When Effects Cannot be Estimated: Redefining Estimands to Understand the Effects of Naloxone Access Laws.
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ABSTRACT:
SUBMITTER: Rudolph KE
PROVIDER: S-EPMC9373236 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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When Effects Cannot be Estimated: Redefining Estimands to Understand the Effects of Naloxone Access Laws.
Rudolph Kara E KE Gimbrone Catherine C Matthay Ellicott C EC Díaz Iván I Davis Corey S CS Keyes Katherine K Cerdá Magdalena M
Epidemiology (Cambridge, Mass.) 20220624 5
Violations of the positivity assumption (also called the common support condition) challenge health policy research and can result in significant bias, large variance, and invalid inference. We define positivity in the single- and multiple-timepoint (i.e., longitudinal) health policy evaluation setting, and discuss real-world threats to positivity. We show empirical evidence of the practical positivity violations that can result when attempting to estimate the effects of health policies (in this ...[more]
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Project description:Background and aimsWhether expanded access to naloxone reduces perceptions of risk about opioid use has been subject to debate. Our aim was to assess how implementation of naloxone access laws shapes perceived risk of heroin use.DesignUsing data from the restricted-access National Survey on Drug Use and Health, Prescription Drug Abuse Policy System and the US Census, we applied two-way fixed-effects models to determine whether naloxone access laws decreased perceived risk of any heroin use or regular heroin use. We used Bayes factors (BFs) to confirm evidence for null findings.SettingUnited States.ParticipantsA total of 884 800 respondents aged 12 and older from 2004 to 2016.MeasurementsA binary indicator of whether a state implemented naloxone access laws was regressed on respondent-perceived risk of (1) any heroin use and (2) regular heroin use. Ratings of perceived risk were assessed on a scale of 1 (none) to 4 (great risk).FindingsIn all instances, the BFs support evidence for the null hypothesis. Across models with three distinct specifications of naloxone access laws, we found no evidence of decreased risk perceptions, as confirmed by BFs ranging from 0.009 to 0.057. Across models of specific vulnerable subgroups, such as people who use opioids (BFs = 0.039-0.225) or young people (BFs = 0.009-0.158), we found no evidence of decreased risk perceptions. Across diverse subpopulations by gender (BFs = 0.011-0.083), socio-economic status (BFs = 0.015-0.168) or race/ethnicity (BFs = 0.016-0.094), we found no evidence of decreased risk perceptions.ConclusionsThere appears to be no empirical evidence that implementation of naloxone access laws has adversely affected perceptions of risk of heroin in the broader US population or within vulnerable subgroups or diverse subpopulations.
| S-EPMC8844056 | biostudies-literature
Project description:Background and aimsNaloxone access laws (NALs) have been suggested to be an important strategy to reduce opioid-related harm. We describe the evolution of NALs across states and over time and review existing evidence of their overall association with naloxone distribution and opioid overdose as well as the potential effects of specific NAL components.MethodsDescriptive analysis of temporal variation in US regional adoption of NAL components, accompanied by a systematic search of 13 databases for studies (published between 2005 and 20 December 2019) assessing the effects of NALs on naloxone distribution or opioid-related health outcomes. Eleven studies, all published since 2018, met inclusion criteria. Study time-frames spanned 1999-2017. Opioid-related overdose mortality, emergency department episodes and naloxone distribution were correlated with the presence of a NAL and, where data were available, NAL components.ResultsExisting evidence suggests mixed, but generally beneficial, effects for NALs. Nearly all studies show that NALs, particularly those that permit naloxone distribution without patient-specific prescriptions, are associated with increased naloxone access [incidence rate ratios (IRR) range from 1.40, 95% confidence interval (CI) = 1.15-1.66 to 7.75, 95% CI = 1.22-49.35] and increased opioid-related emergency department visits (IRR range from 1.14, 95% CI = 1.07-1.20 to 1.15, 95% CI = 1.02-1.29). Most studies show NALs are associated with reduced overdose mortality, although findings vary depending on the specific NAL components and time-period analyzed (IRR range from 0.66, 95% CI = 0.42-0.90 to 1.27, 95% CI = 1.27-1.27). Few studies account for the variation in opioid environments (i.e. illicit versus prescription) or other policy dimensions that may be correlated with outcomes.ConclusionsThe existing literature on naloxone access laws in the United States supports beneficial effects for increased naloxone distribution, but provides inconclusive evidence for reduced fatal opioid overdose. Mixed findings may reflect variation in the laws' design and implementation, confounding effects of concurrent policy adoption, or differential effectiveness in light of changing opioid environments.
| S-EPMC8051142 | biostudies-literature
Project description:ImportanceTo mitigate the opioid overdose crisis, states have implemented a variety of legal interventions aimed at increasing access to the opioid antagonist naloxone. Recently, Virginia and Vermont mandated the coprescription of naloxone for potentially at-risk patients.ObjectiveTo assess the association between naloxone coprescription legal mandates and naloxone dispensing in retail pharmacies.Design, setting, and participantsThis was a population-based, state-level cohort study. The sample included all prescriptions dispensed for naloxone in the retail pharmacy setting contained in IQVIA's national prescription audit, which represents 90% of all retail pharmacies in the United States. The unit of observation was state-month and the study period was January 1, 2011, to December 31, 2017.ExposuresState legal intervention mandating naloxone coprescription.Main outcomes and measuresNumber of naloxone prescriptions dispensed. State rates of naloxone prescriptions dispensed per month per 100 000 standard population were calculated.ResultsThe rate of naloxone dispensing increased after implementation of legal mandates for naloxone coprescription. An estimated 88 naloxone prescriptions per 100 000 were dispensed in Virginia and 111 prescriptions per 100 000 were dispensed in Vermont during the first full month the legal requirement was effective. In comparison, 16 naloxone prescriptions per 100 000 were dispensed in the 10 states (including the District of Columbia) with the highest opioid overdose death rates and 6 prescriptions per 100 000 were dispensed in the 39 remaining states. The number of naloxone prescriptions dispensed was associated with the legal mandate for naloxone coprescription (incidence rate ratio [IRR], 7.75; 95% CI, 1.22-49.35). Implementation of the naloxone coprescription mandate was associated with an estimated 214 additional naloxone prescriptions dispensed per month in the period following the mandates, holding all other variables constant. Among covariates, naloxone access laws (IRR, 1.37; 1.05-1.78), opioid overdose death rates (IRR, 1.06; 95% CI, 1.04-1.08), the percentage of naloxone prescriptions paid by third-party payers (IRR 1.009; 1.008-1.010), and time (IRR, 1.06; 95% CI, 1.05-1.07) were significantly associated with naloxone prescription dispensing.Conclusions and relevanceThese study findings suggest that legally mandated naloxone prescription for those at risk for opioid overdose may be associated with substantial increases in naloxone dispensing and further reduction in opioid-related harm.
| S-EPMC6593960 | biostudies-literature
Project description:ObjectivesWe sought to examine the association between policies governing access to tobacco during adolescence and subsequent adult smoking.MethodsWe analyzed adult smoking data from the 1998 through 2006-2007 administrations of the US Current Population Survey Tobacco Use Supplement by employing a quasi experimental approach. Participants (n = 105,519) were adults, aged 18 to 34 years at the time of the survey. Smoking outcomes included having ever smoked 100 cigarettes, smoking at the time of the survey, and having smoked 10 or more cigarettes a day conditioned on being an ever smoker. These were predicted from exposure to state youth access policies at age 17 years.ResultsFour of the 9 policies exhibited significant associations with reduced prevalence of 1 or more smoking outcomes, primarily among women. Lesser effects for other policies could not be ruled out.ConclusionsRestrictions on youth access to tobacco might lead to reduction in smoking prevalence later in adulthood. The effect might be limited to women; we estimate that having all policies in place could be associated with a 14% reduction in lifetime smoking prevalence for women, and an additional 29% reduction in heavy smoking among ever smokers.
| S-EPMC3710295 | biostudies-literature
Project description:Most reported treatment effects in medical research studies are ambiguously defined, which can lead to misinterpretation of study results. This is because most authors do not attempt to describe what the treatment effect represents, and instead require readers to deduce this based on the reported statistical methods. However, this approach is challenging, because many methods provide counterintuitive results. For example, some methods include data from all patients, yet the resulting treatment effect applies only to a subset of patients, whereas other methods will exclude certain patients while results will apply to everyone. Additionally, some analyses provide estimates pertaining to hypothetical settings in which patients never die or discontinue treatment. Herein we introduce estimands as a solution to the aforementioned problem. An estimand is a clear description of what the treatment effect represents, thus saving readers the necessity of trying to infer this from study methods and potentially getting it wrong. We provide examples of how estimands can remove ambiguity from reported treatment effects and describe their current use in practice. The crux of our argument is that readers should not have to infer what investigators are estimating; they should be told explicitly.
| S-EPMC10236519 | biostudies-literature
Project description:AimsTreatment 'effects' are often inferred from non-randomized and observational studies. These studies have inherent biases and limitations, which may make therapeutic inferences based on their results unreliable. We compared the conflicting findings of these studies to those of prospective randomized controlled trials (RCTs) in relation to pharmacological treatments for heart failure (HF).Methods and resultsWe searched Medline and Embase to identify studies of the association between non-randomized drug therapy and all-cause mortality in patients with HF until 31 December 2017. The treatments of interest were: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists (MRAs), statins, and digoxin. We compared the findings of these observational studies with those of relevant RCTs. We identified 92 publications, reporting 94 non-randomized studies, describing 158 estimates of the 'effect' of the six treatments of interest on all-cause mortality, i.e. some studies examined more than one treatment and/or HF phenotype. These six treatments had been tested in 25 RCTs. For example, two pivotal RCTs showed that MRAs reduced mortality in patients with HF with reduced ejection fraction. However, only one of 12 non-randomized studies found that MRAs were of benefit, with 10 finding a neutral effect, and one a harmful effect.ConclusionThis comprehensive comparison of studies of non-randomized data with the findings of RCTs in HF shows that it is not possible to make reliable therapeutic inferences from observational associations. While trials undoubtedly leave gaps in evidence and enrol selected participants, they clearly remain the best guide to the treatment of patients.
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Project description:BackgroundNaloxone is a prescription medication that reverses opioid overdoses. Allowing naloxone to be dispensed directly by a pharmacist without an individual prescription under a naloxone standing order (NSO) can expand access. The community-level factors associated with naloxone dispensed under NSO are unknown.MethodsUsing a dataset comprised of pharmacy reports of naloxone dispensed under NSO from 70% of Massachusetts retail pharmacies, we examined relationships between community-level demographics, rurality, measures of treatment for opioid use disorder, and overdose deaths with naloxone dispensed under NSO per ZIP Code-quarter from 2014 until 2018. We used a multi-variable zero-inflated negative binomial model, assessing odds of any naloxone dispensed under NSO, as well as a multi-variable negative binomial model assessing quantities of naloxone dispensed under NSO.ResultsFrom 2014-2018, quantities of naloxone dispensed under NSO and the number of pharmacies dispensing any naloxone under NSO increased over time. However, communities with greater percentages of people with Hispanic ethnicity (aOR 0.91, 95% CI 0.86-0.96 per 5% increase), and rural communities compared to urban communities (aOR 0.81, 95% CI 0.73-0.90) were less likely to dispense any naloxone by NSO. Communities with more individuals treated with buprenorphine dispensed more naloxone under NSO, as did communities with more opioid-related overdose deaths.ConclusionNaloxone dispensing has substantially increased, in part driven by standing orders. A lower likelihood of naloxone being dispensed under NSO in communities with larger Hispanic populations and in more rural communities suggests the need for more equitable access to, and uptake of, lifesaving medications like naloxone.
| S-EPMC8714703 | biostudies-literature
Project description:ImportanceGiven high rates of opioid-related fatal overdoses, improving naloxone access has become a priority. States have implemented different types of naloxone access laws (NALs) and there is controversy over which of these policies, if any, can curb overdose deaths. We hypothesize that NALs granting direct authority to pharmacists to provide naloxone will have the greatest potential for reducing fatal overdoses.ObjectivesTo identify which types of NALs, if any, are associated with reductions in fatal overdoses involving opioids and examine possible implications for nonfatal overdoses.Design, setting, and participantsState-level changes in both fatal and nonfatal overdoses from 2005 to 2016 were examined across the 50 states and the District of Columbia after adoption of NALs using a difference-in-differences approach while estimating the magnitude of the association for each year relative to time of adoption. Policy environments across full state populations were represented in the primary data set. The association for 3 types of NALs was associated: NALs providing direct authority to pharmacists to prescribe, NALs providing indirect authority to prescribe, and other NALs. The study was conducted from January 2017 to January 2019.ExposuresFatal and nonfatal overdoses in states that adopted NAL laws were compared with those in states that did not adopt NAL laws. Further consideration was given to the type of NAL passed in terms of its association with these outcomes. We hypothesize that NALs granting direct authority to pharmacists to provide naloxone will have the greatest potential for reducing fatal overdoses.Main outcomes and measuresFatal overdoses involving opioids were the primary outcome. Secondary outcomes were nonfatal overdoses resulting in emergency department visits and Medicaid naloxone prescriptions.ResultsIn this evaluation of the dispensing of naloxone across the United States, NALs granting direct authority to pharmacists were associated with significant reductions in fatal overdoses, but they may also increase nonfatal overdoses seen in emergency department visits. The effect sizes for fatal overdoses grew over time relative to adoption of the NALs. These policies were estimated to reduce opioid-rated fatal overdoses by 0.387 (95% CI, 0.119-0.656; P = .007) per 100 000 people in 3 or more years after adoption. There was little evidence of an association for indirect authority to dispense (increase by 0.121; 95% CI, -0.014 to 0.257; P = .09) and other NALs (increase by 0.094; 95% CI, -0.040 to 0.227; P = .17).Conclusions and relevanceAlthough many states have passed some type of law affecting naloxone availability, only laws allowing direct dispensing by pharmacists appear to be useful. Communities in which access to naloxone is improved should prepare for increases in nonfatal overdoses and link these individuals to effective treatment.
| S-EPMC6503576 | biostudies-literature
Project description:PurposeAn influential covariate for pharmacokinetics is (body) size. Recently, the method of estimation of normal fat mass (NFM) has been advocated. Here, the relative contribution of fat mass, estimated as a fraction fat (Ffat), is used to explain differences in pharmacokinetic parameters. This concept is more and more applied. However, it remains unclear whether NFM can be reliably estimated in these typical studies.MethodsWe performed an evaluation of the reliability of NFM estimation in a typical study size (n = 30), otherwise best-case scenario, by means of a pharmacokinetic simulation study. Several values of Ffat were investigated.ResultsIn a typical pharmacokinetic study, high imprecision was observed for NFM parameter estimates over a range of scenarios. For example, in a scenario where the true value of Ffat on clearance was 0.5, we found a 95% confidence interval of - 0.1 to 2.1, demonstrating a low precision. The implications for practice are that one could conclude that fat-free mass best describes the relationship of the pharmacokinetics with body size, while the true relationship was between fat-free mass and total body weight. Consequently, this could lead to incorrect extrapolation of pharmacokinetics to extreme body sizes.ConclusionIn typical pharmacokinetic studies, NFM should be used with caution because the Ffat estimates have low precision. The estimation of Ffat should always be preceded by careful study design evaluation before planning a study, to ensure that the design and sample size is sufficient to apply this potentially useful methodology.
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Project description:Randomized controlled trials are the gold standard for determining the efficacy of a new intervention. Trials conducted for regulatory approval of an intervention compare the effect of the intervention with the standard of care or placebo to demonstrate efficacy. Randomization attempts to ensure that all known and unknown confounding factors are evenly distributed between the groups, and that the groups will be comparable at the end of the study, so that any inter-group differences in outcomes can be attributed to the intervention. However, in reality, intercurrent events may impact the assessment and subsequent interpretation of the outcome of interest. To address this, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in 2017, released an addendum to the E9 guideline (ICH E9 R1) putting forth the concept of Estimands and Sensitivity Analysis in Clinical Trials. This addendum addresses how these intercurrent events are to be handled using the Estimand concept, which is now expected to be detailed in a separate section of the study protocol. In this paper, we discuss what estimands are, and their likely impact on how regulatory trial protocols and their statistical analyses plans are written and implemented. We also look at the application of the concept of estimands to routine clinical practice.
| S-EPMC8112325 | biostudies-literature