Lessons Learned on Observed-to-Expected Analysis Using Spontaneous Reports During Mass Vaccination.

During the COVID-19 vaccination campaign, observed-to-expected analysis was used by the European Medicines Agency to contextualise data from spontaneous reports to generate real-time evidence on emerging safety concerns that may impact the benefit-risk profile of COVID-19 vaccines. Observed-to-expected analysis compares the number of cases spontaneously reported for an event of interest after vaccination ('observed') to the 'expected' number of cases anticipated to occur in the same number of individuals had they not been vaccinated. Observed-to-expected analysis is a robust methodology that relies on several assumptions that have been described in regulatory guidelines and scientific literature. The use of observed-to-expected analysis to support the safety monitoring of COVID-19 vaccines has provided valuable insights and lessons on its design and interpretability, which could prove to be beneficial in future analyses. When undertaking an observed-to-expected analysis within the context of safety monitoring, several aspects need attention. In particular, we emphasise the importance of stratified and harmonised data collection both for vaccine exposure and spontaneous reporting data, the need for alignment between coding dictionaries and the crucial role of accurate background incidence rates for adverse events of special interest. While these considerations and recommendations were determined in the context of the COVID-19 mass vaccination setting, they are generalisable in principle.

A collaborative study of the impact of N-nitrosamines presence and ARB recall on ARB utilization - results from IQVIA™ Disease Analyzer Germany.

PURPOSE: Regulators are increasingly concerned with  the impact of recalls on drug adherence. In 2018, N-nitrosamines impurities were detected in valsartan containing medical products. Concerned products were immediately recalled in July 2018 by regulatory agencies internationally. In Germany, recalls were issued for valsartan, losartan and irbesartan from July 2018 to March 2019. This study examined angiotensin II receptor blocker (ARB) utilization trends and switching patterns in Germany before and after July 2018. METHODS: Patients prescribed ARBs from January 2014 to June 2020 in general practices in Germany were included in a collaborative framework common protocol drug utilization study led by the US Food and Drug Administration. Trends in monthly and quarterly proportions of total ARB prescribing were analysed for individual ARBs using descriptive statistics and interrupted time series analysis. The rate of switching to an alternative ARB was analysed before and after the recalls. RESULTS: The proportion of valsartan prescriptions immediately decreased from 35.9 to 17.8% following the first recalls in July 2018, mirrored by an increased proportion for candesartan. Increased switching from valsartan to candesartan was observed. No increased switching was observed after losartan recalls, whereas for irbesartan, increased switching was observed 6-12 months after the last recall. Increased switching from ARBs to angiotensin-converting enzyme (ACE) inhibitors or ARB treatment discontinuations were not observed. CONCLUSION: This study showed that patients were able to continue ARB treatment despite the July 2018-March 2019 recalls, although many patients needed to switch to an alternative ARB. The duration of the impact of ARB recalls appeared to be limited.

Prescribing Patterns of Codeine and Alternative Medicines in Children in Europe.

INTRODUCTION: Concerns over serious respiratory depression in children led to two European Union (EU) referral procedures (in 2013 and 2015) to review the benefit-risk balance of codeine in this population when used for pain relief, cough or cold. Consequently, codeine should no longer be used in children aged < 12 years and restrictions were introduced for treatment in children ≥ 12 years. OBJECTIVE: This multinational collaborative study aimed to assess the effectiveness of these risk minimisation measures by evaluating changes in prescribing of codeine and alternative treatments. METHOD: Children under 12 and 12-18 years old were followed between 2010 and 2017 to analyse quarterly trends in prescribing of codeine and alternative treatments in electronic health records from France, Germany, Norway, Spain and the United Kingdom using interrupted time series analysis. RESULTS: Overall prescribing of codeine in children decreased in all five countries, reaching near zero prevalence in children under 12 years of age. This was accompanied by an increase in use of other opioid analgesics in France (from 0.15 to 0.56 prevalence per 100 person-years immediately after the first referral), Norway (from 0.0006 to 0.0013 at the end of the study), the United Kingdom (from 0.018 to 0.05 at the end of the study), and an increase in non-opioid analgesics in Norway (from 0.045 to 0.075 at the end of the study) after the referral on pain relief indication. The referral on cough/cold indication led to a decrease in use of opioid and non-opioid antitussives in children aged < 12 years in France (from 10 to 7 and 20 to 16, respectively) and had no impact in other countries. Overall prescribing trends for codeine and alternatives were similar across both age groups within each country. CONCLUSION: The decrease in use of codeine shows that healthcare professionals followed the adopted measures and switched prescribing practices for pain management in children aged < 18 years towards opioid or non-opioid analgesics depending on national clinical and reimbursement settings. Whist the magnitude of the first referral on pain differed between countries, the second referral on cough/cold had only a minimal impact on the use of codeine and antitussives.

Is There an Increased Risk of Hepatotoxicity with Metamizole? A Comparative Cohort Study in Incident Users.

INTRODUCTION: The analgesic metamizole, which has been withdrawn from the market in several countries due to the risk of agranulocytosis but is still available on the market in Germany and some other countries, has been associated with liver injury in published case reports; however, epidemiological studies on the risk of liver injury are limited. OBJECTIVE: The aim of this study was to compare the risk of liver injury up to 270 days after the first start of treatment with metamizole with the corresponding risk in patients starting treatment with paracetamol, using a retrospective cohort incident user design. METHODS: The first prescription for either metamizole or paracetamol in the Intercontinental Medical Statistics (IMS)® Disease Analyzer Germany database during the study period (2009-2018) was identified in patients with at least 365 days of observation and no prior diagnosis of liver events, cancer or HIV, or treatment within the last 6 months with hepatotoxic drugs typically administered for chronic conditions. Each patient was followed for specific liver events for 90 days after the prescription. In case of a new prescription within 90 days, a new 90-day observation period started, up to a maximum of 270 days. Cox regression was used to compare the risk of liver injury in the two groups. RESULTS: Metamizole was associated with a higher risk of liver injury compared with paracetamol (adjusted hazard ratio 1.69, 95% confidence interval 1.46-1.97). Sensitivity analyses were performed to evaluate the robustness of these findings. In all the sensitivity analyses, metamizole was still associated with a higher risk of liver injury, including an analysis where naproxen was used as a comparator instead of paracetamol. CONCLUSIONS: Results from this study support previous studies suggesting that metamizole is associated with a significant risk of liver injury. Nevertheless, a possible impact of residual confounding cannot be excluded.

Can We Rely on Results From IQVIA Medical Research Data UK Converted to the Observational Medical Outcome Partnership Common Data Model?: A Validation Study Based on Prescribing Codeine in Children.

Exploring and combining results from more than one real-world data (RWD) source might be necessary in order to explore variability and demonstrate generalizability of the results or for regulatory requirements. However, the heterogeneous nature of RWD poses challenges when working with more than one source, some of which can be solved by analyzing databases converted into a common data model (CDM). The main objective of the study was to evaluate the implementation of the Observational Medical Outcome Partnership (OMOP) CDM on IQVIA Medical Research Data (IMRD)-UK data. A drug utilization study describing the prescribing of codeine for pain in children was used as a case study to be replicated in IMRD-UK and its corresponding OMOP CDM transformation. Differences between IMRD-UK source and OMOP CDM were identified and investigated. In IMRD-UK updated to May 2017, results were similar between source and transformed data with few discrepancies. These were the result of different conventions applied during the transformation regarding the date of birth for children younger than 15 years and the start of the observation period, and of a misclassification of two drug treatments. After the initial analysis and feedback provided, a rerun of the analysis in IMRD-UK updated to September 2018 showed almost identical results for all the measures analyzed. For this study, the conversion to OMOP CDM was adequate. Although some decisions and mapping could be improved, these impacted on the absolute results but not on the study inferences. This validation study supports six recommendations for good practice in transforming to CDMs.

Ability of Primary Care Health Databases to Assess Medicinal Products Discussed by the European Union Pharmacovigilance Risk Assessment Committee.

This study measured the exposure to different categories of medicinal products discussed by the European Union (EU) Pharmacovigilance Risk Assessment Committee from September to November 2018 in four electronic primary care health databases: IQVIA Medical Research Data-UK, IQVIA Medical Research Data-France, IQVIA Medical Research Data-Germany, and Clinical Practice Research Datalink Aurum, in the entire lifespan of each database until August 31, 2018. The assessment of 83 centrally authorized products and 45 nationally authorized products showed that coverage was better for products marketed for longer duration and worse for orphan drugs. The ability to detect associations against hypothetical comparators was better for more common events and for larger effect sizes. Coverage of advanced therapies was worse for those typically administered in a specialized rather than primary care setting. This study shows that to enable better informed regulatory decisions there is a need to access complementary data sources, particularly capturing secondary care prescribing.

A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children.

PURPOSE: In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the "real-world" setting and (b) test feasibility of a study using a common protocol by regulators with access to databases. METHODS: The study was performed using BIFAP (Spain), CPRD (UK), and IMS® Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within ±30 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated. RESULTS: Over the 5-year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany. CONCLUSIONS: Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.

Effect of withdrawal of fusafungine from the market on prescribing of antibiotics and other alternative treatments in Germany: a pharmacovigilance impact study.

PURPOSE: Knowledge on unintended consequences of product withdrawals is limited. Fusafungine, indicated for treatment of upper respiratory airways disease (URAD), was withdrawn in the EU on May 28, 2016. Given concerns about possible substitution with antibiotics, this study aimed to assess the impact of the withdrawal of fusafungine on prescribing of antibiotics and other treatments. METHODS: The study was conducted using data from general practitioner (GP) and ear, nose and throat (ENT) practices in IMS® Disease Analyzer Germany. The quarterly prevalence of fusafungine prescribing was analysed for consultations involving the most common URAD between May 29, 2013 and May 28, 2017 in regular fusafungine-prescribing practices. Trends in the quarterly prevalence of antibiotics (AB), other nasal or throat preparations (N&T) and tyrothricin were analyzed. Practices with no fusafungine prescribing during the study served as controls. Changes in prescribing trend were evaluated using interrupted time series regression analysis. RESULTS: In fusafungine-prescribing practices, withdrawal of fusafungine was associated with an immediate increase in prescribing of other N&Ts among patients consulting for URAD (+ 6.4%, 95% CI 2.3-10.5% in GP practices and + 9.0%, 95% CI 5.5-12.5% in ENT practices). There was no increase in antibiotic prescribing. In ENT practices; a small transient increase in tyrothricin prescribing occurred. No changes were seen in non-fusafungine-prescribing practices. CONCLUSIONS: Withdrawal of fusafungine was not associated with increased prescribing of antibiotics but was associated with increased prescribing of other N&Ts. The unintended impact of substitution to other treatments should be considered routinely when products are withdrawn or restricted in other ways.

Prescribing patterns of tramadol in adults in IMS® primary care databases in France and Germany between 1 January 2006 and 30 June 2016.

PURPOSE: There is increasing concern with regard to fatal intoxications with prescription opioids and tramadol poisonings. This study aimed to characterise prescribing patterns for tramadol in primary care in France and Germany and identify long-term treatment and potential risk factors for such treatment. METHODS: Adult patients-prescribed tramadol between January 2006 and June 2016 in GP practices in IMS® Disease Analyzer databases in France and Germany were identified. Six-monthly prevalence and mean doses and durations were calculated by gender, age group and type of tramadol product. The proportion of incident use that resulted in treatment ≥ 366 days was calculated. The odds for long-term treatment was analysed in relation to gender, age group, type of tramadol product, start dose, indication and a diagnosis of abuse or misuse. RESULTS: Overall prescribing of tramadol decreased in Germany and increased, then plateaued in France. Prescribing was higher in females. Predominantly prescribed products were tramadol in combination with paracetamol (COMB) in France and slow release formulations of tramadol (SR-TRAM) in Germany. SR-TRAM had the highest mean doses and durations, followed by immediate release formulations of tramadol (IR-TRAM) and COMB. Around 1.5% of incident tramadol use in France and 8.2% in Germany resulted in long-term treatment. Long-term treatment was associated with increasing age, SR-TRAM and a diagnosis of abuse or misuse. CONCLUSIONS: The risk of long-term treatment appeared to increase with increasing age. Potential risk factors for long-term treatment included initiating treatment with SR-TRAM and a diagnosis of abuse or misuse.

Indications for Systemic Fluoroquinolone Therapy in Europe and Prevalence of Primary-Care Prescribing in France, Germany and the UK: Descriptive Population-Based Study.

BACKGROUND AND OBJECTIVES: In the USA the benefit-risk profile of fluoroquinolones for treating patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections (uUTIs) is considered unfavorable. However, the number of fluoroquinolone products in the EU indicated and prescribed for these infections is uncertain. The objective of this study was to provide data on indications for fluoroquinolones in Europe and examine the prevalence of prescribing in France, Germany and the UK. METHODS: Descriptive analysis of indications for systemic fluoroquinolone antibiotics across the European Economic Area (EEA) and descriptive analysis of systemic fluoroquinolone antibiotic prescribing in France, Germany and UK electronic health records (2000-2015). RESULTS: All EEA countries had fluoroquinolone products indicated for acute sinusitis, acute bronchitis, or uUTIs, with differences in the number of products between countries for: acute sinusitis (19.5-51.9%), acute bronchitis (22.2-73.4%), and uUTIs (52.0-89.1%). The prevalence of fluoroquinolone prescribing for the treatment of respiratory tract infections (RTIs) appeared to fall with time in all countries and for UTI in France and UK only. Changes were greatest in the UK. In France, Germany, and the UK, respectively: acute sinusitis accounted for 29.5, 20.6, and 40.7% of all oral fluoroquinolone prescriptions for upper RTIs; acute bronchitis accounted for 63.0, 83.0, and 89.9% of all fluoroquinolone prescriptions for lower RTIs; uUTIs accounted for 83.3, 89.9, and 32.2% of all fluoroquinolone prescriptions for UTIs. CONCLUSION: Large numbers of fluoroquinolone products in Europe are listed for the treatment of milder infections such as acute bronchitis, acute sinusitis and uUTIs. Among the countries assessed, fluoroquinolones were commonly prescribed for these conditions and potentially should lead to a review of therapeutic guidelines.

Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-based case-control study including 1st and 2nd degree relatives.

PURPOSE: Case reports have suggested an association between susceptibility to malignant hyperthermia (MH) and other muscle diseases in subjects with statin-induced muscle toxicity. The aim of the study was to further scrutinize this association in a population-based case-control study including 1st and 2nd degree relatives. METHODS: Spontaneously reported cases with muscle disorders associated with statin therapy until September 2006 were identified in the Swedish Adverse Drug Reaction Registry at the Medical Products Agency. For each case, ten population-based controls, matched on year of birth and gender, were randomly selected from the National Registry of Swedish Citizens. First and 2nd degree relatives to cases and controls were identified in the Swedish Multi-Generation Registry. ICD codes that could be associated with susceptibility to MH or other muscle diseases were chosen, and subjects were followed until December 2007 with regard to occurrence of selected ICD codes in the Swedish Registries for Cause of Death and Hospital Discharge Diagnoses, respectively. RESULTS: The chosen ICD codes were significantly overrepresented in case families compared with control families (RR 1.56; 95 % CI 1.15-2.10). The strongest associations were identified for a diagnosis of drug-induced or specified or unspecified myopathy (RR 52; 95 % CI 22-123) or a diagnosis of unspecified hyperthermia in combination with drug-induced or specified or unspecified myopathy (RR 30; 95 % CI 6-148). In contrast, a diagnosis of unspecified hyperthermia in the absence of drug-induced or specified or unspecified myopathy was significantly underrepresented among case families (RR 0.42; 95 % CI 0.23-0.76). CONCLUSIONS: In a case-control study including 1st and 2nd degree relatives, statin-induced muscle toxicity was significantly associated with a diagnosis of drug-induced or specified or unspecified myopathy and with a diagnosis of unspecified hyperthermia in combination with a diagnosis of drug-induced or specified or unspecified myopathy.

Non-steroidal anti-inflammatory drugs and venous thromboembolism in women.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) might increase the risk of venous thromboembolism (VTE), and risks might differ by type of NSAID. Compared with men, women have a higher incidence of VTE at younger age, and they more often use NSAIDs. OBJECTIVES: To assess risks of VTE in young and middle-aged women in association with use of NSAIDs. PATIENTS/METHODS: In a nationwide case­control study (Thrombo Embolism Hormone Study) performed in Sweden 2003­2009, we included as cases 1433 women, 18 to 64 years of age with a first time VTE. Controls were 1402 randomly selected women, frequency matched by age. Information was obtained by telephone interviews and DNA analyses of blood samples. We calculated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) adjusting for degree of immobilization, chronic disease, smoking, body mass index, use of hormonal contraception, hormone therapy or other NSAIDs. RESULTS: Use of NSAIDs was not associated with increased risks of VTE (OR = 0.98, 95% CI 0.80­1.19). The OR was 0.88 for propionic acid derivatives (95% CI 0.72­1.10), 1.18 for acetic acid derivatives (95% CI 0.82­1.70) and 1.76 for coxibs (95% CI 0.73­4.27). For users of acetic acid derivatives and coxibs, the ORs increased by cumulative dose. Carriership of the prothrombin gene mutation or factor V Leiden had only minor effects on the results. CONCLUSIONS: We found no increased risks of VTE in association with use of NSAIDs. Users of high cumulative doses of acetic acid derivatives and coxibs had the highest risks, suggesting a relationship with cyclooxygenase selectivity and dose.

Risk factors for venous thromboembolism in pre-and postmenopausal women.

INTRODUCTION: Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women. METHOD: In a nationwide case-control study we included as cases 1470 women, 18 to 64years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status. CONCLUSION: Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE.

Prematurely ended phase III trials in Sweden during the years 2002-2008.

PURPOSE: The aim of this study was to identify prematurely ended phase III clinical trials (CTs) and the proportion of such trials among all phase III CTs, review the reasons for the premature discontinuation of the CT, determine whether a data monitoring committee (DMC) was involved in this decision-making process, identify the data source on which the decision was based and review the consequences of the premature ending for product development. An additional aim was to identify risk factors for a premature ending. METHODS: Prematurely ended phase III CTs in Sweden between 2002 and 2008 were identified by database searches. Identified trials were reviewed for treatment tested, study design, reasons for the premature ending, data source on which the decision was based and existence of and recommendation from a DMC. Three randomly selected but not prematurely ended control trials were identified, starting 1 May 2004, that were matched on the basis of application year. RESULTS: A total of 84 phase III CT applications (8%) were prematurely ended during the study period. Most trials were ended due to safety and/or efficacy concerns. A DMC was more common among trials in which mortality was the primary endpoint and oncology trials. A recommendation from the DMC to terminate the trial was most likely in the case of combined safety- and efficacy-related issues arising from within the trial. Possible risk factors for a premature ending included mortality as an endpoint, obesity as an indication and a longer than planned study duration. Approximately 30% of prematurely ended trials with active substances that did not have a marketing authorization at the time of the clinical trial application resulted in the discontinuation of further development of the substance. CONCLUSIONS: The DMCs in the phase III CTs reviewed here were used in accordance with guidelines. The use of DMCs was associated with possible risk factors for a premature ending and numerically, but not significantly associated with a premature ending.

Muscle toxicity with statins.

PURPOSE: Statins rarely cause serious muscle toxicity and rhabdomyolysis. The aim of our investigation was to identify and quantify potential risk factors for statin-induced rhabdomyolysis. METHODS: All cases of suspected adverse reactions to statins reported to the Swedish Adverse Drug Reactions Advisory Committee until 15 September 2006 containing the codes myalgia, myopathy, increased serum creatine kinase (CK), myoglobinuria or rhabdomyolysis were included in the study. Cases were classified into different CK categories, where cases with CK levels >10 times the upper limit of normal (ULN) laboratory range were compared with cases with normal CK levels (in some analyses cases with CK not measured were also included as controls). Fisher's test and multiple logistic regression were used to test the degree of association. RESULTS: A total of 338 cases with muscle toxicity were identified. CK had not been measured in 148 cases. Of the remaining 190 cases, 59 were classified as rhabdomyolysis, 62 had CK increases below the level of rhabdomyolysis, 69 had normal CK and 2 contained insufficient information to classify the degree of CK increase. A high statin dose and concomitant interacting drug treatment were over-represented among cases with rhabdomyolysis compared with cases with normal CK. Renal disease and unusual strenuous muscular activity were also associated with an increased risk of rhabdomyolysis when the control group included cases with CK not measured. CONCLUSION: Results from our study support previous studies indicating that the risk of rhabdomyolysis with statin treatment increases with increase in systemic exposure to the statin. Renal disease and unusual strenuous muscular activity may also contribute to an increased risk of rhabdomyolysis.

Antipsychotics associated with pulmonary embolism in a Swedish medicolegal autopsy series.

To determine the association between fatal pulmonary embolism and use of antipsychotic drugs in a Swedish medicolegal autopsy series. Persons aged 18-65 years and subjected to a medicolegal autopsy in 1992-2005 were selected. On the basis of external cause of death, determined by the forensic pathologist, unnatural deaths (including fatal intoxications) were excluded and participants in whom pulmonary embolism was the cause of death were identified. Use of antipsychotics was based on the results of the postmortem analyses and categorized as use of high-potency first-generation antipsychotics, low-potency first-generation antipsychotics, second-generation antipsychotics or no use of antipsychotics. Logistic regression analyses were performed. Use of antipsychotics was verified in 538 of the 14,439 included participants. Pulmonary embolism was recorded as the cause of death in 279 participants and 33 of these used antipsychotics. Use of low-potency first-generation antipsychotics and second-generation antipsychotics was significantly associated with fatal pulmonary embolism (adjusted odds ratio: 2.39; 95% confidence interval: 1.46-3.92 and 6.91; 95% confidence interval: 3.95-12.10, respectively). Out of 26 participants classified as high-potency first-generation antipsychotic drug users, none had pulmonary embolism as the cause of death. Pulmonary embolism was overrepresented among medicolegal autopsy cases identified as users of low-potency first-generation and second-generation antipsychotics.

The conscientious judgement of a DSMB--statistical stopping rules re-examined.

OBJECTIVE: In the light of the recent failure of a large cardiovascular mortality and morbidity study with torcetrapib, we have undertaken a post hoc review of the decisions taken by the Data and Safety Monitoring Board (DSMB) in that study. A number of other studies in which complex decisions were made by DSMBs are also reviewed. RESULTS: The examples illustrate the complexities involved in the decision-making process by DSMBs and indicate that too much reliance on formal statistical stopping rules should be avoided due to a risk of delaying the identification of an unacceptable emergent safety signal. METHODS: The review was based on information submitted by the sponsors of the studies to the Medical Products Agency. CONCLUSIONS: Multiple approaches to assessing the efficacy and safety in clinical trials need to be considered in order to facilitate early stopping of clinical trials with a negative risk benefit balance. Such systems may, for example, include the use of p-value flags and/or a complementary statistical analysis of the likelihood of achieving the study objective based on the data obtained to date.