The Structured Process to Identify Fit-For-Purpose Data: A Data Feasibility Assessment Framework.

To complement real-world evidence (RWE) guidelines, the 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) framework elucidated a process for designing valid and transparent real-world studies. As an extension to SPACE, here, we provide a structured framework for conducting feasibility assessments-a step-by-step guide to identify decision grade, fit-for-purpose data, which complements the United States Food and Drug Administration (FDA)'s framework for a RWE program. The process was informed by our collective experience conducting systematic feasibility assessments of existing data sources for pharmacoepidemiology studies to support regulatory decisions. Used with the SPACE framework, the Structured Process to Identify Fit-For-Purpose Data (SPIFD) provides a systematic process for conducting feasibility assessments to determine if a data source is fit for decision making, helping ensure justification and transparency throughout study development, from articulation of a specific and meaningful research question to identification of fit-for-purpose data and study design.

Do FDA label changes work? Assessment of the 2010 class label change for proton pump inhibitors using the Sentinel System's analytic tools.

PURPOSE: To pilot use of the US Food and Drug Administration's (FDA's) Sentinel System data and analytic tools by a non-FDA stakeholder through the Innovation in Medical Evidence Development and Surveillance system of the Reagan Udall Foundation. We evaluated the US FDA 2010 proton pump inhibitor (PPI) class label change that warned of increased risk of bone fracture, to use PPIs for the lowest dose and shortest duration, and to manage bone status for those at risk for osteoporosis. METHODS: The cohort consisted of adults aged 18 years or older prescribed PPIs without fracture risk factors. We evaluated incident and prevalent uses of the 8 PPIs noted in the label change. Outcomes evaluated before and after label change were PPI dispensing patterns, incident fractures, and osteoporosis screening or interventions. Consistent with FDA use of descriptive tools, we did not include direct comparisons or statistical testing. RESULTS: There were 1 488 869 and 2 224 420 incident PPI users in the before [PRE] and after [POST] periods, respectively. Users with 1 year or more of exposure decreased (8.4% vs 7.5%), as did mean days supplied/user (130.4 to 113.7 d among all users and 830.8 to 645.4 d among users with 1 y or more of exposure). Osteoporosis screening and interventions did not appear to increase, but the proportion of patients with fractures decreased (4.4% vs 3.1%). Prevalent user results were similar. CONCLUSIONS: This analysis demonstrated the ability to use Sentinel tools to assess the effectiveness of a label change and accompanying communication at the population level and suggests an influence on subsequent dispensing behavior.

Synthesis and preliminary assessment of the anticancer and Wnt/ß-catenin inhibitory activity of small amide libraries of fenamates and profens.

As part of an ongoing program to study the anticancer activity of non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries of multiple NSAID scaffolds, we synthesized a series of NSAID amide derivatives and screened these sets against three cancer cell lines (prostate, colon and breast) and Wnt/ß-catenin signaling. The evaluated amide analog libraries show significant anticancer activity/cell proliferation inhibition, and specific members of the sets show inhibition of Wnt/ß-catenin signaling.

The IMI PROTECT project: purpose, organizational structure, and procedures.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

Efficacy and the strength of evidence of U.S. alcohol control policies.

BACKGROUND: Public policy can limit alcohol consumption and its associated harm, but no direct comparison of the relative efficacy of alcohol control policies exists for the U.S. PURPOSE: To identify alcohol control policies and develop quantitative ratings of their efficacy and strength of evidence. METHODS: In 2010, a Delphi panel of ten U.S. alcohol policy experts identified and rated the efficacy of alcohol control policies for reducing binge drinking and alcohol-impaired driving among both the general population and youth, and the strength of evidence informing the efficacy of each policy. The policies were nominated on the basis of scientific evidence and potential for public health impact. Analysis was conducted in 2010-2012. RESULTS: Panelists identified and rated 47 policies. Policies limiting price received the highest ratings, with alcohol taxes receiving the highest ratings for all four outcomes. Highly rated policies for reducing binge drinking and alcohol-impaired driving in the general population also were rated highly among youth, although several policies were rated more highly for youth compared with the general population. Policy efficacy ratings for the general population and youth were positively correlated for reducing both binge drinking (r=0.50) and alcohol-impaired driving (r=0.45). The correlation between efficacy ratings for reducing binge drinking and alcohol-impaired driving was strong for the general population (r=0.88) and for youth (r=0.85). Efficacy ratings were positively correlated with strength-of-evidence ratings. CONCLUSIONS: Comparative policy ratings can help characterize the alcohol policy environment, inform policy discussions, and identify future research needs.

The role of the general practitioner in the Australian approach to HIV care: interviews with 'key informants' from government, non-government and professional organisations.

OBJECTIVES: HIV care is provided in a range of settings in Australia, but advances in HIV treatment and demographic and geographic changes in the affected population and general practitioner (GP) workforce are testing the sustainability of the special role for GPs. This paper explores how a group of 'key informants' described the role of the GP in the Australian approach to HIV care, and conceptualised the challenges currently inspiring debate around future models of care. METHODS: A thematic analysis was conducted of semistructured interviews carried out in 2010 with 24 professionals holding senior roles in government, non-government and professional organisations that influence Australian HIV care policy. RESULTS: The strengths of the role of the GP were described as their community setting, collaborative partnership with other medical and health professions, and focus on patient needs. A number of associated challenges were also identified including the different needs of GPs with high and low HIV caseloads, the changing expectations of professional roles in general practice, and barriers to service accessibility for people living with HIV. CONCLUSIONS: While there are many advantages to delivering HIV services in primary care, GPs need flexible models of training and accreditation, support in strengthening relationships with other health and medical professionals, and assistance in achieving service accessibility. Consideration of how to support the GP workforce so that care can be made available in the broadest range of geographical and service settings is also critical if systems of HIV care delivery are to be realistic and cost-effective and meet consumer needs.

Activist emotions: gay radicalism and melancholic attachments.

It has been argued recently that Australian historians have overlooked histories of emotion. In this article, through the life-history analysis of two long-standing Sydney gay activists, I trace the emotional currents of radical gay activism and suggest these histories point to a wider story of Left melancholy in the closing decades of the twentieth century. I argue that their melancholia is not a trauma-like despair but surprisingly is tinged with a sustaining hope.

Early adverse drug event signal detection within population-based health networks using sequential methods: key methodologic considerations.

PURPOSE: Active surveillance of population-based health networks may improve the timeliness of detection of adverse events (AEs). Our objective was to expand our previous signal detection work by investigating the effect on signal detection of alternative study specifications. METHODS: We compared the signal detection performance under various study specifications using historical data from nine health plans involved in the HMO Research Network's Center for Education and Research on Therapeutics (CERT). Five drug-event pairs representing generally accepted associations with an AE and two pairs representing "negative controls" were analyzed. Alternative study specifications related to the definition of incident users and incident AEs were assessed and compared to our previous findings. RESULTS: Relaxing the incident AE exclusion criteria by (1) including members with prior outpatient diagnoses of interest and (2) halving (to 90 days) the time window specified to define incident exposure and diagnoses increased the number of members under surveillance and as a consequence increased the number of exposed days and diagnoses by about 10-20%. The alternative specifications tend to result in earlier signal detection by 10-16 months, a likely consequence of more exposures and events entering the analysis. CONCLUSIONS: This paper provides additional preliminary information related to conducting prospective safety monitoring using health plan data and sequential analytic methods. Our findings support continued investigation of using health plan data and sequential analytic methods as a potentially important contribution to active drug safety surveillance.

Implications of new petrographic analysis for the Olmec "mother culture" model.

Petrographic analysis of Formative Mexican ceramics by J. B. Stoltman et al. (see the companion piece in this issue of PNAS) refutes a recent model of Olmec "one-way" trade. In this paper, we address the model's more fundamental problems of sampling bias, anthropological implausibility, and logical non sequiturs. No bridging argument exists to link motifs on pottery to the social, political, and religious institutions of the Olmec. In addition, the model of unreciprocated exchange is implausible, given everything that the anthropological and ethnohistoric records tell us about non-Western societies of that general sociopolitical level.

International collaborative study of cardiovascular disease in Asia: design, rationale, and preliminary results.

OBJECTIVES: The overall objective of the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was to estimate the prevalence and distribution of cardiovascular disease risk factors, including hypertension, hypercholesterolemia, diabetes, obesity, cigarette smoking, and physical inactivity, in the general population of both China and Thailand. METHODS AND RESULTS: A multistage cluster sampling method was used to select a nationally representative sample of 15,838 adults, aged 35-74 years, in China, and 5,350 similarly aged adults in Thailand. Data on medical history, cigarette smoking, alcohol consumption, diet, physical activity, and awareness and control of risk factors for cardiovascular disease, were collected. Blood pressure, body weight and height, and hip and waist circumferences, were measured using standard methods. Fasting blood specimens were collected to measure levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and creatinine. All data were carefully collected by specially trained, experienced observers using standardized methods and a stringent level of quality control. The prevalence of self-reported cardiovascular disease in Chinese adults aged 35-74 years was 3.3% in men and 3.6% in women (representing 8,147,000 male and 8,270,000 female cases nationally). The prevalence of self-reported cardiovascular disease in Thai adults was 1.5% in men and 1.7% in women (representing 184,000 male and 226,000 female cases). CONCLUSIONS: The InterASIA study provides important information on the current prevalence and control of both cardiovascular disease and its risk factors in the region. These findings will be useful for developing national strategies to reduce the large, and increasing, burden of cardiovascular disease in China and Thailand.

Serious cardiovascular events and mortality among patients with schizophrenia.

This study compared the risks of cardiovascular morbidity and mortality in people with schizophrenia who use antipsychotic medications to risks in individuals without schizophrenia in a large managed care organization. A sample of 1920 schizophrenia patients was matched by age, sex, date, and health plan to 9600 persons randomly selected from the health plan general membership. Death, myocardial infarction, arrhythmia, and new-onset diabetes were identified using a National Death Index search and medical claims records. The adjusted all-cause mortality rate in the group of treated schizophrenics was four times higher than in the control group regardless of whether patients were given a typical or an atypical antipsychotic medication. Users of typical antipsychotics had a fivefold higher risk of myocardial infarction than the control subjects. Among patients with schizophrenia, cardiovascular risk was inversely associated with intensity of use of antipsychotic drugs, suggesting that the observed risks may not be due to a simple or direct effect of drugs. Patients treated for schizophrenia had higher rates of new-onset diabetes than did the general population controls. This risk was most pronounced in persons with more intense exposure to drugs and appeared to be indistinguishable in users of typical antipsychotics, of atypical products, or of both.

The role of treatment intentions and concerns about side effects in women's decision to discontinue postmenopausal hormone therapy.

OBJECTIVES: To investigate the factors that influence women's decisions about hormone therapy use and the duration of use, in particular the effect of women's reasons for initiating hormone therapy, the source of information about hormones, women's symptom experience, and their concerns about side effects from hormone therapy. METHODS: Eight hundred and sixteen women aged 45-59 who began hormone therapy between July 1993 and June 1995 in a Massachusetts health maintenance organization were followed for two years from the day they received a prescription for estrogen. This cohort has been previously studied for health, treatment and demographic determinants of hormone therapy discontinuation. In March 1999, these women were mailed a questionnaire containing closed and open-ended questions. 449 women (55%) completed the survey. Discrete-time hazards models were used to identify determinants of discontinuation, controlling for medical predictors of survey nonresponse. RESULTS: Women's assessment of the difficulty of their decision to use hormone therapy (RR=1.25 for each point on a 7-point scale, 95% CI: 1.16, 1.35) was associated with discontinuation. Women who described their decision as extremely difficult had the greatest likelihood of discontinuing. The importance placed on preventing osteoporosis (RR=0.93 for each point on a 7-point scale, 95% CI: 0.86, 0.99) and cardiovascular disease (RR=0.94 for each point on a 7-point scale, 95% CI: 0.88, 0.99) were also statistically significant predictors of discontinuation. Women for whom the prevention of osteoporosis and cardiovascular disease were extremely important in deciding to use hormone therapy were the most likely to continue using hormones. Concerns about the return of monthly bleeding (RR=3.00, 95% CI: 1.45, 6.17) and weight gain (RR=2.06, 95% CI: 1.16, 3.67) at the time hormone therapy was initiated, but not the actual experience of these side effects while using hormones, were associated with a higher rate of discontinuation. Symptoms around the time of initiating hormone therapy, including the perceived severity of the symptom, were not statistically associated with discontinuation. CONCLUSIONS: Discontinuation of hormone therapy is the result of a complex process of decision-making that is influenced by the value placed on the prevention of osteoporosis and cardiovascular disease at the time of initiation and women's perceptions and interpretations of side effects. Concerns about the potential side effects of hormone therapy, in particular weight gain and monthly bleeding, lead women to discontinue hormone therapy.

Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data.

OBJECTIVE: To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls. DESIGN: Cohort study of outpatients using administrative data. SETTING: 3 US Medicaid programmes. PARTICIPANTS: Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis. MAIN OUTCOME MEASURE: Diagnosis of cardiac arrest or ventricular arrhythmia. RESULTS: Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses > or =600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038). CONCLUSIONS: The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.