Some Thoughts on the Use of Predictive Probability in Clinical Trials.

In this short note, we express our viewpoint regarding declaring study success based on Bayesian predictive probability of study success.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses.

Purpose: To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy.

Methods: We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models.

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis.

In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia.

Unlabelled: On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older.

FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia.

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin.

Bayesian hierarchical methods for meta-analysis combining randomized-controlled and single-arm studies.

Meta-analysis of interventions usually relies on randomized controlled trials. However, when the dominant source of information comes from single-arm studies, or when the results from randomized controlled trials lack generalization due to strict inclusion and exclusion criteria, it is vital to synthesize both sources of evidence. One challenge of synthesizing both sources is that single-arm studies are usually less reliable than randomized controlled trials due to selection bias and confounding factors.

U.S. Food and Drug Administration approval summary: Eltrombopag for the treatment of pediatric patients with chronic immune (idiopathic) thrombocytopenia.

The U.S. Food and Drug Administration (FDA) approved eltrombopag for pediatric patients with chronic immune (idiopathic) thrombocytopenia (ITP) ages ≥6 on June 11, 2015, and ages ≥1 on August 24, 2015.

FDA Drug Approval: Elotuzumab in Combination with Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma.

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR).

FDA Approval: Blinatumomab.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager.

FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease.

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC.

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.

U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia.

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc.

Relationship Between Progression-Free Survival and Overall Survival Benefit: A Simulation Study.

Unlabelled: This study evaluated the circumstances under which the observed progression-free survival (PFS) benefit may translate into an overall survival (OS) benefit.

Methods: A simulation study, based on PFS and OS joint model decomposition, was conducted to evaluate the impact of crossover rates, survival post progression (SPP) lengths, and magnitudes of difference in median PFS on OS. Under different simulation scenarios, the degree of impact was investigated based on the probability of observing a significant OS benefit given an observed PFS benefit.

A systematic comparison of cockcroft-gault and modification of diet in renal disease equations for classification of kidney dysfunction and dosage adjustment.

Background: The dosing of drugs in patients with kidney dysfunction is often based on the estimates of kidney function.

Objective: To systematically compare the performance of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations for dosage adjustment.

Methods: We assessed agreement (concordance, kappa statistics [κ,κ(ω)]) between CG and MDRD using a Food and Drug Administration database to evaluate the effect of renal function on the pharmacokinetics of 36 approved drugs.

The influence of body size descriptors on the estimation of kidney function in normal weight, overweight, obese, and morbidly obese adults.

Background: Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCl) because measuring kidney function is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations.

Objective: To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCl (mCrCl).

Hearing threshold levels at age 70 years (65-74 years) in the unscreened older adult population of the United States, 1959-1962 and 1999-2006.

Objectives: To provide hearing threshold percentiles from unscreened older adults for creating new Annex B reference standards.

Design: Percentiles are calculated, and 95% confidence intervals for medians from two U.S.

Term pregnancy: a period of heterogeneous risk for infant mortality.

Objective: To estimate the trend of maternal racial and ethnic differences in mortality for early-term (37 0/7 to 38 6/7 weeks of gestation) compared with full-term births (39 0/7 to 41 6/7 weeks of gestation).

Methods: We analyzed 46,329,018 singleton live births using the National Center for Health Statistics U.S.

Americans hear as well or better today compared with 40 years ago: hearing threshold levels in the unscreened adult population of the United States, 1959-1962 and 1999-2004.

Objectives: (1) To present hearing threshold data from a recent nationally representative survey in the United States (National Health and Nutrition Examination Survey, 1999-2004) in a distributional format that might be appropriate to replace Annex B in international (ISO-1999) and national (ANSI S3.44) standards and (2) to compare these recent data with older survey data (National Health Examination Survey I, 1959-1962) on which the current Annex B is based.

Design: Better-ear threshold distributions (selected percentiles and their confidence intervals) were estimated using linear interpolation.

Vision, hearing, balance, and sensory impairment in Americans aged 70 years and over: United States, 1999-2006.

Sensory impairments are a substantial problem for older Americans: One out of six has impaired vision; one out of four has impaired hearing; one out of four has loss of feeling in the feet; and three out of four have abnormal postural balance testing. Sensory impairments increase with age: Vision and hearing impairments each double, and loss of feeling in the feet increases by 40% in persons aged 80 years and over compared with persons aged 70-79 years. One in five Americans below the poverty threshold has impaired vision: 50% higher than other Americans.

Racial disparities in stillbirth risk across gestation in the United States.

Objective: We sought to determine factors associated with racial disparities in stillbirth risk.

Study Design: Stillbirth hazard was analyzed using 5,138,122 singleton gestations from the National Center of Health Statistics perinatal mortality and birth files, 2001-2002.

Results: Black women have a 2.

Delivery indications at late-preterm gestations and infant mortality rates in the United States.

Objective: The rate of preterm births has been increasing in the United States, especially for births 34 to 36 weeks of gestation (late preterm), which now constitute 71% of all preterm births. The causes for these trends remain unclear. We characterized the delivery indications for late preterm births and their potential impact on neonatal and infant mortality rates.

FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2.

On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2-overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab.

Bortezomib for the treatment of mantle cell lymphoma.

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma.

Experimental Design: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy.

Results: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease.

Toxicity of substituted anilines to Pseudokirchneriella subcapitata and quantitative structure-activity relationship analysis for polar narcotics.

This study evaluated the toxic effects of substituted anilines on Pseudokirchneriella subcapitata with the use of a closed algal toxicity testing technique with no headspace. Two response endpoints (i.e.

Maternal age and the risk of stillbirth throughout pregnancy in the United States.

Objective: The objective of the study was to examine the relationship of maternal age with stillbirth risk throughout gestation.

Study Design: A total of 5,458,735 singleton gestations without reported congenital anomalies from the 2001 to 2002 National Center for Health Statistics perinatal mortality and natality files were analyzed. Hazard rates (risk) of stillbirth (fetal death 20 weeks or longer) were calculated for each week of gestation.