Cytel Case Study Series III: Dose Finding & Dose Response Modeling in Pediatric Asthma

Posted by Cytel

Oct 22, 2015 2:28:53 PM

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Topics: Case Study, Pediatric, MCP-Mod


3 Statistical Challenges for Pooling Phase 1 Data

Posted by Esha Senchaudhuri

Oct 19, 2015 5:15:40 PM

It is often necessary to pool safety data from late phase studies, in preparation for regulatory submission. Some of our clients have also begun to add Phase 1 safety data to this pool. On some occasions this is required by regulators. In many cases, however, these Phase 1 data simply provide further evidence that a new therapeutic lives up to the promise of safety across patient populations.

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Topics: Data Management, Safety, Early Phase Trials, Small Sample Sparse Data


MCPMod: An Introduction

Posted by Cytel

Oct 15, 2015 5:31:00 PM

The method for dose-response modeling that is widely called MCPMod allows a sponsor to measure the likelihood that particular dose-response curves are the right mathematical model for a given set of data. Since several different dose-response curves might be able to fit the data, how can you determine which is the best curve for your purposes?

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Topics: MCP-Mod


Statistical Primer for Cardiovascular Research

Posted by Cytel

Oct 13, 2015 4:39:00 PM

In honor of World Obesity Day (celebrated on Oct. 11 2015) here is an American Heart Association Statistical Primer on Cardiovascular Research. Cardiovascular outcome trials (sometimes called CVOTs) are clinical trials that are critical for determining the safety of new anti-obesity and diabetes drugs. Early CVOTs like TECOS and SAVOR-TIMI enrolled over 14,000 and 16,000 patients respectively.

Cyrus Mehta, president and co-founder of Cytel, has been on the forefront of developing novel designs to shorten the length of these trials while maintaining high statistical rigor. In this primer he provides an overview of fixed sample, GS and adaptive designs for cardiovascular trials. Other topics include: adaptive sample size re-estimation, and SSR with enrichment for high and low risk subpopulations. 

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Topics: Cardiovascular


Being a Statistician: An Art, a Science or Just Job?

Posted by Cytel

Oct 8, 2015 4:25:00 PM

A recent American Statistical Association conference featured a town hall meeting to discuss the role of the statistician within the pharmaceutical industry, and in particular within the subfield of precision medicine. The panel of distinguished academics, regulators and members of industry confronted the concern that the era of precision medicine heralds an emerging need for statisticians to play a different role than the ones normally associated with technique and craft. Statisticians are now charged with discovering insightful applications to new statistical methodologies, and ensuring that clinical development reflects as many innovative statistical methods as necessary to achieve a successful study. According to the panel, statisticians may even find themselves in a position where they are required to anticipate scientific and technological advances for a study’s benefit.

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Topics: Statistical Programming, statistical communication


2 Methods for Evaluating Biomarker Subpopulations in (Adaptive Enrichment) Time to Event Trials

Posted by Cytel

Oct 5, 2015 4:14:58 PM

One consideration every sponsor of a biomarker-stratified confirmatory trial must take into account, is whether to evaluate the biomarker subpopulation (S) against the rest of the population (S') or against the full population (F).

Mathematically, one would think this makes very little difference as F is partitioned into S and S'. If the null hypothesis is rejected for both S and S' then clearly it is rejected for F too. Similarly, if it is rejected for S and not for S' then the therapy is effective for the biomarker subpopulation, and ineffective for the rest of the population.

As it turns out, whether or not a given biomarker is indeed a predictive biomarker should affect the choice of statistical methodology in time-to-event trials.

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Topics: Cyrus Mehta, Enrichment, Simulation & Biomarkers, time-to-even trials, Biomarkers


It’s Time to Bridge the Gap Between Pharmacometrics and Biostats

Posted by Esha Senchaudhuri

Oct 1, 2015 5:22:00 PM

This week marks the sixth annual American Conference on Pharmacometrics, held this year in Crystal City, VA. Situated at the intersection of mathematical modeling, simulation and big data, the field of pharmacometrics is delivering on its promise to revolutionize clinical research and by extension clinical development.

No wonder then that biostatisticians are now fully engaged with the enterprise.  

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Topics: Adaptive Clinical Trials, Statistical Innovations in Clinical Development, pharmacometrics


5 Skills Needed by All Highly Effective Statisticians

Posted by Cytel

Sep 29, 2015 5:02:00 PM

The Head of the DIA’s Adaptive Design Working Group Asks Us to Consider 5 ‘Soft-Skills’ All Effective Statisticians Should Cultivate

The advent of adaptive designs has meant that statisticians have a new role to play in the drug development process. Not only are they responsible for tackling the precise statistical issues that can arise during the course of a study, but their knowledge and vision can result in innovations that substantially alter study design, strategic decision-making, probability of trial success and level of revenue.  

Given this new role played by statisticians, what skills do statisticians now need to cultivate to be as effective as possible in the boardroom and on their project teams?

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Topics: Statistical Analysis, Entrepreneurship, Clinical Development Strategy


Virtual Teams and Clinical Data Management

Posted by Esha Senchaudhuri

Sep 24, 2015 3:35:00 PM

Earlier this week, Patti Arsenault, Cytel’s Global Head of Clinical Data Management, sat on an SCDM panel with members of Gilead and Westat. The panel partook in an interactive discussion on both the opportunities and challenges which arise from managing virtual teams.

As teams become more global in nature – optimizing delivery by around the clock work hours –many have weighed in on the best way to manage virtual teams. Unfortunately, there seems to be very little agreement on such best practices. The panel provided insights from industry leaders in clinical data management, and then invited audience members to share their experiences.

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Topics: Data Management, Training and Education


Inference on Confidence Intervals for Adaptive Designs: The Latest Breed of Adaptive Clinical Trials

Posted by Esha Senchaudhuri

Sep 17, 2015 3:51:00 PM

Most people familiar with adaptive clinical trial designs are familiar with those statistical designs that reject the null hypothesis. These include now familiar designs like the promising zone design and the adaptive switch design

A newer breed of adaptive designs, however, aims to apply adaptation techniques to confidence intervals.

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Topics: Cyrus Mehta, Exact Tests, Adaptive Clinical Trials


Cytel Case Study Series II: Adaptive Bayesian Design with Informative Prior

Posted by Cytel

Sep 15, 2015 3:56:42 PM

 

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Topics: Bayesian Methods, Cytel Consulting, Case Study, Adaptive Clinical Trials


Cytel Case Studies Series #1: Using Simulation for Accelerated Early Phase Drug Development

Posted by Cytel

Sep 4, 2015 10:30:00 AM

Our Client's Challenge:

Can knowledge of the relationship between biomarkers and clinical endpoints help us to optimize an early development program and improve the probability of selecting the right dose in Phase 3?

Our client approached us hoping to expedite dose-finding with biomarkers in Phase 1b, and to design an optimal Phase 2b clinical endpoint trial to maximize probability of correct Phase 3 dose selection.

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Topics: Cytel Consulting, Early Phase Trials, Clinical Development Strategy, Proof-of-Concept, Case Study, Biomarkers, Simulations


Modern Early Phase Clinical Trial Design Primer

Posted by Cytel

Sep 1, 2015 4:01:39 PM

If you’re in the practice of conducting early phase clinical trials, you’ve probably heard that modern trial designs include a number of new methodologies. There’s CRM and BLRM, model-based methods versus rule-based methods, and a number of other developments that might affect your clinical strategy. Each of these methods affects operational, financial and regulatory objectives in unique ways.

As a part of this year’s Joint Statistical Meeting, Cytel statisticians created a primer to go along with a workshop for early phase clinical trial design.

In the primer you will find: 

  • 1. An overview of 3+3, CRM, BLRM and mTPI methods
  • 2. A synopsis of basic concepts like Bayesian and frequentist statistics, models and rules, etc.
  • 3. Reflections on regulatory considerations
  • 4. Case studies and topical exercises with Cytel’s high-powered simulations
  • 5. A solution guide for those with access to Cytel's East software  

 Click to download the Primer

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Topics: Bayesian Methods, CRM, Early Phase Trials, Clinical Development Strategy, BLRM


Do you really need a full service CRO? An exploration of strategic options

Posted by Esha Senchaudhuri

Aug 13, 2015 9:00:00 AM

Full service or specialized? Full service or specialized?

For many looking to hire a CRO, the answer is obvious.

Obvious Answer #1: A full service CRO simplifies your life by ensuring you need only one point of contact in stressful situations or when things appear to be going wrong. Clearly you want a full service CRO because clearly you want to keep things simple.  
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Obvious Answer #2: A specialized CRO is exactly that, specialized. It sustains itself by being extremely good at doing the thing you hired it to do, and doing it better than everyone else. Clearly you want a specialized CRO because clearly you want the best.
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The decision is difficult in part because it touches upon various crucial points of a clinical trial sponsor's strategy: top-notch knowledge and expertise, timely delivery, simple responses to unforseeable events. Your business and development strategy should ultimately affect your decision-making. 

Here are a few things you might consider to avoid making a decision that is wrong for you. 

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Topics: Data Management, Clinical Research Services, Clinical Data


Mitigate Phase 3 Clinical Trial Risk by Optimizing Phase 2 Data

Posted by Esha Senchaudhuri

Aug 10, 2015 2:32:34 PM

When approaching a Phase 3 clinical trial, the need to ‘de-risk’ the massive investment often leads sponsors on a quest for the perfect risk mitigating adaptation. While a strategically planned clinical trial design can be an important step in giving a new medicine its best possible chance of success, there are a number of other ways that a trial sponsor can minimize study risk.

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Topics: Dose-Finding, Early Phase Trials, Proof-of-Concept, Clinical Data, MCP-Mod


Evidence Based Medicine: 25 Years Later

Posted by Esha Senchaudhuri

Jul 27, 2015 5:47:00 PM

We were saddened to learn earlier this year, of the passing of Professor David Sackett. Widely recognized as the father of evidence based medicine, Professor Sackett confronted tough criticism in advancing the cause of evidence based medicine during the early nineties. During his four years at the Centre for Evidence Based Medicine at Oxford, Sackett’s team produced an array of books, articles, curricular and pedagogical practices, and software techniques which remain foundational to EBM's teaching and learning.

Evidence based medicine refers to the practice of incorporating “current best evidence” when determining care for individual patients [1]. Clinicians use their clinical expertise to specify the problem and the evidence necessary to solve it; the evidence itself, however, makes reference to biostatistics and epidemiology [2].More generally, evidence based medicine defends the view that clinicians should use both their clinical expertise and the findings of general clinical research in their practices, and that neither alone is sufficient to provide an appropriate level of care [1].

In a widely-cited paper, Sackett explains the irony of having to combat criticisms of championing a practice that was simultaneously ‘too old hat’ and yet also ‘too revolutionary’ [1]. In celebration of David Sackett, we consider Evidence Based Medicine in the early 1990s, and consider new developments twenty-five years later.  

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Topics: Precision Medicine, Evidence Based Medicine


MCP-Mod for the Modern Dose-Ranging Clinical Trial

Posted by Esha Senchaudhuri

Jul 21, 2015 3:41:00 PM

MCP-Mod methodology for dose-ranging clinical trials has been gaining popularity since the 2013 publication of the qualification opinion by the European Medicines Agency Committee for Medical Products for Human Use. Since its development at Novartis, MCP-Mod promises to devise proof-of-concept and dose-ranging trials which generate superior statistical evidence for dose-selection, while providing safety and efficacy data that can prove critical data for Phase III clinical trial design. 

Although the general framework of the MCP-Mod method are becoming more familiar, its added complexity raises the question of whether it is a necessary supplement (or even substitute) for traditional dose-ranging trials. Here are a few shortfalls of the traditional approach that MCP-Mod is equipped to handle. 

 

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Topics: Dose Selection, phase 2, MCP-Mod


Why and When to Use Profile Likelihood Based Confidence Intervals

Posted by Ashwini Joshi

Jul 14, 2015 11:00:00 AM

When conducting Maximum Likelihood Estimation, it is assumed that the maximum likelihood estimate follows a normal distribution. However, this may not be true in the case of small sample or sparse data.

Since the standard errors of the general linear model are based on asymptotic variance, they may not be a good estimator of standard error for small samples. In particular, Wald Confidence Intervals may not perform very well. One should only use the Wald Confidence Interval if the likelihood function is symmetric about the MLE.

 
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Special Update: US House of Representatives Passes 21st Century Cures Act

Posted by Cytel

Jul 10, 2015 12:54:00 PM

Here at Cytel, we are engaging in a small celebration this afternoon, as the US House of Representatives has just passed the FDA Reform Bill more generally known as the 21st Century Cures Act.

Although this bill is widely viewed as a reform bill, it will provide extensive funding to both the FDA and NIH to ensure that clinical and pharmaceutical research lives up to its potential to deliver life-saving technologies in a faster, smarter way.

Title II of the act contains approximately 150 pages on drug development. We're sure some of you have read it through and through. However, for those putting off their summer reading until August, here are 4 exciting developments that we want all of our friends and affiliates to be aware: 

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Topics: Bayesian Methods, Regulation, Medical Devices, Adaptive Clinical Trials


3 Questions to Ask About Your Trial's Enrollment

Posted by Charles Liu

Jul 2, 2015 1:33:01 PM

 

Clyde Haberman, a columnist for the New York Times, once commented on the remarkable consistency of train arrival times on the Tokyo subway: "Every station lists the scheduled arrival times: 9:01, 9:04, 9:08 and so on. I lived in that city for five years...I never saw a train arrive so much as a minute late, not once. A posting of 9:01 meant 9:01." [1]. Such predictability is rarely observed in the messy world of clinical operations, yet many study plans are formulated like a Tokyo subway timetable. In a previous blog entry [2], we cited an example trial that targeted 1,800 patients across 50 sites over a 10-month period. Let us examine three underlying assumptions in this plan, with the help of a modeling and simulation tool.

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Topics: feasibility studies, patient enrollment, enforesys


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