Shortages of antiseizure medications in Australia and the association with patient switching, and adherence in a community setting

Purpose: To quantify sponsor-reported shortages of oral antiseizure medications in Australia, estimate the number of patients impacted, and the association between shortages and brand or formulation switching, and changes in adherence. Methods: A retrospective cohort study of sponsor-reported shortages (deﬁned as where the supply of a medicine will not or will not be likely to meet the demand over a 6-month period) of antiseizure med- ications reported to the Medicine Shortages Reports Database (Therapeutic Goods Administration, Australia); cross-referencing shortages to the IQVIA-NostraData Dispensing Data (LRx) database, a dei- dentiﬁed, population-level dataset collecting longitudinal dispensation data on individual patients from (cid:1) 75% of Australian community pharmacy scripts. Results: Ninety-seven sponsor-reported ASM shortages were identiﬁed between 2019 and 2020; of those, 90 (93%) were shortages of generic ASM brands. Of 1,247,787 patients dispensed (cid:3) 1 ASMs, 242,947 (19.5%) were impacted by shortages. Sponsor-reported shortages occurred more frequently before the COVID-19 pandemic versus during the pandemic, however, shortages were estimated to affect more patients during the pandemic than before the pandemic. An estimated 330,872 patient-level shortage events were observed, and 98.5% were associated with shortages of generic ASM brands. Shortages occurred at a rate of 41.06 shortages per 100 person-years in patients on generic ASM brands versus 0.83 shortages per 100 person-years in patients on originator ASM brands. In patients taking a formula- tion of levetiracetam affected by a shortage, 67.6% switched to a different levetiracetam brand or formulation during shortages compared with 46.6% in non-shortage periods. Conclusions: Approximately 20% of patients on ASMs were estimated to have been impacted by an ASM shortage in Australia. The rate of patient-level shortages was approximately 50 times higher for patients on generic ASM brands versus originator brands. Shortages of levetiracetam were associated with formulation and brand switching. Improved supply chain management amongst sponsors of generic ASMs is needed to maintain the continuity of supply in Australia.

Security Supply Guarantee to strengthen medicine supply to Australia [3].
The Australian regulator of medicines, the Therapeutic Goods Administration (TGA), defines a medication shortage as occurring if at any time over a six-month period ''the supply of that medicine in Australia will not, or will not be likely to, meet the demand for the medicine for all the patients in Australia who take, or who may need to take, the medicine" [4]. Medication shortages can impact the entire health system, including healthcare practitioners through the increased cost and time required to source alternative stock and educate staff and patients on stock and formulation changes.
If the medicine is unavailable due to a shortage, a physician or pharmacist must respond by switching the patient to either: [1] a different formulation of the same brand of ASM (defined in this study as formulation switching; for example prescribing two 100 mg valproate tablets b.i.d instead of one 200 mg valproate tablet b.i.d.), or [2] to switch the patient to a different brand containing the same active ingredient (defined in this study as brand switching), or [3] to discontinue the active ingredient (defined in this study as discontinuation). For the purpose of this study, an ASM 'brand' is defined as all formulations (or presentations) of an ASM produced under the same trade name by a manufacturer or sponsor in Australia (therefore each ASM brand may have multiple formulations). It should also be noted that in the event of a shortage, a physician or pharmacist may be restricted by the availability of alternative formulations and brands of the ASM in shortage.
Although the availability of alternative formulations and brands allows patients to switch to an alternative formulation/brand that is not in shortage and avoid discontinuation of the active ingredient, a number of studies have found that formulation and brand switching of ASMs can be associated with a range of adverse patient outcomes, including medication error, non-adherence, worsening seizure control, adverse drug effects, and anxiety [5][6][7][8][9], suggesting that formulation or brand switching of ASMs may be associated with some risk to patients.
The objectives of the study were to characterize ASM shortages in Australia, estimate the association between shortages and brand or formulation switching, and between brand or formulation switching and patient adherence.

Databases
Sponsor-reported shortages of ASMs were sourced from the TGA Medicines Shortage Reports Database (MSRD), a database maintained by the regulatory authority of medicines in Australia, the Therapeutic Goods Administration (TGA). Sponsors of prescription medicines and a small number of over-the-counter medications are obligated to monitor and self-assess medicine shortages, and self-report by completing an electronic notification form, all shortages and permanent discontinuations to the TGA within 10 days (2 days for critical shortages) after becoming aware, an obligation that became mandatory on 1 January 2019 [10]. Each formulation of a brand is considered separately when submitting a shortage report. Sponsors are also required to update the TGA when new information related to a previously reported shortage becomes available. Sponsor-reported data submitted to the MSRD includes the impact of the shortage, nature of the shortage, duration of the shortage, permanent discontinuation, dosage forms and strengths in shortage, estimation of current stock levels, availability of alternative formulations, impact, and supply management options. Data on sponsor-reported medication shortages was obtained through a freedom of information (FOI) request (FOI 2076, TGA), for the period of 1 January 2019 to 30 November 2020.
Information on shortages from the MSRD was cross-referenced with the IQVIA-NostraData Longitudinal Dispensing (LRx) database to estimate how sponsor-reported shortages were associated with shortages experienced by patients (patient-level shortages), switching behavior, and adherence at an individual patient level. The LRx database collects dispensing data from approximately 4,500 Australian retail pharmacies, representing approximately 75% of all retail pharmacy scripts across Australia. LRx data is aggregated from script data extraction through pharmacy dispensing software or direct data feeds from central systems of certain pharmacy groups. The database comprises dispensed public (Pharmaceutical Benefits Scheme funded) and private scripts from January 2011 onwards, enabling longitudinal tracking of patients (via de-identified Medicare number) and product information. Longitudinal tracking of an individual patient's dispensation data, including medication initiations, repeat dispensations, brand and formulation switching, and discontinuations can be tracked within defined subpopulations. Data were extracted from the LRx database for the period of 1 January 2019 until 30 November 2020 to estimate the number of patients impacted by ASM shortages identified in the MSRD and from 1 July 2017 to 30 November 2019 to allow for analysis of historical dispensing patterns.

Study design
The following drugs were considered ASMs for the purpose of the study, and shortage data of oral formulations (tablets or solution/suspension) was requested from the TGA for brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, phenytoin, sodium valproate, sulthiame, topiramate, vigabatrin, tiagabine, phenobarbital, primidone, pregabalin, and zonisamide. The following variables were provided by the MSRD as part of a freedom of information request: sponsor, brand, active ingredient, strength, dose form, shortage start date, shortage end date, market deletion date, discontinuation date, shortage status, patient impact, and reason. Shortages reported to the TGA by sponsors (sponsor-reported shortages) were quantified and descriptive statistics were generated to understand the number and duration of sponsor-reported shortages.
Patients dispensed oral formulations of ASMs in the LRx database during the study period (1 January 2019 to 30 November 2020) were eligible for inclusion in the study. Dispensation data of included ASMs were extracted from the LRx database and dispensations were followed for individual patients using a deidentified Medicare number. Dispensation data missing a deidentified Medicare number was excluded. As the LRx database does not capture diagnosis, the study population included patients dispensed ASMs for any condition including epilepsy as well as other conditions.
Patients were defined as impacted by an ASM shortage for a given ASM formulation if dispensed that formulation in the 90 days before the start date of the shortage of that formulation reported in the MSRD.
The study period was divided into two time periods to understand the impact of COVID-19 on ASM shortages. The pre-COVID period was defined as the period from 1 January 2019 to 25 January 2020, which was the date of the first recorded case in Australia, and the COVID period was defined as the period from 26 January 2020 to 30 November 2020. A comparison of the frequency of sponsor-reported and patient-level shortages during the pre-COVID and COVID periods was performed.
Shortages experienced by patients (patient-level shortages) were presented as an event rate, using the sum of all shortage events for all formulations of an ASM brand, and divided by patient-years exposure on the respective brand. Patient-years of exposure were calculated at an individual patient level for each brand from the first day of exposure until the date of discontinuation. For each patient, the first day of exposure was defined as the first date of dispensation of each ASM brand in the study period. Subsequent dispensations of any formulation of the same ASM brand within 90 days were considered continuation of the brand to allow for up/down titration within the brand. Discontinuation was defined as a gap of 90 days since the last dispensation of any formulation of the respective ASM brand. The date of discontinuation was defined as 90 days after the date of the last dispensation. Patients were eligible for re-indexation on the same brand after the date of discontinuation. All patients were censored at the end of the study period (30 November 2020). For each patient, the days were then summed by brand and divided by a year to derive the number of exposure years per patient. Then, these years were summed per ASM brand to provide patient-years.

Switching analysis
The analysis of switching was performed only on levetiracetam, which, unlike many ASMs, is not known to be frequently used for conditions other than epilepsy. As the event of a levetiracetam shortage was hypothesized to lead to either formulation switching or brand switching, both formulation and brand switching were included in the analysis. Discontinuation of levetiracetam was also quantified and reported separately. Rates of brand switching (excluding formulation switching within the same brand) were also analyzed.
Switching pattern data for levetiracetam was extracted from the LRx database from 1 July 2018 to 30 November 2020. The rate of formulation/brand switching in patients on levetiracetam during sponsor-reported shortages between 1 January 2019 and 30 November 2020 was quantified and compared to a ''nonshortage" reference period defined for each shortage as the same date range in the previous calendar year. Shortages of all formulations and brands, including the originator brand of levetiracetam were eligible for inclusion in this analysis. Patients were included in this analysis if dispensed two levetiracetam formulations experiencing a shortage in either (a) the 180 days prior to that shortage and/or (b) the 180 days prior to the non-shortage period.
Patients were followed for the duration of the shortage and categorized as ''continuing" (1 dispensation of index levetiracetam formulation and 0 dispensations of other levetiracetam brands/formulations throughout shortage), ''brand/formulation switching" (dispensation of 1 levetiracetam brand/formulation excluding the index formulation at any point throughout shortage), or ''discontinuing" (0 dispensations of any levetiracetam brand/formulation) during the shortage period. Brand switching was characterized as the dispensation of 1 different brand of levetiracetam brand compared with the index brand. This analysis was also performed for patients who were on therapy during the reference (non-shortage) period for a particular levetiracetam formulation/brand.

Adherence
An exploratory analysis was conducted to investigate change in adherence in patients switching between formulations or brands of levetiracetam. To maximize the number of patients eligible for inclusion in the analysis, all brand or formulation switches regardless of whether the switching occurred during a shortage or not were included, and the analysis period was extended to include switches between 1 September 2017 and 30 November 2020. Patients were eligible for indexation in this cohort for analysis after having received consecutive treatment with two different levetiracetam brands, each lasting 180 days with gaps of 90 days between consecutive dispensations of the relevant formulation. Adherence to levetiracetam was calculated over a 180-day period prior to and after brand switch, using the proportion of days covered (PDC) and medication possession ratio (MPR) methodologies [11]. For the pre-switch period, adherence was calculated from the most recent dispensation at least 180 days prior to the switch; post-switch adherence was calculated 180 days from the dispensation where the brand switch occurred. Patients were categorized during pre-switch and post-switch periods as ''under-adherent" (MPR <80%), ''adherent" (MPR 80% to <110%), or ''overadherent" (MPR 110%) [12]. The analysis was also performed on the subpopulation of patients who only switched brands, excluding patients who switched formulations.
The prescribed daily dose (PDD) was used for the calculation of MPR and PDC and is not captured in the LRx database. The analysis used the ''PDD75" derived from the 75th percentile of time between dispensations for the population of patients on a levetiracetam formulation [13]. PDD75 estimates for levetiracetam brands with shortages are presented in Supplementary Table 4.

Statistical analysis
Descriptive statistics were reported using percentages and proportions for categorical variables and mean or median (with standard deviations [SD], interquartile range [IQR], or range) for continuous variables. A paired t-test was used to compare mean MPR and PDC scores.

ASM drug shortages
A total of 401 ASM shortages were reported to the MSRD during the study period. Overlapping shortages of the same formulation were consolidated, leaving 97 individual sponsor-reported shortages ( Fig. 1). Two shortages extracted from the MSRD had a shortage duration of 0 days, one of which was for a levetiracetam formulation that has not been included in the secondary analyses (but is reported in the primary objective). The median shortage duration was 109 days (IQR 56, 215). Of the 97 sponsor-reported shortages, 90 (93%) were shortages of generic ASM brands. Levetiracetam experienced the greatest number of shortages (24), followed by pregabalin (15), gabapentin, and topiramate (14) ( Table 1). The sponsor-reported reasons for the shortages included ''manufacturing" in 47 (48.5%), ''commercial changes" in 19 (19.6%), ''unexpected increase in demand" in 19 (19.6%), and ''other" in 21 (21.7%) (Supplementary Table 2).
Over the study period, 1,247,787 unique patients were dispensed 1 oral ASMs in the LRx database and 242,947 (19.47%) unique patients were impacted by 1 ASM shortage. A total of 330,852 patient-level shortage events were observed across all ASMs, with 325,829 (98.5%) events due to shortages of generic ASM brands. The event rate of patient-level shortage events was 41.06 shortages per 100-person years of exposure for generic ASM brands versus 0.83 shortage events per 100-person years of exposure for originator ASM brands ( Table 2). The event rate ratio for shortages of generic ASM brands versus originator ASM brands was 49.56.  Of the 97 sponsor-reported shortages during the study period, 64 occurred during the pre-COVID period, representing a shortage on average every 6.08 days, and a median shortage duration of 129 days (IQR 56.75, 273.75). A total of 33 sponsor-reported shortages were reported during the COVID period, representing a shortage on average every 8.42 days, and a median shortage duration of 101 days (IQR 44.5, 137.25). The sponsor-reported shortages during the pre-COVID period were estimated to impact 156,269 patients (median, 1685.5; IQR 441.5, 2901.25) compared with 174,583 patients during the COVID period (median, 2285 patients; IQR 614, 5053).

Shortage period switching patterns
A total of 23 shortages of levetiracetam were included in the switching analysis. One shortage with a duration of 0 days was excluded from the analysis (decision made post hoc) based on the assumption that a shortage of 0 days would not be expected to impact patients at the pharmacy. Descriptive statistics of levetiracetam shortages stratified by brand are described in Table 3. The median shortage duration of the 22 remaining levetiracetam shortages was 133 days (IQR 80, 229.5). Under unique columns, unique represents the number of unique patients in each cell. The 'Total' unique patients column represents unique patients across both originator and generic formulations for a given ASM, and the 'Total' unique patients row represents unique patients across all ASM provided for originator, generic, and across both originator and generic brands. Person years exposure for each ASM included all formulations and brands of oral ASM with the respective active pharmaceutical ingredients. Summary data for (A) sponsor-reported shortages of levetiracetam brands, and patient-level shortages. Patients may have received more than one brand of levetiracetam and were eligible to be included as a unique patient for each brand they were dispensed. One shortage of Brand A had a duration of 0 days and was excluded from this analysis. Levetiracetam brands were deidentified at the request of the TGA.
A total of 231,220 brand or formulation switches (176,979 brand switches only) were observed during the study period. In levetiracetam shortage and non-shortage periods (respectively), 24 Table 3). Discontinuation of levetiracetam occurred in 8.2% (95% CI 7.8%, 8.6%) and 7.1% (95%CI 6.7%, 7.5%) patients in shortage and non-shortage periods respectively ( Table 4). Note that not all shortages had comparable non-shortage periods; three formulations (of the same brand) experienced shortages within one year of market entry.

Antiseizure medication switching and association with adherence
A total of 3,593 formulation or brand switches were eligible and included in the adherence analysis. In the univariate analysis, a statistically significant increase in mean MPR from 1.20 pre-switch to 1.22 post-switch was observed (p < 0.05, paired t-test). A 1percentage point decrease in adherent patients was observed in patients in the post-switch period versus the pre-switch period; a 3-percentage point increase in over-adherent patients was observed, and a 2 percentage point decrease in patients categorized as under-adherent was also observed ( Table 5). An analysis of brand switches only is provided in the supplementary data (Supplementary Table 5). Table 4 Switching behavior of patients on levetiracetam during ASM shortage, and non-shortage periods.
Number and proportion of patients that continued, switched (brand or formulation), or discontinued levetiracetam during periods of shortage, and non-shortage periods. The sum of proportions is 100% in each respective shortage or non-shortage period. Levetiracetam brand G did not have a corresponding non-shortage period due to having entered the market < 1 year before shortage dates. Levetiracetam brands were deidentified at the request of the TGA.

Discussion
This study provides the first real-world evidence showing that shortages of ASMs are common in Australia and impact a considerable number of patients. Shortages occurred more frequently in the study period before the COVID pandemic, suggesting that sponsorreported ASM shortages are common and are likely to continue outside of major global events affecting supply chains, including pandemics. However, the number of patients estimated to be impacted by shortages was higher during the COVID-19 pandemic, which suggests that brands that supply a higher volume of ASMs experienced shortages during the COVID-19 pandemic.
The results of this Australian study are consistent with data from around the world where medication shortages have been identified as a global issue in need of intervention in countries including the US, Canada, China, Belgium, Israel, and countries in South America [3]. There is little data investigating the economic and market dynamics driving manufacturer entry and supply in Australia. In the US, the increasing rate of medication shortages has been attributed to the high market concentration of manufacturers, manufacturers having limited capacity for spare production, and 'just in time' inventory practices, meaning that small changes in supply or demand can result in shortages [14]. An FDA report on US drug shortages identified economic forces, including the limited profitability of producing older generic drugs, as well as increasing complexity of supply and logistics, and regulatory hurdles making global supply chains more vulnerable as root causes for medication shortages [15,16].
In light of the disruption seen in global supply chains during the COVID-19 pandemic, it is important for policymakers to prioritize further understanding the vulnerabilities of pharmaceutical supply chains, and develop strategies to improve supply chain resilience [16]. Solutions may include developing redundancy in manufacturing and supply, holding additional stock or production capacity, holding 'buffer' stock, or increasing domestic manufacturing capacity [15,16]. For medications with low profit margins, which are predominantly genericized medicines, penalties for failure-tosupply, and increasing drug prices have also been proposed to incentivize manufacturers to maintain continuity of supply [17]. The FDA has further recommended increasing the understanding of shortages and resulting harms, to incentivize manufacturers to provide mature quality management systems and to promote sustainable contracting practices [15,16].
In Australia, the importance of continuity of supply was addressed in the 2021 Strategic Agreement between the Commonwealth of Australia and both Medicines Australia (the representative body for innovator pharmaceutical companies) and the Generic and Biosimilar Medicines Association. According to the agreement, sponsors will be required from July 2023 to hold 4-6 months of stock in Australia to minimize the risk of shortages impacting patients [18,19], recognizing that 'just in time' supply chain practices were contributing to shortages in Australia. However, the results of this study suggest that even mandating a buffer of 6 months of stock may not eliminate all ASM shortages, as approximately one in three sponsor-reported shortages continued beyond 180 days.
Recognizing the increasing issue of ASM shortages, the International League Against Epilepsy (ILAE) recently published a narrative review and recommendations for the management of patients in the event that switching between different ASMs and ASM brands is unavoidable [20]. In Australia, ASM shortages where an alternative brand was not available were rare, which is an important finding as involuntary or sudden discontinuation of ASMs in instances where alternative brands are unavailable can have serious consequences for patients.
This study found that a higher number of sponsor-reported ASM shortages were reported for generic ASM brands. This finding may be partly explained by the presence of multiple generic brands available for a number of different ASMs, where there is only one originator brand. For example, in the case of lamotrigine and levetiracetam, there were 5 and 7 generic brands that reported shortages respectively, compared with one originator brand. However, when taking into account the number of person-years of exposure to each brand, patients taking generic brands were far more likely to experience an ASM shortage on a generic ASM brand compared with an originator ASM brand. These findings suggest that supply chain management is an area in need of improvement, particularly for manufacturers and sponsors of generic ASMs to ensure continuity of supply for patients.
High rates of patients switching brands of levetiracetam were observed during non-shortage periods, which suggests that brand switching is a common behavior in Australia. This may be partly explained by the introduction of legislation to encourage prescribing by active ingredient rather than brand, and to permit switching of brands at the pharmacy for most medications [21]. The observed increased proportion of patients that switched brands during ASM shortage periods demonstrated redundancy in the supply chain for genericizsed ASMs, where substitute brands were able to supply patients and manage the increased demands during a shortage of other brand/s. Clinical authorities for epilepsy recognize that the bioequivalence of different manufacturer's brands of an ASM brand is within acceptable limits, and conclude that there is no reason to avoid brand switching of ASMs due to perceived differences in bioequivalence [22][23][24][25][26][27]. However, the American Epilepsy Society (AES) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) state that the changes in the preparation of the medication may contribute to changes in patient adherence and subsequently adverse patient outcomes [23,24]. The AES and MHRA as well as a number of internationally regarded clinical epilepsy authorities provide varying degrees of caution in regard to brand switching of ASMs, including maintaining a consistent supply of a brand of ASM, cautioning against switching the brand of ASM entirely [26], or discouraging brand switching in patients with wellcontrolled seizures [22,25], or in any patient with epilepsy without consultation between the Neurologist, patient, and/or caregiver [22,23,25,26,28].
This guidance is based on the findings of a number of studies that reported adverse outcomes when switching brands of ASM, including decreased adherence due to changes in the appearance of the medication or its packaging (medication error) [29], increased rates of breakthrough seizures or seizure worsening, and increased healthcare resource utilization [29][30][31][32][33][34][35]. Conversely, multiple studies have also found that brand switching of antiseizure medications in epilepsy is not associated with adverse patient or health system outcomes. Although there remain questions as to the true nature of the risks associated with brand switching of ASM, based on the advice of epilepsy guidelines, additional caution may be warranted for use of ASM brands with ongoing issues with continuity of supply, where supply shortages may result in involuntary and unavoidable brand switching.
In the exploratory analysis of adherence, a small, but statistically significant increase in mean adherence was observed after formulation or brand switching of levetiracetam, however, it is unlikely that such a small change represents a clinically meaningful change in adherence. Using previously reported MPR cut-offs to define under-, over-, and -adherent patients [12], small, inconsequential changes in the proportion of patients categorized as adherent patients were observed. It should be recognized that there may be uncontrolled variables confounding the observed association between formulation/brand switching and adherence in this exploratory analysis. It is also not well understood how long changes in adherence as a result of formulation/brand switching persist, and the choice of 180 days may have been too long a timeframe to observe a change in adherence. The results of the levetiracetam adherence are also unlikely to be generalizable to other ASMs as previous research has shown differing levels of adherence between ASMs, with levetiracetam having the highest adherence [30]. Further research using multivariate analyses to control for confounding is needed to understand the association between brand switching and changes in medication adherence.

Strengths and limitations
The MSRD provided a reliable database of sponsor-reported shortages; however, heterogeneity in sponsors' interpretation and reporting of shortages may have occurred. The extent to which a shortage reported by a sponsor resulted in the unavailability of a brand at the pharmacy is uncertain from the MSRD, and as sponsors are required to report when national shortages are anticipated in the coming 6-months, it is possible that some reported shortages, and shortages of short duration may have had a negligible impact on supply at the pharmacy level. This may have led to the overestimation of the number of patients impacted by a sponsor-reported shortage. The LRx database provided a large and broadly representative dataset of Australian patients; however, as the database covers approximately 75% of retail pharmacy scripts, it underestimates the true number of patients impacted by shortages. Patients may have also received dispensations from pharmacies not captured in the LRx database, potentially overestimating rates of switching, and/or discontinuation; this effect would be expected to be similar in both the shortage and nonshortage periods, and the observed differences are expected to be reliable. The estimation of person years of exposure to ASMs is limited by the lack of a variable for the quantity of medication dispensed. A conservative method for estimation of discontinuation date was used, which likely overestimate total days exposure to an ASM brand, and therefore underestimated the event rate of patient-level shortages. The statistical tests undertaken in the comparison of MPR and PDC should be regarded as exploratory in nature.

Conclusions
Shortages of oral ASMs in Australia are common and affect approximately one in every five patients on ASMs. The rate of patient-level shortages was approximately 50 times higher for patients on generic ASM brands versus originator brands. Patients taking levetiracetam during a shortage were more likely to switch brands than patients on levetiracetam during a non-shortage period, suggesting that patients on generic brands of ASMs have a higher likelihood of involuntary brand switching. These results suggest that improvements in supply chain management are needed by sponsors and manufacturers of generic ASMs to ensure continuity of supply for patients on ASMs.
Ethical publication statement We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. This research has previously been presented as an abstract and poster presentation at the Epilepsy Society of Australia 35th Annual Meeting, November 2 -4, 2021, and the American Epilepsy Society 75th Annual Meeting, Chicago, IL, USA, December 3 -7, 2021. This research manuscript has not been previously published.
This study was sponsored and funded by UCB Pharma, Australia, the sponsor of the originator brand of levetiracetam in Australia. Support for study design, statistical analysis, and medical writing was provided by IQVIA, Australia which was funded by UCB Pharma, Australia in accordance with Good Publication Practice (GPP3) guidelines. UCB Pharma, Belgium provided a formal review of the publication, but the authors had final authority, including the choice of journal.
Author roles and responsibilities JW, an employee of UCB Pharma, Australia was the designated study lead, responsible for the overall management of the study. JW, GS, BS, and WD were involved in the study design and statistical analysis plan. MHL performed the statistical coding and generated the statistical analysis report. JW, GS, AM, and WD were involved in the analysis and interpretation of the data. JW reviewed the literature and was the lead author in writing the manuscript. All authors critically reviewed the manuscript and approved the final version for submission.
Ethics Statement This study did not involve the collection, use, or transmission of individually identifiable data; therefore, Human Research Ethics Committee (HREC) review or approval was not required.
Patient consent statement Not applicable.

Funding Source
This work was supported by UCB Australia Pty Ltd.

Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeremy Welton and Anita Moody are employees of UCB Pharma, Australia. Wendyl D'Souza's salary is part-funded by The University of Melbourne. He has received travel, investigatorinitiated, scientific advisory board, and speaker honoraria from UCB Pharma Australia & Global; investigator-initiated, scientific advisory board, travel, and speaker honoraria from Eisai Australia & Global; advisory board honoraria from Liva Nova and Tilray; educational grants from Novartis Pharmaceuticals, Pfizer Pharmaceuticals, and Sanofi-Synthelabo; educational; travel and fellowship grants from GSK Neurology Australia, and honoraria from SciGen Pharmaceuticals. He has an equity interest in the device company EpiMinder. Giles Stratton, Min Hui Low, and Brittany Schoeninger are employees of IQVIA who performed this study on behalf of UCB Australia.