like Civica. The FDA could support such a scheme by finally launching its QMM program. Congress could require manufacturers to disclose more details about their products and suppliers, so that supply chains can be fully mapped. HHS could offer loans to generic-drug manufacturers for upgrading or expanding their facilities. The point, Wosińska told me, is to do all of this at once, and shift the market into a new stable state. The solution, she said, needs to be comprehensive.

It also needs to be coordinated. The drug-shortage problem lingers partly because “it’s not obvious who’s responsible for solving it,” Joshua Sharfstein, a health-policy expert at Johns Hopkins, told me. The FDA is a candidate, but economic matters sit outside its wheelhouse. Instead, Sharfstein and others suggest that the drug-shortage problem could be owned by the Administration for Strategic Preparedness and Response. It already works to shore up medical supplies in the event of emergencies such as pandemics or natural disasters, and ongoing shortages of generic drugs are effectively a perpetual state of emergency that we’re trapped in.

Meanwhile, the exact consequences of the shortages are hard to measure. Some of today’s cancer patients will suffer, or even die, because they couldn’t get treated in time, or were given lower doses, or were given more toxic drugs as substitutes. But it’s almost impossible to know if any individual person would have fared better in a world where shortages never happened: If they died, was it because of a few weeks’ delay or because their tumor was always going to be hard to treat? The impact of the shortages can only really be assessed at a population level, and that evidence takes a long time to collect. “I don’t think we’ll see the full downside for many years,” Yoram Unguru told me.

The measures needed to prevent such shortages will also take years to implement—if they ever are. The coronavirus pandemic revealed just how frail our supply chains and health-care system are, but it also showed how quickly attention and resources can disappear once a problem is thought to abate. But the drug problem isn’t abating, and is actually compounding the problems the pandemic created. When health-care workers can’t help their patients, whether because their hospitals are inundated by COVID or because their drugs have run out, the resulting moral distress can be unbearable. Such conditions during the pandemic drove so many health-care workers to quit that “you can feel the system shaking,” Patrick Timmins III said. He worries that this exodus followed by the current drug shortages are “a one-two punch” that will be visible to outsiders only when they have neither the drugs to cure them nor the health-care workers to treat them.