Adapting the in vitro micronucleus assay (OECD Test Guideline No. 487) for testing of manufactured nanomaterials: recommendations for best practices.

The current Organisation for Economic Co-Operation and Development test guideline number 487 (OECD TG No. 487) provides instruction on how to conduct the in vitro micronucleus assay. This assay is one of the gold standard approaches for measuring the mutagenicity of test items; however, it is directed at testing low molecular weight molecules and may not be appropriate for particulate materials (e.g. engineered nanoparticles [ENPs]). This study aimed to adapt the in vitro micronucleus assay for ENP testing and underpins the development of an OECD guidance document. A harmonized, nano-specific protocol was generated and evaluated by two independent laboratories. Cell lines utilized were human lymphoblastoid (TK6) cells, human liver hepatocytes (HepG2) cells, Chinese hamster lung fibroblast (V79) cells, whole blood, and buffy coat cells from healthy human volunteers. These cells were exposed to reference ENPs from the Joint Research Council (JRC): SiO2 (RLS-0102), Au5nm and Au30nm (RLS-03, RLS-010), CeO2 (NM212), and BaSO4 (NM220). Tungsten carbide-cobalt (WC/Co) was used as a trial particulate positive control. The chemical controls were positive in all cell cultures, but WC/Co was only positive in TK6 and buffy coat cells. In TK6 cells, mutagenicity was observed for SiO2- and both Au types. In HepG2 cells, Au5nm and SiO2 showed sub-two-fold increases in micronuclei. In V79 cells, whole blood, and buffy coat cells, no genotoxicity was detected with the test materials. The data confirmed that ENPs could be tested with the harmonized protocol, additionally, concordant data were observed across the two laboratories with V79 cells. WC/Co may be a suitable particulate positive control in the in vitro micronucleus assay when using TK6 and buffy coat cells. Detailed recommendations are therefore provided to adapt OECD TG No. 487 for testing ENP.

Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts.

OBJECTIVES: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. METHODS: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region. RESULTS: In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. CONCLUSIONS: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.

A comprehensive high cost drugs dataset from the NHS in England - An OpenSAFELY-TPP Short Data Report.

Background: At the outset of the COVID-19 pandemic, there was no routine comprehensive hospital medicines data from the UK available to researchers. These records can be important for many analyses including the effect of certain medicines on the risk of severe COVID-19 outcomes. With the approval of NHS England, we set out to obtain data on one specific group of medicines, "high-cost drugs" (HCD) which are typically specialist medicines for the management of long-term conditions, prescribed by hospitals to patients. Additionally, we aimed to make these data available to all approved researchers in OpenSAFELY-TPP. This report is intended to support all studies carried out in OpenSAFELY-TPP, and those elsewhere, working with this dataset or similar data. Methods: Working with the North East Commissioning Support Unit and NHS Digital, we arranged for collation of a single national HCD dataset to help inform responses to the COVID-19 pandemic. The dataset was developed from payment submissions from hospitals to commissioners. Results: In the financial year (FY) 2018/19 there were 2.8 million submissions for 1.1 million unique patient IDs recorded in the HCD. The average number of submissions per patient over the year was 2.6. In FY 2019/20 there were 4.0 million submissions for 1.3 million unique patient IDs. The average number of submissions per patient over the year was 3.1. Of the 21 variables in the dataset, three are now available for analysis in OpenSafely-TPP: Financial year and month of drug being dispensed; drug name; and a description of the drug dispensed. Conclusions: We have described the process for sourcing a national HCD dataset, making these data available for COVID-19-related analysis through OpenSAFELY-TPP and provided information on the variables included in the dataset, data coverage and an initial descriptive analysis.

Redesigning ambulatory care management for uncontrolled type 2 diabetes: a prospective cohort study of the impact of a Boot Camp model on outcomes.

Objective: Type 2 diabetes care management (DCM) is challenging. Few studies report meaningful improvements in clinical care settings, warranting DCM redesign. We developed a Boot Camp to provide timely, patient-centered, technology-enabled DCM. Impact on hemoglobin A1c (HbA1c), emergency department (ED) visits and hospitalizations among adults with uncontrolled type 2 diabetes were examined. Research design and methods: The intervention was designed using the Practical Robust Implementation and Sustainability Model to embed elements of the chronic care model. Adults with HbA1c>9% (75 mmol/mol) enrolled between November 2014 and November 2017 received diabetes education and medication management by diabetes educators and nurse practitioners via initial clinic and subsequent weekly virtual visits, facilitated by near-real-time blood glucose transmission for 90 days. HbA1c and risk for ED visits and hospitalizations at 90 days, and potential savings from reducing avoidable medical utilizations were examined. Boot Camp completers were compared with concurrent, propensity-matched chart controls receiving usual DCM in primary care practices. Results: A cohort of 366 Boot Camp participants plus 366 controls was analyzed. Participants were 79% African-American, 63% female and 59% Medicare-insured or Medicaid-insured and mean age 56 years. Baseline mean HbA1c for cases and controls was 11.2% (99 mmol/mol) and 11.3% (100 mmol/mol), respectively. At 90 days, HbA1c was 8.1% (65 mmol/mol) and 9.9% (85 mmol/mol), p<0.001, respectively. Risk for 90-day all-cause hospitalizations decreased 77% for participants and increased 58% for controls, p=0.036. Mean potential for monetization of US$3086 annually per participant for averted hospitalizations were calculated. Conclusions: Redesigning diabetes care management using a pragmatic technology-enabled approach supported translation of evidence-based best practices across a mixed-payer regional healthcare system. Diabetes educators successfully participated in medication initiation and titration. Improvement in glycemic control, reduction in hospitalizations and potential for monetization was demonstrated in a high-risk cohort of adults with uncontrolled type 2 diabetes. Trial registration number: NCT02925312.

Use of real-world evidence in postmarketing medicines regulation in the European Union: a systematic assessment of European Medicines Agency referrals 2013-2017.

OBJECTIVES: To assess the use, and evaluate the usefulness, of non-interventional studies and routinely collected healthcare data in postmarketing assessments conducted by the European Medicines Agency (EMA). DESIGN: We reviewed and systematically assessed all referrals to the EMA made due to safety or efficacy concerns that were evaluated between 1 January 2013 and 30 June 2017. We extracted information from the assessment report and the referral notification. Two reviewers independently assessed the contribution of non-interventional evidence to decision-making. RESULTS: The preliminary evidence leading to the assessment in 52 eligible referrals was mostly from spontaneous reports (cited in 26 of 52 referrals) and randomised trials (22/52). In contrast, many evidence types were used for the full assessment. Non-interventional studies were frequently used in the full assessment for the evaluation of product safety (31/52) and product efficacy (18/52). In particular, non-interventional studies were relied on for the evaluation of safety and efficacy in subgroups, the evaluation of safety relating to a rare adverse event, understanding product usage and misuse and for evaluation of the effectiveness of risk minimisation measures. The most common recommendations were changes to product information (43/52) and marketing authorisation withdrawal or suspension (12/52). In the majority of referrals, non-interventional evidence was judged to contribute to the decision made (30/52) and in three referrals it was the primary source of evidence. CONCLUSIONS: European regulatory decision-making relies on multiple evidence types, particularly randomised trials, spontaneous reports and non-interventional studies. Non-interventional studies had an important role particularly for the characterisation and quantification of adverse events, the evaluation of product usage and for evaluating the effectiveness of regulatory action to minimise risk.

Application and optimisation of the Comparison on Extreme Laboratory Tests (CERT) algorithm for detection of adverse drug reactions: Transferability across national boundaries.

PURPOSE: The Singapore regulatory agency for health products (Health Sciences Authority), in performing active surveillance of medicines and their potential harms, is open to new methods to achieve this goal. Laboratory tests are a potential source of data for this purpose. We have examined the performance of the Comparison on Extreme Laboratory Tests (CERT) algorithm, developed by Ajou University, Korea, as a potential tool for adverse drug reaction detection based on the electronic medical records of the Singapore health care system. METHODS: We implemented the original CERT algorithm, comparing extreme laboratory results pre- and post-drug exposure, and 5 variations thereof using 4.5 years of National University Hospital (NUH) electronic medical record data (31 869 588 laboratory tests, 6 699 591 drug dispensings from 272 328 hospitalizations). We investigated 6 drugs from the original CERT paper and an additional 47 drugs. We benchmarked results against a reference standard that we created from UpToDate 2015. RESULTS: The original CERT algorithm applied to all 53 drugs and 44 laboratory abnormalities yielded a positive predictive value (PPV) and sensitivity of 50.3% and 54.1%, respectively. By raising the minimum number of cases for each drug-laboratory abnormality pair from 2 to 400, the PPV and sensitivity increased to 53.9% and 67.2%, respectively. This post hoc variation, named CERT400, performed particularly well for drug-induced hepatic and renal toxicities. DISCUSSION: We have demonstrated that the CERT algorithm can be applied across national boundaries. One modification (CERT400) was able to identify adverse drug reaction signals from laboratory data with reasonable PPV and sensitivity, which indicates potential utility as a supplementary pharmacovigilance tool.

Detecting Signals of Disproportionate Reporting from Singapore's Spontaneous Adverse Event Reporting System: An Application of the Sequential Probability Ratio Test.

INTRODUCTION: The ability to detect safety concerns from spontaneous adverse drug reaction reports in a timely and efficient manner remains important in public health. OBJECTIVE: This paper explores the behaviour of the Sequential Probability Ratio Test (SPRT) and ability to detect signals of disproportionate reporting (SDRs) in the Singapore context. METHODS: We used SPRT with a combination of two hypothesised relative risks (hRRs) of 2 and 4.1 to detect signals of both common and rare adverse events in our small database. We compared SPRT with other methods in terms of number of signals detected and whether labelled adverse drug reactions were detected or the reaction terms were considered serious. The other methods used were reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN) and Gamma Poisson Shrinker (GPS). RESULTS: The SPRT produced 2187 signals in common with all methods, 268 unique signals, and 70 signals in common with at least one other method, and did not produce signals in 178 cases where two other methods detected them, and there were 403 signals unique to one of the other methods. In terms of sensitivity, ROR performed better than other methods, but the SPRT method found more new signals. The performances of the methods were similar for negative predictive value and specificity. CONCLUSIONS: Using a combination of hRRs for SPRT could be a useful screening tool for regulatory agencies, and more detailed investigation of the medical utility of the system is merited.

Risks and benefits of psychotropic medication in pregnancy: cohort studies based on UK electronic primary care health records.

BACKGROUND: Although many women treated with psychotropic medication become pregnant, no psychotropic medication has been licensed for use in pregnancy. This leaves women and their health-care professionals in a treatment dilemma, as they need to balance the health of the woman with that of the unborn child. The aim of this project was to investigate the risks and benefits of psychotropic medication in women treated for psychosis who become pregnant. OBJECTIVE(S): (1) To provide a descriptive account of psychotropic medication prescribed before pregnancy, during pregnancy and up to 15 months after delivery in UK primary care from 1995 to 2012; (2) to identify risk factors predictive of discontinuation and restarting of lithium (multiple manufacturers), anticonvulsant mood stabilisers and antipsychotic medication; (3) to examine the extent to which pregnancy is a determinant for discontinuation of psychotropic medication; (4) to examine prevalence of records suggestive of adverse mental health, deterioration or relapse 18 months before and during pregnancy, and up to 15 months after delivery; and (5) to estimate absolute and relative risks of adverse maternal and child outcomes of psychotropic treatment in pregnancy. DESIGN: Retrospective cohort studies. SETTING: Primary care. PARTICIPANTS: Women treated for psychosis who became pregnant, and their children. INTERVENTIONS: Treatment with antipsychotics, lithium or anticonvulsant mood stabilisers. MAIN OUTCOME MEASURES: Discontinuation and restarting of treatment; worsening of mental health; acute pre-eclampsia/gestational hypertension; gestational diabetes; caesarean section; perinatal death; major congenital malformations; poor birth outcome (low birthweight, preterm birth, small for gestational age, low Apgar score); transient poor birth outcomes (tremor, agitation, breathing and muscle tone problems); and neurodevelopmental and behavioural disorders. DATA SOURCES: Clinical Practice Research Datalink database and The Health Improvement Network primary care database. RESULTS: Prescribing of psychotropic medication was relatively constant before pregnancy, decreased sharply in early pregnancy and peaked after delivery. Antipsychotic and anticonvulsant treatment increased over the study period. The recording of markers of worsening mental health peaked after delivery. Pregnancy was a strong determinant for discontinuation of psychotropic medication. However, between 40% and 76% of women who discontinued psychotropic medication before or in early pregnancy restarted treatment by 15 months after delivery. The risk of major congenital malformations, and neurodevelopmental and behavioural outcomes in valproate (multiple manufacturers) users was twice that in users of other anticonvulsants. The risks of adverse maternal and child outcomes in women who continued antipsychotic use in pregnancy were not greater than in those who discontinued treatment before pregnancy. LIMITATIONS: A few women would have received parts of their care outside primary care, which may not be captured in this analysis. Likewise, the analyses were based on prescribing data, which may differ from usage. CONCLUSIONS: Psychotropic medication is prescribed before, during and after pregnancy. Many women discontinue treatment before or during early pregnancy and then restart again in late pregnancy or after delivery. Our results support previous associations between valproate and adverse child outcomes but we found no evidence of such an association for antipsychotics. FUTURE WORK: Future research should focus on (1) curtailing the use of sodium valproate; (2) estimating the benefits of psychotropic drug use in pregnancy; and (3) investigating the risks associated with lifestyle choices that are more prevalent among women using psychotropic drugs. FUNDING DETAILS: The National Institute for Health Research Health Technology Assessment programme.

Exploring the role and function of trial steering committees: results of an expert panel meeting.

BACKGROUND: The independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of this executive committee, known as the Trial Steering Committee (TSC), have not previously been studied or reviewed since those originally proposed by the MRC in 1998. METHODS: An expert panel (n = 7) was convened comprising statisticians, clinicians and trial methodologists with prior TSC experience. Twelve questions about the role and responsibilities of the TSC were discussed by the panel at two full-day meetings. Each meeting was transcribed in full and the discussions were summarised. RESULTS: The expert panel reached agreement on the role of the TSC, to which it was accountable, the membership, the definition of independence, and the experience and training needed. The management of ethical issues, difficult/complex situations and issues the TSC should not ask the DMC to make recommendations on were more difficult to discuss without specific examples, but support existed for further work to help share issues and to provide appropriate training for TSC members. Additional topics discussed, which had not been identified by previous work relating to the DMCs but were pertinent to the role of the TSC, included the following: review of data sharing requests, indemnity, lifespan of the TSC, general TSC administration, and the roles of both the Funder and the Sponsor. CONCLUSIONS: This paper presents recommendations that will contribute to the revision and update of the MRC TSC terms of reference. Uncertainty remains in some areas due to the absence of real-life examples; future guidance on these issues would benefit from a repository of case studies. Notably, the role of a patient and public involvement (PPI) contributor was not discussed, and further work is warranted to explore the role of a PPI contributor in independent trial oversight.

Treatment outcomes for substance use disorder among women of reproductive age in Massachusetts: a population-based approach.

INTRODUCTION: Longitudinal patterns of treatment utilization and relapse among women of reproductive age with substance use disorder (SUD) are not well known. In this statewide report spanning seven years we describe SUD prevalence, SUD treatment utilization, and differences in subsequent emergency department (ED) use and post-treatment relapse rates by type of treatment: none, 'acute only' (detoxification/stabilization), or 'ongoing' services. METHODS: We linked a statewide dataset of hospital discharge, observation stay and ED records with SUD treatment admission records from hospitals and freestanding facilities, and birth/fetal death certificates, in Massachusetts, 2002-2008. We aggregated episodes into individual woman records, identified evidence of SUD and treatment, and tested post-treatment outcomes. RESULTS: Nearly 150,000 (8.5%) of 1.7 million Massachusetts women aged 15-49 were identified as SUD-positive. Nearly half of SUD-positive women (71,533 or 48.3%) had evidence of hospital or facility-based SUD treatment; among these, 12% received acute care/detoxification only while 88% obtained 'ongoing' treatment. Treatment varied by substance type; women with dual diagnosis and those with opiate use were least likely to receive 'ongoing' treatment. Treated women were older and less likely to have a psychiatric history or chronic illness. Women who received 'acute only' services were more likely to relapse (12.4% vs. 9.6%) and had a 10% higher rate of ED visits post-treatment than women receiving 'ongoing' treatment. CONCLUSIONS: Many Massachusetts women of reproductive age need but do not receive adequate SUD treatment. 'Ongoing' services beyond detoxification/stabilization may reduce the likelihood of post-treatment relapse and/or reliance on the ED for subsequent medical care.

The risk of adverse outcomes in hospitalized older patients in relation to a frailty index based on a comprehensive geriatric assessment.

BACKGROUND: prognostication for frail older adults is complex, especially when they become seriously ill. OBJECTIVES: to test the measurement properties, especially the predictive validity, of a frailty index based on a comprehensive geriatric assessment (FI-CGA) in an acute care setting in relation to the risk of death, length of stay and discharge destination. DESIGN AND SETTING: prospective cohort study. Inpatient medical units in a teaching, acute care hospital. SUBJECTS: individuals on inpatient medical units in a hospital, n = 752, aged 75+ years, were evaluated on their first hospital day; to test reliability, a subsample (n = 231) was seen again on Day 3. MEASUREMENTS: all frailty data collected routinely as part of a CGA were used to create the FI-CGA. Mortality data were reviewed from hospital records, claims data, Social Security Death Index and interviews with Discharge Managers. RESULTS: thirty-day mortality was 93 (12.4%; 95% confidence interval (CI) = 10-15%) of whom 52 died in hospital. The risk of dying increased with each 0.01 increment in the FI-CGA: hazard ratio (HR) = 1.05, (95% CI = 1.04-1.07). People who were discharged home had the lowest admitting mean FI-CGA = 0.38 (±standard deviation 0.11) compared with those who died, FI-CGA = 0.51 (±0.12) or were discharged to nursing home, FI-CGA = 0.49 (±0.11). Likewise, increasing FI-CGA values on admission were significantly associated with a longer length of hospital stay. CONCLUSIONS: frailty, measured by the FI-CGA, was independently associated with a higher risk of death and other adverse outcomes in older people admitted to an acute care hospital.

The influence of neighborhood socioeconomic status and walkability on TV viewing time.

BACKGROUND: Influences on TV viewing time, which is associated with adverse health outcomes such as obesity and diabetes, need clarification. We assessed the relation of neighborhood socioeconomic status (SES) and walkability with TV viewing time in the Black Women's Health Study, a prospective study of African American women. METHODS: We created neighborhood SES and walkability scores using data from the U.S. census and other sources. We estimated odds ratios for TV viewing 5+ hours/day compared with 0-1 hours/day for quintiles of neighborhood SES and walkability scores. RESULTS: Neighborhood SES was inversely associated with TV viewing time. The odds ratio for watching 5+ hours/day in the highest compared with the lowest quintile of neighborhood SES was 0.66 (95% CI 0.54-0.81). Neighborhood walkability was not associated with TV viewing time. CONCLUSIONS: Neighborhood SES should be considered in devising strategies to combat the high levels of sedentariness prevalent in African American women.

Longitudinal assessment of urban form and weight gain in African-American women.

BACKGROUND: Numerous cross-sectional studies have found higher levels of obesity among residents of auto-oriented, sprawling areas compared to residents of more urban areas. PURPOSE: The association between neighborhood urban form and 6-year weight change was prospectively analyzed in the Black Women's Health Study, a cohort study of U.S. black women who enrolled in 1995 and are followed biennially with mailed questionnaires. METHODS: The analysis included 17,968 women who lived in New York City, Chicago, or Los Angeles and were followed from 1995 to 2001. Factor analysis was used to combine variables describing the urban form of participants' residential neighborhoods into an "urbanicity" score. Mixed linear regression models were used to calculate least-squares means for weight change across quintiles of the urbanicity score. Incidence rate ratios (IRRs) and 95% CIs for incident obesity in relation to the urbanicity score among women who were not obese at baseline were derived from Cox regression models. All results were adjusted for age, region, lifestyle factors, and neighborhood SES. Analyses were conducted in 2008-2010. RESULTS: In multivariate analysis, mean weight gain for women in the highest quintile of urbanicity score (most urban) was 0.79 kg less than for those in the lowest quintile, with a significant trend (p=0.003). The IRR for incident obesity in the highest quintile relative to the lowest was 0.83 (95% CI=0.71, 0.97), with a significant trend (p=0.042). CONCLUSIONS: Policies that encourage dense, urban residential development may have a positive role to play in addressing obesity in black women.

Oral antibiotic prescribing during pregnancy in primary care: UK population-based study.

OBJECTIVES: To examine patterns of prescribing of oral antibiotics during pregnancy and to determine whether women were more or less likely to receive specific types of antibiotics in pregnancy than in the years before and after pregnancy. Finally, to identify socio-demographic factors associated with antibiotic prescribing in pregnancy. PATIENTS AND METHODS: We identified 114 999 women who gave live birth between 1992 and 2007 in The Health Improvement Network (THIN) UK primary care database. Antibiotic prescribing during pregnancy was estimated for each calendar year between 1992 and 2007. Self-controlled case series (SCCS) methodology was used to compare antibiotic prescribing during pregnancy with the years before and after pregnancy, and Poisson regression to examine association between demographic factors and antibiotic prescribing. RESULTS: A third of pregnant women received at least one antibiotic prescription during pregnancy. In each trimester, 14% of women received at least one antibiotic. Prescribing of antibiotics was lower in pregnancy than during a comparable period 1 year earlier [incidence rate ratio (IRR) 0.91 (95% CI 0.90-0.93)], but some antibiotics were prescribed more frequently in pregnancy: broad-spectrum penicillins [IRR 1.46 (1.42-1.49)]; cephalosporins [IRR 2.22 (2.13-2.31)]; and antibiotics for urinary tract infections [IRR 2.29 (2.01-2.61)]. Respiratory, urinary, skin and ear infections were the commonest indications. Urinary indications increased and respiratory, skin and ear infection indications declined during pregnancy, although a large proportion were prescribed without indication. Young age and social deprivation were associated with increased antibiotic prescribing during pregnancy. CONCLUSIONS: Antibiotic prescribing is widespread in pregnancy although marginally reduced compared with the year before pregnancy. There were substantial changes in types of antibiotics as well as in their indications during pregnancy. This may be explained by changes in threshold for treatment, diseases, detection and recording. Younger women and women from deprived areas were most likely to receive antibiotics in pregnancy.

Cutting feedback in Bayesian regression adjustment for the propensity score.

McCandless, Gustafson and Austin (2009) describe a Bayesian approach to regression adjustment for the propensity score to reduce confounding. A unique property of the method is that the treatment and outcome models are combined via Bayes theorem. However, this estimation procedure can be problematic if the outcome model is misspecified. We observe feedback that can bias propensity score estimates. Building on new innovation in Bayesian computation, we propose a technique for cutting feedback in a Bayesian propensity analysis. We use the posterior distribution of the propensity scores as an input in the regression model for the outcome. The method is approximately Bayesian in the sense that it does not use the full likelihood for estimation. Nonetheless, it severs feedback between the treatment and outcome giving propensity score estimates that are free from bias but modeled with uncertainty. We illustrate the method in a matched cohort study investigating the effect of statins on primary stroke prevention.

Developing tools for the safety specification in risk management plans: lessons learned from a pilot project.

PURPOSE: Following the adoption of the ICH E2E guideline, risk management plans (RMP) defining the cumulative safety experience and identifying limitations in safety information are now required for marketing authorisation applications (MAA). A collaborative research project was conducted to gain experience with tools for presenting and evaluating data in the safety specification. This paper presents those tools found to be useful and the lessons learned from their use. METHODS: Archive data from a successful MAA were utilised. Methods were assessed for demonstrating the extent of clinical safety experience, evaluating the sensitivity of the clinical trial data to detect treatment differences and identifying safety signals from adverse event and laboratory data to define the extent of safety knowledge with the drug. RESULTS: The extent of clinical safety experience was demonstrated by plots of patient exposure over time. Adverse event data were presented using dot plots, which display the percentages of patients with the events of interest, the odds ratio, and 95% confidence interval. Power and confidence interval plots were utilised for evaluating the sensitivity of the clinical database to detect treatment differences. Box and whisker plots were used to display laboratory data. CONCLUSIONS: This project enabled us to identify new evidence-based methods for presenting and evaluating clinical safety data. These methods represent an advance in the way safety data from clinical trials can be analysed and presented. This project emphasises the importance of early and comprehensive planning of the safety package, including evaluation of the use of epidemiology data.

Human papilloma virus immunization in adolescent and young adults: a cohort study to illustrate what events might be mistaken for adverse reactions.

BACKGROUND: The large-scale implementation of human papilloma virus (HPV) immunization will be followed by cases of autoimmune diseases occurring in temporal association with immunizations. To anticipate events that might be mistakenly assumed to be caused by immunization, their prevalence was monitored before vaccine introduction. METHOD: Cohort study carried out within a database of female adolescents (n = 214,896) and young adults (n = 221,472) followed in the pre-HPV vaccine era (2005), computing rates of emergency consultations, hospitalizations and outpatient consultations, and estimation of risks of coincident associations. RESULTS: Immune-mediated conditions were a frequent cause (10.3%) of emergency room consultation by adolescent girls. Nonallergic immune-mediated conditions affected 86 per 100,000, diabetes ranking first. In 2005, 53 per 100,000 adolescents and 389 per 100,000 women were hospitalized for diseases of presumed autoimmune origin, thyroiditis being the most frequent diagnosis. If HPV immunization had been used with 80% coverage, 3 per 100,000 adolescents would have required emergency care for asthma/allergy within 24 hours and 2 per 100,000 for diabetes within 1 week of an injection. The risks of hospitalization in temporal association with immunization are 4 times higher for thyroiditis than for multiple sclerosis or Guillain-Barré's syndrome, and more than 20 times higher in young women than in adolescents. CONCLUSION: The distinction between HPV vaccine-caused adverse reactions and events only observed by chance in temporal association is difficult. The prior use of population-based data allows for identification of issues of potential concern, for monitoring the impact of large-scale interventions and for addressing rapidly vaccine-safety issues that may compromise vaccine programs.