Purpose: To present the prevalence of medicine use for headache in a nationally representative sample of adolescents in Denmark, and to examine the association between poor mental health, frequent headache, and medicine use for headache. Our hypothesis was that poor mental health increases the risk of headache which triggers medicine use for headache. Methods: The Danish arm of the 2022 Health Behaviour in School-aged Children (HBSC) study included 5,767 11-, 13- and 15-year-old students with self-reported data about headache frequency, medicine use for headache, and five indicators of mental health: Life satisfaction, emotional symptoms, loneliness, self-efficacy, and self-esteem. We used multivariate logistic regression analyses to examine whether the indicators of mental health were associated with medicine use for headache and whether inclusion of headache frequency in the statistical models changed the associations. Results: The prevalence of headache at least weekly was 32.7%. In the last month, 42.7% had used medicine for headache. Students with poor mental health had significantly higher rates of headache and significantly higher rates of medicine use for headache. For example, the OR (95% CI) for medicine use for headache was 2.27 (1.90-2.72) among students with low life satisfaction. When headache frequency was included in the statistical models, the associations between poor mental health and medicine use for headache attenuated and became insignificant. For example, the OR for medicine use for headache attenuated to 1.18 (0.96-1.41) among students with low life satisfaction. Conclusions: Poor mental health was associated with medicine use for headache. Poor mental health was also associated with frequent headache. The analyses suggest that frequent headache may be the explanatory factor behind the association between poor mental health and medicine use for headache. There is a need for promotion of rational medicine use among adolescents and mental health promotion may contribute to this effort.

Background and purpose: The aim of the study was to provide valuable real-world long-term safety data of the fixed pravastatin 40 mg/fenofibrate 160 mg combination in comparison of monotherapy with statins of moderate intensity. Materials and methods: POSE study was an observational, comparative study conducted in three European countries. Patients treated or planned to be treated with pravastatin 40 mg/fenofibrate 160 mg or with a moderate-intensity statin in monotherapy were assessed over 3 years. The main safety endpoints included the incidence of renal or urinary disorder, musculoskeletal or connective tissue disorder, hepatobiliary disorder and cardiovascular events. Results: The study included 3075 patients treated for dyslipidemia, with diabetes mellitus (47%), hypertension (56%) and/or established cardiovascular disease (61%). Over the three years of follow-up, the incidence of each safety event was low (≤3%) and similar in both treatment groups. The most frequently occurring events were; musculoskeletal and connective tissue disorders (44 events in the pravastatin 40 mg/fenofibrate 160 mg group and 36 in the statin group), renal and urinary disorders (28 versus 24), and aggravated diabetes mellitus (31 versus 21). Most events occurred during the first year, then incidence decreased over the three-year period. The incidence of cardiovascular events was low in both groups (≤1.6%), with no new signal emerged from the long-term follow-up. Conclusions: This study demonstrates a reassuring long-term safety profile of the fixed pravastatin 40 mg/fenofibrate 160 mg combination in routine clinical practice, with low and similar incidence of events over the three years follow-up compared to a monotherapy with statins of moderate intensity.

Purpose Prior approval for reimbursement is a cost containment policy, aimed at reducing demand. It has been employed in Ireland to address financial challenges due to the shift from warfarin to Direct Oral Anticoagulant (DOACs). Studies assessing the effectiveness of this policy are limited. Thus, we aimed to examine the effectiveness of prior approval for reimbursement of DOACs (apixaban, rivaroxaban) as a cost containment policy in Ireland. Methods The Irish Health Service Executive-Primary Care Reimbursement Service database was used in this cross-sectional study. We examined the prescribing frequencies and associated costs of the oral anticoagulants; ((OACs) apixaban, rivaroxaban, and warfarin) listed in the top 100 most frequently prescribed drugs, between 2018 and 2021. Interrupted time series Poisson regression was used to assess the impact of removing the approval requirement of apixaban in September 2019 followed by the other DOACs in November 2020. Results The prescribing frequency of OACs increased by almost 20% from 2018-2021. This study showed there were significant differences in the proportion of OACs prescribed among the Community Drug Schemes. A statistically significant decreased use of apixaban (<1%, p<0.05) occurred when prior approval was removed for all DOACs. Conclusions The removal of prior approval for reimbursement of DOACs in Ireland had a minimal impact on the prescribing frequency trends of the OACs. Future use of these potentially useful policies by healthcare systems requires careful consideration of drug type, approval criteria and length of time the policy remains in place to minimise any negative effects associated with their use.

Pharmacoepidemiological studies provide important information on the safety and effectiveness of medications, but the validity of study findings can be threatened by residual bias. Ideally, biases would be minimised through appropriate study design and statistical analysis methods. However, residual biases can remain, for example due to unmeasured confounders, measurement error, or selection into the study. A group of sensitivity analysis methods, termed quantitative bias analyses, are available to assess, quantitatively and transparently, the robustness of study results to these residual biases. These approaches include methods to quantify how the estimated effect would be altered under specified assumptions about the potential bias, and methods to calculate bounds on effect estimates. This article introduces quantitative bias analyses for unmeasured confounding, misclassification, and selection bias, with a focus on their relevance and application to pharmacoepidemiological studies.

Purpose: This study aims to investigate the potential causal relationship between the use of indapamide and rhabdomyolysis. Previous research and pharmacovigilance monitoring activities have suggested a potential association between indapamide use and rhabdomyolysis. However, limited information is available on this association. Methods: A case-control study conducted using EHR data, between July 1,2016, and December 31,2022. Patients who have rhabdomyolysis event (cases) were matched to four controls bases on age, gender and date. We examined the odds for indapamide exposure through three risk periods: current use, recent use, and former. The study outcome was ascertained through the presence of CK level over 1,000 U/L (i.e. rhabdomyolysis event). Subsequently, a multivariable conditional logistic regression analysis was utilized to assess the causal impact of indapamide exposure on the likelihood of developing rhabdomyolysis, while accounting for potential confounding variables. Results: The study population consisted of 2,965 cases and 11,860 controls. The results of the conditional logistic regression analysis indicated a lack of association between exposure to indapamide for the current users the OR was 0.7 (95% CI: 0.49 - 0.92) and the AOR was 0.6 (95% CI: 0.39 - 1.05). The recent users showed OR of 0.9 (95% CI: 0.56 - 1.50) and AOR of 0.2 (95% CI: 0.14 - 0.47). Lastly, the former users demonstrated an OR of 0.8 (95% CI: 0.47 - 1.26), and AOR of 0.1 (95% CI: 0.07 - 0.23). Conclusions: In this study, we did not find association between indapamide use and rhabdomyolysis regardless timing of exposure.

Background: Adverse drug events (ADEs) are a frequent cause of injury in patients. Our aim was to assess pharmacist interventions and their association with ADEs and potential adverse drug events (PADE). Methods: The search criteria: a published RCT, evidence of a pharmacist intervention, a comparison control group, and measurement of ADEs or PADEs. The information sources included MEDLINE, Embase, and two other databases through September 19, 2022. The risk of bias was assessed using the Cochrane tool for RCTs. A random-effects model for pooled studies was employed Results: Fifteen references meeting inclusion criteria were discovered. For ADEs, the pooled results showed a statistically significant benefit of pharmacist intervention in comparison to the control group (RR = 0.86; [95% CI 0.80-0.94); P = 0.0005. The heterogeneity was insignificant (P = 0.72; I 2 = 0%). Patients receiving a pharmacist intervention were 14% less likely for ADE than those who did not receive a pharmacist intervention. The estimated number of patients needed to prevent one ADE across all patient locations was 33. For PADEs, the pooled results did not show a statistically significant benefit for pharmacist intervention in comparison to the control group (RR = 0.79; [95% CI 0.47 – 1.32]; P =0.37.There was substantial heterogeneity in the pooled studies (P = 0.01; I 2 = 77%). However, there was a statistically significant subgroup difference (P = 0.005) for the intervention type. Conclusions: To our knowledge, this is the first systematic review and meta-analysis of RCTs seeking to understand the association of pharmacist interventions with ADEs and PADEs. The risk of having an ADE is reduced by a seventh for patients receiving a pharmacist care intervention versus no such intervention. This fraction could be higher for certain high-risk patients. The estimated number of patients needed to be followed across all patient locations to prevent one preventable ADE across all patient locations is 33. Also, a subgroup analysis of pharmacist intervention focus suggests that further research is necessary to fully understand the impact of TOC pharmacist intervention on PADEs. If validated, these findings have potential to significantly reduce drug-related morbidity and related healthcare costs.

Comorbidity Influence in Observational Studies: Why Ignore the Real World ?Comorbidity is any coexisting disease or medical condition with another medical condition, at a particular time point or during a particular period, in a patient. As such they can be acute or of chronic nature. Comorbidities may or may not interact with each other. Indeed, comorbid conditions may elevate the risk of the development of other conditions, increase the risk of death, reduce the quality of life, worsen the mental and physical health and impair the general functional ability of the patient. However, the literature on empirical evidence of treatment effect modification by comorbidity from randomized clinical trials (RCTs) is very limited, although this has been attributed to the underrepresentation of people with comorbidities in trials.1 Despite this, the standard assumption that efficacy is constant across subgroups of patients by levels of comorbidity in trials, is often criticised despite the power granted by treatment randomization to such studies.2 In contrast, the influence of comorbidity on health outcomes and treatment effectiveness is well established from observational studies.3-4In most observational studies, the influence of comorbidity on treatment effect is modelled as constant regardless of how long the patient has had the condition up to the start of follow-up, with the inherent assumption that the duration does not influence the outcome of interest. The question we inadvertently fail to address is whether it is reasonable to assume a constant influence for each of the comorbidities- namely, a level of influence that is independent of how long the patient has had each comorbid condition since diagnosis? We readily ignore the reality that there may be no evidence on the assumption of a constant, unchanging effect over time by the comorbidity of interest. For example, in assessing the treatment effect of a particular drug in a diabetic cohort, we generally consider the risk associated with each of the comorbidities of interest, such as hypertension as the same between patients diagnosed five years ago and those diagnosed recently. By so doing, we run the risk of not properly controlling for the influence of some of these comorbidities on the outcome of interest. Indeed, this assumption was challenged in a study that demonstrated the duration-dependent nature of the influence of certain comorbidities on survival among chronic obstructive pulmonary disease (COPD) patients in the UK’s Clinical Practice Research Datalink (CPRD) and since then, using similar approaches that are easy to apply, two other studies have also demonstrated the duration-dependent nature of certain comorbidities within the real-world evidence generation space.5-7Another common practice we find in observational studies is the modelling of and adjusting for comorbidity influence additively, either as the number of comorbidities or as an index (such as the Charlson Comorbidity Index), and we do so often without regard to the specific outcome of interest, which may be different from the outcome used in the derivation of the index.8-10 In so doing, we are inadvertently assuming that (1) the outcome is associated linearly with the comorbidity count or index and (2) the impact of every comorbidity is one directional- namely, to elevate the risk of the outcome and hence, the weights we derive from combining the set of comorbidities must be positive (i.e. the null hypothesis that outcome worsens with increasing comorbidity is inadvertently assumed as already proven). Although these common practices are generally suitable in many observational studies, there is evidence some of these assumptions may not necessary hold true in some disease populations, such as in COPD patients.11-13 One such evidence is that as a result of adequate control of COPD by medications and lifestyle changes, among others, its influence on the risk of an outcome of interest, may not necessarily be as a risk elevator - suggesting, risk reduction by an adequately managed comorbid condition is possible in real-life studies. An additional, possible consequence of these approaches is our likely loss of ability to adequately identify specific interactions between those comorbidities that influence prognosis.Some of the problems associated with our current simplistic approach to handling comorbidity influence were first highlighted in a 2012 paper on the conduct of prospective observational post-authorization safety studies.14 The paper recommends assessing the suitability of the assumptions that underpin the methodologies we intend to apply to the data within the context of the specific outcome(s) of interest as the least we could do with real-life data. In other words, we need to demonstrate that such assumptions are appropriate and reasonable on the basis of the results from exploratory assessments of the data. We need not ignore what the specific study data may reveal about the nature of the true association between the outcome and each specific comorbidity and/or combination of comorbidities. We particularly need not ignore evidence from routine clinical practice. The current common assumption in observation studies, that the influence of every comorbid condition on any health outcome of interest is independent of both its duration and management in routine clinical practice, is unlikely to be tenable in the real world.Acknowledgement :The authors are grateful to Professor Gilbert MacKenzie for his valuable contributions to initial discussions on the subject.Prof Victor A Kiri MPH, PhDEpidemiology DirectorMarket Access Consulting, RWE & AnalyticsFortreaMaidenhead, Berkshire SL6 3QHUnited [email protected] iD: https://orcid.org/0000-0001-7171-2011Dr Maurille Feudjo-Tepie PhDVice PresidentHead of GlobalRWE & Digital sciences Head of Global RWE & Digital sciencesUCBSlough, Berkshire SL1 3WEUnited [email protected] P, Hannigan L, Rodriguez-Perez J, et al. Representation of people with comorbidity and multimorbidity in clinical trials of novel drug therapies: an individual-level participant data analysis. BMC Med. 2019; 17(1):201Hanlon P, Butterly EW, Shah ASV, et.al. Treatment effect modification due to comorbidity: Individual participant data meta-analyses of 120 randomised controlled trials. PLoS Med 2023; 20(6): e1004176Iversen LH, Nørgaard M, Jacobsen J, et al. The impact of comorbidity on survival of Danish colorectal cancer patients from 1995 to 2006 – a population-based cohort study. Dis Colon Rectum 2009;52(1):71–78Lund L, Jacobsen J, Nørgaard M, et al. The prognostic impact of comorbidities on renal cancer, 1995 to 2006: a Danish population based study. J Urol. 2009;182(1):35–40; discussion 40.Kiri VA, Oyee J. Assessing the time-dependency nature of comorbidity influence in COPD, Pharmacoepidemiology and Drug Safety (2006); 15 (Suppl 2): S8Plana-Ripoll O, Pedersen CB, Holtz Y, et al. Exploring comorbidity within mental disorders among a Danish national population. JAMA Psychiatry 2019b; 76: 259–270McGrath JJ, Lim CCW, Plana-Ripoll O, et al. Comorbidity within mental disorders: A comprehensive analysis based on 145,990 survey respondents from 27 countries. Epidemiology and Psychiatric Sciences 2020; 29: [e153]Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40 (5):373-383Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613–619.Yngvar Nilssen, Trond-Eirik Strand, Robert Wiik, et al. Utilizing national patient-register data to control for comorbidity in prognostic studies, Clinical Epidemiology 2014;395-404Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36(1):8–27Kiri VA, Visick G, Muellerova H, MacKenzie G. A Novel Methodology for Measuring the Influence of Comorbidity in Disease Outcome Studies, Pharmacoepidemiology and Drug Safety (2005); 14 (Suppl 2): S135Kiri VA, Muellerova H, Visick G, MacKenzie G. Assessing the multivariate structure and influence of comorbidity in COPD, Eur Respir J (2005); 26 (Suppl 49):A470sKiri VA. A Pathway to Improved Prospective Observational Post-Authorization Safety Studies. Drug Saf 2012; 35 (9): 711-724

Purpose. We aimed to investigate the awareness of oral retinoid teratogenicity and the adherence to the pregnancy prevention measures related to oral retinoid use by physicians, pharmacists and patients in Denmark. Methods. As part of the multi-country survey, web-based questionnaires were distributed among Danish dermatologists, general practitioners, community pharmacists, and women of childbearing age, who were using or had used oral retinoids within the past five years. Results. A total of 62 physicians, 96 pharmacists, and 50 oral retinoid using women responded; 95%, 100%, and 98%, respectively, were aware of the teratogenic risks of oral retinoids. For physicians, the most applied PPP measures were the usage of the patient (44%) and the healthcare professional (19%) guides, while the least applied measure was signing medication risk awareness form (3%). Among the pharmacists, the warning sign on the outer medication package was the most used measure (45%). Among the women, a majority (90%) had read the patient information leaflet included in the medication package and 72% discussed the use of contraception with their healthcare provider, while risk awareness forms and patient cards were seen by only few. Conclusions. In Denmark, physicians, pharmacists and medicine users are aware about the teratogenic effects of oral retinoids. Adherence to pregnancy prevention measures varied, suggesting unwillingness to use the measures that require patients’ signatures among physicians and a lack of awareness of pharmacy targeting measures. Accessibility of the latter measures need to be optimized to improve the safety of oral retinoid use.

Purpose Pregnancies ending before gestational week 12 are common but not notified to the Medical Birth Registry of Norway. Our goal was to develop an algorithm that more completely detects and dates pregnancy outcomes by using diagnostic codes from primary and secondary care registries to complement information from the birth registry. Methods We used nationwide linked registry data between 2008 and 2018 in a hierarchical manner: We developed an algorithm to arrive at unique pregnancy outcomes, considering codes within 56 days as the same event. To infer gestational age of pregnancy outcomes before gestational week 12, we used the median gestational week of pregnancy markers (45 ICD-10 codes and 9 ICPC-2 codes). When no pregnancy markers were available, we assigned outcome-specific gestational age estimates. The performance of the algorithm was assessed by blinded clinicians. Results Using only the medical birth registry, we identified 649,703 pregnancies, including 1,369 (0.2%) miscarriages and 3,058 (0.5%) elective terminations. With the new algorithm, we detected 859,449 pregnancies, including 642,712 live-births (74.8%), 112,257 miscarriages (13.1%), 94,664 elective terminations (11.0%), 6,429 ectopic pregnancies (0.7%), 2,564 stillbirths (0.3%), and 823 molar pregnancies (0.1%). The median gestational age was 10 +0 weeks (IQR 10 +0-11 +3) for miscarriages and 8 +0 weeks (IQR 8 +0-9 +6) for elective terminations. Gestational age could be inferred using pregnancy markers for 66.3% of miscarriages and 47.2% of elective terminations. Conclusion The pregnancy algorithm improved the detection and dating of early non-live pregnancy outcomes that would have gone unnoticed if relying solely on the medical birth registry information.

Background: Several cases of renal complications including acute kidney injury (AKI) after influenza vaccination have been reported, but the association remains unproven. We evaluated the association between influenza vaccination and AKI occurrence among the Korean elderly in the 2018–2019 and 2019–2020 seasons. Methods: We used a large database that combined vaccination registration data from the Korea Disease Control and Prevention Agency and the claims data from the National Health Insurance Service. The study subjects were patients hospitalized with AKI for the first time following vaccination among those who received one influenza vaccine in the 2018–2019 or 2019–2020 season. Only those who were 65 or older at the date of vaccination were included in our study. We performed a self-controlled case series study in which the risk period was designated as 1 to 28 days after vaccination, and the observation period as each influenza season. We conducted sensitivity analyses with varied risk periods and observation periods. Results: A total of 16,713 and 16,272 AKI events were identified during each influenza season. The adjusted incidence rate ratio (aIRR) for AKI was 0.83 (95% confidence interval [CI]= 0.79–0.87) in the 2018–2019 season. The IRR of the 2019–2020 influenza vaccination was similar to the 2018–2019 season (aIRR=0.86; 95% CI=0.82–0.90). Sensitivity analyses showed similar results. Conclusions: We suggest that influenza vaccination is associated with a lower risk of AKI in the elderly over 65.

Purpose The generation of representative disease phenotypes is important for ensuring the reliability of the findings of observational studies. The aim of this manuscript is to outline a reproducible framework for reliable and traceable phenotype generation based on real world data for use in the Data Analysis and Real-World Interrogation Network (DARWIN EU®). We illustrate the use of this framework by generating phenotypes for two complex diseases: pancreatic cancer and systemic lupus erythematosus (SLE). Methods The phenotyping process involves a 14-step process based on a standard operating procedure co-created by the DARWIN EU® Coordination Centre in collaboration with the European Medicines Agency. A number of bespoke R packages were utilised to generate and review codelists for two phenotypes based on real world data mapped to the OMOP Common Data Model. Results Phenotypes were generated for both pancreatic cancer and SLE, and cohorts were generated using the Clinical Practice Research Datalink (UK primary care records) and Pharmetrics (US health claims data). Diagnostic checks were performed, which showed these cohorts had broadly similar incidence and prevalence figures to previously published literature. Additionally, co-occurrent symptoms, conditions, and medication use were in keeping with pre-specified clinical descriptions based on previous knowledge. Conclusions Our detailed phenotyping process makes use of bespoke tools and allows for comprehensive codelist generation and review, as well as large-scale exploration of the characteristics of the generated cohorts. Wider use of structured phenotyping methods will be important in ensuring the reliability of observational studies for regulatory purposes.

Background: Bleeding is an important health outcome of interest in epidemiological studies. We aimed to develop and validate rule-based algorithms to identify major bleeding and all bleeding within real-world electronic healthcare data. Methods: We took a random sample (n=1630) of patient admissions to Singapore public hospitals in 2019 and 2020, stratifying by hospital and year of admission. We adopted the International Society on Thrombosis and Haemostasis definition for major bleeding. Presence of major bleeding and all bleeding was ascertained by two annotators through chart review. A total of 630 and 1,000 records were used for algorithm development and validation, respectively. We formulated two algorithms: sensitivity- and positive predictive value (PPV)-optimized algorithms. A combination of hemoglobin test patterns and diagnosis codes were used in the final algorithms. Results: During validation, diagnosis codes alone yielded low sensitivities for major bleeding (0.14) and all bleeding (0.24), although specificities and PPV were high (>0.97). For major bleeding, the sensitivity-optimized algorithm had much higher sensitivity and negative predictive values (NPV) (sensitivity=0.94, NPV=1.00), however false positive rates were also relatively high (specificity=0.90, PPV=0.34). PPV-optimized algorithm had improved specificity and PPV (specificity=0.96, PPV=0.52), with little reduction in sensitivity and NPV (sensitivity=0.88, NPV=0.99). For all bleeding events, our algorithms had less optimal performances, with lower sensitivities (0.53 to 0.61). Conclusions: The use of diagnosis codes alone misses many genuine major bleeding events. We have developed major bleeding algorithms with high sensitivities which can be used in conjunction with chart reviews to ascertain events within populations of interest.

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies published in “Pharmacoepidemiology and Drug Safety” (PDS) between 2017 and 2022, Data was extracted on the frequency and types of programming code shared, and other key open science practices (clinical codelist sharing, data sharing, study pre-registration, and use of reporting guidelines). We developed six recommendations for investigators who choose to share to programming code and gathered feedback from members of the International Society of Pharmacoepidemiology (ISPE). Results: Programming code sharing by articles published in PDS ranged from 2.4% in 2017 to 13.4% in 2022. It was more prevalent among articles with a methodological focus, simulation studies, and papers which also shared record-level data. We recommend that reporting of open science practices, including code sharing, is standardised to enable continued monitoring. When sharing programming code, we recommend the use of permanent digital identifiers, appropriate licenses, and, where possible, adherence to good software practices around the provision of metadata and documentation, computational reproducibility, and data privacy. Conclusion: Programming code sharing is rare but increasing in pharmacoepidemiology studies published in Pharmacoepidemiology and Drug Safety. We recommend improved and consistent reporting of code sharing, and adherence to good programming practices in order to maximize the utility of code when this is shared.

Purpose: Sickle cell disease (SCD) affects all organ systems and is characterized by numerous acute and chronic complications and comorbidities. Standardized codes are needed for complications/comorbidities used in real-world evidence (RWE) studies that rely on administrative and medical coding. This systematic literature review was conducted to produce a comprehensive list of complications/comorbidities associated with SCD, along with their diagnosis codes used in RWE studies. Methods: A search in MEDLINE and Embase identified studies published from 2016-2023. Studies were included if they were conducted in US SCD populations and reported complications/comorbidities and respective International Classification of Diseases, Clinical Modification (ICD-CM) codes. All identified complications/comorbidities and codes were reviewed by a certified medical coding expert and hematologist. Results: Of 1,851 identified studies, 40 were included. The most reported complications/comorbidities were stroke, acute chest syndrome, pulmonary embolism, venous thromboembolism, vaso-occlusive crisis, and priapism. Most of the studies used ICD-9-CM codes (n=21), while some studies used ICD-10-CM codes (n=3) or both (n=16), depending on the study period. Most codes reported in literature were heterogeneous across complications/comorbidities. The medical coding expert recommended modifications for several conditions. Conclusion: While many studies we identified did not report their codes and were excluded from this review, the studies with codes exhibited diverse coding definitions. By providing a standardized set of diagnosis codes that were reported by studies and reviewed by a coding expert and hematologist, our review can serve as a foundation for accurately identifying complications/comorbidities in future research, and may reduce heterogeneity, enhance transparency, and improve reproducibility.

Purpose: Removing medicines from market may benefit public health by preventing adverse drug reactions (ADRs), which should be quantified. This study’s aim was to identify a model to quantify the impact of medicines’ marketing authorisation (MA) withdrawal and revocation in terms of morbidity and mortality. Methods: MA withdrawals and revocations for safety reasons in France, Germany, and/or the United Kingdom (UK) between July 2012 and December 2016 were identified for prescription medicines. Annual exposure was estimated for each medicine, using IQVIA Medical Research Data (IMRD)-France, IMRD-Germany, and IMRD-UK primary care electronic health record databases. European Medicines Agency records provided reasons for regulatory action for each medicine. Absolute risks of ADRs in patients exposed to each medicine were estimated by systematic review of quantitative research. Public health impact, expressed as annual number of ADRs avoided, was estimated by modelling exposure and ADR risk. Results: Four MA withdrawals and two revocations met study inclusion criteria. Each product’s usage decreased following MA withdrawal or revocation. Absolute risk for ADRs was 0.1-41.25%. To estimate impact of each withdrawal or revocation, its average annual exposure within each IMRD population was multiplied by the absolute risk to give the crude number of ADRs prevented annually due to regulatory action. Conclusions: This model quantifies the public health impact of MA withdrawal and revocation in terms of serious morbidity, resulting from eliminated or reduced usage of medicines. This method can be applied to products in other settings to quantify the impact of other pharmacovigilance actions.

Comparing causal effect estimates obtained using observational data to those obtained from the gold standard (i.e., randomized controlled trials, RCTs) helps us assess the validity of these estimates. However, comparisons are challenging due to differences between observational data and RCT generated data: First, the treatment assignment mechanism is often unknown for observational data, and second, the sampling mechanism often differs between the RCT and the observational data. Differences in the treatment assignment mechanism introduce potential confounding, whereas differences in the sampling mechanism introduce sampling bias. This article proposes a two-step framework for the validation of causal effect estimates obtained from observational data by adjusting for both mechanisms. A simulation study is conducted to show that our suggested two-step framework enables observational data to produce causal effect estimates similar to those of an RCT. An application of our approach to validate treatment effects of adjuvant chemotherapy obtained from registry data is demonstrated. This article establishes a novel framework for comparing causal effect estimates between observational data and RCT data, facilitating the assessment of the validity of causal effect estimates obtained from observational data.

Purpose Exposure of hydrochlorothiazide (HCTZ) has been linked to the increase of skin cancer in the Caucasian population, especially for the squamous cell carcinoma (SCC) but not for basal cell carcinoma (BCC). This study aimed to evaluate the risks of skin cancer between patients receiving HCTZ and those receiving other antihypertensives. Methods This retrospective cohort study was derived from the National Health Insurance Database in Taiwan. We enrolled patients aged 20 years and older who newly receiving antihypertensive medications between 2004 - 2015. We calculated the medication possession ratio (MPR) of the first two years of treatment for patient enrollment and treatment classification, in which patients with MPR above 80% were enrolled and patients were subsequently categorized into receiving HCTZ, other thiazide diuretics, non-thiazide diuretics, and non-diuretic antihypertensives. The Cox proportional hazards model was used to evaluate the risk of skin cancer, and further divided into SCC, and BCC. Results Our study enrolled 41,086, 27,402, 19,613, and 856,782 patients receiving HCTZ, other thiazide diuretics, non-thiazide diuretics, and non-diuretic antihypertensives, respectively. We found BCC risks were similar when comparing HCTZ with other thiazides (adjusted hazard ratio, 0.84; 95% CI: 0.54-1.33), non-thiazide diuretics (0.93; 0.51-1.67), and non-diuretic antihypertensives (0.91; 0.66-1.26). Higher SCC risk was observed in the HCTZ group, compared to other thiazide (1.24; 0.74-2.08), non-thiazide diuretics (1.32; 0.70- 2.51), and non-diuretic antihypertensives (1.23; 0.87-1.73), although the differences were not statistically significant. Conclusions We conclude that skin cancer need not be of major concern to physicians when prescribing antihypertensives for an Asian population.

Purpose: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by “indication” are important considerations in ADF post-marketing studies. Methods: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. Results: We identified 8,415 (NC claims) and 147,978 (MarketScan) ADF, and 10,114 (NC claims) and 232,028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. Conclusions: Careful consideration of the study design, comparator choice, and confounding by “indication” is crucial when examining ADF opioid use-related outcomes.