Accelerating drug development at Bristol Myers Squibb through innovation.

This paper focuses on the use of novel technologies and innovative trial designs to accelerate evidence generation and increase pharmaceutical Research and Development (R&D) productivity, at Bristol Myers Squibb. We summarize learnings with case examples, on how we prepared and continuously evolved to address the increasing cost, complexities, and external pressures in drug development, to bring innovative medicines to patients much faster. These learnings were based on review of internal efforts toward accelerating R&D focusing on four key areas: adopting innovative trial designs, optimizing trial designs, leveraging external control data, and implementing novel methods using artificial intelligence and machine learning.

Data-driven strategies for increasing patient diversity in Bristol Myers Squibb-sponsored US oncology clinical trials.

BACKGROUND/AIMS: Determining whether clinical trial findings are applicable to diverse, real-world patient populations can be challenging when the full demographic characteristics of enrolled patients are not consistently reported. Here, we present the results of a descriptive analysis of racial and ethnic demographic information for patients in Bristol Myers Squibb (BMS)-sponsored oncology trials in the United States (US) and describe factors associated with increased patient diversity. METHODS: BMS-sponsored oncology trials conducted at US sites with study enrollment dates between 1 January 2013 and 31 May 2021 were analyzed. Patient race/ethnicity information was self-reported in case report forms. As principal investigators (PIs) did not report their own race/ethnicity, a deep-learning algorithm (ethnicolr) was used to predict PI race/ethnicity. Trial sites were linked to counties to understand the role of county-level demographics. The impact of working with patient advocacy and community-based organizations to increase diversity in prostate cancer trials was analyzed. The magnitude of associations between patient diversity and PI diversity, US county demographics, and recruitment interventions in prostate cancer trials were assessed by bootstrapping. RESULTS: A total of 108 trials for solid tumors were analyzed, including 15,763 patients with race/ethnicity information and 834 unique PIs. Of the 15,763 patients, 13,968 (89%) self-reported as White, 956 (6%) Black, 466 (3%) Asian, and 373 (2%) Hispanic. Among 834 PIs, 607 (73%) were predicted to be White, 17 (2%) Black, 161 (19%) Asian, and 49 (6%) Hispanic. A positive concordance was observed between Hispanic patients and PIs (mean = 5.9%; 95% confidence interval (CI) = 2.4, 8.9), a less positive concordance between Black patients and PIs (mean = 1.0%; 95% CI = -2.7, 5.5), and no concordance between Asian patients and PIs. Geographic analyses showed that more non-White patients enrolled in study sites in counties with higher proportions of non-White residents (e.g. a county population that was 5%-30% Black had 7%-14% more Black patients enrolled in study sites). Following purposeful recruitment efforts in prostate cancer trials, 11% (95% CI = 7.7, 15.3) more Black men enrolled in prostate cancer trials. CONCLUSION: Most patients in these clinical trials were White. PI diversity, geographic diversity, and recruitment efforts were related to greater patient diversity. This report constitutes an essential step in benchmarking patient diversity in BMS US oncology trials and enables BMS to understand which initiatives may increase patient diversity. While complete reporting of patient characteristics such as race/ethnicity is critical, identifying diversity improvement tactics with the highest impact is essential. Strategies with the greatest concordance to clinical trial patient diversity should be implemented to make meaningful improvements to the diversity of clinical trial populations.

Emulating Randomized Controlled Trials with Hybrid Control Arms in Oncology: A Case Study.

This proof-of-concept study retrospectively assessed the feasibility of applying a hybrid control arm design to a completed phase III randomized controlled trial (RCT; CheckMate-057) in advanced non-small cell lung cancer using a real-world data (RWD) source. The emulated trial consists of an experimental arm (patients from the RCT experimental cohort) and a hybrid control arm (patients from the RCT and RWD control cohorts). For the RWD control cohort, this study used a nationwide electronic health record-derived de-identified database. Three frequentist statistical borrowing methods were evaluated: a two-step Cox model, a fixed Cox model, and propensity score-integrated composite likelihood ("Methods 1-3"). The experimental treatment effect for hybrid control designs were evaluated using hazard ratios (HRs) with 95% confidence interval (CI) estimated from the Cox models accounting for covariate differences. The reduction in study duration compared to the RCT was also evaluated. All three statistical borrowing methods achieved comparable experimental treatment effects to that observed in the CheckMate-057 clinical trial, with HRs of 0.73 (95% CI: 0.59, 0.92), 0.74 (95% CI: 0.61, 0.91), 0.72 (95% CI: 0.59, 0.88) for Methods 1-3, respectively. Reduction in study duration time was 99-115 days when borrowing 30-38 events for Methods 1-3, respectively. This study demonstrated that it is feasible to emulate an RCT using a hybrid control arm design using three frequentist propensity-score based statistical borrowing methods. Selection of an appropriate, fit-for-use RWD cohort is critical to minimizing bias in experimental treatment effect.

Assessing Patient Participation Burden Based on Protocol Design Characteristics.

BACKGROUND: Although a number of studies have quantitatively measured investigative site burden to administer increasingly complex protocol designs, robust scholarly research has not been performed to quantify the burden that patients face as participants in clinical trials. METHODS: This paper presents the results of a cross-sectional pilot study conducted by the Tufts Center for the Study of Drug Development and ZS Associates among nearly 600 patients via an online survey conducted between February and March 2019. Respondents rated the perceived burden of 60 commonly administered protocol procedures. The association and relationship between overall patient burden-derived from aggregating mean perceived burden ratings for individual procedures-and performance (eg, screen failure and retention rates, clinical trial cycle times) for a cross-sectional sample of 137 individual protocols was assessed. Descriptive statistics, significance tests, and univariate analyses were performed. RESULTS: Strong positive, statistically significant associations were observed between a composite measure of patient burden and protocol-specific design and performance measures, most notably study visits above the tolerable mean and the study conduct duration from first patient first visit to last patient last visit. CONCLUSIONS: The study results suggest a new and viable approach to optimize protocol design and improve patient engagement.

Assessing Patient Participation Burden Based on Protocol Design Characteristics.

BACKGROUND: Although a number of studies have quantitatively measured investigative site burden to administer increasingly complex protocol designs, robust scholarly research has not been performed to quantify the burden that patients face as participants in clinical trials. METHODS: This paper presents the results of a cross-sectional pilot study conducted by the Tufts Center for the Study of Drug Development and ZS Associates among nearly 600 patients via an online survey conducted between February and March 2019. Respondents rated the perceived burden of 60 commonly administered protocol procedures. The association and relationship between overall patient burden-derived from aggregating mean perceived burden ratings for individual procedures-and performance (eg, screen failure and retention rates, clinical trial cycle times) for a cross-sectional sample of 137 individual protocols was assessed. Descriptive statistics, significance tests, and univariate analyses were performed. RESULTS: Strong positive, statistically significant associations were observed between a composite measure of patient burden and protocol-specific design and performance measures, most notably study visits above the tolerable mean and the study conduct duration from first patient first visit to last patient last visit. CONCLUSIONS: The study results suggest a new and viable approach to optimize protocol design and improve patient engagement.

On evaluation of consistency in multi-regional clinical trials.

In recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of 'consistency' and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.

A Systematic Review and Pooled Analysis of Select Safety Parameters Among Normal Healthy Volunteers Taking Placebo in Phase 1 Clinical Trials.

A systematic review of the Bristol-Myers Squibb normal healthy volunteers (NHVs) database identified phase 1 trials that included NHVs administered placebo with the aim of characterizing normal inter- and intraindividual safety parameter variability. Twenty-five single and multiple ascending dose studies, median duration 28 (2 to 63) days, were included in the pooled analysis (355 NHVs). Laboratory evaluations, vital signs, electrocardiograms, and adverse events were assessed. The most commonly occurring adverse event was headache (28 [7.9%] NHVs; 519.5 events/100 person-years). During the dosing period (on placebo), evaluations showed 5.1 events/100 measures of alanine aminotransferase and 7.3 events/100 measures of creatine kinase 1× above the upper limit of normal. Alanine aminotransferase and creatine kinase elevations occurred in 28 (7.9%) and 39 (11.0%) NHVs, respectively; 105 (30.3%) NHVs had low and 46 (13.3%) had high diastolic blood pressure. This analysis may inform future study designs and provide a context for interpretation of safety signals in early phase clinical trials.

Use of statistical and pharmacokinetic-pharmacodynamic modeling and simulation to improve decision-making: A section summary report of the trends and innovations in clinical trial statistics conference.

The application of modeling and simulation (M&S) methods to improve decision-making was discussed during the Trends & Innovations in Clinical Trial Statistics Conference held in Durham, North Carolina, USA on May 1-4, 2016. Uses of both pharmacometric and statistical M&S were presented during the conference, highlighting the diversity of the methods employed by pharmacometricians and statisticians to address a broad range of quantitative issues in drug development. Five presentations are summarized herein, which cover the development strategy of employing M&S to drive decision-making; European initiatives on best practice in M&S; case studies of pharmacokinetic/pharmacodynamics modeling in regulatory decisions; estimation of exposure-response relationships in the presence of confounding; and the utility of estimating the probability of a correct decision for dose selection when prior information is limited. While M&S has been widely used during the last few decades, it is expected to play an essential role as more quantitative assessments are employed in the decision-making process. By integrating M&S as a tool to compile the totality of evidence collected throughout the drug development program, more informed decisions will be made.

Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants.

Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6ß-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.

On power and sample size calculation in ethnic sensitivity studies.

In ethnic sensitivity studies, it is of interest to know whether the same dose has the same effect over populations in different regions. Glasbrenner and Rosenkranz (2006) proposed a criterion for ethnic sensitivity studies in the context of different dose-exposure models. Their method is liberal in the sense that their sample size will not achieve the target power. We will show that the power function can be easily calculated by numeric integration, and the sample size can be determined by bisection.

Statistical consideration in testing for assay sensitivity in a "thorough" QT study.

The current guidelines, ICH E14, for the evaluation of non-antiarrhythmic compounds recommends a "thorough" QT study (TQT) to be conducted during clinical development. Typically the treatment arms in the TQT study should include study drug at therapeutic and supra-therapeutic doses, placebo and a positive control such as Moxifloxacin (Avelox). The current hypothesis for assay sensitivity involves testing at pre-selected time points, where electrocardiograms (ECG) are obtained, if the mean baseline adjusted differences between positive control and placebo are greater than 5 ms. Since multiple time points are tested, the overall type I error rate should be adjusted using an appropriate multiple comparison procedure. In this article, we consider some recently proposed tests (Zhang, 2008) and explore the use of some standard global test procedures such as O'Brien's ordinary least squares (OLS) and Lauter's standardized sum (SS) tests for testing sensitivity of positive control. The powers of several test procedures are evaluated using simulation. The simulation shows that Zhang's method performs quite well in general but the OLS and SS tests have higher power when the coefficient of variations of QTc intervals have high heterogeneity.

Balanced 2(n) factorial designs when observations are spatially correlated.

In this article we focus on the optimal factorial and fractional-factorial designs when observations within blocks are correlated. The topic was motivated by a problem when the pharmaceutical experimenter needed to develop a controlled release, once-daily tablet formulation. Typically, in order to compare different formulations, trials are conducted in healthy human volunteers where each formulation is administered and bioavailability is estimated. Since each subject is administered more than one formulation, the observations within subjects are correlated. Balanced designs for 2(n) factorial experiments when observations within blocks are spatially correlated, AR(1) with positive correlation (rho > 0), are characterized. An explicit construction and analytical proof of balanced designs for both 2(n) full and 2(n-1) fractional factorial experiments is provided. In order to illustrate the construction, two examples using a complete 2(3) factorial and a half replicate of 2(4) factorial experiment are provided. We consider the optimal or near-optimal designs provided by Cheng and Steinberg (1991), Martin et al. (1998c), and Elliott et al. (1999) as the starting point to obtain balanced designs. We compare the relative efficiencies of our balanced designs with these designs.

Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study.

BACKGROUND: Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%. OBJECTIVE: This study compared the pharmacokinetics of nilotinib in subjects with hepatic impairment and subjects with normal hepatic function. METHODS: Hepatic impairment was classified as mild (Child-Pugh grade A), moderate (Child-Pugh grade B), or severe (Child-Pugh grade C). Healthy control subjects were matched with hepatically impaired subjects by age (+/-10 years) and body weight (+/-20%). All subjects received a single oral dose of nilotinib 200 mg under fasted conditions, and serial blood samples were collected at specific times up to 120 hours after dosing. Serum nilotinib concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification of 2.5 ng/mL. The pharmacokinetic parameters analyzed were C(max), T(max), AUC(0-last), AUC(0-infinity), t(1/2), CL/F, and Vz/F. Tolerability assessments included adverse events (AEs), regular monitoring of clinical laboratory measures (eg, hematology, blood chemistry, urinalysis), physical examinations, vital signs, and ECGs. Each AE was evaluated in terms of its clinical significance, severity, duration, relation to study drug, and action taken. RESULTS: The study enrolled 18 subjects with hepatic impairment (all male; age range, 47-67 years; weight range, 73.9-103.9 kg) and 9 healthy controls (all male; age range, 36-62 years; weight range, 73.3-109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC(0-infinity) was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t(1/2) was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in Vz/F in the latter 2 groups. All AEs were mild or moderate, and the frequency of AEs was not associated with the degree of hepatic impairment. AEs included abdominal pain (1 subject with mild impairment), dyspepsia (2 with mild impairment), flatulence (1 with severe impairment), nausea (1 with mild impairment), urinary tract infection (1 with mild impairment), back pain (1 each with mild impairment and severe impairment, 1 control subject), and headache (1 each with mild impairment and severe impairment). CONCLUSIONS: After a single 200-mg dose, nilotinib pharmacokinetics were modestly affected by hepatic impairment. The extent of change in nilotinib exposure in subjects with hepatic impairment was generally within the range of variability that has been observed clinically. The results of this study suggest that dose adjustment may not be necessary in patients with hepatic impairment. Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626.

Impact of baseline ECG collection on the planning, analysis and interpretation of 'thorough' QT trials.

The current guidelines, ICH E14, for the evaluation of non-antiarrhythmic compounds require a 'thorough' QT study (TQT) conducted during clinical development (ICH Guidance for Industry E14, 2005). Owing to the regulatory choice of margin (10 ms), the TQT studies must be conducted to rigorous standards to ensure that variability is minimized. Some of the key sources of variation can be controlled by use of randomization, crossover design, standardization of electrocardiogram (ECG) recording conditions and collection of replicate ECGs at each time point. However, one of the key factors in these studies is the baseline measurement, which if not controlled and consistent across studies could lead to significant misinterpretation. In this article, we examine three types of baseline methods widely used in the TQT studies to derive a change from baseline in QTc (time-matched, time-averaged and pre-dose-averaged baseline). We discuss the impact of the baseline values on the guidance-recommended 'largest time-matched' analyses. Using simulation we have shown the impact of these baseline approaches on the type I error and power for both crossover and parallel group designs. In this article, we show that the power of study decreases as the number of time points tested in TQT study increases. A time-matched baseline method is recommended by several authors (Drug Saf. 2005; 28(2):115-125, Health Canada guidance document: guide for the analysis and review of QT/QTc interval data, 2006) due to the existence of the circadian rhythm in QT. However, the impact of the time-matched baseline method on statistical inference and sample size should be considered carefully during the design of TQT study. The time-averaged baseline had the highest power in comparison with other baseline approaches.

Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Imatinib, a tyrosine kinase inhibitor, exhibits a competitive inhibition on the CYP450 2D6 isozyme with a K(i) value of 7.5 microm. However, the clinical significance of the inhibition and its relevance to 2D6 polymorphisms have not been evaluated. The pharmacokinetics of imatinib have been well studied in Caucasians, but not in a Chinese population. Metoprolol, a CYP2D6 substrate, has different clearances among patients with different CYP2D6 genotypes. It is often used as a CYP2D6 probe substrate for clinical drug-drug interaction studies. WHAT THIS STUDY ADDS: Co-administration of imatinib at 400 mg twice daily increased the plasma AUC of metoprolol by approximately 23% in 20 Chinese patients with chronic myeloid leukaemia (CML), about 17% increase in CYP2D6 intermediate metabolizers (IMs) (n = 6), 24% in extensive metabolizers (EMs) (n = 13), and 28% for the subject with unknown 2D6 status (n = 1) suggesting that imatinib has a weak to moderate inhibition on CYP2D6 in vivo. * The clearance of imatinib in Chinese patients with CML showed no difference between CYP2D6 IMs and EMs, and no major difference from Caucasian patients with CML based on data reported in the literature. AIMS To investigate the effect of imatinib on the pharmacokinetics of a CYP2D6 substrate, metoprolol, in patients with chronic myeloid leukaemia (CML). The pharmacokinetics of imatinib were also studied in these patients. METHODS: Patients (n = 20) received a single oral dose of metoprolol 100 mg on day 1 after an overnight fast. On days 2-10, imatinib 400 mg was administered twice daily. On day 8, another 100 mg dose of metoprolol was administered 1 h after the morning dose of imatinib 400 mg. Blood samples for metoprolol and alpha-hydroxymetoprolol measurement were taken on study days 1 and 8, and on day 8 for imatinib. RESULTS: Of the 20 patients enrolled, six patients (30%) were CYP2D6 intermediate metabolizers (IMs), 13 (65%) extensive metabolizers (EMs), and the CYP2D6 status in one patient was unknown. In the presence of 400 mg twice daily imatinib, the mean metoprolol AUC was increased by 17% in IMs (from 1190 to 1390 ng ml(-1) h), and 24% in EMs (from 660 to 818 ng ml(-1) h). Patients classified as CYP2D6 IMs had an approximately 1.8-fold higher plasma metoprolol exposure than those classified as EMs. The oral clearance of imatinib was 11.0 +/- 2.0 l h(-1) and 11.8 +/- 4.1 l h(-1) for CYP2D6 IMs and EMs, respectively. CONCLUSIONS: Co-administration of a high dose of imatinib resulted in a small or moderate increase in metoprolol plasma exposure in all patients regardless of CYP2D6 status. The clearance of imatinib showed no difference between CYP2D6 IMs and EMs.

Sample size calculation for the Power Model for dose proportionality studies.

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope. Here we propose analytical derivations of sample sizes for various designs (including crossover, incomplete block and parallel group designs) to be analysed according to the Power Model.

Comparison of transcranial electric motor and somatosensory evoked potential monitoring during cervical spine surgery.

BACKGROUND: There has been little enthusiasm for somatosensory evoked potential monitoring in cervical spine surgery as a result, in part, of the increased risk of motor tract injury at this level, to which somatosensory monitoring may be insensitive. Transcranial electric motor evoked potential monitoring allows assessment of the motor tracts; therefore, we compared transcranial electric motor evoked potential and somatosensory evoked potential monitoring during cervical spine surgery to determine the temporal relationship between the changes in the potentials demonstrated by each type of monitoring and neurological sequelae and to identify patient-related and surgical factors associated with intraoperative neurophysiological changes. METHODS: Somatosensory evoked potential and transcranial electric motor evoked potential data recorded for 427 patients undergoing anterior or posterior cervical spine surgery between January 1999 and March 2001 were analyzed. All patients who showed substantial (at least 60%) or complete unilateral or bilateral amplitude loss, for at least ten minutes, during the transcranial electric motor evoked potential and/or somatosensory evoked potential monitoring were identified. RESULTS: Twelve of the 427 patients demonstrated substantial or complete loss of amplitude of the transcranial electric motor evoked potentials. Ten of those patients had complete reversal of the loss following prompt intraoperative intervention, whereas two awoke with a new motor deficit. Somatosensory evoked potential monitoring failed to identify any change in one of the two patients, and the change in the somatosensory evoked potentials lagged behind the change in the transcranial electric motor evoked potentials by thirty-three minutes in the other. No patient showed loss of amplitude of the somatosensory evoked potentials in the absence of changes in the transcranial electric motor evoked potentials. Transcranial electric motor evoked potential monitoring was 100% sensitive and 100% specific, whereas somatosensory evoked potential monitoring was only 25% sensitive; it was, however, 100% specific. CONCLUSIONS: Transcranial electric motor evoked potential monitoring appears to be superior to conventional somatosensory evoked potential monitoring for identifying evolving motor tract injury during cervical spine surgery. Surgeons should strongly consider using this modality when operating on patients with cervical spondylotic myelopathy in general and on those with ossification of the posterior longitudinal ligament in particular.

Evaluation of vardenafil and sildenafil on cardiac repolarization.

This novel study evaluated the effects of vardenafil and sildenafil on QT and corrected QT (QTc) duration using a model that minimizes experimental error to obtain the most accurate assessment of observed QTc effects. A placebo-controlled and positive-controlled, period-balanced, double-blinded, 6-way crossover study evaluated therapeutic and supratherapeutic oral doses of vardenafil (10 and 80 mg, respectively) and sildenafil (50 and 400 mg, respectively), therapeutic doses of moxifloxacin (400 mg), and a placebo in 58 healthy men (mean age 53 years), with dosing every 3 days. Six replicate, 12-lead, digital electrocardiograms (ECGs) were recorded at 3 time points before and 5 time points after dosing to cover the time course of maximum exposure to study drugs and their metabolites. An independent laboratory blindly analyzed approximately 17,000 ECGs. For the placebo, mean change in QTcF (Fridericia) duration 1 hour after dose (approximate Tmax of vardenafil and sildenafil) was 0 ms (+/-0.7 SD). QT/QTc variability was small across regimens, indicating statistically powerful results. Moxifloxacin demonstrated an expected 8-ms mean change and was the only drug to prolong absolute QT. Placebo-corrected mean changes in QTcF duration (90% confidence interval) at 1 hour after dose were 8 ms (range 6 to 9) for vardenafil 10 mg and 6 ms (range 5 to 8) for sildenafil 50 mg. QTci (linear and nonlinear per patient) yielded similar trends: 4 ms (range 3 to 6) for vardenafil 10 mg and 4 ms (range 2 to 5) for sildenafil 50 mg. Dose response demonstrated very shallow QTc relations for study drugs. Therapeutic and supratherapeutic doses produced only small increases in the QTcF interval, which were considered to be clinically irrelevant. This well-controlled, statistically powerful study in middle-aged men demonstrated that vardenafil and sildenafil produced no increase of absolute QT and only similar, small increases of the QTc interval, with a shallow dose-response curve. The study design and conduct may serve as a guide for future QT assessment of new drugs.