Esha Senchaudhuri

Recent Posts

Old and New Drug Development Paradigms: Cytel Infographic

Posted by Esha Senchaudhuri

Jan 16, 2015 11:05:00 AM

Adaptive designs are thought to be the new paradigm in drug development, allowing statisticians and trial designers to create trials that give the best probability of success for each drug, while diminishing clinical development costs. Over the next weeks we'll be releasing 2-3 infographics on adaptive trials and clinical development.  

Old and New Drug Development Paradigms

This infographic demonstrates three critical differences between old and new drug development paradigms: the budget allocations, the decision-making oportunities, and the resulting decrease in the length of a highly powered trial.

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Simulation and Prediction for Adaptive Licensing Decision-Making

Posted by Esha Senchaudhuri

Jan 13, 2015 3:03:54 PM

Janus was the Roman God of transitions, a deity with two faces, one looking towards the past and the other the future. It was only a matter of time therefore, that clinical trial simulators, and other purveyors of predictive analytics would adopt him as an embodiment of their core initiatives. The aptly named Janus Initiative aims to model decision pathways in clinical development, using powerful simulations to help inform multiple stakeholders on adaptive licensing decisions. The objective is to give every stakeholder in the process a sense of what consequences his or her decision-making will have on other stakeholders involved.

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Topics: Prediction, Clinical Development Strategy, Software Simulations, Adaptive Licensing

Our Readers Choice: Top 10 Posts from 2014

Posted by Esha Senchaudhuri

Jan 8, 2015 5:24:25 PM

Happy 2015!

We look forward to bringing you more stories and discussion on statistical methods and clinical development in the year ahead. In case you missed any of our popular stories from 2014, here are the posts that generated the most buzz in the preceding year. 

Number 10:

Adaptive Clinical Trials: Your Questions Answered

In this interview style blog post, we we got a roundtable of our consultants together to help a customer who was curious but anxious about adaptive designs.

Number 9:

Cytel's ClipLab: Training the Next Generation of Clinical Programmers

The Cytel ClipLab is one of Cytel's educational initiatives. As the pharmaceutical industry changes, new questions arise about educating the next generation of researchers, clinicians and programmers. This post looks at the ClipLab approach to preparing recent graduates for successful careers in the industry. 

Number 8:

Data Management and Biostatistics III: Statistical Innovation and Clinical Data Management

This post was the last in a three part series on data management and biostatistics. It looked specifically at the idea of statistical innovation in the field of data management, such as that currently used in risk-based monitoring. 

Number 7:

Cultivating Versatility in Statistical Consultants

All consulting requires versatile consultants who can bring insight and innovation to a variety of challenges in strategic development. Yet the nature of the pharmaceutical industry is that it requires participants to be specialists, which in turn takes time and practice and leaves little room to develop versatility. This post examines how statistical consultants can still cultivate versatility without compromising the quality and rigour expected of specialists. 

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Early Phase Development Strategy: Bayesian Methods for Go/No-Go Rules

Posted by Esha Senchaudhuri

Dec 18, 2014 3:40:00 PM

Earlier this week, we at Cytel enjoyed a riveting in-house discussion on the uses of Bayesian decision rules for Go/No-Go (GNG) decision-making. GNG rules establish the trajectory of a particular clinical program’s development by assessing whether or not a trial has met particular objects (e.g. target regions for PK, PD and safety endpoints.)

Traditionally, statisticians have used p-values and confidence intervals to construct GNG rules. However, moving to the Bayesian paradigm opens up exciting new possibilities for clinical development strategy. Our discussion earlier this week centered around three key benefits of using Bayesian statistics for GNG decision-making:

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Topics: Early Phase Trials, Clinical Development Strategy, Adaptive Clinical Trials

Cultivating Versatility in Statistical Consultants

Posted by Esha Senchaudhuri

Dec 16, 2014 4:56:00 PM

Richard Branson once wrote: “I have always valued capability over expertise. While you may need to hire specialists for some positions, take a close look at people who have thrived in different industries and jobs – they are usually more versatile, have transferable skills, and can potentially tackle problems creatively.”

He goes on to write: “Obviously a healthy mix of experience and novel thinking is the ideal, but on balance I would anticipate more fresh and objective solutions to flow from the smart and curious inexpert outsider than the ‘been there done that’ experts.”

Although the versatility to which Branson alludes is instrumental for successful statistical consulting, it is also obvious that an inexpert outsider would not be able to waltz into the drug development industry and make successful contributions. The expertise that is required is simply too much for a non-specialist. This raises an important question:

How should we, as an industry, walk this fine line between specialized expertise and versatile capabilities? 

Consider, for example, the list of seven questions provided below. 

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Topics: Nitin Patel, Cytel Consulting, Entrepreneurship, Clinical Development Strategy, Richard Branson

Adaptive Designs for Infectious Diseases Clinical Development Strategy

Posted by Esha Senchaudhuri

Dec 11, 2014 1:14:00 PM


A common framework for the clinical development of vaccines involves the study of several candidate compounds in Phase 1 followed by the selection of potential vaccine regimens for study in Phase 2 and Phase 3. In the attached presentation, Cytel Consulting’s Jim Bolognese compares traditional and adaptive Phase 1/Phase 2 studies for vaccines and infectious diseases, providing simulations results for both 2-stage and multi-stage adaptive designs. Jim also outlines a structure for a Hybrid Adaptive Study.

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Topics: Infectious Diseases, Clinical Development Strategy, Adaptive Clinical Trials

Drug Supply Planning for Dose-Ranging Adaptive Trials

Posted by Esha Senchaudhuri

Dec 9, 2014 12:17:28 PM

When planning a conventional trial, one can anticipate the drug supply necessary for the trial by determining how the number of patients reflected in the sample size will distribute across the trial sites. Implementing an adaptive trial, by contrast, raises many challenges for predicting the necessary drug supply. It can require planning for different sample sizes depending on the outcome of an interim look; or preparing different dosages if certain arms of a multi-arm trial are to drop after the interim look. In the case of a biomarker-driven adaptive design, determining adequate drug supply may require the ability to predict which doses are necessary for different subpopulations at particular trial sites.

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Topics: Nitin Patel, Access to Slides PDF, Bayesian Methods, Interim Analyses, optimization, Dose-Finding, Adaptive Clinical Trials

Operationally Seamless & Inferentially Seamless Adaptive Designs

Posted by Esha Senchaudhuri

Dec 4, 2014 11:30:00 AM

Fulyzaq® from Napo/Salix was the first drug ever to be approved using an adaptive two-stage "seamless" clinical trial design. However, when Napo Pharmaceuticals sought orphan drug status for Crofelemer (made from the croton lechleri plant, pictured above left), it received a short window from the FDA in which to complete a Phase 3 trial for safety and efficacy. Aiming to diminish both time and cost, Napo submitted an adaptive design for a Crofelemer trial to the FDA. Initially, the design was rejected on grounds that it would not demonstrate strong control of the type-1 error rate.

Napo then approached Cytel consultants which advised it to consider a seamless adaptive trial. A seamless adaptive trial combines 2 phases of a study into one trial, thereby allowing a trial to complete within a short window. Using appropriate techniques, it is possible to conduct such studies while maintaining strong control of type-1 error.  

A seamless adaptive design may be operationally seamless or inferentially seamless. An operationally seamless design is one in which a confirmatory trial proceeds after an exploratory one, but the data from the two are kept distinct. By contrast, an inferentially seamless trial combines data from both phases to make the final inference. Due to these two varieties of seamless adaptive designs, Napo/Salix had the following 3 trial designs from which to choose:

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Topics: Sample Size, Trial Design, Safety, type 1 error, Dose-Finding

A Bayesian Industry Approach to Phase I Combination Trials in Oncology

Posted by Esha Senchaudhuri

Nov 18, 2014 4:32:00 PM

Statisticians and scientists at Novartis have been at the forefront of developing a new method in early phase oncology trials called the BLRM. Many believe that the BLRM, (short for the Bayesian Logistic Regression Method,) allows for the construction of clinical trials that have the dual benefit of improving treatment for patients participating in the trials, and allowing the trial to complete in a more timely and efficient manner. 

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Topics: Dose-Escalation, Bayesian Methods, Phase 1, Early Phase Trials

Ranking Adaptive Dose-Finding Designs using Clinical Utility Functions

Posted by Esha Senchaudhuri

Nov 12, 2014 4:04:25 PM

Clinical utility functions provide Phase 2 trial sponsors with an intuitive metric by which to measure the quality of a selected dose. Such functions reveal the efficacy-to-tolerability ratio of doses under consideration, thereby enabling trials to move forward with doses that are highly effective and which have minimal side-effects. While this is arguably the most popular use of clinical utility functions, they can also help trial designers determine which design ought to be chosen for dose-finding studies. A design which consistently chooses doses with high clinical utility should instill greater confidence than those which often miss this critical target. 

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Topics: Dose-Finding, Adaptive Clinical Trials

Translational Statistics: How to Move Beyond the Comfort Zone

Posted by Esha Senchaudhuri

Nov 6, 2014 11:09:00 AM

Professor LJ Wei holds that rules are for lawyers, not (necessarily) clinicians. When designing modern clinical trials, the impetus is often to use “efficient and reliable procedures, to obtain clinically interpretable results with respect to risk-benefit analysis…” Yet these efficient and reliable procedures are often just conventions and rules that provide information that is incomplete or difficult to make clinically interpretable.

In a presentation to the East User Group Meeting, Professor Wei identifies 11 problematic areas that currently challenge trial designers. After giving an overview of the challenges that arise in each, Professor Wei provides a few simple solutions about how to overcome them. All the solutions, however, require moving beyond the comfort zone of conventional procedures.

In the slides attached Wei discusses:

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Topics: East, East 6.3, Access to Slides PDF, Trial Design, Trial Monitoring, Training and Education, Predictive Enrichment, Precision Medicine, Translational Statistics, Translational Medicine

New Exploratory Trial Method Translates into Better Financial Strategy

Posted by Esha Senchaudhuri

Nov 4, 2014 8:30:00 AM

A key stage of exploratory drug development is implementing a proof-of-concept study to demonstrate the safety of a drug. Given the importance of accurate dose-finding for Phase 3 success, methodological improvements to proof-of-concept studies in Phase 2 can translate into greater likelihood of getting a drug to market. 

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Topics: Oncology, Access to Slides PDF, Enrichment, Safety, Precision Medicine, Entrepreneurship, R&D, Adaptive Clinical Trials

Adaptive Dose Finding Using Toxicity Probability Intervals

Posted by Esha Senchaudhuri

Oct 28, 2014 9:30:00 AM

Phase 1 oncology trials typically use either rule-based methods or model-based methods to determine the most acceptable level of dose toxicity with which to move forward in Phase 2. This level of toxicity, called the maximum tolerated dose (or the MTD), is the dose which best balances the medical benefits of a higher dose with the risk of toxicity which comes from subjecting a patient to that same dose. Both rule-based methods and model-based methods determine the MTD by relying on small cohorts of patients who test a set of doses against their dose limiting toxicity.

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Topics: Oncology, East 6.3, Access to Slides PDF, East ESCALATE, Adaptive Clinical Trials

Clinical Impact Beyond 'Time to First' Analyses

Posted by Esha Senchaudhuri

Oct 21, 2014 9:00:00 AM

Every year, the East Users Group Meeting brings together notable experts from industry and academia to discuss the future of biostatistical advances in clinical trials, as well as the role of software in facilitating these breakthroughs. In honor of this year’s event, which will be taking place at the Loews Hotel in Philadelphia on October 22, the Cytel Blog will spend the next couple of weeks providing glimpses into the range of discussion presented at the EUGM table.

One debate that has already received quite some attention, involves the weighting of various morbidities in studies with composite endpoints. In a 2013 editorial in the European Heart Journal of the European Society of Cardiology, EUGM speaker Professor L.J. Wei and his colleagues wrote, "A reported P-value must not be confused with an assessment of the magnitude of a treatment's effect in a way that is meaningful to the patient, the clinician and the regulator." [1]

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Topics: East, East 6.3, Statistical Programming, Statistical Puzzles, Statistical Analysis, Cardiovascular

Statisticians on Software Development Part II: The Philosophy Behind a Software Package

Posted by Esha Senchaudhuri

Sep 25, 2014 10:06:00 AM


East: Learn More  StatXact: Learn More Compass: Learn More

A few weeks ago, we posted a synopsis of an event held at ISCB Vienna in which statisticians from Cytel, SAS and Stata spoke about processes for developing software for statisticians. The button below will guide you to a copy of the presentation by Cytel's Vice President of Consulting, Yannis Jemiai.

In the presentation, Yannis talks about the decision-making process behind software development, and how it aligns with a general philosophy to empower, simplify and educate. He explains how software developers choose from a variety of statistical algorithms in putting together a classic software package. "Just because we can," he cautions, "doesn't mean that we should." 

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Topics: East 6.3, Cytel Consulting, Regulation, Statistical Programming, Entrepreneurship

5 Scenarios When ‘Keep it Simple’ May Be Bad Advice for Clinical Trial Designers

Posted by Esha Senchaudhuri

Sep 18, 2014 10:44:00 AM

When designing clinical trials, many trial designers are advised to keep the trial simple. Prima facie, the keep it simple principle seems like sound advice. There are various logistical uncertainties that arise when implementing a clinical trial, and the more simple a trial – so conventional wisdom says – the easier it is to respond to these uncertainties.

According to Zoran Antonijevic, a Senior Director at Cytel Consulting, there is reason to doubt such conventional wisdom. After all, flexibility is hardly a virtue of a traditional trial design. Simple designs may seem to make it easier to monitor data and report results. However, a flexible design can better address remaining uncertainties in product development. These uncertainties are related to treatment effect, dose selection, or a sub-population that would experience the best benefit/risk from the treatment.

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Topics: Oncology, Promising Zone, sample size re-estimation, Enrichment, Cytel Consulting, Efficacy, Interim Analyses, forecasting, optimization, Program and Portfolio Optimization, R&D, Adaptive Clinical Trials

Empirical Study Confirms Positive Impact of Adaptive Designs

Posted by Esha Senchaudhuri

Sep 11, 2014 11:56:00 AM

According to a recent Impact Report from the Tufts Center for the Study of Drug Development, 21% of active clinical trials improve trial success rates and cut operating costs by designing trials with simple adaptive elements like sample size re-estimation and opportunities for early stopping. 

Cytel Senior Biostatistician Zoran Antonjevic, who also chairs the DIA’s Adaptive Design Scientific Working Group (ADSWG), says the CSDD's findings come very close to the numbers reported by the ADSWG. The ADSWG recently updated its published findings in a Therapeutic Innovation & Regulatory Science article entitled, ‘Adaptive Design: Results of 2012 Survey on Perception and Use.’ The Survey team, led by Cytel statistician and Senior Director Caroline Morgan, used a variety of source material to report on adaptive designs in clinical trials between 1996 and 2012.

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Topics: White Paper, Adaptive Clinical Trials

FDA-Industry Session on Cardiovascular Outcome Trials: Mehta on EXAMINE Trial’s Promising Zone Design

Posted by Esha Senchaudhuri

Sep 9, 2014 10:41:00 AM


The FDA requires sponsors of new antidiabetic drugs to conduct cardiovascular outcome trials (CVOTs). CVOTs demonstrate that new therapies do not place unacceptable cardiovascular risk on patients suffering from Type 2 diabetes. The average CVOT requires about 5000 patients and takes an average of 5 years to complete. However, a recent white paper by the Cardiac Safety Research Consortium outlines a variety of methods to decrease sample size and study duration, by employing group sequential and adaptive CVOT designs. 

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Topics: Cyrus Mehta, Promising Zone, Trial Design, FDA, Interim Analyses, Cardiovascular, Adaptive Clinical Trials

Adaptive Designs for Evidence Based Oncology: Insights from the Experts

Posted by Esha Senchaudhuri

Sep 4, 2014 1:10:00 PM

Imagine if we were to count the number of possible reasons that investigators might have for monitoring a biomarker during a clinical trial, and multiply that number by the number of possible adaptive designs available for such investigation. We would naturally assume that whatever the number, it would be rather large. This poses an interesting question for a sponsor of an adaptive clinical trial. Are there any general principles for trial design that may be gleaned from these various possible scenarios?

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Topics: Access to Paper PDF, Dose-Escalation, Cytel Strategic Consulting, Adaptive Clinical Trials

Impact of Study Design and Development Strategy on Pharmaceutical Programs and Portfolios

Posted by Esha Senchaudhuri

Sep 2, 2014 11:19:00 AM

As more clinical trials make use of adaptive designs, investors have come to realize that high quality trial designs can result in significant improvements to a trial’s financial risk profile. Regardless of a trial’s eventual success or failure, a well-constructed design provides a drug with the highest possible probability of success while mitigating financial risk.

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Topics: Nitin Patel, Cyrus Mehta, Promising Zone, Trial Quality, Cytel Strategic Consulting, Trial Design, Entrepreneurship, Program and Portfolio Optimization, R&D, Adaptive Clinical Trials

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