The impacts of medication shortages on patient outcomes: A scoping review

Background In recent years, medication shortages have become a growing worldwide issue. This scoping review aimed to systematically synthesise the literature to report on the economic, clinical, and humanistic impacts of medication shortages on patient outcomes. Methods Medline, Embase, Global Health, PsycINFO and International Pharmaceutical Abstracts were searched using the two key concepts of medicine shortage and patient outcomes. Articles were limited to the English language, human studies and there were no limits to the year of publication. Manuscripts included contained information regarding the shortage of a scheduled medication and had gathered data regarding the economic, clinical, and/or humanistic outcomes of drug shortages on human patients. Findings We found that drug shortages were predominantly reported to have adverse economic, clinical and humanistic outcomes to patients. Patients were more commonly reported to have increased out of pocket costs, rates of drug errors, adverse events, mortality, and complaints during times of shortage. There were also reports of equivalent and improved patient outcomes in some cases. Conclusions The results of this review provide valuable insights into the impact drug shortages have on patient outcomes. The majority of studies reported medication shortages resulted in negative patient clinical, economic and humanistic outcomes.


Findings
We found that drug shortages were predominantly reported to have adverse economic, clinical and humanistic outcomes to patients. Patients were more commonly reported to have increased out of pocket costs, rates of drug errors, adverse events, mortality, and complaints during times of shortage. There were also reports of equivalent and improved patient outcomes in some cases.

Conclusions
The results of this review provide valuable insights into the impact drug shortages have on patient outcomes. The majority of studies reported medication shortages resulted in negative patient clinical, economic and humanistic outcomes. PLOS  Introduction outcomes related to medicines shortages (S1 File). Medline, Embase, Global Health, PsycINFO and International Pharmaceutical Abstracts were searched using the two key concepts of medication shortage and patient outcomes (S2 File). Searches were limited to the English language, human studies and there were no limits to the year of publication.

Study selection
After the removal of duplicates, conference abstracts, editorials, and opinion pieces, titles and abstracts were scanned for relevance. Manuscripts were included if they were about a shortage of a scheduled medicine, had gathered data regarding the economic, clinical, and/or humanistic outcomes of drug shortages on human patients, and followed the IMRAD format [18] (containing an introduction, methods, results and discussion section). Manuscripts were excluded if the impact to patients was not attributed to shortages.

Data extraction
Study location, data collection method, the medicines(s) affected by the shortage, and patient outcomes were extracted from each manuscript. Economic outcomes were those that directly affected a patients' finances as a consequence of the shortage; clinical outcomes were defined as a change in a patient's health status due to a drug shortage. Subsets of clinical outcomes included mortality; adverse drug reactions; drug errors; changes in hospitalisation, such as increased length of stay or readmission; and other clinical outcomes, e.g. changes in a measured parameter such as blood pressure. Humanistic outcomes were defined as non-clinical and non-economic impacts on patients such as quality of life, satisfaction and concerns as a result of the shortage.

Results
A total of 230 unique articles were found after the initial search. After application of inclusion and exclusion criteria, 40 manuscripts were included in the final review (Fig 1). These 40 studies all contained data regarding economic, clinical, and/or humanistic impacts of drug shortages on patients. Included manuscripts were from 11 countries worldwide. The majority of manuscripts were from North America (n = 28), followed by Africa (n = 5), Europe (n = 3) and the Western Pacific (n = 3) the remaining manuscript was from Saudi Arabia in the Middle East. All manuscripts were observational studies, retrospective cohort studies (n = 19) and surveys (n = 15). Studies gathered information from patient charts (n = 21), reports of healthcare professionals (n = 19), and patient reports (n = 3). Some studies used multimodal methods to gather data on patient outcomes due to shortages.
There were 19 studies which reported on an individual medicine, of these 15 were unique medicines. Three medicines were reported multiple times: daunorubicin (n = 2), piperacillintazobactam (n = 2) and propofol (n = 3). In 13 studies, a group of medicines was reported, of these, there were seven unique groups. The most common groupings were: oncology medicines (n = 6), antimicrobials (n = 2). Other groups were anaesthetics, antihypertensives, antiretrovirals, paediatric medicines and glaucoma medicines. Eight studies did not specify a particular medicine in shortage, instead they reported on medication shortages in general.

Economic outcomes
Economic outcomes due to medication shortages were reported in five studies ( Table 1). The only economic outcome reported was patient out of pocket (OOP) costs. All five studies reported an increase in patient OOP costs [7,[19][20][21][22].
Drug errors were reported in nine studies. Eight of these reported an increase in drug errors [13,19,23,24,26,29,42,46]. The study by Abdelrahman et al. [36] reported both increased and equivalent drug errors because it reported physicians' perspectives.

Humanistic outcomes
Humanistic outcomes due to shortages were reported in eight studies (Table 3). Patient complaints were reported in three studies [5,13,29] and increased travel time was reported in four studies [13,24,26,47]. Other outcomes reported included patients being frustrated, angry and feeling like a burden to themselves and caregivers. These can be seen in Table 3. One study by Lukmanji et al. [22] used a quantitative quality of life (QOL) tool which found no statistical difference between participants QOL pre-and during-shortage. The same study also collected qualitative quotes from participants,-"When I first found out about the shortage I panicked and I was immediately worried that I was going to run out of pills and thought far ahead-I have a problem with catastrophic thinking. I thought far ahead about if I ran out of [Frisium] and if I have a seizure and worried about losing my license and house and then losing AISH [financial support]. When it got to that point I thought about killing myself. The anxiety got that bad" demonstrating that there were some impacts on patients' humanistic outcomes not captured via the QOL tool.

Discussion
The results of this review demonstrate that medication shortages are a complex, global phenomenon, which affects patients' economic, clinical, and humanistic outcomes. While drug shortages have been reported to be a global issue which are reported by 99% of pharmacists each year [19], there were only 40 studies gained from our comprehensive search strategy which reported patient outcomes that met inclusion criteria for review. The reasons for such Fiji Semi-structured interviews of key stakeholders in the Fijian medicine supply chain.

General medicines Mortality Hospitalisation Other
Medicine shortages were causing ill-health.
Interviewees reported that shortages resulted in longer hospital stays, shorter times to patient readmission and even mortality (Continued ) Idarubicin was used instead of daunorubicin due to shortage resulting in similar rates of complete remission, all-cause mortality, and adverse drug reactions. Subset analysis revealed patients over 55 years old had significantly higher rates of complete remission using the alternative drug idarubicin.
(Continued ) Changes in anaesthetic practice were reported as a result of shortages. Drug errors, complications, postponement of surgery, prolonged recovery and perioperative deaths were reported to be attributed to drug shortages. Improved outcomes were also reported such as less pruritis due to fentanyl shortage.
(Continued ) The shortened course of nimodipine was not associated with mortality, ADRs or LOS. Neurological outcomes and mechanical ventilation duration were also similar.
(Continued ) underreporting may be due to the problem being so ubiquitous that no one has ever really questioned it, or that drug shortages are a new phenomenon which has not yet been fully explored, or that clinician time is spent dealing with workarounds, and time for research, audits, documentation and follow-up is not available. Even though research evidence of patient consequence may be an underreported phenomenon, this review highlighted that regardless of the medicine that was in short supply, the majority of patient outcomes resulting from the shortage were disadvantageous to patients' clinical, economic and humanistic outcomes. There were no statistically significant differences in participants' pre-and during shortage responses on epilepsy-related quality of life distress and fear of having a seizure using the QOLIE-10-P tool. Qualitative analysis revealed themes such as burden on patients and caregivers, physical and psychological impacts of the shortage. Participants emphasised the increased financial and time burden that the clobazam shortage imposed on patients and their caregivers. https://doi.org/10.1371/journal.pone.0215837.t003 The impacts of medication shortages on patient outcomes With respect to economic outcomes, these were only reported in five studies. This could be attributed to lack of economic data generated as the majority of studies focused on clinical outcomes and used retrospective chart analysis for information. Economically, drug shortages in all reported instances increased OOP costs for patients. These increased costs were attributed to factors such as switching brand of the same medicine, switching to an alternative medicine, and expenses such as fuel for travelling further distances to acquire medicines. Patient OOP expenses were the only economic outcome reported, perhaps this may be due to health research being biased towards clinical outcomes or that it is difficult to capture the actual economic cost of drug shortages. No studies reported other economic outcomes such as productivity costs (e.g. time off work) or cost-utility, demonstrating that there may be a lack of sophistication in analysing the actual economic impact that shortages have on patients [53].
It should be noted that other economic considerations were reported in some studies such as institutional costs. One institution reported having to pay 300-500% more for shortage medicines [46], another reported having to pay up to 1704% more for an alternative agent [40]. Furthermore, studies reported having to have dedicated staff to manage shortages [30]. As many of these studies were from the USA, it is unknown if or how these costs would be passed onto the patients directly or their insurance companies and affect premiums and as these other economic considerations were not reported to affect patients directly, we can only theorise their impacts. Furthermore, different countries have different healthcare systems, where the costs of access to medicines during times of shortage may vary.
Clinical outcomes were reported in the majority of studies. However, these were generally retrospective reviews of data from patient records. Data gathered via this medium included specific patient outcomes related to the treatment, such as rates of infection or seizures. Other outcomes such as adverse drug reactions and drug errors were also often gathered via this retrospective audit of notes. Utilising this modality may have its limitations, as clinical documentation may not always be complete [54]. For example, studies which reported only on adverse events did not give a full depiction as to whether the alternative treatments were beneficial in treating the primary condition [38,39]. The other method utilised to report the clinical outcomes of drug shortages were self-report mainly from clinicians via survey or semi-structured interviews. These data collection methods may also lead to a problematic interpretation of the actual impact of the medication shortages on patient outcomes, as they may generate recall bias, particularly if participants were surveyed some-time after the shortage. Furthermore, survey questions may be leading, inflating the perceived outcomes of the shortage, also, these methods are only reporting perceptions of the impact of the shortage on the patient from the lens of the health professional and not from the patients themselves.
Rates of adverse events were reported in 20 studies. The majority of reports indicated an increase in adverse events such as increased toxicity of the alternative treatment. Interestingly, two studies reporting on the impact of piperacillin-tazobactam shortages on secondary Clostridium difficile infection and had conflicting results. One study reported an increased rate of Clostridium difficile infection [38], whereas the other, a decrease [39]. The changes in infection rate and adverse events may be attributed to the alternative therapy used, rather than the shortage itself. Thus, in order to use data from shortages, comprehensive clinical documentation is needed to guide future research and treatment protocols, particularly if improved responses to alternative treatments are reported. Interestingly, many of the studies reviewed were regarding drug shortages of antimicrobials or oncology medicines. These shortages may be more likely to be studied, due to the perceived importance placed on these medicines. However due to the heterogenous reporting of patient outcomes across studies, few comparisons of results can be compared.
Drug shortages were also associated with increased medication errors. This was attributed to factors such as unfamiliarity with alternative agents. Pharmacy staff noted in a 2003 study reporting on 109 shortages at one institute that in 54% of shortages clinicians may be unfamiliar with the alternative product regarding its mechanism of action, adverse effects, or interactions [55].
Lack of medication availability causing death is the most severe consequence of drug shortages and mortality was reported in 18 studies. Some of these studies reported few deaths, whereas others could attribute hundreds. In a 5-year retrospective cohort study of 27,835 patients with septic shock during a norepinephrine shortage, alternative vasopressor use resulted in an increased mortality of 3.7% (p = 0.3) [30]. In contrast to this long-term comparative study, others directly gathered physician perspectives on the relationships between drug shortages and mortality. This was the case in the study by Abdelrahman et al. where approximately 1/3 of physicians stated that shortages caused death, 1/3 said they did not, and 1/3 responded neutrally on the survey tool [36]. These heterogeneous methods used to report the impact of shortages, again making it difficult to draw firm conclusions on true impacts, and more comprehensive studies comparing those receiving no drug, or alternative treatment are required to highlight the full clinical consequence of shortages.
In addition to clinical and economic outcomes, it has been stated that health care is more than just treating a condition, and humanistic outcomes such as quality of life is also an important measure of successful health care [56]. However, in our review, we found only ten studies which reported humanistic outcomes. These studies reported patients having difficulty accessing their medications, patients complaining to health professionals about drug shortages, patients having to be transferred to other facilities to find suitable health care, and patients being anxious and distressed. One study used a quantitative tool to measure QOL during a clobazam shortage and reported no significant difference [22]. However, within the same study, there were extracts from patient interviews which suggest otherwise. Previous literature has also reported that often QOL tools may not be sensitive enough to capture the true impact of an intervention on the patient and that other tools measuring humanistic outcomes may need to be developed [56]. It is doubtful that this review captured the entire range of humanistic impacts of drug shortages, however, those reported predominantly seem to be negatively affecting the patient. Further research investigating humanistic outcomes and the patients' perspective of how drug shortages affect them is warranted in order to create holistic solutions to the shortage problem.
It has been commonly reported that drug shortages are a global problem. However, the majority of the studies included in this review were from developed nations such as the United States. The World Health Organisation reports that up to a third of the world's population does not have access to medications, where this rate is even higher in low-to-middle income countries [57], yet these nations are not well represented in this review. This prompts the question as to whether the impacts of drug shortages may differ in these nations. Due to the majority of studies reporting outcomes of shortages in developed countries, the results found in this review may not be generalisable to developing countries.
Due to the dearth of research literature reporting patient outcomes due to medication shortages, as well as the lack of homogeneity in the tools used to report these outcomes, this scoping review provides a snapshot of some of the economic, clinical and humanistic outcomes that may result from medication shortages. However, it may not allow one to make any firm conclusions about their true impact on patient outcomes.
It should be noted that much of the data comes from study types of low research validity, as the majority of studies were retrospective cohort studies or surveys. While cohort studies are observations of real outcomes of shortages, they may lack rigour. Surveys of healthcare professionals were the other common research method utilised. As mentioned, these are subject to biases and only gather the perspectives of the clinicians and not the patients themselves who are experiencing the treatment changes due to the shortage. Only one study in this review, actually asked patients themselves about the impacts they faced as a result of their medication shortage [22]. Additionally, the researchers may have had preconceived ideas of what data to record and may not have reported the full impact of the shortage for each individual involved. We believe a recording method for shortages should be created in order to capture the entire clinical, economic, and humanistic picture of drug shortages for the future. Due to the nature and small numbers of these manuscripts, the risk of bias was not assessed in this review. This scoping review therefore had both strengths and limitations. This is one of the first reviews that we are aware of attempting to synthesise the literature on the consequences of drug shortages specifically on patient outcomes. The systematic and comprehensive search strategy in many academic databases and the use of two authors applying the inclusion and exclusion criteria across all articles lead us to believe that we have captured most of the research data in this field. However, limiting the search to English only and not searching grey literature may mean that some studies (and accounts) have been missed. In addition, this review did not attempt to extract the root cause of these shortages or the strategies that have been put in place to overcome drug shortages when they occur. Lists of root causes and strategies can often be found on National Health System websites [6,58]. Furthermore, it did not attempt to make any comparisons between different health systems, and as already stated, much of the data was from developed nations and studies reporting patient outcomes in other parts of the world were lacking.
Whilst it was difficult to combine outcomes from different study types, this review highlights the need for creation of guidelines or a tool to record the impacts of drug shortages for future in order to allow better comparison and reporting of meaningful outcomes. More structured data should be gathered during times of shortage, which in turn can be used to guide further research and treatment protocols. Particularly, the economic and humanistic impact of medication shortages needs to be addressed.

Conclusion
The results of this review provide valuable insights into the impact drug shortages have on patient outcomes. The majority of studies reported medication shortages resulted in negative patient clinical, economic and humanistic outcomes.