Bridging blinded and unblinded analysis for ongoing safety monitoring and evaluation.

In order to better characterize the safety profile of investigational new drugs (INDs) during clinical development, more interest and attention have been paid to ongoing safety monitoring and evaluation. The 2015 US FDA IND safety reporting draft guidance compels sponsors to periodically evaluate unblinded safety data. However, maintaining the trial blind is necessary to avoid jeopardizing the validity of study findings. In this article, we propose an innovative new approach which includes analyzing both blinded and unblinded data. The proposed two-stage framework incorporates periodic analyses of blinded safety data to detect and flag adverse events that may have potential risk elevation related to experimental treatment, as well as planned unblinded analyses to quantify associations between the drug and adverse events, and to determine thresholds for referring adverse events for medical review and safety reporting.

Methodology to Estimate the Longitudinal Average Attributable Fraction of Guideline-recommended Medications for Death in Older Adults With Multiple Chronic Conditions.

BACKGROUND: Persons with multiple chronic conditions receive multiple guideline-recommended medications to improve outcomes such as mortality. Our objective was to estimate the longitudinal average attributable fraction for 3-year survival of medications for cardiovascular conditions in persons with multiple chronic conditions and to determine whether heterogeneity occurred by age. METHODS: Medicare Current Beneficiary Survey participants (N = 8,578) with two or more chronic conditions, enrolled from 2005 to 2009 with follow-up through 2011, were analyzed. We calculated the longitudinal extension of the average attributable fraction for oral medications (beta blockers, renin-angiotensin system blockers, and thiazide diuretics) indicated for cardiovascular conditions (atrial fibrillation, coronary artery disease, heart failure, and hypertension), on survival adjusted for 18 participant characteristics. Models stratified by age (≤80 and >80 years) were analyzed to determine heterogeneity of both cardiovascular conditions and medications. RESULTS: Heart failure had the greatest average attributable fraction (39%) for mortality. The fractional contributions of beta blockers, renin-angiotensin system blockers, and thiazides to improve survival were 10.4%, 9.3%, and 7.2% respectively. In age-stratified models, of these medications thiazides had a significant contribution to survival only for those aged 80 years or younger. The effects of the remaining medications were similar in both age strata. CONCLUSIONS: Most cardiovascular medications were attributed independently to survival. The two cardiovascular conditions contributing independently to death were heart failure and atrial fibrillation. The medication effects were similar by age except for thiazides that had a significant contribution to survival in persons younger than 80 years.

Longitudinal average attributable fraction as a method for studying time-varying conditions and treatments on recurrent self-rated health: the case of medications in older adults with multiple chronic conditions.

PURPOSE: The objective is to modify the longitudinal extension of the average attributable fraction (LE-AAF) for recurrent outcomes with time-varying exposures and control for covariates. METHODS: We included Medicare Current Beneficiary Survey participants with two or more chronic conditions enrolled from 2005 to 2009 with follow-up through 2011. Nine time-varying medications indicated for nine time-varying common chronic conditions and 14 of 18 forward-selected participant characteristics were used as control variables in the generalized estimating equations step of the LE-AAF to estimate associations with the recurrent universal health outcome self-rated health (SRH). Modifications of the LE-AAF were made to accommodate these indicated medication-condition interactions and covariates. Variability was empirically estimated by bias-corrected and accelerated bootstrapping. RESULTS: In the adjusted LE-AAF, thiazide, warfarin, and clopidogrel had significant contributions of 1.2%, 0.4%, 0.2%, respectively, to low (poor or fair) SRH; whereas there were no significant contributions of the other medications to SRH. Hyperlipidemia significantly contributed 4.6% to high SRH. All the other conditions except atrial fibrillation contributed significantly to low SRH. CONCLUSIONS: Our modifications to the LE-AAF method apply to a recurrent binary outcome with time-varying factors accounting for covariates.

Thymic carcinoma outcomes and prognosis: results of an international analysis.

OBJECTIVES: The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free survival (RFS). METHODS: Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures. RESULTS: In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval [CI], 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS. CONCLUSIONS: R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS.

Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases.

OBJECTIVE: Primary neuroendocrine tumors of the thymus (TNET) are exceedingly rare. We studied a large series of TNET identified through the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. METHODS: This was a retrospective multicenter study of patients undergoing operation for TNET between 1984 and 2012. Outcome measures were: overall survival (OS) and cumulative incidence of recurrences (CIR). OS was analyzed using the Kaplan-Meier method and CIR was analyzed using competing risk analysis. Associations with clinical and prognostic factors for OS and CIR were evaluated using the log rank test and Gray test. RESULTS: Two hundred five patients with TNET were treated: 25 patients received induction therapy (19 chemotherapy [CT] and 6 radiotherapy [RT]). Data about resection status were available in 47% of cases: complete resection was performed in 52 patients (54%). Masaoka-Koga stages I, II, III, and IV were observed in 12, 33, 56, and 47 patients, respectively. Atypical carcinoid was the commonest histologic subtype (71 cases; 40%). One hundred one patients with TNET received adjuvant treatment; 52 patients died and 36 experienced a recurrence. The median OS was 7.5 years; 5-year OS was 68%, and 5-year CIR was 39%. OS was significantly influenced by Masaoka-Koga stage (P = .02) and completeness of resection (P = .03). CIR significantly increased in high Masaoka-Koga stages (P = .04). Histologic subtype was not associated with either OS or CIR. CONCLUSIONS: Our results confirm the high biologic aggressiveness of these rare neoplasms; pathologic stage and completeness of resection were demonstrated to be strong prognostic factors, whereas histology did not influence patients outcome.

Matricellular protein CCN1 (CYR61) expression is associated with high-grade ductal carcinoma in situ.

Cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene (CCN) comprise a family of matricellular proteins that have multiple physiologic functions including development, tissue repair, cell adhesion, migration, and proliferation. The expression of CCN1, cyclin D1, ß-catenin, and p53 was explored by immunohistochemistry in different grades of ductal carcinoma in situ (DCIS) cases. These cases did not contain any infiltrating carcinoma components. In addition, all cysteine-rich protein 61 gene exons (encoding the CCN1 protein) were sequenced in 30 samples. Allred and H-scores were calculated for expression in both DCIS and the surrounding benign breast tissue. All cases of DCIS showed degrees of cytoplasmic CCN1 staining with median H-scores of 170, 160, and 60 in grades 3, 2, and 1, respectively (P = .043). Twelve of 28 DCIS 3, 1 of 15 DCIS 2, and 0 of 18 DCIS 1 also showed nuclear staining for CCN1. The cytoplasmic staining difference was preserved when the cases were divided into estrogen receptor (ER)+/DCIS grade 1, ER+/DCIS 2 and 3, and ER-/DCIS 2 and 3 by the H-score (P = .037). Cyclin D1 expression was positively correlated with the CCN1 cytoplasmic H-score in all DCIS samples (P = .038). Membranous ß-catenin expression correlated with the grade of intraepithelial carcinoma by both H-score (P = .047) and Allred score (P = .026). Our results suggest that CCN1 has a role in the development of intraepithelial carcinoma. CCN1 expression correlates with grade of DCIS independent of ER status. It can induce cell cycle progression through cyclin D1. It is warranted to study high expression of CCN1 in DCIS as an independent risk factor in a larger cohort.