SPOTLIGHT has forced them to consider other approaches .
“ For us , it ’ s difficult because some of the children will only get four to eight courses of these medications ,” Dr . Tasian explained . “ Just because we have the medications right now doesn ’ t necessarily mean that the children are going to get everything that they need to complete their gold-standard curative treatment regimens .”
Now , her hospital documents the severity of any reaction and uses real-time laboratory testing to check patients ’ serum asparaginase activity levels before deciding whether to make a switch . “ For children who had a rash or some symptoms of hypersensitivity , but whose labs showed that they had effective asparagine depletion , we would try to push on and maximize their PEG-asparaginase dosing ,” she said .
They also changed their proactive practice by premedicating all patients with allergy medications and slowing infusion to two hours instead of one .
“ These were some of the rescue strategies in the past for patients who had allergic reactions , but we put them in proactively and empirically to try to reduce the risk of patients developing allergic or anaphylactic symptoms ,” Dr . Tasian said . “ That was actually something good that came out of the shortage . It forced us to think critically about our practices and also coincided nicely with real-time clinical serum asparaginase activity monitoring .”
Clinicians at Massachusetts General Hospital ( MGH ) also had success reexamining their use of heparin when that drug went into critical shortage in 2019 . The shortage was triggered by an outbreak of African swine fever in pigs in China , dramatically reducing the pig population and restricting a key ingredient in heparin production . 3
MGH responded by activating its Hospital Incident Command System , a program designed to respond to a variety of drug shortages and other emergencies . That activation triggered a multidisciplinary task force to create detailed clinical algorithms that allowed them to reduce the use of heparin by 80 % in less than two months .
The algorithms employed a tiered approach : Heparin was recommended for life-saving cases , and alternatives were used when appropriate . “ We never denied someone heparin ,” said Rachel P . Rosovsky , MD , a hematologist at MGH and an assistant professor of medicine at Harvard Medical School , who served on the task force . In the cases where the algorithm called for an alternative , MGH disseminated robust data supporting the efficacy and safety of low molecular weight heparin for venous thromboembolism ( VTE ) prophylaxis . The team also shared literature to support the use of fondaparinux , apixaban , rivaroxaban , dabigatran , and betrixaban for VTE prophylaxis in certain patient populations . The task force stratified its recommendations based on the strength of the evidence and what agents were available on the hospital formulary .
In this experience , the key to safely reducing heparin use was inclusion and education , Dr . Rosovsky explained . The task force included representatives from across specialties and updates were communicated regularly on an internal website . “ Everybody knew what we were doing at all times .”
MGH also rolled out extensive education around the heparin alternatives , providing lectures to every department in the hospital and integrating information into the hospital ’ s electronic medical record system . Dr . Rosovsky and a member of the pharmacy team responded around the clock to calls with questions about the therapeutic changes . Through that education , many physicians were more comfortable moving away from heparin . “ We saw this as a real opportunity to change practices ,” Dr . Rosovsky said .
The FDA ’ s Role
The FDA plays a key role in alerting clinicians to shortages , working with drug manufacturers to prevent them in the first place , and also working with the manufacturers to address the issues in a timely manner . Drug manufacturers are required to notify the FDA at least six months in advance of a product discontinuation or an anticipated manufacturing interruption . When that type of notice is not possible , manufacturers must notify the agency as soon as they become aware of an issue . The FDA recently issued guidance to industry requesting that manufacturers also provide notification of increased demand . 4
The agency works directly with companies to address manufacturing and quality problems , ranging from incorrect labeling to sterility issues , and can exercise regulatory discretion to address shortages that pose a public health risk . The agency estimated that , through its work to mitigate shortages , it prevented 199 new shortages in 2020 . 5
When a shortage occurs , the FDA communicates with other companies who are producing the drug to ramp up their production , by expediting approval of new production lines or new raw material sources . The agency can also help bolster supply by extending the expiration date , when the evidence supports it , to enable companies to ship out drugs that are close to expiration or already expired .
When U . S . manufacturers are unable to resolve a shortage quickly or the shortage drug is in critical demand , the FDA may look for a firm that is able to redirect product into the U . S . market . The agency has a list of criteria to evaluate overseas products to ensure efficacy and safety , including the drug formulation and the quality of the manufacturing site . 6
Working Toward Solutions
In its 2019 report on drug shortages , the FDA recommended a few enduring strategies for tackling drug shortages , including developing a rating system to incentivize drug manufacturers to invest in quality management practices in their facilities . The agency also proposed promoting private sector contracts that have built in risk-adjusted financial incentives to encourage manufacturers to stay in the market .
ASH has also played a critical role in keeping hematologists informed of drug shortages , working with both the FDA and manufacturers to obtain early notice of drugs in short supply , the reasons behind those shortages , and estimates of when the products will be available .
In addition , ASH has worked with members of Congress to vet legislative proposals aimed at the root causes of drug shortages and continues to monitor legislation focused on drug shortage issues .
In 2019 , during the last session of Congress , Sens . Patty Murray ( D-WA ) and Lamar Alexander ( R-TN ) introduced “ The Mitigating Emergency Drug Shortages ( MEDS ) Act ” ( S . 2723 ), which would have increased manufacturer requirements for shortage reporting . It also called on the Department of Health and Human Services to provide guidance on market-based incentives that would encourage the manufacture of drugs in shortage , as well as the domestic manufacturing of finished drugs and key ingredients for drugs in shortage . The bill was referred to committee but did not advance in the Senate . 7 A more recent proposal , introduced in the U . S . House of Representatives in June 2021 , calls for providing incentives to maintain , expand , and relocate manufacturing of active pharmaceutical ingredients and other items in the U . S . The “ MADE in America Act ” ( H . R . 3927 ) was introduced by Rep . Earl L . “ Buddy ” Carter ( R-GA ). 8
The Congressional response to the COVID-19 pandemic also included measures to prevent and address potential drug shortages . In March 2020 , as part of the Coronavirus Aid , Relief , and Economic Security ( CARES ) Act , Congress required the FDA to prioritize the review of applications for generic drugs in shortage and expedite inspections and review for abbreviated new drug applications and supplements . The law also mandates more detailed manufacturer reporting about a shortage ’ s precipitating events , its likely duration , and its expected impact . Manufacturers are also required to develop risk management and redundancy plans for their supply chains and perform risk assessments to identify factors that could negatively impact manufacturing of drugs . 9
As Congress considers additional legislative fixes to the drug shortage issue , advocacy from hematologists through efforts such as the ASH Grassroots Network will continue to play a crucial role . Drs . Pommert and Tasian added , though , that advocacy from parents and families will also be critical to moving bills forward .
“ I would like to leverage the power of parents in these discussions ,” Dr . Tasian said . “ A lot of physicians and families are not aware of these drug shortages until they hit close to home . Once we learn that a life-saving chemotherapy drug is unavailable for their child because of shortages , it feels completely egregious . The voices of impassioned parents are honestly so much more effective than what we can do as pediatric oncologists . We need their partnership .” — Mary Ellen Schneider
References
1 . American Society of Hematology . Letter to the FDA : Identifying the Root Causes of Drug Shortages and Finding Enduring Solutions ; Public Meeting ; Request for Comments . January 11 , 2019 .
2 . U . S . Food and Drug Administration . Drug Shortages : Root Causes and Potential Solutions . March 11 , 2020 . Accessed September 1 , 2021 . https :// www . fda . gov / drugs / drug-shortages / report-drug-shortages-root-causes-and-potential-solutions .
3 . Rosovsky R , Barra ME , Roberts RJ , et al . When pigs fly : a multidisciplinary approach to navigating a critical heparin shortage . Oncologist . 2020 ; 25 ( 4 ): 334-347 .
4 . U . S . Food and Drug Administration . Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD & C Act : Guidance for Industry . March 2020 . https :// www . fda . gov / media / 136486 / download .
5 . U . S . Food and Drug Administration . Report to Congress : Drug Shortages for Calendar Year 2020 . Accessed September 1 , 2021 . https :// www . fda . gov / media / 150409 / download .
6 . U . S . Food and Drug Administration . Frequently Asked Questions about Drug Shortages . November 13 , 2020 . Accessed September 1 , 2021 . https :// www . fda . gov / drugs / drug-shortages / frequently-asked-questions-about-drug-shortages .
7 . Congress . gov . S . 2723 – Mitigating Emergency Drug Shortages Act , 116th Congress ( 2019-2020 ). October 29 , 2019 . Accessed September 1 , 2021 . https :// www . congress . gov / bill / 116th-congress / senate-bill / 2723 / text .
8 . Congress . gov . H . R . 3927 - MADE in America Act , 117th Congress ( 2021-2022 ). June 16 , 2021 . Accessed September 1 , 2021 . https :// www . congress . gov / bill / 117th-congress / house-bill / 3927 / text .
9 . American Society of Health-System Pharmacists . Issue Brief : CARES Act Provisions on Shortages and Readiness . March 20 , 2020 . Accessed September 1 , 2021 . https :// www . ashp . org / covid-19 / issue-brief-cares-shortages .
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