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chemotherapy doses , and we also know that patients who receive less than their intended doses have a higher risk of relapse ,” Dr . Pommert said . “ For vincristine , we don ’ t know the result of a couple of missed doses . How many missed doses is too many ? What number would cause an increased risk of relapse ? We don ’ t know the answers .”
The vincristine crisis is just one example of the intermittent drug shortages across oncology and hematology therapies and supportive medications that occur at any given time , prompting clinicians and pharmacists to search for supplies , make substitutions , and identify evidence-based alternatives . “ It is unacceptable that , in such a resource-rich country , we are forced to alter well-studied treatment plans and are endangering our ability to maintain or improve cure rates for pediatric cancers ,” Dr . Pommert stressed .
ASH Clinical News spoke with Dr . Pommert and other clinicians and pharmacists about the challenges of navigating drug shortages and strengthening the supply chain .
A Constant State of Shortage
The American Society of Hematology ( ASH ) has been active on the issue of drug shortages for over 10 years , informing the U . S . Food and Drug Administration ( FDA ) that ongoing shortages of critical hematology therapies have negatively affected treatment decisions , caused rationing of care , increased costs , and created emotional distress for patients and families . 1
Tabitha Alvarado , the oncology infusion compliance coordinator at the University of Kentucky , handles inventory in oncology and deals with shortages and procurement . She estimated that she spends about one-third of her time dealing with shortagerelated issues . When learning about drug shortages , her first point of contact is usually the drug wholesaler , followed by the FDA and associations like the American Society of Health-System Pharmacists ( ASHP ).
The FDA maintains a list of current drug shortages on its website , which includes the formulations and doses in shortage , the availability and estimated shortage duration , and the reason for the shortage . An additional list of vaccine and biologics shortages is available through the FDA ’ s Center for Biologics Evaluation and Research . ASH also hosts its own list of reported shortages affecting hematology , along with information about recently resolved shortages and discontinued drugs .
Unfortunately , it can take up to a week for news of a shortage to make it onto these lists , Ms . Alvarado said . When it does , the information provided can be vague , leaving those in the drug supply chain with limited information about how long they will struggle to obtain medications .
Why Do Shortages Happen ?
Most drug shortages are a result of manufacturing issues , experts said , whether it ’ s a problem with obtaining raw materials , an issue of contamination at a manufacturing facility , or a producer leaving the market . In some cases , like with the current shortage of intravenous tocilizumab ( Actemra ), demand for a drug outpaces the available supply .
Genentech announced that as of August 16 , 2021 , the company would stock out of Actemra IV 200 mg and 400 mg . By mid-August , Actemra IV 80 mg was in short supply and expected to go out of stock soon . The company said it expected replenishments of stock by the end of August , but anticipated intermittent stockouts in the coming months , depending on the impact of the COVID-19 pandemic .
Another recent demand-related shortage has been seen with tocilizumab , an immunosuppressive drug that is used for rheumatoid arthritis and is part of the management of cytokine release syndrome for patients undergoing antibody-based or chimeric antigen receptor ( CAR ) T-cell immunotherapy . The spike in demand comes as tocilizumab is increasingly being used to treat severely ill patients hospitalized with COVID-19 .
Scott Soefje , PharmD , director of pharmacy cancer care services at Mayo Clinic in Rochester , Minnesota , said his institution is having trouble obtaining tocilizumab . “ The volume and use of that drug has skyrocketed over the last month or so because of the [ COVID-19 ] surge . We ’ re scrambling to make sure that we have enough ,” he said . “ We won ’ t even start a patient on CAR T-cell therapy until we know we have the drug on hand .”
In most cases , oncology-related shortages occur with generic medications . For those typically older and less expensive drugs , profit margins are slim and fewer manufacturers are likely to produce them , making the supply chain even more vulnerable . The fact that many drugs and their raw materials are manufactured outside of the U . S . can also create supply chain problems , simply because of transportation issues .
“ Some of our most important drugs , our curative drugs , are generics ,” said Leslie T . Busby , MD , a medical oncologist and hematologist at Rocky Mountain Cancer Centers and chairman of the US Oncology Network ’ s pharmacy and therapeutics committee . “ One of the questions we have to ask is : Should some of these critical drugs be repatriated ? What would that look like ? What would it take so that they can still meet their costs ?”
Even when drug supplies are stocked , problems can arise . For example , severe winter storms in Texas delayed shipments of drugs to cancer centers around the country early in the year .
Shortages in hematology / oncology drugs saw a spike about 10 years ago but have been less frequent in recent years , according to experts who spoke with ASH Clinical News . However , an FDA spokesperson said that the agency is continuing to see shortages of older sterile injectable drugs , including those used for hematology-related therapies . Examples from recent years include etoposide , bleomycin , and vincristine .
“ Manufacturing of sterile injectables is a complex process . When a problem or delay occurs at one manufacturer , even if other manufacturers are making the drug , the limited manufacturing capacity at the other manufacturers can still lead to a shortage ,” the FDA spokesperson explained . “ In addition , these older drugs are often less profitable than newer therapies and companies may lack incentives to continue to make them .”
In 2019 , the FDA published a paper outlining three root causes for drug shortages : a lack of incentives for manufacturers to produce drugs that are less profitable ; a market that fails to recognize and reward manufacturers who engage in continuous quality improvement and early detection of supply chain issues ; and logistic and regulatory challenges that make it difficult to recover from a disruption . 2
The Drug Supply Chain Gang
Health systems devote much time to managing the drug supply chain , with a goal of mitigating any potential drug shortages , identifying early warning signs of shortage , and maintaining adequate supplies of critical medications .
“ We try to be as forward-thinking as we can ,” Dr . Busby said .
As chairman of the pharmacy and therapeutics ( P & T ) committee for the US Oncology Network , Dr . Busby works with the supply chain and inventory management teams to let them know which drugs need to be on hand because they are essential curative treatments without alternatives . Shortages occur most often in the background of clinical care . Even though a drug may be in short supply for a limited time , health systems are able to rely on existing stock , find it from other wholesalers , or even acquire it from another institution .
The P & T committee , which includes physicians and pharmacists from across the network , usually gets involved when a drug shortage is prolonged . At that point , they need to consider the clinical picture – discussing potential alternatives and how to direct curative therapies to the most appropriate patients .
For example , when the chemotherapy agent etoposide was in shortage , the P & T committee shared information about alternatives that could achieve outcomes and asked clinicians to save etoposide for curative regimens .
The Mayo Clinic team also spends time and resources to proactively manage drug shortages . “ One of the problems with drug shortages is that we often don ’ t know there ’ s a drug shortage until we place an order and the wholesaler notifies us that they ’ re going to back-order or short the drug ,” Dr . Soefje said .
At the start of the COVID-19 pandemic , the Mayo Clinic cancer pharmacy team met with the drug supply chain group to discuss what critical cancer medications could potentially be disrupted , likely because a drug or key ingredient was manufactured overseas , Dr . Soefje explained . In some cases , they increased their supply of those drugs for several months to guard against a potential shortage . They backed off the practice this spring , but they are revisiting the idea now in light of the surge in cases involving the Delta variant .
A Scarcity of Evidence
As clinicians are increasingly asked to consider alternatives to established regimens , they are turning to the medical literature to aid their decision-making . Sarah K . Tasian , MD , chief of the Hematologic Malignancies Program at the Children ’ s Hospital of Philadelphia , said an evidence-based approach has helped her institution cope with shortages without jeopardizing patient outcomes .
Dr . Tasian , who is also an associate professor of pediatrics at University of Pennsylvania ’ s Perelman School of Medicine , said that , over the past five years , her institution has dealt with intermittent shortages of L-asparaginase and Erwinia L-asparaginase – key components of pediatric acute lymphocytic leukemia treatment . While in the past they were quick to switch children to these drugs if they became allergic to treatment with PEG-asparaginase , the lack of availability
24 ASH Clinical News October 2021