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.

Relative Performance of Propensity Score Matching Strategies for Subgroup Analyses.

Postapproval drug safety studies often use propensity scores (PSs) to adjust for a large number of baseline confounders. These studies may involve examining whether treatment safety varies across subgroups. There are many ways a PS could be used to adjust for confounding in subgroup analyses. These methods have trade-offs that are not well understood. We conducted a plasmode simulation to compare relative performance of 5 methods involving PS matching for subgroup analysis, including methods frequently used in applied literature whose performance has not been previously directly compared. These methods varied as to whether the overall PS, subgroup-specific PS, or no rematching was used in subgroup analysis as well as whether subgroups were fully nested within the main analytical cohort. The evaluated PS subgroup matching methods performed similarly in terms of balance, bias, and precision in 12 simulated scenarios varying size of the cohort, prevalence of exposure and outcome, strength of relationships between baseline covariates and exposure, the true effect within subgroups, and the degree of confounding within subgroups. Each had strengths and limitations with respect to other performance metrics that could inform choice of method.

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.

A review of the performance of different methods for propensity score matched subgroup analyses and a summary of their application in peer-reviewed research studies.

PURPOSE: When evaluating safety signals, there is often interest in understanding safety in all patients for whom compared treatments are reasonable alternatives, as well as in specific subgroups of interest. There are numerous ways that propensity score (PS) matching can be implemented for subgroup analyses. METHODS: We conducted a systematic literature review of methods papers that compared the performance of alternative methods to implement PS matched subgroup analyses and examined how frequently different PS matching methods have been used for subgroup analyses in applied studies. RESULTS: We identified 5 methods papers reporting small improvements in covariate balance and bias with use of a subgroup-specific PS instead of a mis-specified overall PS within subgroups. Applied research papers frequently used PS for subgroups in ways not evaluated in methods papers. Thirty three percent used PS to match in the overall cohort and broke the matched sets for subgroup analysis without further adjustment. CONCLUSIONS: While the performance of several alternative ways to use PS matching in subgroup analyses has been evaluated in methods literature, these evaluations do not include the most commonly used methods to implement PS matched subgroup analyses in applied studies. There is a need to better understand the relative performance of commonly used methods for PS matching in subgroup analyses, particularly within settings encountered during active surveillance, where there may be low exposure, infrequent outcomes, and multiple subgroups of interest.

Antihypertensive drug associated angioedema: effect modification by race/ethnicity.

PURPOSE: Assess angioedema risk with exposure to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) compared with beta-blockers, by race/ethnicity. METHODS: New-user cohorts of Medicare beneficiaries 65 years or older initiating ACEI, ARB, or beta-blocker treatment from March 2007 to March 2014 were constructed. Angioedema incidence rates by drug and race/ethnicity were computed for 1-30 and 31-365 days of treatment. Cox proportional hazards regression was used to examine angioedema risk between cohorts. RESULTS: Angioedema incidence rates (per 1000 person years) in beta-blocker users were 1.80 (whites), 4.11 (blacks), 1.89 (Asians), and 2.10 (Hispanics); in ACEI users, 4.03, 23.77, 2.94, and 4.27; and in ARB users, 1.73, 3.11, 1.10, and 1.90, respectively. Incidence rates were significantly higher in the first 30 days of exposure for all drug × race/ethnic groups. Overall, angioedema risk increased among ACEI users (hazard ratio, 2.91; 95% confidence interval, 2.75-3.07) but not ARB users (0.93, 0.85-1.02) versus beta-blocker users. Angioedema risk with ACEIs versus beta-blockers increased more in blacks (6.28, 5.44-7.24) than whites (2.33, 2.19-2.48), Hispanics (2.04, 1.36-3.07), and Asians (1.48, 0.94-2.35). Compared with white beta-blocker users, angioedema risk was increased 2.9-fold in whites, 20.2-fold in blacks, and 2.3-fold in other race/ethnic groups combined during the first 30 days of ACEI exposure. CONCLUSIONS: There was significant effect modification of angioedema risk by race and ACEI use for blacks, but not for other race/ethnicity groups. Angioedema risk was significantly greater in the first 30 days of exposure for all, and highest among blacks.

The role of quantitative safety evaluation in regulatory decision making of drugs.

Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general.

A unified approach for analyzing exchangeable binary data with applications to developmental toxicity studies.

In this article, we present a general procedure to analyze exchangeable binary data that may also be viewed as realizations of binomial mixtures. Our approach unifies existing models and is practical and computationally easy. Resulting from completely monotonic functions, we introduce a rich family of parametric parsimonious binomial mixtures, including the incomplete Beta-, Gamma-, Normal-, and Poisson-binomial, generalizing the Beta-binomial. We show that the family is closed under convex linear combinations, products, and composites. We also give the moments and the Markov property of the family. With such distributions, we can perform statistical inference on correlated binary data and, in particular, overdispersed data. We propose a regression procedure that generalizes logistic regression. We provide a forward model selection procedure. We run a small simulation to validate the inclusion of the binomial distribution. Finally, we apply the proposed procedure to analyze the 2, 4, 5-Trichlorophenoxyacetic acid and E2 data and compare the results with existing procedures.