Drug shortages have been more prevalent in recent years. Now, the US Food and Drug Administration (FDA), pharmaceutical companies, and other stakeholders are beginning to work together to open conversations about the issue’s causes and potential solutions to address them.
Since 1999, the FDA has worked together with pharmaceutical companies and stakeholders to combat drug shortages. However, in 2011, there were a record 251 drug shortages, followed by 117 shortages in 2012. In addition, the FDA has tracked shortages for five specific drugs—including injectable fentanyl citrate and liotrix tablets—that have lasted between 6.9 years and 8.7 years.
Erin R. Fox, PharmD, BCPS, FASHP, senior director of the Drug Information and Support Services at University of Utah Health in Salt Lake City, UT, explained to First Report Managed Care that reasons for drug shortages vary but tend to include problems with quality such as manufacturing issues, delays due to capacity, scarcity of the raw material needed to manufacture the drug, increased demand for the drug, and discontinuation of the drug by the manufacturer.
While drug shortages can occur when a company is one of the only manufacturers of a drug, if a raw material or active pharmaceutical ingredient is in short supply, this can cause problems for the supply chain regardless of how many companies are producing that drug, said Dr Fox. “[When a raw material] is contaminated, that can also lead to a shortage like we have with some of the most popular blood pressure medicines right now.”
Other problems exist with how drugs are produced, added S. Russell Spjut, PharmD, manager of formulary management at MagellanRx Management. Pharmaceutical companies will batch produce a drug before moving to the next product on their list.
“If there are any sort of delays in their processes before they make it back to the product in question, it can cause a shortage,” Dr Spjut said.
Concentrated manufacturing causes shortages
The most common kinds of drug shortages are sterile injectables, according to the FDA, which includes chemotherapy, anesthesia, and other acute drugs. Hospital injection drugs in particular constitute the majority of drug shortages in 2018.
As of September 2018, there were 139 new national drug shortages and a total of 238 overall drug shortages, according to data from the University of Utah Drug Information Service Shortage. Natural disasters also can contribute to drug shortages, as seen in the more than 50 manufacturing facilities that were affected by Hurricane Maria in Puerto Rico.
One of the leading manufacturers of sterile injectable drugs, Hospira, was acquired by Pfizer in 2015. Prior to the acquisition, the manufacturer had been plagued with drug shortages and between 2015 and 2018, Pfizer invested $800 million to rehabilitate these facilities. The company recently pledged another $1.4 billion in funds to shore up the plants in 2018, which they said would help mitigate future supply issues.
“The reason we have so many shortages of those [medications] is it’s a very concentrated market. In general, most of those products that hospitals need every day for patients are made only by one or two companies,” Dr Fox said. “When one of those companies has a bad problem,
like is going on right now, we’re just having these constant shortages mainly because of that concentrated market.”
In a statement to First Report Managed Care, Steve Danehy, director of corporate affairs and global media relations at Pfizer, said the current supply shortages with Pfizer have been caused by a combination of manufacturing and distribution factors as well as delays with third-party suppliers. He also noted that several products in their portfolio had fully recovered in 2018 despite these setbacks.
“Manufacturing sterile injectable medicines is incredibly complex, and requires highly sophisticated manufacturing equipment and processes, highly trained colleagues, and major financial investment,” Mr Danehy said in the statement.
Invisible consequences for patients
Regardless of how a drug shortage occurs, patient care can be affected. A survey conducted by the Institute for Safe Medication Practices in Horsham, PA. between August and October 2017 of nearly 300 pharmacy directors, managers, and other staff members found that drug shortages within the last 6 months were an almost “daily struggle.” These shortages affected several therapeutic areas including emergency care, anesthesia care, pain management, infectious disease treatment, and cardiovascular care.
Inside a hospital, staff members attempt to make shortages invisible to patients, ensuring their patients receive their drugs in spite of supply issues. This can include breaking down a vial of pain medication into smaller syringes, Dr Fox said, but in other situations, hospitals may have to ration out medication and decide which patients require it the most.
“Usually, what it means is using the product wisely. For example, if there is clear evidence that sodium bicarbonate injection is absolutely needed for patients getting specific cancer treatments, that is priority number one,” said Dr Fox. “Do you need to also use that sodium bicarbonate injection to take the sting out of a lidocaine injection? Probably not during a shortage. So, we triage how we’re going to use that medication.”
Drug substitutions strain resources
For the majority of drug shortages, there are a few alternatives for patients, but acquiring those substitute therapies requires extra time and effort, which can include the patient or their pharmacy contacting the doctor, receiving a prescription for the alternate therapy and hoping the new treatment will work well for the patient, explained Dr Spjut.
“While everyone within the health care team is dedicated to taking care of patients stuck in these kinds of situations, it takes time and resources away from other activities and puts a lot of stress on everyone involved,” said Dr Spjut.
Drug shortages can also have a more serious impact on patient care. Dr Spjut noted the ongoing shortage of saline, which is used to make nearly every intravenous solution, has put patients in need of these medications at risk or in some cases delaying doses.
In a 2018 paper published in New England Journal of Medicine, Maryann Mazer-Amirshahi, PharmD, MD, MPH, and colleagues, wrote that shortages of saline can result in medication errors and adverse drug events when “medications that are typically administered as short infusions are given by intravenous push or when providers choose less familiar but more readily available products as substitutes.” She also added that ad hoc compounding of drugs can lead to
dilution errors and microbial contamination.
“If you have patients taking a product that is not effective because the ingredients aren’t doing what they’re supposed to do, sometimes those effects are invisible,” Dr Fox said. “Patients may not know that their blood pressure is not controlled. They may not know that their cholesterol is not being controlled. And those can have long-term consequences and result in increased hospitalizations.”
In the worst cases, there can be severe consequences, or lacking alternatives to treatment, such as when there are shortages for medications needed in chemotherapy treatment. Monika L. Metzger, MD, and colleagues published results in The New England Journal of Medicine in 2012 where children with Hodgkin lymphoma treated with a modified Stanford V regimen of mechlorethamine had a 2-year event-free survival of 88% compared with an event-free survival of 75% for patients who received a modified Stanford V regimen of cyclophosphamide during the same time period.
The effects are not limited to cancer therapies: Emily Vail, MD, and colleagues studied the 2011 national shortage of norepinephrine on patients with septic shock and identified increased phenylephrine use among 27,835 patients within 3-month periods of active norepinephrine shortage, which translated to an increased risk of in-hospital mortality.
Pricing is often impacted as well, as the prices of generic drugs increase but sometimes do not go down after a shortage, Dr Fox said. In addition, because there are a limited number of suppliers and a consolidated market, those who purchase drugs in shortage have little choice but to make do with what is available from drug manufacturers. In a recent study in the September 2018 issue of Annals of Internal Medicine, Inmaculada Hernandez, PharmD, PhD, estimated that prescription drug shortages result in an estimated $230 million in additional costs each year.
“It’s more expensive for patients, especially when their insurance might prefer a generic product,” Dr Fox said. “They’re going to have to pay a higher copay. In some cases, their providers are going to have to switch them to an alternative, which will work. But, the hassle factor there is that might not be a preferred medication with their insurance plan.”
In cases where alternative options must be provided, maintaining patient safety and communication remain paramount. Dr Fox said, “Electronic health record changes are essential to make sure safety factors such as bar code scanning and dose checks are operational. Communication is also essential. It’s important to provide education about new therapies, especially if the therapy hasn’t been used before in the health system.”
FDA Agency Drug Shortage Task Force
The FDA is not standing idly by as these shortages occur. The Food and Drug Administration Safety and Innovation Act, passed in 2012 by Congress, gave the FDA a more active role in proactively helping with drug shortages. This included performing more inspections or expedited inspections to get shuttered facilities with problems back up and running, asking other companies to ramp up production, and requiring manufacturers to notify the FDA when a discontinuation or interruption in the manufacturing of a drug product could lead to a drug shortage.
However, the FDA is still limited in how it can intervene to restore supplies during a shortage. FDA cannot force a company to create a drug, make more of a drug or change how much, where and to whom a drug is distributed, or control drug pricing. In addition, “Manufacturers don’t have to tell FDA why they’re having a shortage, so that really makes it hard for FDA to help that company out,” Dr Fox said.
In July 2018, FDA Commissioner Scott Gottlieb, MD, created the Agency Drug Shortage Task Force to identify the underlying causes of drug shortages and find solutions to combat the issue. The FDA held a public meeting in November 2018 together with Duke University, pharmaceutical companies, and other stakeholders to discuss the issue of drug shortages.
“I’ve been to a lot of meetings and shortage summits, and I think that was one of the most productive that I’ve seen,” Dr Fox said. “The stakeholders were all together in the room having pretty frank conversations. I’ve been to shortage meetings in the past where folks from industry wouldn’t actually say anything while FDA was in the room.”
According to FDA, the taskfoce “does not intend to publish a transcript or summary. However, listening session participants are free to enter their comments in the docket, where they will be visible to the public” via Regulations.gov.
Increasing capacity to meet demand
Pharmaceutical companies and other stakeholders are also working to meet demand. Mr Danehy said Pfizer is “actively leveraging” their network to increase capacity, manufacturing products in multiple locations to meet demand , and considering qualifying third-party suppliers to manufacture.
However, while Dr Fox is hopeful Pfizer’s renovations will help reduce drug shortages, she is concerned Pfizer may eventually decide to shift their business to more profitable products after they finish their facilities. “That’s a lot of money for Pfizer to invest in products that are not very expensive,” she said. “My worry is that Pfizer will fix these factories and then they will just stop making these essential products in favor of making more profitable drugs.”
To prevent that scenario from occurring, the government should consider offering incentives to companies that produce low-cost, in-demand generic medications that are widely used—or consider them part of critical infrastructure, said Dr Fox.
“This is a hard problem for government to fix because of the way we have our free market system,” she said. “If these products are so cheap that nobody wants to make them, or we have these factories that are so essential and we only have one factory that makes one of the most essential medications we need for patients, these companies are ‘too big to fail.’ So, what can we do to shore that up?”
Dr Fox continued, “On the one hand, there are some things the government has to do. But on the other hand, we need industry to do their job.”
In terms of preparations, “It’s impossible to predict shortages for a variety of reasons,” said Dr. Fox. “The most significant shortages right now of narcotic injectables and local anesthetics due to manufacturing challenges at Pfizer. These are not anticipated to resolve until at least the first quarter of 2019.”
Ultimately, FDA cannot prevent all shortages from occurring, and while lowering drug costs should always be a priority, “we should as a whole be willing to pay a little bit more for some of these drugs in order to incentivize additional manufacturers to produce these drugs which will help stabilize the supply chain,” Dr Spjut noted.