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AIM: The growing number of antidiabetics has broadened therapeutic options, leading to heterogeneity in prescribing patterns. Studies identifying antidiabetics modification patterns are lacking in Saudi Arabia. Therefore, the aim of this study is to describe modification patterns in Saudi patients. METHODS: Patients ≥ 18 years old with at least one antidiabetic between 2016 and 2022 were included. Follow-up started from the earliest to the last prescription.Two modification types were evaluated: "add-on," prescribing new antidiabetics within a treatment episode, and "switching", starting a new treatment episode after the preceding ends. Descriptive statistics were used to characterize patients and estimate events proportions. RESULTS: Of 122,291 patients, 47.2 % had treatment interruption or modification, totaling 303,781 events. Interruptions accounted for 54 %, add-on for 11 %, and switching for 35 %. The median time to first event was 159 days. The most add-on included dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitors to biguanide and sulfonylurea (8 %), and sulfonylurea to biguanide (8 %). Among 106,405 switching events, 23 % shifted from dual to monotherapy and 17 % from monotherapy to dual therapy. CONCLUSION: Nearly half of patients experienced modifications or interruptions, with notable shifts between monotherapies and dual therapies. These findings highlight the evolving landscape of treatment patterns in Saudi Arabia and guide future research and decision-making.

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BACKGROUND: Levetiracetam is an anti-seizure medication (ASM) with an established safety profile. However, a potential safety signal of hypokalemia following levetiracetam use was published in the World Health Organization newsletter. OBJECTIVE: To investigate the possible causal association between the use of levetiracetam and the development of hypokalemia. METHOD: This was a new-user, active-comparator retrospective cohort study using Real-world Evidence Research Network data at the Saudi Food and Drug Authority from 2016 to 2022. Adults (≥ 18 years old) with an incident prescription for either levetiracetam or carbamazepine were followed for up to 6 months from the prescription date. Hypokalemia was ascertained by using diagnostic code (i.e., E87.6) or by serum potassium level below 3.5 mmol/L. A Cox proportional hazards model, adjusted with stabilized inverse probability of treatment weight, was fitted to compare the hazard of hypokalemia between levetiracetam and carbamazepine exposed patients. RESULTS: A total of 8,982 patients entered the study cohort. The incidence rate of hypokalemia was 303 cases per 10,000 patient-years in the levetiracetam-exposed cohort compared to 57 cases per 10,000 patient-years among carbamazepine users. Compared to carbamazepine users, patients exposed to levetiracetam had an adjusted hazard ratio related to induced hypokalemia of 1.99 (95% confidence interval, 0.88-4.49). Results of sensitivity analyses were comparable to the main analysis. CONCLUSION: The hazard ratio for hypokalemia with the use of levetiracetam versus carbamazepine was statistically comparable. However, the potential association between levetiracetam use and hypokalemia cannot be ruled out given the elevated hazard ratios from the main and sensitivity analyses. Further studies may provide a more precise assessment of this association.

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BACKGROUND: This retrospective analysis aimed to comprehensively review the design and regulatory aspects of bioequivalence trials submitted to the Saudi Food and Drug Authority (SFDA) since 2017. METHODS: This was a retrospective, comprehensive analysis study. The Data extracted from the SFDA bioequivalence assessment reports were analyzed for reviewing the overall design and regulatory aspects of the successful bioequivalence trials, exploring the impact of the coefficient of variation of within-subject variability (CVw) on some design aspects, and providing an in-depth assessment of bioequivalence trial submissions that were deemed insufficient in demonstrating bioequivalence. RESULTS: A total of 590 bioequivalence trials were included of which 521 demonstrated bioequivalence (440 single active pharmaceutical ingredients [APIs] and 81 fixed combinations). Most of the successful trials were for cardiovascular drugs (84 out of 521 [16.1%]), and the 2 × 2 crossover design was used in 455 (87.3%) trials. The sample size tended to increase with the increase in the CVw in trials of single APIs. Biopharmaceutics Classification System Class II and IV drugs accounted for the majority of highly variable drugs (58 out of 82 [70.7%]) in the study. Most of the 51 rejected trials were rejected due to concerns related to the study center (n = 21 [41.2%]). CONCLUSION: This comprehensive analysis provides valuable insights into the regulatory and design aspects of bioequivalence trials and can inform future research and assist in identifying opportunities for improvement in conducting bioequivalence trials in Saudi Arabia.

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BACKGROUND: Previous studies have suggested that drug pricing could contribute to drug shortages; however, there is limited quantitative assessment of this potential causal association. This retrospective database analysis aimed to investigate the association between drug prices and drug shortage incidents in Saudi Arabia. METHODS: This was a retrospective database analysis study. Drugs with shortage notifications sent to the Saudi Food and Drug Authority (SFDA) between January 2017 and December 2020 were included. Each drug's foreign-to-Saudi price ratio (FTSPR) was calculated by dividing the mean international price by the Saudi price. Drugs were categorized into three groups based on their FTSPR: Group 1 (FTSPR > 1), Group 2 (FTSPR = 1), and Group 3 (FTSPR < 1). The primary outcome was the ratio of mean counts (mCR) between the three groups, with Group 3 serving as the control group. The analysis was adjusted for the measured confounders using a negative binomial regression model. RESULTS: A total of 900 drugs were included in the study, with 348 in Group 1, 345 in Group 2, and 209 in Group 3. The mean count in Group 1 was higher compared to Group 3 (mCR: 1.88; 95% confidence interval [CI] 1.24 to 2.83), while the mean counts between Group 2 and Group 3 were comparable (mCR: 1.39; 95% CI 0.92 to 2.09). CONCLUSIONS: Our findings indicate an association between drug shortage incidents and higher prices of drugs outside Saudi Arabia. Further studies are needed to explore this causal relationship in different contexts.

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OBJECTIVES: This study was conducted to assess the validity of recording (and the original diagnostic practice) of type 2 diabetes mellitus at a hospital whose records were integrated to a centralised database (the standardised common data model (CDM) of the Saudi National Pharmacoepidemiologic Database (NPED)). DESIGN: A retrospective single-centre validation study. SETTINGS: Data of the study participants were extracted from the CDM of the NPED (only records of one tertiary care hospital were integrated at the time of the study) between 1 January 2013 and 1 July 2018. PARTICIPANTS: A random sample of patients with type 2 diabetes mellitus (≥18 years old and with a code of type 2 diabetes mellitus) matched with a control group (patients without diabetes) based on age and sex. OUTCOME MEASURES: The standardised coding of type 2 diabetes in the CDM was validated by comparing the presence of diabetes in the CDM versus the original electronic records at the hospital, the recording in paper-based medical records, and the physician re-assessment of diabetes in the included cases and controls, respectively. Sensitivity, specificity, positive predictive value and negative predictive value were estimated for each pairwise comparison using RStudio V.1.4.1103. RESULTS: A total of 437 random sample of patients with type 2 diabetes mellitus was identified and matched with 437 controls. Only 190 of 437 (43.0%) had paper-based medical records. All estimates were above 90% except for sensitivity and specificity of CDM versus paper-based records (54%; 95% CI 47% to 61% and 68%; 95% CI 62% to 73%, respectively). CONCLUSIONS: This study provided an assessment to the extent of which only type 2 diabetes mellitus code can be used to identify patients with this disease at a Saudi centralised database. A future multi-centre study would help adding more emphasis to the study findings.

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PURPOSE: The Saudi Food and Drug Authority (SFDA) added pregabalin to the list of controlled substances in December 2017 to minimize the risk of its possible abuse and misuse. This study was aimed at assessing the impact of this decision on the overall use of pregabalin in Saudi Arabia and in comparison with drugs prescribed to treat neuropathic pain (i.e., vs. gabapentin, tramadol, duloxetine, and amitriptyline). METHODS: This was an interrupted time-series analysis of the Saudi quarterly sale data of the study drugs from October/2015 to September/2020. These data were obtained from IQVIA and were converted into use estimates (defined daily dose per 1000 inhabitant-days [DDD/TID]). Segmented regression models were conducted to assess the direct (level) and prolonged (trend) changes in use data after the decision. All analyses were completed using RStudio Version 1.4.1103. RESULTS: Before the SFDA's decision, there was an increased quarter-to-quarter use of pregabalin (DDD/TID: 0.16; 95% confidence interval [CI] 0.04 to 0.28). Pregabalin overall use dropped sharply by -1.85 DDD/TID (95% CI -2.71 to -0.99) directly after the decision with a prolonged quarter-to-quarter declining effect (DDD/TID: -0.22, CI to -0.37 to -0.05). The decision was associated with a direct increase in the use of gabapentin by 0.62 DDD/TID (95% CI 0.52-0.72) without any impact on the use of other drugs. CONCLUSIONS: The results of our study showed that the SFDA decision was associated with a decrease in the overall use of pregabalin, which may help minimize the risk of its abuse and misuse.

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INTRODUCTION: Since December 2020, three COVID-19 vaccines have been authorized in the United States (U.S.) and were proceeded by large immunization programs. The aim of this study was to characterize the U.S. post-marketing safety (PMS) profiles of these vaccines with an in-depth analysis of mortality data. METHODS: This was a retrospective database analysis study. Details of the U.S. PMS reports (15 December 2020 to 19 March 2021) of the three vaccines (Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S) were retrieved from the U.S. Vaccine Adverse Event Reporting System (VAERS). A descriptive analysis was conducted to characterize the reported adverse events (AEs). A comparative (Pfizer-BioNTech vs. Moderna) analysis of mortality was conducted. The mean count ratio of death between the two vaccines was estimated using a negative binomial regression model adjusting for the measured confounders. RESULTS: A total of 44,451 AE reports were retrieved (corresponding to 0.05% of the U.S. population who received at least one dose). The most commonly reported AEs were injection site reactions (30.4% of the reports), pain (reported in 26.7% of the reports), and headache (18.6% of the reports). Serious AEs were reported in only 14.6% of the reports with 4,108 hospitalizations. The total number of deaths was 1,919 with a mean count ratio of Moderna (n = 997) vs. Pfizer-BioNTech (n = 899) of 1.07 (95% confidence interval 0.86 to 1.33). CONCLUSIONS: The vast majority of PMS AEs in the U.S. were non-serious, and the number of serious AEs is very low given the total number of vaccinated U.S. population.

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BACKGROUND: The risk of surgical site infections (SSIs), particularly methicillin-resistant Staphylococcus aureus (MRSA) SSIs, after spinal surgeries is one of the most daunting experiences to patients and surgeons. Some authors suggest applying vancomycin powder on the wound before skin closure to minimize the risk of SSIs; however, this practice is not supported by well-established evidence. This study sought to assess the effectiveness of topical (i.e. intra-wound) vancomycin in minimizing the risk of SSIs in patients who underwent spinal surgeries at a Saudi hospital. METHODS: A retrospective cohort study was conducted using the hospital database. Patients who underwent spinal surgeries from the period of 09/2013 to 09/2019 were included and followed up (observed from the time of the surgery) to 30 days (surgeries without implants) or 90 days (with implants). The odds ratio (OR) of the primary outcome between vancomycin treated versus non-treated patients was estimated using a logistic regression model adjusting for the measured confounders. A sensitivity analysis was conducted using propensity score analysis (inverse probability of treatment weighting [IPTW] with stabilized weights) to control for confounding by indication. All study analyses were completed using RStudio Version 1.2.5033. RESULTS: We included 81 vancomycin treated vs. 375 untreated patients with 28 infections (8/81 vs. 20/375; respectively). The adjusted OR of SSIs between the two groups was 0.40 (95% confidence interval [CI] 0.11 to 1.34). The result of the propensity score analysis was consistent (OR: 0.97 [95% CI 0.35 to 2.68]). CONCLUSIONS: We could not find a lower association of SSIs with intra-wound vancomycin in patients who underwent spinal surgeries. Further studies are needed to assess benefits of using topical vancomycin for this indication vs. the risk of antimicrobial resistance.

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Choosing a noninferiority margin is one of the main challenges when designing a noninferiority trial. The European Medicines Agency (EMA) published a guidance report on the choice of margins in 2005. Nonetheless, in 2008 and 2009 they did not accept 41% (35 of 86) of the noninferiority margins that were proposed by pharmaceutical companies in the context of scientific-advice letters. In this study, we focus on whether the EMA's recommendations were followed by pharmaceutical companies, and on a possible relationship with eventual drug approval. Five of the 35 unaccepted margins were equivalence margins; we considered only the 30 unaccepted noninferiority margins in our analysis. Twelve of these margins were defined based on clinical and statistical considerations (the approach recommended by the EMA) and were rejected due to unacceptable clinical considerations. The other 18 margins were rejected because they were considered too wide. The EMA's recommendations were followed in the cases of 10 of the 15 margins (67%) for which information on follow-through of recommendations was available. The main reason for ignoring the EMA's recommendation in the other 5 cases was that the margins had been accepted by the US Food and Drug Administration. The proportions of approved drugs for which recommendations were and were not followed were similar, yet numbers were too low for formal statistical testing. This study shows that the main concern of regulators with regard to noninferiority trials was the strictness of margins from a clinical perspective. Future studies using more recent data, including data on the US Food and Drug Administration, may help in assessing the impact of guideline recommendations on noninferiority margins used for drug approval and may assist in reaching consensus among regulators about the choice of margins.

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PURPOSE: To compare the effectiveness and safety of a drug in daily practice with the outcomes of a target non-inferiority trial by rigorously mimickingin an observational study the trial's design features. METHODS: This cohort study was conducted using the British Clinical Practice Research Datalink (CPRD) to emulate the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. Patients with atrial fibrillation who were newly prescribed (>=12 months of no use) either rivaroxaban or warfarinfrom October 2008 to December 2017 were included. Non-inferiority of rivaroxaban to warfarin in the prevention of stroke or systemic embolism was assessed in different analysis populations (intention-to-treat [ITT], per-protocol [PP], and as-treated populations) using a hazardratio (HR) of 1.46 as the non-inferiority margin. Major bleeding (safety outcome) was also assessed and compared to that of the target trial. All outcomes were analyzed using Cox-proportional hazard analyses. RESULTS: We included 25,473 incident users of rivaroxaban (n=4,008) or warfarin(n=21,465). Similar to the trial, non-inferiority in the primary out come was demonstrated in all three analysis populations: HR=1.04 (95%CI 0.84 to 1.30) (ITT), HR=0.98 (95%CI 0.70 to 1.38) (PP), and HR=1.11 (95%CI 0.86 to 1.42) (as-treated). Risk of major bleeding was also similar to the target trial. CONCLUSION: The results of this study provide supportive evidence to the effectiveness of rivaroxaban and adds knowledge on the usefulness of emulating a non-inferiority trial to assess drug effectiveness.

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OBJECTIVE: To assess the impact on noninferiority decisions when using a single margin or single preserved fraction (PF) for all noninferiority trials within a pharmacological class. STUDY DESIGN AND SETTING: A search in PubMed, EMBASE, and CENTRAL resulted in seven active-controlled statin trials (nine noninferiority comparisons) for treating hyperlipidemia. The impact of using a single margin was assessed by calculating whether this margin corresponds to different PFs among comparator statins which will demonstrate that the threshold of demonstrating noninferiority (in terms of the PF) varies among comparator statins. The use of a single PF was assessed by reanalyzing noninferiority in the included trials with new margins (based on the single PF) for each comparator statin. RESULTS: The use of a single margin resulted in PFs that range between 81% and 89% for the different comparators (i.e., different thresholds). The use of a single PF resulted in four of nine (44%) different noninferiority conclusions compared with the original analyses. CONCLUSION: The threshold of demonstrating noninferiority with a single margin or single PF of the effect per pharmacological class may not be consistent with using a margin/PF for each comparator separately and may impact the conclusions of noninferiority.

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Noninferiority trials are used to assess whether the effect of a new drug is not worse than an active comparator by more than a noninferiority margin. If the difference between the new drug and the active comparator does not exceed this prespecified margin, noninferiority can be concluded. This margin must be specified based on clinical and statistical reasoning; however, it is considered as one of the most challenging steps in the design of noninferiority trials. Regulators recommend that the margin should be defined based on the historical evidence of the active comparator (the latter is often the well-established standard treatment of the disease), which can be performed by different approaches. There are several factors and assumptions that need to be accounted for during the process of defining the margin and during the analysis of noninferiority. Three methods are commonly used to analyse noninferiority trials: the fixed-margin method; the point-estimate method; and the synthesis method. This article provides an overview of analysing noninferiority and choosing the noninferiority margin.

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BACKGROUND: There is no consensus on the preferred method for defining the non-inferiority margin in non-inferiority trials, and previous studies showed that the rationale for its choice is often not reported. This study investigated how the non-inferiority margin is defined in the published literature, and whether its reporting has changed over time. METHODS: A systematic PubMed search was conducted for all published randomized, double-blind, non-inferiority trials from January 1, 1966, to February 6, 2015. The primary outcome was the number of margins that were defined by methods other than the historical evidence of the active comparator. This was evaluated for a time trend. We also assessed the under-reporting of the methods of defining the margin as a secondary outcome, and whether this changed over time. Both outcomes were analyzed using a Poisson log-linear model. Predictors for better reporting of the methods, and the use of the fixed-margin method (one of the historical evidence methods) were also analyzed using logistic regression. RESULTS: Two hundred seventy-three articles were included, which account for 273 non-inferiority margins. There was no statistically significant difference in the number of margins that were defined by other methods compared to those defined based on the historical evidence (ratio 2.17, 95% CI 0.86 to 5.82, p = 0.11), and this did not change over time. The number of margins for which methods were unreported was similar to those with reported methods (ratio 1.35, 95% CI 0.76 to 2.43, p = 0.31), with no change over time. The method of defining the margin was less often reported in journals with low-impact factors compared to journals with high-impact factors (OR 0.20; 95% CI 0.10 to 0.37, p < 0.0001). The publication of the FDA draft guidance in 2010 was associated with increased reporting of the fixed-margin method (after versus before 2010) (OR 3.54; 95% CI 1.12 to 13.35, p = 0.04). CONCLUSIONS: Non-inferiority margins are not commonly defined based on the historical evidence of the active comparator, and they are poorly reported. Authors, reviewers, and editors need to take notice of reporting this critical information to allow for better judgment of non-inferiority trials.

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