Important statistical considerations in the evaluation of post-market studies to assess whether opioids with abuse-deterrent properties result in reduced abuse in the community.

PURPOSE: Abuse, misuse, addiction, overdose, and death associated with non-medical use of prescription opioids have become a serious public health concern. Reformulation of these products with abuse-deterrent properties is one approach for addressing this problem. FDA has approved several extended-release opioid analgesics with abuse-deterrent labeling, the bases of which come from pre-market studies. As all opioid analgesics must be capable of delivering the opioid in order to reduce pain, abuse-deterrent properties do not prevent abuse, nor do pre-market evaluations ensure that there will be reduced abuse in the community. Utilizing data from various surveillance systems, some recent post-market studies suggest a decline in abuse of extended-release oxycodone after reformulation with abuse-deterrent properties. We discuss challenges stemming from the use of such data. METHODS: We quantify the relationship between the sample, the population, and the underlying sampling mechanism and identify the necessary conditions if valid statements about the population are to be made. The presence of other interventions in the community necessitates the use of comparators. We discuss the principles under which the use of comparators can be meaningful. CONCLUSIONS: Results based on surveillance data need to be interpreted with caution as the underlying sampling mechanisms can bias the results in unpredictable ways. The use of comparators has the potential to disentangle the effect due to the abuse-deterrence properties from those due to other interventions. However, identifying a comparator that is meaningful can be very difficult.

Cardiovascular and mortality risks in older Medicare patients treated with varenicline or bupropion for smoking cessation: an observational cohort study.

PURPOSE: To compare cardiovascular and mortality risks in elderly patients treated with varenicline or bupropion for smoking cessation. METHODS: Elderly Medicare beneficiaries were entered into new-user cohorts of varenicline or bupropion for smoking cessation and followed on therapy for primary outcomes of acute myocardial infarction (AMI), stroke, mortality, and a composite of any of these events. Secondary outcomes were unstable angina, coronary revascularization, and a composite of any primary or secondary outcome event. Propensity score stratification was used to adjust for baseline differences in potential confounding factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards, with bupropion as reference. RESULTS: In cohorts of 74 824 varenicline and 14 133 bupropion users, there were 164 AMI, 96 stroke, 87 death, 317 primary composite, and 814 secondary composite events while on therapy. The HRs (95%CI) were 0.79 (0.50-1.24) for AMI, 1.27 (0.63-2.55) for stroke, 0.58 (0.30-1.13) for death, 0.84 (0.58-1.23) for the primary composite, and 0.92 (0.73-1.14) for the secondary composite. The risk of AMI or the primary composite outcome did not differ in subgroups defined by age, diabetes status, or presence of underlying ischemic heart disease. Only 30% of patients remained on either study drug beyond their first prescription. CONCLUSION: Cardiovascular and mortality risks were not increased in older patients treated with varenicline compared with bupropion for smoking cessation. A potential increase in the risk of stroke with varenicline could not be excluded. Treatment persistence with either drug was low. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study.

BACKGROUND: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. METHODS: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. FINDINGS: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). INTERPRETATION: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. FUNDING: BeiGene.

Deletion diagnostics for alternating logistic regressions.

Deletion diagnostics are introduced for the regression analysis of clustered binary outcomes estimated with alternating logistic regressions, an implementation of generalized estimating equations (GEE) that estimates regression coefficients in a marginal mean model and in a model for the intracluster association given by the log odds ratio. The diagnostics are developed within an estimating equations framework that recasts the estimating functions for association parameters based upon conditional residuals into equivalent functions based upon marginal residuals. Extensions of earlier work on GEE diagnostics follow directly, including computational formulae for one-step deletion diagnostics that measure the influence of a cluster of observations on the estimated regression parameters and on the overall marginal mean or association model fit. The diagnostic formulae are evaluated with simulations studies and with an application concerning an assessment of factors associated with health maintenance visits in primary care medical practices. The application and the simulations demonstrate that the proposed cluster-deletion diagnostics for alternating logistic regressions are good approximations of their exact fully iterated counterparts.

FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia.

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30-0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.See related commentary by Fathi, p. 6015.

Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study.

BACKGROUND: An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting. OBJECTIVE: To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis. METHODS: Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry. RESULTS: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone-treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts. CONCLUSIONS: Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer.

ORTH: R and SAS software for regression models of correlated binary data based on orthogonalized residuals and alternating logistic regressions.

This article describes a new software for modeling correlated binary data based on orthogonalized residuals, a recently developed estimating equations approach that includes, as a special case, alternating logistic regressions. The software is flexible with respect to fitting in that the user can choose estimating equations for association models based on alternating logistic regressions or orthogonalized residuals, the latter choice providing a non-diagonal working covariance matrix for second moment parameters providing potentially greater efficiency. Regression diagnostics based on this method are also implemented in the software. The mathematical background is briefly reviewed and the software is applied to medical data sets.

Role of allostatic load in sociodemographic patterns of pain prevalence in the U.S. population.

UNLABELLED: Persistent stressors associated with sociodemographic disadvantage exert a physiologic toll, labeled "allostatic load," that contributes to disparities in some health conditions. We investigated the contribution of allostatic load to pain prevalence in U.S. adults. Interviews with 14,184 adults in the 1999-2004 National Health and Nutrition Examination Survey asked about severe headache, pain that lasted >24 hours, and widespread pain. Ten biomarkers of allostatic load were quantified from blood (glycated hemoglobin), serum (C-reactive protein, homocysteine, cholesterol, triglycerides), urine (creatinine, albumin), and physical measurements (body mass index, systolic and diastolic blood pressure). Log-binomial regression models estimated prevalence ratios (PRs) and 95% confidence intervals (95% CIs). Prevalence ranged from 3.4% for widespread pain to 26.9% for pain >24 hours. After adjustment for demographic characteristics, low income was associated with greater prevalence of pain >24 hours (PR = 1.65, 95% CI = 1.49, 1.83), severe headache (PR = 2.05, 95% CI = 1.68, 2.50), and widespread pain (PR = 3.67, 95% CI = 2.56, 5.27). Racial/ethnic minorities had lower prevalence of all 3 pain conditions than non-Hispanic whites. While greater allostatic load was associated with elevated prevalence of pain, allostatic load did not meaningfully attenuate PRs associated with income or race/ethnicity. We conclude that greater pain prevalence among low-income groups is not explained by greater allostatic load. PERSPECTIVE: In U.S. adults, pain occurs more frequently in lower-income groups, although the relationship is not attributable to their experience of greater allostatic load. While allostatic load contributes to population variation in pain, other etiologic mechanisms contributing to pain are needed to account for income disparities in pain.

Excess risk of temporomandibular disorder associated with cigarette smoking in young adults.

UNLABELLED: Evidence suggests that the effect of cigarette smoking on chronic pain is stronger in younger than older adults. This case-control study investigated whether age modified an effect of smoking on temporomandibular disorder (TMD) in 299 females aged 18 to 60 years. It also investigated the extent to which this relationship was explained by psychological profile, inflammatory response, and allergy. Cases were defined using the Research Diagnostic Criteria for Temporomandibular Disorders based on clinical examination. Psychological profile was evaluated using standardized instruments. Inflammatory response was evaluated with 11 cytokines isolated in plasma. History of allergy conditions was self-reported. Odds ratios (ORs) for the effect of smoking were calculated using binary logistic regression. Stratified analyses and the likelihood ratio test examined effect modification by smoking. Compared with nonsmokers, ever smokers aged <30 years had higher odds of TMD (OR = 4.14, 95% CI: 1.57, 11.35) than older adults (OR = 1.23, 95% CI: .55, 2.78) (P (effect modification) = .038). Adjustment for psychological profile, cytokines, and history of allergy-like conditions attenuated the effect by 45% to statistical nonsignificance. The main finding was reproduced with secondary analyses of 2 nationally representative surveys of adults conducted in the US and Australia. PERSPECTIVE: This study showed that smoking was associated with TMD risk in females, but only in young adulthood. It replicated this finding in 2 nationally representative surveys of females in the US and Australia. Findings may alert clinicians to recognize that smoking is a concern for TMD in younger female patients.

Study methods, recruitment, sociodemographic findings, and demographic representativeness in the OPPERA study.

UNLABELLED: This paper describes methods used in the project "Orofacial Pain Prospective Evaluation and Risk Assessment" (OPPERA) and evaluates sociodemographic characteristics associated with temporomandibular disorders (TMD) in the OPPERA case-control study. Representativeness was investigated by comparing sociodemographic profiles of OPPERA participants with population census profiles of counties near study sites and by comparing age and gender associations with TMD in OPPERA and the 2007 to 2009 US National Health Interview Survey. Volunteers aged 18 to 44 years were recruited at 4 US study sites: 3,263 people without TMD were enrolled into the prospective cohort study; 1,633 of them were selected as controls for the baseline case-control study. Cases were 185 volunteers with examiner-classified TMD. Distributions of some demographic characteristics among OPPERA participants differed from census profiles, although there was less difference in socioeconomic profiles. Odds of TMD was associated with greater age in this 18 to 44 year range; females had 3 times the odds of TMD as males; and relative to non-Hispanic-Whites, other racial groups had one-fifth the odds of TMD. Age and gender associations with chronic TMD were strikingly similar to associations observed in the US population. Assessments of representativeness in this demographically diverse group of community volunteers suggest that OPPERA case-control findings have good internal validity. PERSPECTIVE: Demographic associations with TMD were consistent with population benchmarks and with other studies, suggesting broad applicability of these OPPERA findings. Greater occurrence of TMD in non-Hispanic-Whites than in other racial/ethnic groups and the lack of a socioeconomic gradient contradicts the disparities seen in many other health conditions.