An Adverse Drug Reaction (ADR) is “a response to a drug, which is noxious and unintended, and which occurs at dosages normally used for prophylaxis, diagnosis, or therapy of human disease or for the modification of physiologic function” [1] . ADRs represent a large component of the global problem of drug-related adverse events, and they have a huge negative impact on patient well-being, healthcare resources, and healthcare spending (approximately $30 billion per year in the United States [USA]) [2] . In emergency departments in the USA, ADRs are the cause of misdiagnoses and add a significant burden to the healthcare system [3] . Most investigations of ADRs are primarily in hospital settings. There are few reports from outpatient clinics, medical offices or nursing homes. This evidence suggests that the economic and healthcare impact of ADRs may be underestimated. While systems to address this issue are frequently recommended, few have been tested and none are widely available or implemented.

ADRs are just one of many pressures facing healthcare organizations, which include cost control while efficiently evaluating patients and providing high-quality care. These two goals seemingly conflict and are challenging as patients, particularly in the USA, are increasingly taking multiple drugs from a rapidly expanding list of medications. Many new agents, such as the “biologics” used to treat cancer and autoimmune disorders, have far-reaching effects that are often not fully understood when commercial use is initiated. Almost every drug can cause some degree of dysfunction or frank toxicity in one or more organ systems, which leads to symptomatic side effects. ADRs, particularly when not common, are frequently not considered or are unrecognized in the clinical setting; hence, these iatrogenic complications often worsen and can become severe. Recognized ADRs account for approximately 6.5% of hospitalizations [4] [5] . One report of 30,000 hospital records in the state of New York showed these complications can be irreversible, and lead to serious (6.7%) and fatal (0.32%) injuries, 13.6% of which appeared to be preventable [6] . At least 28% of hospitalizations due to ADRs seem to be preventable [7] . The elderly are at higher risk [8] [9] [10] , perhaps related to multiple medication use. It is likely that the actual scope of the ADR problem is greater than estimated in reports, because most studies investigated a limited number of drugs, or reported drugs with a high frequency of moderate to severe ADRs, or ADRs were defined only by laboratory abnormalities, or only considered high-risk patients [11] . The frequency of ADRs in hospitals remains high [12] [13] [14] [15] , and has not been reduced over the last 15 years, despite attention to the problem [16] .

Although Adverse Drug Effects (ADEs) can also result from drug-drug interactions and prescribing contra-indications, these problems should be identified and managed at the time of prescribing by systems already created to identify these issues, prior to their occurrence. As there are adequate programs in place addressing drug-drug interactions, this report will not consider these issues. One review for primary care healthcare providers suggested that many ADRs are due to errors in prescribing and this could be potentially improved via medication safety programs [17] . As this should be implemented before an ADR occurs, we did not review the various medication safety programs designed to stop or prevent prescribing errors. We describe the status of healthcare addressing the specific problem of ADRs, many of which remain unrecognized and therefore are not addressed until too late, if at all. We focused on potential efficient approaches that are or could be used to identify ADRs to expedite management.

We performed a search of Cochrane Systemic Reviews from 1991 to 2023, PubMed, from January 1, 1984 to April 30, 2023, and JBI Database of Systematic Reviews and Implementation Reports from 2001 to December 31, 2023 using the medical subject heading term, adverse drug reaction reporting systems or management, filtered by clinical trial, meta-analysis, randomized control trial, and systemic reviews for humans. We reviewed the abstract or summary of each report to determine if each contained data about the extent of the ADR problem and proposed approaches to management. Subsequently, we reviewed all the articles of interest and highlighted and critiqued the reports with data in order to address the question: Are there proposed or implemented methods or systems that have potential to reduce adverse drug reactions in hospitals, clinics, or nursing homes? We also reviewed nine digital applications available to clinicians for accessing potential ADR information. We extracted the key elements of each study or application with focus on potential use within healthcare provider workflow.

We could not find a comprehensive tool to identify ADRs that can be used efficiently, whether it is in a clinic, hospital, emergency department, nursing home, pharmacy or telehealth setting. Each available approach can be helpful, but all are of limited use due to complexity of utilization, the amount of time and effort (that interferes with clinical workflow), or incomplete (e.g. out of date) content. Thus, clinicians often remain unaware of many ADRs, continue medications that harm patients, or add medications in a prescribing cascade [39] [40] [41] [42] [43] . Without a process to identify ADRs that fit into clinician workflow, no plan to foster de-prescribing will be successful [44] . A National Action Plan for Adverse Drug Event Prevention, published in 2018, targeted just three types of therapies, anticoagulants, diabetes agents, and opioids [45] . The plan recommended surveillance, prevention, incentives, oversight and research, with federal agencies coordinating and collaborating with public and private sectors. This was followed by funding announcement to address medication safety strategies and tools by the USA Agency for Healthcare Research and Quality in 2019 [46] . Most of the grantees focused on anticoagulation, opioids, and anti-depressant medications [47] . Studies that address a specific group of “high impact” therapeutics have been published, but no global plan or tool to identify unrecognized ADRs has resulted.

There are almost no articles describing efficient potential solutions that can be implemented in clinical practice to reduce ADRs [18] . New prospective data are now being collected and will likely demonstrate that the problem is more widespread [48] , but this is not a substitute for identifying ADRs in real-time and developing processes for ADR reduction. Many articles and reports describe the huge negative impact of ADRs, particularly on hospitalized patients and individuals in long-term care/nursing home facilities, where data is more available. Many ADRs are actually present on admission and often continue while a patient is in the hospital [49] . It appears that the most at-risk individuals are the elderly, dementia patients, and those with chronic illnesses. The actual scale of the problem will be considerably greater once data from outpatient/clinic settings are considered [48] [50] . One report stated that only 5% of ADRs were recognized [51] . We also suspect that federal discussions about requiring mandatory ADR reporting by healthcare providers are tempered by the realization that ADR identification is limited.

Although many ADRs are noted during premarket clinical trials and described and listed in the medical reviews on the drugs@FDA site, many ADRs are discovered post-marketing and reported in published articles. Additionally, some randomized clinical trials do not always accurately report the frequency or severity of ADRs [52] . Thus, it is imperative to consider all potentially available data, including post-marketing monitoring as drug safety information evolves over months and years after approval [53] [54] . Despite these efforts, major challenges remain to the voluntary reporting programs, leading to deficiencies that result in difficulties in diagnosing and reporting ADRs [55] .

Healthcare system and practice decision-makers should prioritize reducing ADRs. This would immediately improve the value of healthcare, besides limiting injury and deaths. Healthcare organizations and systems that have capitated contracts or are “closed systems” would immediately have measurable return on investment. Closed healthcare systems, like the USA Veterans Health Administration (VHA) clinics, hospitals and nursing homes, should be the optimal institutions to demonstrate the benefit of the needed system and should have effective reporting capability. For example, a VA registration system, based on a web-based system to identify ADRs, collected approximately 60,000 reports across the 146 outpatient facilities over a seven-year period [56] . As of May 2020, the VHA reported a directive “for the reporting, monitoring, and surveillance of Adverse Drug Events (ADEs) entered into VHA’s voluntary ADE reporting system for observed Adverse Drug Reactions (ADRs) and new ADEs at Department of Veterans Affairs (VA) medical facilities” [57] . After the many reports describing the huge negative impact on the health of the population of the USA, including Veterans, there is virtually no system in place to improve safety by identifying and reducing ADRs in the VHA system.

The least intrusive and lowest cost process appears to be an approach that informs the healthcare providers and prescribers of prescription drugs within their workflow [13] [18] [27] [29] . Focusing on physicians, nurses, physician assistants, and pharmacists should be an effective strategy. As no clinician can be aware of all potential ADRs, healthcare providers require complete data-driven information [58] [59] . The clinician will always be needed to determine the causality for each potential ADR once the possibility is presented [60] . The report by Smith et al., which notified physicians of potential ADRs, showed under 50% utilization by doctors with just an early pilot effort [18] . Furnishing healthcare professionals with a proper tool that provides comprehensive quality data is required. Using databases like the Systematized Nomenclature of Medicine (SNOMED) and MedDRA preferred terms to organize drug side effects from FDA labels in the strategy has already been described [60] . In the future, deep learning methods should assist the clinician with evaluating an individual patient’s likelihood of having an ADR. Deep learning of electronic health records and other data sources will increase the capabilities to apply all these data. However, the medical records must be accurate, with complete assessments of symptoms, problems, laboratory test results, and all medications to identify potential temporally associated ADRs and possibly predict ADRs from similar new compounds. The creation of a deep learning tool will require vast amount of carefully synthesized data for all drugs and side effects before it can be utilized in clinical situations [61] [62] .

Unfortunately, the current platforms and applications available for clinician searches for drug side effects are not patient-problem-centric. The information platforms available to healthcare providers are not always current, do not rank content by the level of evidence, do not reflect the latest medical literature, do not provide enough information on medications and reported side effects, and are unwieldy and inefficient, they are not routinely utilized in a clinical setting. We are faced with a remarkable inefficiency, where large amounts of publicly available information cannot be accessed in an economical fashion by clinicians. We suggest that providing a platform that addresses the issues at the point of service should effectively change the healthcare culture. ADRs will be routinely considered, which will lead to improved management. We consider this approach the digital equivalent of “hand washing to reduce infection spread” as a method to lessen iatrogenic illness. Patient expectations will be elevated, and use of evidence-based decision-making to identify and reduce ADRs will become an important metric of clinician performance. We should not wait for all-encompassing safety programs to be developed that require significant management by administrators or pharmacists. ADRs are a major healthcare problem that is addressable at fraction of a cost required to create new procedures or drugs. Perhaps, healthcare groups and systems will only take this seriously and implement methods to identify and reduce ADRs when payers and the government require this as part of safety and quality parameters.

Mark J. Kupersmith and Karl Kieburtz are unpaid equity holders in SafeTherapeutics, LLC, which is developing tools to help identify and manage adverse drug reactions. There are no external financial interests.

The authors declare no conflicts of interest regarding the publication of this paper.

Kupersmith, M.J. and Kieburtz, K. (2024) Why Don’t We Adequately Identify and Manage Adverse Drug Reactions despite Having the Needed Information? Health, 16, 148-159. https://doi.org/10.4236/health.2024.162013