Estimand in benefit-risk assessment.

ICH E9(R1) introduces the estimand framework to strengthen dialogues between sponsors and regulators during drug development. A well-structured benefit-risk assessment (BRA) framework also intends to facilitate communication among stakeholders. However, the estimand in ICH E9(R1) is written mainly from the perspective of a single measure of treatment effect in clinical trials. There is lack of systematic discussion on estimand in the context of BRA. This paper initiates the BRA discussion under the estimand framework. By identifying two types of BRA approaches, we summarize and discuss completed clinical trials, using the estimand language for BRA. Benefits and challenges of using estimand for BRA are also discussed.

Win statistics (win ratio, win odds, and net benefit) can complement one another to show the strength of the treatment effect on time-to-event outcomes.

Conventional analyses of a composite of multiple time-to-event outcomes use the time to the first event. However, the first event may not be the most important outcome. To address this limitation, generalized pairwise comparisons and win statistics (win ratio, win odds, and net benefit) have become popular and have been applied to clinical trial practice. However, win ratio, win odds, and net benefit have typically been used separately. In this article, we examine the use of these three win statistics jointly for time-to-event outcomes. First, we explain the relation of point estimates and variances among the three win statistics, and the relation between the net benefit and the Mann-Whitney U statistic. Then we explain that the three win statistics are based on the same win proportions, and they test the same null hypothesis of equal win probabilities in two groups. We show theoretically that the Z-values of the corresponding statistical tests are approximately equal; therefore, the three win statistics provide very similar p-values and statistical powers. Finally, using simulation studies and data from a clinical trial, we demonstrate that, when there is no (or little) censoring, the three win statistics can complement one another to show the strength of the treatment effect. However, when the amount of censoring is not small, and without adjustment for censoring, the win odds and the net benefit may have an advantage for interpreting the treatment effect; with adjustment (e.g., IPCW adjustment) for censoring, the three win statistics can complement one another to show the strength of the treatment effect. For calculations we use the R package WINS, available on the CRAN (Comprehensive R Archive Network).

Design of paediatric trials with benefit-risk endpoints using a composite score of adverse events of interest (AEI) and win-statistics.

A fundamental problem in the regulatory evaluation of a therapy is assessing whether the benefit outweighs the associated risks. This work proposes designing a trial that assesses a composite endpoint consisting of benefit and risk, hence, making the core of the design of the study, to assess benefit and risk. The proposed benefit risk measure consists of efficacy measure(s) and a risk measure that is based on a composite score obtained from pre-defined adverse events of interest (AEI). This composite score incorporates full aspects of adverse events of interest (i.e. the incidence, severity, and duration of the events). We call this newly proposed score the AEI composite score. After specifying the priorities between the components of the composite endpoint, a win-statistic (i.e. win ratio, win odds, or net benefit) is used to assess the difference between treatments in this composite endpoint. The power and sample size requirements of such a trial design are explored via simulation. Finally, using Dupixent published adult study results, we show how we can design a paediatric trial where the primary outcome is a composite of prioritized outcomes consisting of efficacy endpoints and the AEI composite score endpoint. The resulting trial design can potentially substantially reduce sample size compared to a trial designed to assess the co-primary efficacy endpoints, therefore it may address the challenge of slow enrollment and patient availability for paediatric studies.

The win odds: statistical inference and regression.

Generalized pairwise comparisons and win statistics (i.e., win ratio, win odds and net benefit) are advantageous in analyzing and interpreting a composite of multiple outcomes in clinical trials. An important limitation of these statistics is their inability to adjust for covariates other than by stratified analysis. Because the win ratio does not account for ties, the win odds, a modification that includes ties, has attracted attention. We review and combine information on the win odds to articulate the statistical inferences for the win odds. We also show alternative variance estimators based on the exact permutation and bootstrap as well as statistical inference via the probabilistic index. Finally, we extend multiple-covariate regression probabilistic index models to the win odds with a univariate outcome. As an illustration we apply the regression models to the data in the CHARM trial.

Real-World Evidence Utilization in Clinical Development Reflected by US Product Labeling: Statistical Review.

The US Food and Drug Administration (FDA) has shown scientific discretion in interpreting the substantial evidence requirement for the approval of new drugs with its considerations on the use of single controlled or uncontrolled trials (Federal Food, Drug, and Cosmetic Act § 505(d), 21 USC 355(d), 1962). With the passage of the 21st Centuries Cures Act (21st Century Cures-patients. House, Energy and Commerce Committee, Washington, DC, 2019 available at: https://energycommerce.house.gov/sites/republicans.energycommerce.house.gov/files/analysis/21stCenturyCures/20140516PatientsWhitePaper.pdf ), the FDA is mandated to expand the role of real-world evidence (RWE) in support of drug approval. This mandate further broadens the scope of scientific discretion to include data collected outside clinical trials. We summarize the agency's past acceptance of real-world data (RWD) sources for supporting drug approval in new indications which have been reflected in US labels. In our summary, we focus on the type of RWD and statistical methodologies presented in these labels. Furthermore, two labels were selected for in-depth assessment of the RWE presented in these labels. Through these examples, we demonstrate the issues that can be raised in data collection that could affect interpretation. In addition, a brief discussion of statistical methods that can be used to incorporate RWE to clinical development is presented.

Randomized, assessor-blinded trial comparing highly purified human menotropin and recombinant follicle-stimulating hormone in high responders undergoing intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the efficacy and safety of highly purified human menotropin (HP-hMG) and recombinant follicle-stimulating hormone (rFSH) for controlled ovarian stimulation in a population of patients predicted to be high responders. DESIGN: Randomized, open-label, assessor-blinded, parallel-group, noninferiority trial. SETTING: Fertility centers. PATIENT(S): A total of 620 women with serum antimüllerian hormone (AMH) ≥5 ng/mL. INTERVENTION(S): Controlled ovarian stimulation with HP-hMG or rFSH in a GnRH antagonist assisted reproductive technology (ART) cycle. Fresh transfer of a single blastocyst was performed unless ovarian response was excessive, in which all embryos were cryopreserved. Subjects could undergo subsequent frozen blastocyst transfer within 6 months of randomization. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) after fresh transfer (primary endpoint), as well as cumulative live birth, ovarian hyperstimulation syndrome (OHSS), and pregnancy loss rates. RESULTS: OPR/cycle start after fresh transfer was 35.5% with HP-hMG and 30.7% with rFSH (difference: 4.7%, 95% CI -2.7%, 12.1%); noninferiority was established. Compared to rFSH, HP-hMG was associated with significantly lower OHSS (21.4% vs. 9.7% respectively; difference: -11.7%, 95% CI -17.3%, -6.1%) and cumulative early pregnancy loss rates (25.5% vs. 14.5% respectively; difference: -11.0%, 95% CI -18.8%, -3.14%). Despite 43 more transfers in the rFSH group, cumulative live birth rates were similar with HP-hMG and rFSH at 50.6% and 51.5% respectively (difference: -0.8%, 95% CI -8.7%, 7.1%). CONCLUSION(S): In high responders, HP-hMG provided comparable efficacy to rFSH with fewer adverse events, including pregnancy loss, suggesting its optimized risk/benefit profile in this population. CLINICAL TRIAL REGISTRATION NUMBER: NCT02554279 (clinicaltrials.gov).

The win ratio: Impact of censoring and follow-up time and use with nonproportional hazards.

The win ratio has been studied methodologically and applied in data analysis and in designing clinical trials. Researchers have pointed out that the results depend on follow-up time and censoring time, which are sometimes used interchangeably. In this article, we distinguish between follow-up time and censoring time, show theoretically the impact of censoring on the win ratio, and illustrate the impact of follow-up time. We then point out that, if the treatment has long-term benefit from a more important but less frequent endpoint (eg, death), the win ratio can show that benefit by following patients longer, avoiding masking by more frequent but less important outcomes, which occurs in conventional time-to-first-event analyses. For the situation of nonproportional hazards, we demonstrate that the win ratio can be a good alternative to methods such as landmark survival rate, restricted mean survival time, and weighted log-rank tests.

Efficacy and safety of a ready-to-drink bowel preparation for colonoscopy: a randomized, controlled, non-inferiority trial.

BACKGROUND: We performed a randomized, controlled, assessor-blinded, multicenter, non-inferiority (NI) study to compare the safety and efficacy of a ready-to-drink formulation of sodium picosulfate, magnesium oxide, and citric acid (SPMC oral solution) with a powder formulation (P/MC powder) for oral solution. METHODS: Eligible participants (adults undergoing elective colonoscopy) were randomized 1:1 to split-dose SPMC oral solution or P/MC powder. The primary efficacy endpoint assessed overall colon-cleansing quality with the Aronchick Scale (AS), and the key secondary efficacy endpoint rated quality of right colon cleansing with the Boston Bowel Preparation Scale (BBPS). Assessments were performed by a treatment-blinded endoscopist. Tolerability was assessed using the Mayo Clinic Bowel Prep Tolerability Questionnaire. Safety assessments included adverse events and laboratory evaluations. RESULTS: The study included 901 participants: 448 for SPMC oral solution; 453 for P/MC powder. SPMC oral solution demonstrated non-inferiority to P/MC powder {87.7% (393/448) responders versus 81.5% (369/453) responders [difference (95% confidence interval): 6.3% (1.8, 10.9)]}. The key secondary efficacy objective assessing the right colon was also met. According to the prespecified hierarchical testing, after meeting the primary and key secondary objectives, SPMC oral solution was tested for superiority to P/MC powder for the primary endpoint (p = 0.0067). SPMC oral solution was well tolerated. Most common adverse events were nausea (3.1% versus 2.9%), headache (2.7% versus 3.1%), hypermagnesemia (2.0% versus 5.1%), and vomiting (1.3% versus 0.7%) for SPMC oral solution and P/MC powder, respectively. CONCLUSIONS: Ready-to-drink SPMC oral solution showed superior efficacy of overall colon cleansing compared with P/MC powder, with similar safety and tolerability.[ClinicalTrials.gov identifier: NCT03017235.].

Statistical Monitoring in Clinical Trials: Best Practices for Detecting Data Anomalies Suggestive of Fabrication or Misconduct.

BACKGROUND: Traditional site-monitoring techniques are not optimal in finding data fabrication and other nonrandom data distributions with the greatest potential for jeopardizing the validity of study results. TransCelerate BioPharma conducted an experiment testing the utility of statistical methods for detecting implanted fabricated data and other signals of noncompliance. METHODS: TransCelerate tested statistical monitoring on a data set from a chronic obstructive pulmonary disease (COPD) clinical study with 178 sites and 1554 subjects. Fabricated data were selectively implanted in 7 sites and 43 subjects by expert clinicians in COPD. The data set was partitioned to simulate studies of different sizes. Analyses of vital signs, spirometry, visit dates, and adverse events included distributions of standard deviations, correlations, repeated values, digit preference, and outlier/inlier detection. An interpretation team, including clinicians, statisticians, site monitoring, and data management, reviewed the results and created an algorithm to flag sites for fabricated data. RESULTS: The algorithm identified 11 sites (19%), 19 sites (31%), 28 sites (16%), and 45 sites (25%) as having potentially fabricated data for studies 2A, 2, 1A, and 1, respectively. For study 2A, 3 of 7 sites with fabricated data were detected, 5 of 7 were detected for studies 2 and 1A, and 6 of 7 for study 1. Except for study 2A, the algorithm had good sensitivity and specificity (>70%) for identifying sites with fabricated data. CONCLUSIONS: We recommend a cross-functional, collaborative approach to statistical monitoring that can adapt to study design and data source and use a combination of statistical screening techniques and confirmatory graphics.

Nonparametric multivariate inference on shift parameters.

RATIONALE AND OBJECTIVES: Consider a study evaluating the prognostic value of prostate-specific antigen (PSA), in the presence of Gleason score, in differentiating between early and advanced prostate cancer. This data set features subjects divided into two groups (early versus advanced cancer), with one manifest variable (PSA), one covariate (Gleason score), and one stratification variable (hospital, taking three values). We present a nonparametric method for estimating a shift in median PSA score between the two groups, after adjusting for differences in Gleason score and stratifying on hospital. This method can also be extended to cases involving multivariate manifest variable. MATERIALS AND METHODS: Our method uses estimating equations derived from an existing rank-based estimator of the area under the receiver operating characteristic curve (AUC). This existing AUC estimator is adjusted for stratification and for covariates. We use the adjusted AUC estimator to construct a family of tests by shifting manifest variables in one of the treatment groups by an arbitrary constant. The null hypothesis for these tests is that the AUC is half. We report the set of shift values for which the null hypothesis is not rejected as the resulting confidence region. RESULTS: Simulated data show performance consistent with the distributional approximations used by the proposed methodology. This methodology is applied to two examples. In the first example, the mean difference in PSA levels between advanced and nonadvanced prostate cancer patients is estimated, controlling for Gleason score. In the second example, to assess the degree to which age and baseline tumor size are prognostic factors for breast cancer recurrence, differences in age and tumor size between subjects with recurrent and nonrecurrent breast cancer, stratified on Tamoxifen treatment and adjusting for tumor grade, are estimated. CONCLUSIONS: The proposed methodology provides a nonparametric method for a statistic measuring adjusted AUC to be used to estimate shift between two manifest variables.

Time-to-effect with darifenacin in overactive bladder: a pooled analysis.

INTRODUCTION AND HYPOTHESIS: This study was conducted to assess time-to-effect with darifenacin in patients with overactive bladder (OAB). METHODS: Efficacy and safety data were pooled from 1,059 patients (19-88 years, 85% women) randomized to darifenacin 7.5 or 15 mg once daily or matched placebo in three double-blind 12-week studies. Patients completed electronic bladder symptom diaries (number of micturitions/day; incontinence episodes/day; urgency episodes/day). A post hoc efficacy analysis was performed on the earliest recorded timepoints. RESULTS: The full analysis population comprised 1,053 patients. Statistically significant improvements were observed in all OAB symptoms (except nocturnal awakenings) for both darifenacin doses versus placebo at week 2, with further improvements over 6 and 12 weeks. Both darifenacin doses significantly improved all OAB symptoms from as early as days 6-8 versus placebo. CONCLUSIONS: Darifenacin 7.5 and 15 mg significantly reduced OAB symptoms throughout the study. The rapid onset-of-effect is desirable to patients with OAB and useful for their clinical management.

Moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy.

OBJECTIVES: Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy. METHODS: In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥ 150-<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg. RESULTS: At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P < 0.05) from week 4 (-23.0/-10.4 versus -19.2/-8.7 mmHg; primary endpoint) to week 12 (-29.0/-14.8 versus -25.3/-12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P = 0.025). CONCLUSIONS: Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.

Effect of intensive versus standard blood pressure lowering on diastolic function in patients with uncontrolled hypertension and diastolic dysfunction.

Diastolic dysfunction may precede development of heart failure in hypertensive patients. We randomized 228 patients with uncontrolled hypertension, preserved ejection fraction, and diastolic dysfunction to 2 targeted treatment strategies: intensive, with a systolic blood pressure target of <130 mm Hg, or standard, with a systolic blood pressure target of <140 mm Hg, using a combination of valsartan, either 160 or 320 mg, plus amlodipine, either 5 or 10 mg, with other antihypertensive medications as needed. Echocardiographic assessment of diastolic function was performed at baseline and after 24 weeks in a prospective, open-label, blinded end point design. Blood pressure was reduced significantly in both groups, from 161.2+/-13.9/90.1+/-12.0 to 130.8+/-12.3/74.9+/-9.1 mm Hg (P<0.0001) in the intensive arm and from 162.1+/-13.2/93.7+/-12.2 to 137.0+/-12.9/79.6+/-11.0 mm Hg (P<0.0001) in the standard arm (P<0.003 for between-group comparisons). Myocardial relaxation velocity improved from 7.6+/-1.1 to 9.2+/-1.7 cm/s (Delta 1.54+/-1.4 cm/s; P<0.0001) in the intensive arm and from 7.5+/-1.3 to 9.0+/-1.9 cm/s (Delta 1.48+/-1.6 cm/s; P<0.0001) in the standard arm, with no difference between the 2 strategies in the achieved improvement (P=0.58). The degree of improvement in annular relaxation velocity was associated with the extent of systolic blood pressure reduction, and patients with the lowest achieved systolic blood pressure had the highest final diastolic relaxation velocities.

Initial combination therapy compared with monotherapy in diabetic hypertensive patients.

Subgroup analyses were performed for the diabetic and nondiabetic cohorts from 3 randomized clinical trials that had evaluated the systolic blood pressure (SBP)-lowering efficacy and tolerability of an angiotensin receptor blocker, valsartan, alone or in combination with hydrochlorothiazide to determine when and how to initiate combination therapy in hypertensive patients with diabetes. Blood pressure reductions achieved with monotherapy were compared with combination therapy in the diabetic and nondiabetic cohorts. In addition, multivariate models were developed to predict the likelihood of the goal SBP of < 130 mm Hg being reached in a diabetic patient with monotherapy or combination therapy across the range of baseline SBP values. In 2 of the 3 trials, comparable reductions in SBP were seen in the diabetic and nondiabetic cohorts. In all 3 studies, however, combination therapy provided greater blood pressure-lowering efficacy than monotherapy. The probability of achieving goal SBP was greater for diabetic patients started on combination therapy compared with monotherapy.

Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study.

With the objective of enhancing upper gastrointestinal (GI) tolerability, enteric-coated mycophenolate sodium (EC-MPS, myfortic, Novartis Pharma AG, Basel, Switzerland) has been developed. This double-blinded, 12-month study investigated whether renal transplant patients taking mycophenolate mofetil (MMF) can be safely converted to EC-MPS. Stable kidney transplant patients were randomized to receive EC-MPS (720 mg b.i.d.; n=159) or continue receiving MMF (1000 mg b.i.d.; n=163). The incidence of GI adverse events (AEs) was similar at 3 months (primary endpoint: EC-MPS 26.4%; MMF 20.9%; p=NS) and at 12 months (EC-MPS 29.6%; MMF 24.5%; p=NS). The increase from baseline in mean GI AE severity score, adjusted for duration, tended to be lower in EC-MPS patients (3 months: 0.15 vs. 0.20; 12 months: 0.23 vs. 0.47; p=NS). Neutropenia (<1500 cells/mm3) within the first 3 months (coprimary endpoint) was low in both groups (EC-MPS 0.6%; MMF 3.1%; p=NS). Although the overall incidence of infections was similar, the number of serious infections was significantly lower in EC-MPS patients (8.8% vs. 16.0%; p<0.05). Similar rates of efficacy failure (EC-MPS 2.5%; MMF 6.1%; p=NS), biopsy-proven acute rejection (EC-MPS 1.3%; MMF 3.1%; p=NS) and biopsy-proven chronic rejection (EC-MPS 3.8%; MMF 4.9%; p=NS) were observed in both groups. In conclusion, renal maintenance patients can be converted from MMF to EC-MPS without compromising the safety and efficacy profile associated with MMF.