By Sirj Goswami, PhD, and Michael Neely, MD
The nation’s hospitals continue to grapple with COVID-19, a pandemic that has strained staff and resources like never before. But even amid this ongoing public health emergency, it’s important to not forget—and to continue addressing—patient safety concerns that impact outcomes and costs.
Foremost among patient safety issues are adverse drug events (ADE), which are responsible for 100,000 deaths every year and (before COVID-19) were estimated to be the fourth leading cause of death in the United States. ADEs impact 2 million hospital stays annually in the U.S. and prolong inpatient hospital stays by 1.7 to 4.6 days.
Despite efforts to reduce adverse drug events and improve patient safety—including the Centers for Medicare & Medicaid Services’ (CMS) in-depth undertaking to create policies, value-based purchasing programs, and other financial incentives aimed at preventing hospital ADEs—the problem perseveres. The result is an increase of about $136 billion in annual U.S. healthcare costs, much of which could be avoided.
Multiple factors lead to ADEs
During the COVID-19 pandemic, error reports related to remdesivir treatments highlight the importance of strategies to prevent ADEs caused by incorrect dosing, in particular. ADEs related to remdesivir treatment can include acute kidney injury and hepatotoxicity, or respiratory toxicity.
The FDA warned that Veklury® (remdesivir) had limited clinical data for patients who weigh 3.5 kg to less than 40 kg, heightening the risk of ADEs in this patient population. According to the Institute for Safe Medication Practices, the FDA received multiple reports related to the use of remdesivir, including administration of the wrong dose or formulation, missed doses, and improperly prepared or stored doses.
The current “one-size-fits-all” dosing paradigm of drugs is a major contributor to ADEs in hospitals. A recent FDA study determined that 78% of 181 drugs approved from 2013 to 2017 had only one approved dosing regimen, and of the drugs considered to be amenable to response-guided treatment, only 39% provided response-guided dosing instructions in their labeling. In particular, drugs are typically tested in fewer than 1,000 patients, and differences in drug effects are still not well studied for different patient populations, such as patients with more severe forms of renal and hepatic impairment, women who are pregnant or breastfeeding, patients with common comorbidities, and pediatric patients.
Polypharmacy, the simultaneous use of multiple drugs for treatment, also increases the chance of an ADE. Unfortunately, current tools such as the Beers criteria for potentially inappropriate medication use in older adults, the Medication Appropriateness Index, the Screening Tool of Older People’s Prescriptions (STOPP), and the Screening Tool to Alert to Right Treatment (START) have not been able to decrease risks significantly.
At the bedside, dose range checking alerts available in some electronic health record (EHR) systems are unsophisticated and do not account for patient variability in drug response. Alert fatigue and pop-up fatigue from EHR system notifications about potential drug interactions and dosing problems also contribute to ADEs in hospitals. For example, one patient received a 38-fold overdose of an antibiotic because a physician was told to ignore alerts from monitoring systems. Another problem is that alerts are not always clinically significant or relevant. There is no official grading system for classifying drug interactions as truly significant or rating the level of response a patient may have to an interaction.
EHRs primarily document clinicians’ actions for billing, compliance, and other financial and administrative purposes; they are not designed to make data useful for proactively improving outcomes, such as reducing ADEs. Thus, there is an entire ecosystem of clinical decision support, population health, and analytics tools built outside of the EHR that use data from the EHR to aid in reducing ADEs.
Emerging technology can help address some common yet preventable ADEs, especially for drugs with a narrow therapeutic index (NTI). As defined by the FDA, NTI drugs “are drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity.”
Leveraging precision medicine to prevent ADEs
Precision medicine—and more specifically, precision-dosing technology, which uses multiple patient-specific factors to individualize medication doses—is an emerging tool to help prevent ADEs. Model-informed precision dosing (MIPD) takes data from existing patients to predict another patient’s response to a specific dose of a drug. MIPD allows providers to find the optimal dose for each patient based on the patient’s unique characteristics, reducing the potential for adverse events and helping to ensure that drugs work as intended. Importantly, making real-world patient data more widely available for MIPD approaches can help mitigate the effects of testing medications in limited populations.
Precision dosing complements clinical expertise without adding to provider decision or alert fatigue because it is a more active and involved process that uses software. Instead of an alert popping up on a screen that is easy to ignore, a clinician actively assesses a patient’s unique pharmacological profile by leveraging patient-specific data with machine learning and pharmacology models to determine an optimal dosing regimen.
Model-informed precision dosing is particularly useful for NTI drugs, which can have significant drug response variability and for which effective doses can be close to toxic doses. Many therapeutic areas stand to benefit from precision dosing, including anti-infectives such as vancomycin, immunosuppressants, chemotherapeutics, and biologics.
We have already seen the benefits of using precision dosing to treat bacterial infections in pediatric patients with vancomycin because it lowers the risk of ADEs occurring, allows clinical teams to administer the right dose to patients faster, and reduces treatment times. Model-informed precision dosing has also been used for busulfan, a chemotherapy agent for hematopoietic cell transplants. A study in Frontiers in Pharmacology found that using MIPD to personalize busulfan therapy allows providers to more accurately and precisely reach desired therapeutic ranges for dosing.
Other drugs, such as biologics that are being developed or are newly on the market, make the need for precision dosing even greater because they are expensive, so optimizing the dosing for each patient to maximize the likelihood of treatment success is important. As payers increasingly consider value-based reimbursement for these expensive drugs, it is in the interest of patients, clinicians, and payers to optimize dosing such that a medication is most likely to be efficacious and minimally toxic. Precision dosing could be the path forward for these new treatments and payment models.
Emerging technology and looking ahead
The COVID-19 pandemic should not distract us from the continuing importance of developing strategies to reduce ADEs in hospitals. Emerging technology, such as precision-dosing software, should be considered as part of a broader hospital and health system strategy to improve patient safety and outcomes.
Sirj Goswami, PhD, is CEO and co-founder of InsightRX. Michael Neely, MD, is a professor of pediatrics and clinical scholar at the University of Southern California and the Children’s Hospital of Los Angeles (CHLA). He is the director of the Laboratory of Applied Pharmacokinetics and Bioinformatics at the Saban Research Institute, CHLA. Dr. Neely serves on the InsightRX Scientific Advisory Board.