Shortages of essential drugs are threatening to become a crisis in the United States, health care providers say.
While cancer drugs have been most publicized recently, experts in pharmacy say they often find themselves scrambling to find common generic medications such as antibiotics and fear having to resort to rationing.
They say only a national effort to bring generic drug manufacturing back from overseas, among other steps, will help relieve the problem, which mostly affects injectable drugs, including chemotherapy and cardiac medications.
“It is not just cancer, said Dr. Peter Yu, physician-in-chief of the Hartford HealthCare Cancer Institute in Hartford, Connecticut. “It’s pediatrics, it’s infectious diseases, it’s rheumatology.”
Yu said the American Society of Clinical Oncology looked into the problem when he was president in 2014-15. “In part what we learned is it wasn’t just oncology; it really is a health economics issue about how drugs are paid for and manufactured and distributed in the United States and the world,” he said.
“We are experiencing it ourselves across Hartford HealthCare,” Yu said. “We treat hundreds of patients a day with chemotherapy. We tried to keep a several weeks’ supply of our chemotherapy drugs on hand and we’ve been down to as low as a two-day supply, which makes us extremely nervous.”
Yu said health care systems rely on a few large distributors, “big names like Cardinal Health, American BioSource and McKesson, and they’re unable to tell us when they can deliver supplies. We call every day and they say, we’re not sure we can distribute your order.”
He said Hartford HealthCare has been able to shift supplies among its seven hospitals to avoid a total shortage, but “there’s very little margin for error here, or very limited.”
‘A spike in shortages’
“What we’re seeing now is a spike in shortages,” said Eric Arlia, vice president for pharmacy services at Hartford HealthCare.” We’ve gone through these waves on and off over the last five years. We seem to be going through another period where there’s going to be more than the typical number of drug shortages that we’re dealing with.”
Arlia said the business office and pharmacy buyers for the health care system are holding weekly meetings because of the seriousness of the issue.
“The team is tracking 46 drugs in short supply as of this week,” Arlia said last week. “Not all at the same level of criticality, but 46 of them that they’re talking about and talking about mitigation strategies, whether that be trying to buy it from a different company or looking at different dosage forms.”
Other options are looking at therapeutically equivalent medications and switching patients to another drug if necessary. But that isn’t always the best treatment, especially if a patient has been on one medication for a while.
The two main cancer chemotherapy drugs, cisplatin and carboplatin, have been among those in short supply, but Arlia said methylprednisolone, used to treat asthma, arthritis and allergies, is “our No. 1 shortage product at the moment.”
“It’s an anti-inflammatory — probably one of the biggest issues is people with breathing issues to help them breathe better, but it has other uses too,” Arlia said.
However, “the good news with that one is sometimes people can take oral if they’re able to and then there’s a couple other drugs … in the same therapeutic class with similar effects,” he said.
Manufacturing in China and India
According to a U.S. Department of Homeland Security report, drug shortages increased 30% between 2021 and 2022. There was a five-year high of 295 drug shortages at the end of 2022, according to the report.
A major concern is that 90% to 95% of the chemicals that make up acute-care injectable drugs, known as the active pharmaceutical ingredient, are manufactured in India and China, according to the report. The Food and Drug Administration does not have the same level of oversight of those countries, and officials worry about geopolitical threats disrupting supply.
“The drugs are being manufactured overseas and not just the drugs but also the active ingredients” and the inactive ingredients, said C. Michael White, chairman of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy.
“India makes most of the finished pharmaceutical products,” he said. “So that’s the actual tablet or the capsule. China makes a lot of the active ingredients.” And that won’t change anytime soon.
“One of the things that’s actually scary from a national security standpoint is that the United States doesn’t have any capacity to be able to have the fermenting plants that they would need to have to make penicillin and cephalosporin antibiotics,” White said. “They’ve all shut down and they’ve all moved overseas, and most of them are now in China.”
That could cause a major problem if China were to attack Taiwan, for example, he said.
“You can’t just build a manufacturing plant for pharmaceuticals,” White said. “It takes years in order to be able to construct it. And that’s one of the things I think we found with COVID, is that we’re always behind the eight ball because we didn’t have the capacity to be able to manufacture it here, so we were beholden to the normal supply chains, which were all being interrupted.”
A contamination scandal
A major shortage occurred when Ranbaxy USA, based in India, was found to have contaminated drugs and was shut down.
“The FDA did not have any funding in order to be able to go overseas and do any of the inspections of those foreign manufacturing plants,” White said. The companies were put on the honor system, “where you would send them reports of the stuff that you were doing, but they would never visit you.”
After a whistleblower notified the FDA that Ranbaxy was falsifying reports, the FDA began scheduling inspections, but the foreign companies knew when inspectors were coming so that would take plants offline to bring them up to standards. That in itself causes shortages, White said.
Another issue is the age of equipment. “They were beating us on price because they were dealing with equipment that was much much older and then prone to breakdowns and whatnot, but because it was less expensive to be able to use that equipment they ended up dominating the market, putting other people out of business,” White said. “But then when the equipment breaks, then you have a drug shortage.”
However, the quality of foreign-made drugs is higher now than it had been, he said.
“The FDA is behind on inspecting them, and sometimes when they get to them, if they have violations, they can shut them down and then it just has a trickle effect,” Arlia said.
“Obviously, if companies either in the U.S. or in another part of the world can’t get the raw materials needed to make a medication, there’s going to be a shortage.”
Looming threat of rationing
Dr. Daniel Petrylak, an oncologist and professor of urology at the Yale Cancer Center in New Haven, Connecticut, said a notice went out two months ago about a shortage of cisplatin, also known as cisplatinum.
“Unfortunately, for tumors such as testes cancer, there are no alternatives,” Petrylak said. “Cisplatinum is the backbone of treatment for these patients. Same thing with bladder cancer for those patients that can receive cisplatinum.”
He said there was a clinical trial comparing cisplatin and carboplatin in testes cancer patients “because the concept was that (carboplatin) was a less toxic drug, but unfortunately it was found that there was a higher relapse rate in those patients who received carboplatinum versus those patients who received cisplatinum.”
If there is a shortage, decisions about who will get the drug are difficult to make, Petrylak said.
“I’m not trying to say that it’s any less important to treat somebody who is older but most of the testes patients are in their 20s and 30s, and they have long lives ahead of them,” he said. “And this is a pretty much curable disease in most patients. In fact, in a good-risk patient, 90% of those patients are cured.”
Older men have a higher relapse rate, which requires more treatment and could lead to side effects. “So there’s not only a quantity-of-life issue but a quality-of-life issue,” Petrylak said. “Those are important factors, but I view this as a national health emergency. No question.”
Lisa Holle, clinical professor of pharmacy practice at the UConn School of Pharmacy and an oncology pharmacist, also sees rationing as a possibility.
A consideration is, “What is the reason they’re getting the chemotherapy?” she said. “Is it because we know we could cure this patient of their cancer and they can be free from their disease? … But in some instances, we can’t cure the cancer because it’s such an advanced stage of cancer and we’re giving the chemotherapy to try to keep the cancer at bay for as long as we can.”
In that ethical situation, “we might think about the patients who are curable versus those who are not,” Holle said. “And of course we do not ever want to be in that situation because we think it’s really important to also keep some of these cancers at bay, but those are sort of ethical dilemmas I think that one gets faced with when there’s a limited supply of a life-saving drug.”
Another alternative is for the FDA to allow importing of unapproved foreign drugs on an emergency basis, Holle said.
“Back in 2012, 2013, there was a drug that was in short supply, and the FDA allowed an emergency use of an internationally manufactured version of the drugs,” she said. “It required the FDA to be able to approve this drug temporarily so that we could import it into the United States and use it for patients because there was no alternative to that drug for that type of cancer.”
‘Inconsistent availability’
Dr. Pragna Kapadia, assistant professor in hematology and medical oncology at UConn Health, said the health care system has avoided shortages of cisplatin, docetaxel and carboplatin, three common chemotherapy drugs, so far.
“Fortunately, we have not had any issues that have directly impacted a patient, meaning we haven’t had to change a treatment course or substituted therapeutic drugs because of a shortage,” she said.
“We previously had tried to keep a one-month supply of most of our medications on hand,” Kapadia said. “There are certain chemotherapy drugs as of late it’s just not available. So we have more of maybe a two- to three-week supply on hand and it’s just inconsistent availability.”
This causes pharmacists to have to be creative, she said.
“So there may be certain vial sizes that are available and certain concentrations that are available, but then it’s up to us, our pharmacists, to compound the medication to make it what we need it to be, because it’s not available in the form that we need it to be,” she said.
She said UConn Health has not had to resort to rationing of drugs.
“I will say, I’ve been at UConn for five years, and there was a point where … they said, we have X number of doses of this drug and so be mindful of that as you talk to patients about starting them on a treatment regimen that includes that drug,” Kapadia said.
Doctors don’t want to alter a treatment plan because “that is only going to potentially be harmful to the patient, she said.
UConn Health uses a group purchasing organization, Vizient, which helps mitigate shortages. Kapadia said that is more available to large health care systems, whereas smaller hospitals may not have access.
“You never want to be that patient who has to hear, I can’t treat you with what is felt to be our best standard of care because the drug isn’t available,” Kapadia said “You never want to have to have that conversation with a patient.”
She said she hasn’t had to do that recently, “but it’s something that we worry about, and I do think that smaller institutions who don’t have these large purchasing groups, or they don’t have a large volume that they’re purchasing, I think they are at a higher risk of not having enough drugs.”
Cardiovascular drug issues
In cardiovascular medicine, the biggest shortages are in lidocaine, adenosine and dofetilide, White said.
Lidocaine is an anesthetic that also treats arrhythmias. A shortage can lead to delayed procedures, White said.
A lack of adenosine, used for people in arrhythmia, “acutely causes a break so people will go back into a regular heart rhythm.” A lack of it can put patients at risk because the substitute, calcium channel blockers, stay in the system for several hours.
“The adenosine gives you the advantage that you can come in and you could break the person out of that arrhythmia, put them back into a regular heart rhythm,” White said. “And then you only have to do that intensive monitoring for a few minutes.”
If channel blockers must be used, “you may have more low blood pressure and you’ve got to monitor the patient and be concerned for a longer period of time,” he said. Adenosine is also used in stress tests.
Dofetilide is used daily to prevent atrial fibrillation. The problem with the substitute, sotalol, is that dofetilide must be out of the system before the new drug is used, putting the patient at risk for several days, White said. Both drugs require a three-day hospital stay when they are introduced.
“You can’t just on the same day take somebody off dofetilide and put them on sotalol,” White said. “You have to wait until all of the dofetilide is out of the body. And then you have to bring them into the hospital for another three days to put them on sotalol.”
When dofetilide is available again, doctors are faced with a conundrum. “Do you keep them on the sotalol, or do you take them off, give them several days without any antiarrhythmic therapy, and then have to put them back on the dofetilide?” White said.
No one keeps reserves
To Arlia, “the other big issue is that nobody keeps any reserve supplies in the supply chain anymore.”
Companies used to keep inventory reserves, but economics has eliminated that, he said.
“What happens now is, if there’s even a relatively minor disruption, it just hits everybody very fast, because there’s just very little reserves in the system.” He said there are programs where “if you’ll commit to buying a certain product, they’ll guarantee that they’ll hold 90 or 120 days’ supply in a warehouse for you. And we did that with a few drugs.”
Arlia said he would “happily commit to buying one brand of a generic, commit to it for a year or a couple of years at a certain price if I know they’re going to hold stock for me. … Because ultimately, I think you end up spending more money when you have a shortage and you’re changing things around. And of course, it’s bad for patient care.”
For Arlia, the lack of reserves is a critical issue. “I think there just needs to be more of a national focused effort on this,” he said.
“As a country, to me it’s a vulnerability that we don’t have reserve supply of critical pharmaceuticals. And nobody’s going to do it out of the goodness of their heart. Somebody needs to be incentivized, really, to hold more supply than they need to for their general business.”
“You may have everything that you need, but then you don’t have the vial or you don’t have the ampule, or you don’t have one of the really important ingredients but you have all the others,” disrupting the manufacturing process, White said.
Kapadia sees another cause. “If you look across the board at the different medications that have been affected, I think some of it is still a ripple effect from COVID, workforce issues and supply chain issues,” she said. “Even though we feel that the pandemic is behind us, those things I think are still playing a role.”
The problem with generics
The low prices of generics have their own issues, according to Yu. As long as a manufacturer has a patent, the price may be high.
“When that patent drops, you get the entry of generic manufacturers that can now produce that drug … but the price begins to drop, and it drops pretty quickly,” Yu said. “So within a year’s time, the price may fall by 97% or more. So it fairly rapidly reaches a level where that generic manufacturer is no longer so interested in making that drug. … Manufacturers may shift to another generic drug where they have a higher margin.”
White said manufacturers’ move to overseas added to the problem.
Generic drug manufacturing “shifted overseas with the understanding that prices would continue to go down, which they have for generic drugs,” he said. “And that created a lot of pressure on the system so that only the ones that have the cheapest price were the ones that we’re going to be getting a majority of the sale.”
Insurance companies reimburse based on the lowest-priced drug, so there is little incentive to spend money to increase automation or maintain equipment, White said. And companies have consolidated so there may be just two making one drug.
White said of the shortages that “at most points, it’s a severe inconvenience. … Periodically it becomes dangerous when some of the drugs that are in shortage are more vital-type drugs, like the cancer drugs.
“But we have this extreme vulnerability and the extreme vulnerability could really be devastating to the United States if all of the manufacturing was taken away,” he said.
UConn working on problem
White said one faculty member is working on “a new manufacturing-type process that is much, much more efficient and doesn’t use a lot of worker time in order to be able to set up and be able to create.”
“The U.S. had allocated money. I think there’s like a billion dollars or whatever into research specifically on bringing manufacturing back to the United States. … And UConn is is part of a consortium of major universities in the country, called NIfTI (Neuroimaging Informatics Technology Initiative) that have been working on ways to be able to support bringing manufacturing back to the United States and be able to do it in an efficient manner.”
Yu said Congress passed a law requiring manufacturers to notify the FDA if they anticipate a drug shortage within six months.
“Often they don’t know six months in advance if there’s going to be a problem,” Yu said. “And just notifying people that there’s a problem doesn’t solve the problem. It’s not a very satisfying answer.
“I think we need Congress to put sharper focus on this,” Yu said. “I think we need to think about this as a consumer protection issue as well as a public health issue.”
Yu called the health care system “very fragmented and nonsensical in many ways. We have some parts of the health system that are highly regulated, and then some parts like drug manufacturing and production that have a lot less regulation behind pricing and distribution.”
Ed Stannard can be reached at estannard@courant.com.
