East® 6

The Comprehensive Trial Design Solution

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Extensive time and energy is often spent designing feasible clinical studies. East's broad range of statistical tools and expert simulations provides an invaluable resource for the rapid construction of trial designs. Illuminating graphs and charts allow for accessible comparison, while a user-friendly interface encourages exploration and experiment.

East® addresses the concerns and requirements in the FDA guidance “Adaptive Design Clinical Trials for Drugs and Biologics."

East® 6.4 The Software Behind Your Next Successful Trial

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The Advantages of East

Developed by accomplished study design experts, East creates clinical trials that best address key questions confronted by clinical investigators. East is widely validated in practice and referred to by international regulatory agencies.

Powerful simulation tools allow users to compare designs and choose the trial best suited to their study's objectives. Intuitively organized tasks and workflows further enhance productivity. East provides opportunities to optimize the process of selecting superior designs, and ensures access to a range of proven algorithms.

Read the current FDA adaptive trial guidance

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 Empower Your Team

Play a more strategic role in your organization: East simplifies and automates study design and simulation, allowing users to redirect time, attention and critical resources to other vital aspectsof clinical trial success.

 Share Ideas Easily

Convince your team of the merits of your design: Powerful simulations and customizable tables, graphs and charts, facilitate clear communication with colleagues and authorities. Foster a collaborative environment for project teams by sharing designs in real time.

 Assess All Options

Optimize your trial design: Rapidly generate multiple adaptive designs, perform sensitivity analysis to evaluate their robustness to critical assumptions, and use sophisticated tables and graphs to compare their operating characteristics.

 Trusted Results

Be confident you have the right design: Trusted and validated for over 20 years, East has been used to design countless clinical trials performed in industry, government, and academia. Regulatory authorities throughout the world trust East.

The Modular Format Start with the East BASE and add additional features when you need them.

  • East

East BASE

East BASE is a user friendly, validated software package for planning, simulating, analyzing and communicating fixed-sample clinical trial designs. East BASE provides a wide variety of options for Normal, Binomial, and Survival endpoints, with advanced capabilities for complex patterns of accruals, dropouts and response lag. It includes superiority, non-inferiority, equivalence, and confidence-interval based designs.

East MULTIARM

MULTIARM is an East module that offers the ability to plan, simulate, analyze, and communicate multi-arm fixed sample clinical trial designs. MULTIARM provides a wide variety of multiple testing procedures for the strong control of family-wise type-1 error rate when comparing multiple treatment arms to a control for Normal and Binomial endpoints.

East MULTIARM guides users through the complexities of multiplicity adjustment in order to construct reliable trials with multiple arms. A crucial regulatory requirement for multi-arm trials is establishing strong control of the family-wise error rate. East provides a variety of multiplicity adjustment measures to confirm strong control, along with advanced calculations that demonstrate a trial’s statistical power.

East ENDPOINTS

ENDPOINTS is an East module for the design, simulation, and analysis of studies that need to test multiple endpoints. Using a variety of multiple testing procedures, and including both serial and parallel gatekeeping procedures (Dmitrienko and Tamhane, 2007), ENDPOINTS ensures you have the right strategy for the strong control of type-1 error given multiple endpoints testing. Optimize the testing strategy to obtain the best operating characteristics to meet your goals.

East Exact

EXACT is an East module for the design, simulation, and monitoring of binomial response trials using exact distributional assumptions, with particular application to phase 2 single-arm screening trials in oncology. EXACT utilizes the powerful engines of StatXact, to perform sample size and power calculations for clinical trials that require exact tests for binomial superiority, non-inferiority, and equivalence designs. Includes exact single-stage (A’Hern, 2001), both optimal and mini-max two-stage (Simon, 1989), and group sequential designs for single-arm studies.

East Escalate

ESCALATE is an East module for the design, simulation, and monitoring of modern dose-escalation clinical trials. Evaluate and compare the operating characteristics of your designs under different assumptions about the dose-toxicity profile. Provide optimal dose recommendations for the next cohort of patients based on accumulating data. Clearly communicate critical information to clinicians to guide dosing decisions. Model-based dose-escalation methods in this module include the Continual Reassessment Method (mCRM; Goodman et al., 1995), the Bayesian logistic regression model (BLRM; Neuenschwander et al., 2008; 2015), the modified Toxicity Probability Interval (mTPI; Ji et al., 2010), and the Product of Independent Beta Probabilities Escalation method (PIPE; Mander & Sweeting, 2015).

East Sequential

SEQUENTIAL is an East module for planning, simulating, monitoring and communicating group sequential clinical trial designs. Provides a wide variety of options for normal and binomial endpoints in superiority, non-inferiority, and equivalence studies. Evaluate and compare the operating characteristics of different study designs on multiple information scales as well as graphically. Plan sample size, time, and cost savings by building in efficacy and futility boundaries. Quantify your trial’s probability of success while remaining sensitive to deviations both analytically and via simulation.

East Adapt

ADAPT is an East module for planning, simulating, monitoring, and communicating clinical trial designs that incorporate un-blinded sample size re-estimation rules. ADAPT provides a wide variety of options for normal and binomial endpoints, with strong control of the type-1 error rate. ADAPT includes hypothesis testing and adjusted inference based on methods by Cui, Hung, and Wang (1999), Mueller and Schafer (2001), Chen, DeMets, and Lan (2004), Gao, Ware and Mehta (2008), and the Promising Zone Design approach of Pocock and Mehta (2010).

East Survival

SURVIVAL is an East module for planning, simulating, monitoring and communicating group sequential clinical trial designs with survival endpoints. SURVIVAL provides a wide variety of options for survival endpoints in superiority and non-inferiority studies. It includes advanced capabilities to account for subject dropouts, non-uniform accrual, non-constant hazard rates and fixed follow-up time in studies with time-to-event endpoints. Simulate for accurate estimation of the total study duration - even under different enrollment patterns with differential drop out and varying hazard rates for the treatment arms, or to accommodate alternatives for non-proportional hazards. East SURVIVAL provides powerful yet simple to use simulation tools that can illustrate complex survival data at the design stage.

East Predict

PREDICT is an East module that offers the ability to simulate and forecast the future course of a trial based on current data. It includes conditional simulations to assess expected treatment effects and associated repeated confidence intervals at future looks (also called Predicted Interval Plots or PIP; Li et al. 2009), as well as the probability of finishing with a successful trial (conditional power). Plan and simulate clinical trials with greater precision using different accrual patterns and response information for different regions/sites. Make probabilistic statements about accruals, events, and study duration using accumulating data.

East SurvAdapt

SURVADAPT is an East module for planning, simulating, monitoring, and communicating clinical trial designs that incorporate un-blinded sample size re-estimation rules. SURVADAPT provides a wide variety of options for survival endpoints, plus strong control of type-1 error rate. SURVADAPT includes hypothesis testing and adjusted inference based on methods by Cui, Hung, and Wang (1999), Mueller and Schafer (2001), Chen, DeMets, and Lan (2004), Gao, Ware and Mehta (2008), and the Promising Zone Design approach of Pocock and Mehta (2010).

MAMS

Multi-Arm Multi-Stage (MAMS) is an East module that offers the ability to design and monitor multi-arm multi-stage studies with options for early stopping, dose selection, and sample size re-estimation. It has two features:

  • The group sequential theory extended for multi-arm setup (Gao et al., 2014) has been implemented for normal endpoint.
  • The multi-arm two-stage design using p-value combination approach (Posch et al., 2005) has been implemented for both normal and binomial endpoints.

PROCs

East® PROCs is a new tool for SAS users, which allows programmers to access the East® Interim Monitoring Dashboard within a SAS interface. SAS users can now design and monitor group sequential trials, and conduct sample-size re-estimation. Results from East® PROCs are easy to import back to East® for interactive decision-making and simulations.

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The Features of East

 

Sample size and power calculations

Compute the ideal number of subjects for every trial using advanced methods for sample size and power calculations. A broad array of design options addresses your trial’s key objectives.

Trial Monitoring Dashboard

Use simple trial monitoring tools for effective interim data analysis and decision-making. Provide expert support to the data monitoring committee by predicting the timing of interim analyses, the trial’s probability of success, and other essential information.

Documentation and Support

Text-book quality manuals and a world-renowned set of statistical experts provide technical support and advanced consulting services.

Adaptive features planning

Compare and fine-tune your trial’s adaptation rules by running simulations under multiple scenarios. Adaptive design features, based on proven and published methods, increase your trial’s chances of success.

Advanced simulations

Investigate and test hypotheses in silico prior to costly experimental implementation. Powerful simulation engines illustrate potential trial outcomes for simplified design assessment and comparison.

Resources

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How to access adaptive
design features in East® 6

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East BASE

Sample Size and Power

At its core, East BASE is a simple-to-use, validated tool that accurately powers your study. Using an intuitive workflow and a wide-array of time-tested statistical procedures, East BASE helps you:

  • Rapidly simulate and compare a wide variety of fixed sample trial options
  • Accurately calculate required sample sizes across a variety of power levels
  • Construct and assess superiority, non-inferiority, equivalence, and confidence-based designs
  • Rapidly import and analyze clinical study data with on-board tools
  • Run R scripts

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Bayesian Power Calculations: Probability of Success and Predictive Power
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East MULTIARM

Strong Error Control for Multiplicity with East MULTIARM

East MULTIARM guides users through the complexities of multiplicity adjustment in order to construct reliable trials with multiple arms. A crucial regulatory requirement for multi-arm trials is establishing strong control of the family-wise error rate. East provides a variety of multiplicity adjustment measures to confirm strong control, along with advanced calculations that demonstrate a trial’s statistical power.

Benefits

East MULTIARM enables users to compare the operating characteristics of various trial designs with respect to the FWER, global power, conjunctive power and disjunctive power. Insightful charts and graphics allow for simple comparison and selection of optimal trial design. The merits of each design are easy to communicate to the study team by using East MULTIARM’s powerful simulations and intuitive visuals.

Features

  • Multiple Pairwise Comparisons with a Control:
  • Continuous endpoint: Difference of means
  • Binary endpoint: Difference on proportions
  • Parametric Multiple Comparison Procedures:
    • Dunnett’s single step
    • Dunnett's step down
    • Dunnett's step up
  • P-value based Multiple Comparison Procedures:
    • Bonferroni
    • Sidak
    • Weighted Bonferroni
    • Holm's step down
    • Hochberg's step up
    • Hommel's step up
    • Fixed Sequence
    • Fallback

East ENDPOINTS

Plan for Multiplicity Adjustment with East ENDPOINTS

East ENDPOINTS equips users with a premier suite of simulation tools for the construction of trials with multiple endpoints. While useful across several therapeutic areas, multiplicity adjustment presents particular challenges for demonstrating efficacy. East anticipates these challenges and employs advanced statistical calculations to minimize complications.

Benefits

The first software package to offer serial and parallel gatekeeping, East ENDPOINTS enables the resourceful construction of designs for multiplicity adjustment. By simplifying comparisons of different strategies, East ENDPOINTS enables designers to facilitate the selection of optimal trial designs.

Designers can further augment trust in results by performing a range of sensitivity analyses with respect to the assumptions about design parameters, such as the variations and correlations amongst different endpoints. East ENDPOINTS' advanced statistical methods, intuitive visuals and powerful simulations ensure that the complexities of multiple endpoint designs are easy to communicate to the study team.

Features

  • Multiple primary endpoints
  • Multiple primary and secondary endpoints
  • Serial gatekeeping
  • Parallel gatekeeping

East EXACT

Exact Inference in East with East EXACT

Small sample sizes present a unique set of challenges for clinical trials using binomial endpoints. Valid results require careful, knowledgeable implementation of complex exact tests.

Cytel, a leading developer of exact and Monte Carlo tests and simulations for small sample analyses, now provides East EXACT for designs with small samples.

Features

Group Sequential Designs for binomial superiority tests with one sample (single proportion).

Single Look Fixed Sample Designs including: Binomial superiority designs for one and two samples; binomial noninferiority designs for two samples; binomial equivalence designs for two samples; and Simon's Two-Stage Design.

East EXACT's binomial superiority tests include designs for single and paired proportions, difference of proportions and ratio of proportions. The tooklit of noninferiority tests also provide designs for difference of proportions and ratio of proportions.

What are Simon's Two Stage Designs?

Simon's Two Stage Designs are a popular design for Phase II clinical trials. The design, which has been gaining respect and recognition since its introduction in 1980s, is finally available in a validated software package. Learn more about the design at Researchgate:

Simon, Richard. "Optimal two-stage designs for phase II clinical trials."Controlled clinical trials 10.1 (1989): 1-10. (PDF from Researchgate)

East ESCALATE

Advanced Dose Escalation with East® ESCALATE

East® ESCALATE supports the simulation and analysis of Phase 1 dose escalation trials for determining maximum tolerated dose (MTD), for both single-agent and two-agent designs. ESCALATE provides several modern Bayesian and model-based designs, which are known to outperform traditional 3+3 designs in terms of accuracy and safety.

East ESCALATE Benefits

The addition of the ESCALATE module means East 6 delivers a comprehensive package for all phases of oncology trials.

Statisticians can communicate findings to the clinical team by accessing East’s intuitive graphs and tables.

Features

Single-agent designs:

  • Traditional rule-based algorithms (versions of 3+3)
  • Continual Reassessment Method (CRM; Goodman et al. 1995)
  • Modified Toxicity Probability Model (mTPI; Ji et al. 2010)
  • Bayesian Logistic Regression Model for single agent (BLRM; Neuenschwander et al. 2008)

Two-agent designs

  • Bayesian Logistic Regression Model (combBLRM; Neuenschwander et al. 2015)
  • Product of Independent Beta Probabilities Escalation (PIPE; Mander & Sweeting, 2015)

East SEQUENTIAL

Early Stopping with East SEQUENTIAL

East SEQUENTIAL provides accurate early stopping tools that are essential for conducting cost-effective clinical studies. Early stopping calculations report the probability that a trial will yield statistically significant results. They can be conducted midway through the trial to determine whether or not it would be productive for the trial to continue.

A cornerstone of the East guide to clinical success is its selection of finely tested, state-of-the-art methods for early stopping. East provides a host of validated stopping rules for efficacy and futility, to determine the benefits of continuing time-consuming, resource-consuming trials.
East SEQUENTIAL enables customers to implement East ADAPT, East SURVIVAL, East SURVADAPT and East PREDICT.

Benefits

East SEQUENTIAL creates elegant charts that illustrate the value-gained from various early-stopping boundaries, highlighting alternatives that simplify and clarify design options. An extensive selection of stopping-rules and spending functions inform optimal trial design by capturing differences in time, cost-effectiveness and sample size.

The ability to compute and compare conditional and predictive power at the interim stage plays an integral role in enhanced monitoring strategy. East SEQUENTIAL provides opportunities to update efficacy and (or) futility boundaries after each stage of hypothesis testing. A wide assortment of stopping-boundaries and boundary scales provide unparalleled decision-making tools. East SEQUENTIAL can also display boundaries on multiple scales.

East SEQUENTIAL

Features and Options

Charts and Tables

  • Stopping Boundaries
  • Scales: Z, Score, P-value, Delta, Delta/Sigma
  • Error Spending
  • Average Sample Number

Boundaries

  • Error Spending Functions
  • Lan-Demets [Pocock, O’Brien-Fleming]
  • Gamma, Rho, Interpolated
  • Generalized Haybittle-Peto
  • Wang-Tsiatis
  • Non-Binding Futility
  • Pampallona-Tsiatis, P-value, Conditional Power
  • Delta/Sigma
  • Flexible Boundaries
  • Efficacy and/or Futility at Selected Looks
  • Unequal Spacing of Looks

Interim Monitoring Dashboard

  • Track Error Spent, Update Boundaries
  • Conditional and Predictive Power
  • Bias-corrected Inference
  • Adjusted P-values, Point Estimates
  • Confidence Intervals

East SURVIVAL

Survival Endpoints with East SURVIVAL

Trial designs for survival studies present a range of complex challenges. Since statistical power in these studies is measured in events observed, practical realities like patient drop-outs, inconstant rates of patient accrual, and variable follow-ups, can pose substantial problems for calculating power.

East SURVIVAL has a range of design and simulation tools that anticipate these challenges and strengthen capacities for resolution.

East SURVIVAL

Benefits

East SURVIVAL provides powerful yet simple to use simulation tools that can illustrate complex survival data at the design stage. Design options include superiority and non-inferiority trials with fixed and variable follow-up. Elegant graphs clarify alternatives, making it easy for users to explore tradeoffs between duration and patient accrual, choice of boundaries, spending functions and hazard functions. Easy-to-read charts make these alternatives plain to designers.

Data monitoring is simplified using a single Interim Monitoring Dashboard which clearly specifies study details and interim statistics. The Dashboard also displays charts for nominal critical points, error spending and conditional power.

During interim and final looks, East SURVIVAL provides fixed sample size and group sequential hypothesis testing. It also displays Monte Carlo averages of follow-up time, and cumulative accruals, events and drop-outs, for each arm of the trial.

Features

  • Non-uniform accrual
  • Variable subject drop-outs
  • Variable and fixed subject follow-up
  • Piecewise exponential hazard rates
  • Lagged treatment effects and other non-proportional hazards scenarios
  • Option to specify accrual & study duration or accrual rate & sample size
  • Multiple survival and drop-out parameter input methods
  • Interactive event rate charts to predict accrual and accumulation of events over time
  • Power charts based on sample size, accrual duration, study duration and number of events
  • Stratified sampling and stratified Logrank Test

East PREDICT

Predictive Tools for Trial Design & Interim Decision-Making with East PREDICT

The East® PREDICT Module allows for accurate predictions of enrollment milestones, and site-specific performance indicators.

Ongoing trials benefit from updating methods that provide critical information about the likelihood that a study will meet its deadlines.

Benefits

East PREDICT provides an integrated module to address a range of problems faced by both trial designers and DMC members. Trial designers can engage with powerful simulation tools that ensure optimal choice of trial design, no matter what the interim results.

Tools for interim analysis provide users with reliable information for sensible interim decisions. The ‘Predicted Interval Plots’ (PIPs) allows for conditional simulations to assess expected treatment effects and associated repeated confidence intervals at future looks (Li et al. 2009). East PREDICT can also assess the probability of finishing with a successful trial (conditional power), or minimum treatment effect.

East PREDICT

Features

  • Predictions of enrollment milestones and country performance at design stage or at interim
  • Predictions based on blinded or unblinded data, as well as summary data
  • Predicted Interval Plots: Visual summaries of interim data enable statisticians to communicate complex findings to DMC members in an intuitive, easy-to-read format
  • Flexible Interim Computation: Accommodate unexpected changes in number and timing of looks to make designs more efficient
  • Simulate from site-specific treatment effects

East ADAPT and East SURVADAPT

Sample Size Re-estimation with East ADAPT and East SURVADAPT

The Promising Zone: East’s team of statistical experts developed the ‘Promising Zone’ concept to improve statistical power in the absence of established efficacy. The Promising Zone standard is now accepted routinely by regulatory agencies worldwide.

Create efficient, ethical, cost-effective trials with East ADAPT Promising Zone designs. The Promising Zone is also available for survival designs in East SURVADAPT.

Elegant adaptive re-estimation techniques simplify and clarify critical decisions for interim analysis.

Guaranteed Conditional Powerfor Trials in the Promising Zone

Imagine that interim analysis determines that a study’s conditional power lies within the Promising Zone, for example between 30% and 80%. Conditional power can increase significantly with an appropriate increase of sample-size. East provides intricate measurement tools to determine conditional power and novel adaptive techniques to re-estimate sample sizes, ensuring that every trial in the Promising Zone obtains high conditional power.

Adaptive SSR: Debunking the inefficiency myth

 

East ADAPT and East SURVADAPT

Sample Size Re-estimation

  • Adapt trials based on look, number, interim sample size, or information scale
  • Define the Promising Zone based on conditional power, test statistic, or estimated effect size. The Promising Zone allows users to determine increases in sample size given information acquired during the trial.
  • Experiment with multiple adaptation rules and select the best for your trial.
  •  Vary accrual and dropout patterns to perform sensitivity analysis.
  • Fine-tune the design by comparing multiple values of all these parameters.
  • Conditional Power Calculators
  • Accurate analysis at design and interim stage.
  • Useful for early-stopping decisions.

Trial Simulation Tools

  • Evaluate power and expected sample size of Cui, Hung and Wang method (Biometrics, 1999)
  • Evaluate power and expected sample size of Chen, DeMets and Lan extension (Statistics in Medicine, 2004)
  • Evaluate power and expected sample size of Müller and Schäfer method (Biometrics, 2001)

Promising Zone Case Study

East ADAPT and East SURVADAPT

Trial Adaptation Tools

  • Change sample sizes.
  • Modify error spending function.
  • Revise the number and spacing of interim measurements.
  • Refine primary hypothesis.
  • An Interim Monitoring Worksheet specifically for group sequential designs with one sample size reassessment at each interim look
  • Computes the Cui, Hung and Wang weighted statistic at each interim stage
  • Permits unweighted statistic (if the Chen, DeMets and Lan criteria are satisfied)
  • Computes repeated p-values and repeated confidence intervals, adjusted for adaptive changes

Only in East

  • Promising Zone Design
  • Median Unbiased Point Estimates, Confidence Intervals and p-values based on a new publication by Brannath, Mehta and Posch (Biometrics, June 2009). No other software package provides these median unbiased point estimates and their associated confidence intervals.

Learn more about the Valor trial

East Multi-Arm Multi-Stage (MAMS)

Multi-Arm Multi-Stage (MAMS) is an East module that offers the ability to design and monitor multi-arm multi-stage studies with options for early stopping, dose selection, and sample size re-estimation. It has two features:

  • The group sequential theory extended for multi-arm setup (Gao et al., 2014) has been implemented for normal endpoint.
  • The multi-arm two-stage design using p-value combination approach (Posch et al., 2005) has been implemented for both normal and binomial endpoints.

East MAMS guides users through the complexities of multiplicity adjustment in order to construct reliable trials with multiple arms and multiple stages. A crucial regulatory requirement for multi-arm trials is establishing strong control of the family-wise error rate. East provides a variety of multiplicity adjustment measures to confirm strong control, along with advanced calculations that demonstrate a trial’s statistical power.

Features:

  • Multi-arm Multi-stage designs (MAMS)
    • available for normal endpoint trials: analytical design, simulations and interim monitoring
    • can compare up to six treatment arms in five stages
    • treatment selection at any interim stage; drop the loser; stopping for futility
    • different rules for treatment selection
  • Two-stage Treatment selection design using the p-value combination method.
    • available for normal and binomial endpoint trials: design by simulations and interim monitoring
    • can compare up to twelve treatment arms in two stages
    • well-known multiplicity adjusted methods available; “Inverse Normal” for p-value combination
    • treatment selection, drop the loser(s), stop for futility at stage 1
    • different rules for treatment selection; can also integrate R functions to define customized rules
    • adaptive sample size re-estimation; promising zone can be a continuous or step function

The Software Behind Your Next Successful Trial