Albuterol for asthma. Heparin to thin blood. Epinephrine injection for severe allergies. They’re among 128 drugs listed on the U.S. Food and Drug Administration’s drug shortage page this week as being currently in very short supply or having just had a shortage resolved. Amphetamine/dextroamphetamine salts, commonly used for attention-deficit/hyperactivity disorder, has been a search-for-it crisis for well over a year. Cancer centers and oncology specialists are dealing with a worrisome shortage of some chemotherapy medicines.
Meanwhile, some patients who use the long-acting insulin formulation called Levemir are upset after its manufacturer, Novo Nordisk, announced it would discontinue the drug. Speculation is the company wants to free up more room on its production lines for its weight-loss megasellers Ozempic and Wegovy.
Sometimes a drug shortage is a nuisance. Other times, the repercussions could be more serious, as is the case with chemotherapy drugs, among others that people are scrambling to get.
Drug shortages are nothing new, but there are more shortages now than in the past — primarily sterile injectable drugs. “They’re typically older, drugs like lidocaine and morphine and IV-administered antibiotics like vancomycin,” said Dan Liljenquist, chief strategy officer at Intermountain Health, as well as chief architect and board chair of Civica, a not-for-profit generic drug company. “These are drugs we’ve used forever.”
But what causes shortages? And more to the point, what do you do when you can’t get the medication you need?
Old and underpriced
Few people in the country know more about drug shortages than Erin Fox, associate chief pharmacy officer at University of Utah Health. She and her team have been tracking drug shortages since 2001.
Most of the drugs with shortage status are hospital drugs — typically “really old generic products.” They’re cheap and frequently prescribed for patients in the hospital. The very low price is a large part of the problem, she said. “The prices are very, very low in part because the FDA tells us that all generic products are equal. And the only thing left for those companies to compete on is price. Over time they just undercut each other to try to get market share.”
Liljenquist notes that there’s almost never a drug shortage when a company makes a product that lots of people need, that’s still under patent protection to the manufacturer and where there’s no close substitute. “The exception is something like Ozempic or Wegovy, where demand shoots up so fast that they scramble to catch the production up,” he said.
There are about 5,000 hospitals in the U.S. and “millions and millions of people taking medication every day — just not hospital medication,” said Liljenquist. That’s why hospital injectables are the bulk of drugs in shortages. People in hospitals don’t need an endless supply of a drug, as someone outside who has diabetes and needs insulin or who requires high blood pressure medicine might. So drugs infused in hospitals or injected are vital, but an entire year’s supply for the nation might be manufactured by just one or two companies.
“There’s big competition for the contract and cash incentives for hospitals, but if there’s a single point of failure in that sole provider’s chain, the chain goes down,” Liljenquist said. “If there’s only one place you make a certain drug and you have a quality problem or you have a power outage or a natural disaster, that production capacity goes offline. We saw what happens with infant formula.”
Sometimes, with old generic drugs, the prices go so low that the companies don’t want to make them any more, Liljenquist and Fox told the Deseret News.
And that doesn’t even take into account supply chain problems that can occur with raw materials, Fox said. There’s a shortage of a blood pressure medicine right now because an ingredient was contaminated with nitrosamine, “which is also found when you barbecue stuff.”
There are, of course, other reasons for shortages, too. Fox said the shortage of ADHD drugs has been especially interesting, because “these are controlled substances and the amount that can be produced is very, very tightly controlled by the Drug Enforcement Agency. And the DEA determines how much of the raw ingredients each company gets.”
That information’s not publicly available, so it’s hard to sort out who’s right when there are competing versions of the story: The DEA says the medication manufacturers have enough and just haven’t used it. The companies are saying the DEA didn’t give them enough. An interested bystander can’t decide who’s right. “It’s a lot of finger-pointing,” Fox said.
In a real crisis, could someone else step in to make a drug? It’s not simple. “It takes a whole bunch of money to build one of those facilities. And a bunch of time,” according to Liljenquist. He knows, because Civica not long ago did just that. Civica has made 86 drugs that are shortage medications, he said. Drugs that treat 73 million patients. A third of the nation’s hospitals are involved in Civica. “We’re doing our part, but when the market price becomes so low, it would bankrupt Civica.”
Some of the prices, he said, need to reset so companies can afford to make the drugs.
Even more frustrating, sometimes the brand name is available, while the generic is in short supply. But many insurance companies have on their drug formulary only the generic form. So all patients can do is call their insurance company, tell them there’s a shortage and hope the company will temporarily approve the brand-name version. “Insurance companies will not automatically do that, unfortunately,” Fox said.
Another question there is risk versus benefit. “Even though they’ve recalled some of these products, they’ve also encouraged people to not stop taking them if they can’t get” a substitute product, Fox said. Does the blood pressure risk outpace the contamination? Variations play out in different ways.
A national security issue?
Outsourcing is another issue. As Liljenquist points out, China decided decades ago that it wanted to be the pharmaceutical hub of the world. “The Chinese government invested a bunch of money and subsidized investment of capacity into China, so their drug prices are the lowest in the world,” he said.
When a drug gets FDA approval, people tend to assume quality is all the same. It may or may not be, but that assumption made price the king when it came to choosing suppliers. But China has a different regulatory environment, he added. China makes those importing its drugs responsible for vetting the quality. And for generic drugs under the Hatch-Waxman Act, the FDA has authority to do two things, per LIljenquist: approve a new drug based on manufacturer data and inspect the plant. To do that overseas in China or India, there’s no surprise inspection. A lot of notice is required. If a problem is found, there’s new potential for a shortage.
The low prices keep drug manufacturing of certain generics overseas, where costs are lower. But so’s control and sometimes quality. Again: shortages.
Fox describes the supply chain as “opaque,” with no company required to reveal who made the product, where the raw material came from or the location of the factory.
Shortages, she said, are global. They’re felt everywhere because production lines supply many places. If a country takes shortcuts. it hurts a lot in a lot of locations. “You end up either needing to stop manufacturing and remediate when problems are found or kind of try to slow down production and make enough to go while you’re remediating,” Fox said.
COVID-19 prevented inspections overseas for a while due to the risk. Now inspections have resumed and in countries with what Liljenquist calls “low regulatory hurdles,” problems are being found. Even two weeks offline for a production line that normally runs around the clock can have tremendous impact. “Then, boom, you have an international shortage — a single point of failure for the world.”
You’d never run a power plant that way, according to Liljenquist. If you only had one power substation and a storm knocked out power, what would happen? “We have redundancies, we have substations, we have infrastructure” for important services. “Drugs are similar to the economics of a utility. There’s no close substitute. It requires economics of scale and manufacturing. And you may really only need one manufacturer to meet the market demand, but if you don’t have resiliency, if you don’t have excess capacity and you have a single point of failure breakdown, then people can’t get drugs and they die.”
“I think it’s a national security issue,” said Liljenquist.
At least some members of Congress seem to agree. They’re among public officials pondering how to restore resiliency in the supply chain.
Suggestions include having a quality component applied to drugs, so that if hospitals buy from a quality manufacturer, they’ll get an extra incentive payment. That kind of little bonus might make it possible to afford to buy drugs at a slightly higher cost — which would let manufacturers afford to make them.
Liljenquist said there are a number of ideas being knocked around to fund quality assurance, which is expensive, but vital. He’s among those who believe drug manufacturing needs to be “repatriated” to the U.S. as a matter of national security.
“There are ways to do that that are affordable,” he said, “like through nonprofit generic drug companies like Civica. But yeah, this is a big, big problem and it’s going to take us years to unwind.”
Fox isn’t convinced that simply bringing production home fixes shortages.
“There’s been a lot of attention to should we try to make everything in the U.S. But just because something is made in the United States doesn’t mean it’s automatically high quality or will avoid shortages. I would say that because most of the most severe shortages that we have are because of factories that are in the U.S. that have had problems,” she said.
When the manufacturer says no
Perhaps the hardest case for patients is a company deciding not to continue making a drug a patient really does well on. “Pharmaceutical manufacturing is a business. There’s no requirement to make any drug no matter how life-saving,” said Fox. “Nobody can force any company to make anything.”
That’s the problem facing North Salt Lake mom Alison Smart, who’d give anything to convince Novo Nordisk to reverse its decision to stop making a long-lasting form of insulin it markets as Levemir. The company said it based the decision on “global manufacturing constraints, significant insurance formulary losses impacting patient access effective in January 2024, and the availability of alternative options in the U.S. market.”
Smart is passionate — emotional, even — when she talks about the difference Levemir has made for her daughter Ruby, 15. It’s the shortest of the long-acting insulins, at 14 hours, and with simple adjustments her daughter, an athlete, has great control of her diabetes. Smart said Levemir seems to be built for athletes, teens, and menstruating and pregnant women, among others. It doesn’t sting when Ruby injects it. She doesn’t get side effects she had with other insulins. And there’s less weight gain, too.
But the company doesn’t want to market it in the U.S. any more.
The company reportedly said in private conversation that it would not enforce a patent against a biosimilar medication, but Smart wants them to say it publicly, on the record. She wants them to make the drug or share the recipe so someone else can make it. At the very least, she’d like the company to help her — and others — find an alternative that works as well.
Smart said the insulin issues and insurance rules have made people who need it “sort of defeatist.” They do what their insurance benefits say they can do. She believes patients and their families have more clout than that. So she formed the Alliance to Protect Insulin Choice and has taken Ruby’s story to lawmakers, to the media and to others who might be able to help her.
The challenge is, manufacturers stop making drugs all the time, both Liljenquist and Fox agree, though they weren’t specifically addressing Levemir.
“These companies have shareholders and fiduciary responsibilities,” said Fox.
With the generic drug shortages, she said, “the hard part is this isn’t just going without tires or peanut butter. It’s going without critically needed medication. And companies don’t really suffer when there’s a shortage, because the products are usually so low cost. So they don’t bear the brunt of all these shortages.”
What should a consumer do? And not do?
Fox said the Drug Information Service at the University of Utah usually doesn’t see a shortage until it’s happening. Hospitals and other manufacturers may more often see them coming. “There are companies out there that can predict shortages and I think everybody wants advance notice, so they can start hoarding — which is not a good solution.”
Shortages are made worse by people hoarding at the individual, but also the institutional level, Fox said. “You try to hedge your bets and you place as many orders as possible, hoping that a few will come in. A paper by Vizient showed that basically the same amount of product was available, but patients were going without chemotherapy and having their doses adjusted because of hoarding.”
What do you do if there’s a shortage of a product that has no substitute?
That happened with vaccines, Fox said. “It usually means you just wait. Wait until that (drug) is available again. Or you ration care,” targeting it to certain patient populations. CDC has helped prioritize vaccines. With chemo drugs, rationing happens. “One difficult thing is there’s no national strategy for once we get to that point in a shortage. Pretty much every hospital is on its own and deciding things and that makes things really uneven for patients. Patients might have access to a drug if they are in one spot, but maybe not in another. And some companies may save access to people on clinical trials. Or do kids first. It’s very, very random to figure out a rationing strategy,” Fox said.
The national stockpile is not built for these kinds of emergencies, Fox added. It’s intended for a quick surge in a big emergency, like a nerve gas or anthrax attack.
Sometimes, if a medication has been tainted in some way and there’s no alternative, the advice is to take the drug anyway. It depends on what the contamination is and how the risk of not taking the drug compares, Fox said.
Sometimes, a generic drug the insurance company will pay for is not available, but a brand name is. Insurance companies don’t automatically adjust their formulary, but if the patient calls and explains the shortage, exceptions can be made. Fox said to explain and ask.
And while it’s true that drug prices are often high, it’s good to remember that in most drug shortages, prices are often too low.
The good news, per Fox, is that even though this is a “very long-standing, frustrating problem, I think sometimes it sounds scarier than it actually is. Hospitals and pharmacies do a tremendous amount of work to really mitigate the impact for patients.”
That might include finding alternatives — and the care itself doesn’t change. Fox said one problem is the amount of work it adds for staff to figure out how to handle shortages. Hospitals are often paying extra for drugs they don’t even have on hand — in the added labor costs and time spent managing a shortage. “All of that costs money and is then very wasteful in our health care system,” she said. “It probably makes more sense to spend a little bit more and have an assured supply.”