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


Why You Should Not Power for Superiority Upfront: Promising Zone Clinical Trials with "Adaptive Switch"

Posted by Esha Senchaudhuri

Jun 26, 2015 12:00:06 PM

Powering a trial for superiority can be financially risky. In some instances it may also prove unnecessary.

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Topics: Cyrus Mehta, Promising Zone, Cardiovascular, Adaptive Clinical Trials, Adaptive Finance


3 Strategies to Combat Inferential Conservatism in Small Sample Sizes

Posted by Cytel

Jun 25, 2015 4:28:00 PM

When conducting a clinical trial with small or sparse data sets, statistical methods meant for large sample sizes may fail to obtain an accurate interpretation of data. This is where computationally challenging exact methods often come into play.

Exact methods, however, are inferentially conservative in the sense that due to small sample sizes, the actual Type 1 error rate is often smaller than the nominal (intended) rate [1]. There exists an array of strategies to combat this troublesome feature of exact tests, each of which varies along the parameter of computational complexity.

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Topics: Sample Size, Exact Inference, exact statistics, Small Sample Sparse Data


A Cautionary Tale about Composite Endpoint Construction: The ARISE Trial

Posted by Esha Senchaudhuri

Jun 18, 2015 5:38:45 PM

In August 2006 AstraZeneca completed the ARISE trial, which aimed to determine whether AGI-1067 was effective in reducing atherosclerosis in patients with acute coronary artery disease [1][2]. A double-blind, placebo controlled, Phase 3 trial, the primary efficacy endpoint was a composite endpoint which included major adverse cardiovascular events (MACE) like cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction and non-fatal stroke. However, it also included two less serious but more frequently observed events, namely hospitalization due to coronary revascularization and hospitalization due to unstable angina with evidence of ischemia [2]. 

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Topics: Cardiovascular, Composite Endpoints


Aligning Clinical Development & Regulatory Objectives for Cardiovascular Outcome Trials

Posted by Esha Senchaudhuri

Jun 11, 2015 5:21:09 PM

DIA_DC_Cyrus

When the FDA first began to require pharmaceuticals to perform cardiovascular outcome trials to establish the safety of certain new drugs, many worried that this new regulatory requirement would diminish investments in therapeutic areas like diabetes and obesity [1]. CVOTs are typically designed as massive time-to-event trials that need to enroll several thousands of patients to establish safety [2][3]. The sheer number of patients and size of the trial increases the time that it takes for these drugs to get to market.

So what is it the makes US and EU regulatory strategy different for diabetes and weightloss drugs, and how should this effect clinical development strategy?

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Topics: Cardiovascular, Clinical Development Strategy, Adaptive Clinical Trials


Building Teams to Handle Unexpected Regulatory Agency Requests

Posted by Esha Senchaudhuri

Jun 5, 2015 11:00:00 AM

Not long ago, one of our clients submitted Phase 2 and Phase 3 data for a new rare disease drug which had received priority review status. Following submission, regulators requested that our client also submit pooled data from its Phase 1 studies along with a safety analysis. This analysis had the potential to clinch NDA approval for the new product.

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Topics: Data Management, Clinical Research Services, Regulation, Phase 1


Patient Recruitment Feasibility: Would you bet $12 million dollars on it?

Posted by Charles Liu

Jun 4, 2015 3:11:26 PM

Two insightful papers from Applied Clinical Trials should be of interest to many clinical trial planners. The first by Kenneth Getz describes the problem of enrollment performance, while the second by Matthew Kibby proposes a potential solution.

The Facts

Getz reports a study providing recent estimates of industry-wide rates of enrollment delays [1]. In 2012, the Tufts Center for the Study of Drug Development (CSDD) requested data from 10 pharmaceutical companies and two CROs. The combined database covered nearly 16,000 investigative sites involved in 151 clinical trials from years 2008-2010. A few significant findings are worth highlighting:

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Topics: feasibility studies, patient enrollment, enforesys


How to Use Outsourcing to Reduce Clinical Development Risk

Posted by Esha Senchaudhuri

May 28, 2015 4:47:00 PM

Risks in drug development range from taking the wrong drugs forward to Phase 3 to investing in a drug development program at a time when regulatory standards are evolving, or competition is catching up with comparable products.

There is a particular source of risk, however, which deserves special attention. Currently, the pharmaceutical and biologics industry outsources approximately $25 billion dollars worth of clinical development projects. That is over a quarter of the $98 billion dollars currently devoted to clinical drug development.

This naturally raises several questions:

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Topics: Data Management, Clinical Research Services, outsourcing, Clinical Development Strategy


Seamless Adaptive Clinical Trials: Now that we get the statistics, what’s really at stake?

Posted by Esha Senchaudhuri

May 20, 2015 5:56:47 PM

Seamless adaptive clinical trials have gained popularity for reducing the projected time it takes to complete the process of drug development.  However, a study by Cuffe et al., shows that despite a tremendous amount of statistical knowledge about seamless trials, sponsors remain unsure about how to calculate the financial and operational costs of a seamless clinical development program [1]. This in turn results in many unnecessary risks and missed opportunities. This post offers advice on what you need to keep in mind in order to implement a successful seamless adaptive clinical study.

 

 

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Topics: Phase 1, Early Phase Trials, Clinical Development Strategy, Phase 3, Adaptive Clinical Trials, phase 2


Regulation and Reproducibility: Can You Reproduce Your Clinical Trial Results?

Posted by Esha Senchaudhuri

May 15, 2015 1:33:15 PM

Cytel Clinical Research Services

Imagine that it’s been three years since the completion of a trial, and that suddenly a regulatory body calls into question the findings:

  • Was a particular trial site operating properly?
  • Can you clarify an aspect of the results? 
  • Why did you make a particular decision at an interim look?

Suddenly, your somewhat old data needs to be able to reproduce your initial findings. In such a case, how long would it take you to satisfy the regulatory body?

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Topics: Data Management, Trial Quality, Trial Monitoring, FDA, ACES


‘A blend of courage and foolhardiness’: Marvin Zelen's 8 Predictions for the Future of Biostatistical Sciences

Posted by Esha Senchaudhuri

May 14, 2015 3:32:00 PM

Ten years ago, in May 2005, world-renowned biostatistician Marvin Zelen was asked to deliver a keynote address before the Eastern Mediterranean Region of the Biometric Society. His address, entitled ‘Biostatisticians, Biostatistical Science and the Future,’ [1] offered a reflection on the direction which the field at large would have to take, given the anticipated leaps in software and the rise of big data.

This included eight predictions on how short and longer term advances in technology would shape the field.

As we prepare to celebrate the annual Marvin Zelen Leadership Award in Statistical Science, this year awarded to Professor Nan Laird (Harvard University) [2] [3] we can take a moment to re-examine the predictions and insights of Cytel's beloved friend and Board Member. 

 


Where will the field of biostatistical sciences be ten years from now? Thirty years from now? How about one hundred years from now? It is perhaps a guessing game full of imprecise probabilities and chances for Bayesian updating.

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Topics: Movers & Shapers, Education, Marvin Zelen


New Articles on Adaptive Clinical Trials & Adaptive Financing

Posted by Esha Senchaudhuri

Apr 30, 2015 5:00:00 PM

Adaptive financing (not to be confused with adaptive licensing) explores how biotechs, pharmaceuticals and potential investors, can use adaptive designs for more strategic financial decision-making, as well as for efficient drug development.  

“For example,” writes Zoran Antonijevic, Senior Director at Cytel Consulting, “Reduction in costs and development time can be accomplished by combining stages of development, or by early stopping for efficacy or futility. Investment risks at late stage of development can be reduced by incorporating a sample size reassessment at an interim analysis, or simply by incorporating stopping rules for efficacy and/or futility."

Zoran has just edited a volume of Clinical Investigation featuring articles on the financial and developmental benefits of adaptive clinical trial design. The volume contains a broad spectrum of issues beginning with a couple of articles on adaptive financing by Tessella’s Tom Parke, and Christopher Weir of the Health Services Research Unit at the University of Edinburgh. 

The volume also stresses the pivotal nature of dose-finding for efficient development, with contributions on Phase 2 oncology trials from Anastasia Ivanova, Guochen Song, Olga Marchenko and Stergios Moschos; as well as Meinhard Kieser, Stefan Englert and Geraldine Rauch. Thomas Jaki also explains the use of multi-arm trials in treatment selection with a look at an Alzheimer’s case.

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Topics: Clinical Development Strategy, Adaptive Clinical Trials, Adaptive Finance


Dose-finding with Sequential Parallel Comparison Designs

Posted by Esha Senchaudhuri

Apr 23, 2015 3:53:00 PM

Last week the Cytel Blog discussed the benefits of using the Adaptive Maximizing Design [AM Design] for dose-finding trials involving clinical utility limiting therapies. However, there are other ways that a dose-finding trial can make use of frequent-adaptation maximizing designs. Here we look at what happens to early phase clinical development when an AM Design combines with another adaptive design that is slowly gaining popularity, namely the Sequential Parallel Comparison Design. 

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Topics: Cytel Consulting, Early Phase Trials, Clinical Development Strategy, Adaptive Clinical Trials, psychiatry and neuroscience


Adaptive SSR for Small Sample Sizes?

Posted by Esha Senchaudhuri

Apr 21, 2015 6:09:28 PM

“We shouldn’t use an adaptive design, our sample size is too small.”

Most clinical trial planners have heard this line of reasoning so often it has come to be taken as true. Never mind the fact that the first product to receive FDA approval using an adaptive sample size re-estimation design, was for a genetic condition affecting fewer than two thousand children worldwide [1].

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Topics: Clinical Research Services, Rare Disease, Clinical Development Strategy, Adaptive Clinical Trials


Phase 2 Designs for Clinical Utility Limiting Therapies

Posted by Esha Senchaudhuri

Apr 16, 2015 5:28:00 PM

When testing certain types of new drugs it is known in advance that the adverse side-effects of the medication will limit dose selection. For example, it is well-established that for many new pain medications, the side effects of nausea and vomiting will place constraints on the selection of higher dose levels.

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Topics: Dose-Finding, Adaptive Clinical Trials


New Cytel Whitepaper: Monte Carlo Simulations for Patient Recruitment

Posted by Cytel

Apr 13, 2015 11:23:00 AM

Cytel has published a new whitepaper on Monte Carlo Simulations for Patient Recruitment, which illustrates how a technique already popular within industrial and business environments is now changing the game of data-driven patient enrollment forecasting. 

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Topics: White Paper, Software Simulations, patient enrollment, Monte Carlo


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