Monte Carlo Simulations II: Reassessing Strategic Options During an Interim Look

Posted by Esha Senchaudhuri

Apr 2, 2015 1:32:00 PM

 

Midway through a trial is a terrible time to realize that you need a new strategy to complete the study. Sadly, it is typically midway through a trial when drug supply, patient recruitment and budget all tend to deviate from the planned development path. Sometimes this is because the initial plan utilized idealized assumptions, (i.e. non-random patient enrollment), which failed to give the desired ballpark estimate of timelines and resource constraints. Other times, responding to unexpected operational or statistical challenges might have proven difficult due to inflexible trial designs [1].

Enforesys: Learn More We have spoken in some depth about how thorough planning and room for flexible decision-making can avoid some of these potential difficulties [1] [2] [3].  However, sometimes the specter of trial discontinuity arises anyway. Here is a scenario which recently confronted the Cytel Consulting Team.

 

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Topics: Clinical Development Strategy, patient enrollment, enforesys, Adaptive Clinical Trials


Leveraging the Flexibility of an Adaptive Clinical Trials: A Case Study

Posted by Esha Senchaudhuri

Mar 27, 2015 5:43:52 PM

We have often said that one of the greatest benefits of an adaptive clinical trial is the flexibility it affords for decision-making [1]. Often this flexibility is taken to mean that sponsors have some leeway to accommodate events - foreseen or unforeseen, challenging or advantageous - midway through a trial. However, when designing a trial, it is often possible to leverage this flexibility towards the sponsor's advantage. 

Recently, a client approached us, determined to select the best of eight candidate doses to move forward into a pivotal Phase 3 trial. Like many in their situation, our client worried that testing all eight doses would require unnecessary time and expense. However, given a variety of other constraints, a subpar Phase 3 dose was simply not an option.  

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Topics: Clinical Development Strategy, Adaptive Clinical Trials, Multi-Arm Studies


Statistical and Operational Challenges of the VALOR Trial: Mehta on the Promising Zone

Posted by Esha Senchaudhuri

Mar 26, 2015 4:00:00 PM

Last year Sunesis completed the VALOR trial, the first clinical study to make use of the groundbreaking promising zone design. The promising zone design implements an unblinded sample re-estimation after an interim look, but only if conditional power during the interim look falls within a designated promising zone. Although the VALOR trial did not confirm the efficacy of the new therapeutic, it provided the drug with the best possible chance to prove its efficacy.

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Topics: Promising Zone, Adaptive Clinical Trials, Statistical Innovations in Clinical Development


How Bayesian Strategies Can Expedite a Pediatric Clincial Trial Time by 20 - 40%

Posted by Esha Senchaudhuri

Mar 20, 2015 4:29:00 PM

Sometimes a new candidate drug for a pediatric study has already been tested on adults for safety and efficacy. We know that the drug is likely to work quite differently in children, but we do not know the degree to which the effects will be different. As a result, a conventional approach is to discard much of the information that has already gathered during studies of adults, and then to start from scratch with a pediatric trial.

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Topics: Bayesian Methods, Adaptive Clinical Trials, Pediatric


How to Plan Interim Looks in Adaptive Clinical Trials: 3 Strategies

Posted by Esha Senchaudhuri

Mar 19, 2015 5:26:00 PM

A well-timed interim analysis can generally supply added benefits to the operational and administrative aspects of a clinical trial. Particularly when clean data and safety adjudications provide information that is instrumental for stopping a trial early or informing sensitive interim decisions, the timing of an interim look may play a crucial role in leveraging all of the flexibility that a complex, adaptive design has to offer. 

 
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Topics: Interim Analyses, Cardiovascular, Cytel Events, Statistical Innovations in Clinical Development


Monte Carlo Simulations for Patient Enrollment: A Presentation by the Director of Pfizer's Feasibility Center for Excellence

Posted by Esha Senchaudhuri

Mar 12, 2015 5:08:00 PM

 

Enforesys: Learn More Recently, we published an interview with Chris Conklin, the Director of the Center for Feasibility Excellence at Pfizer. During the interview, Chris spoke about how his team navigates the complex terrain of trial planning and patient recruitment, and achieves those high flying enrollment milestones for each and every trial. His key message was to utilize modern methods in data-driven feasibility studies, augmenting historic and site-level data with new techniques in forecasting. 

Since our interview, Chris gave a talk at the annual SCOPE conference, in which he divulged a few more tips on obtaining consistent patient enrollment figures. An important feature was the use of Monte Carlo simulations, a popular tool from industrial and business operations, which is now gaining popularity amongst clinical operations specialists.

Monte Carlo simulations are easy to implement with the right tools, and yet can achieve target enrollment with 99% confidence. You can find below, a simple explanation of how this method works. Chris's slides (attached) contain a case study.    

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Topics: Software Simulations, patient enrollment, Monte Carlo, What are...


Embracing the Adaptive Mindset

Posted by Esha Senchaudhuri

Mar 10, 2015 11:35:00 AM

Most of us are primed to think about the design of adaptive clinical trials as a narrow set of techniques applied to a specific set of problems. If you’re worried about the power of your study, for example, you can turn to your toolkit of adaptive methods and find a suitable use for sample size re-estimation. If the concern is getting the best possible dose, a multi-arm study which drops doses after an interim look seems like the perfect solution.

Clinical development teams often look to adaptive designs, only after identifying specific objectives that a conventional trial may struggle to resolve. However, this approach has its limitations. An adaptive strategy might improve a trial design, even when a conventional strategy supplies a reasonable, (though less efficient,) alternative.   

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Topics: Adaptive Clinical Trials, Multi-Arm Studies


Adaptive vs. Group Sequential Designs in Survival Analysis

Posted by Esha Senchaudhuri

Mar 5, 2015 11:00:00 AM

 

 

View Slides

The Mehta-Pocock promising zone is often used to carry out unblinded sample size re-estimation during interim analysis. However, according to Jin Wang of Abbott Vascular, it can also be used to re-estimate follow-up times in the interim look of a survival analysis study.

According to simulations run by Jin, the Mehta-Pocock promising zone design offers the highest power and lowest Type 1 Error when compared to other common group sequential and adaptive designs. However, Jin questions whether this necessarily makes it the design of choice. 

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Topics: Adaptive Clinical Trials


Successful Adaptive Confirmatory Dose-Response Pediatric Study

Posted by Esha Senchaudhuri

Feb 26, 2015 4:48:00 PM

Cytel President and co-founder Cyrus Mehta has co-authored a paper on Infantile Hemangioma, recently published in the New England Journal of Medicine. The successful study was designed as an adaptive confirmatory dose-response which confirmed that 3mg per kilogram per day of propranolol for 6 months is an effective resolution for hemangioma.

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Topics: Cyrus Mehta, Adaptive Clinical Trials


How Proposed Regulatory Reforms Will Affect Your Clinical Trial

Posted by Esha Senchaudhuri

Feb 17, 2015 6:40:00 PM

21st Century Cures (also called Cures2015) is a bipartisan initiative undertaken by the Committee on Energy and Commerce of the US House of Representatives. Amongst the many factors motivating this landmark legislation is the concern  that regulatory procedures must keep up to date with innovations in clinical development. Cures2015 aims to reform the regulation of drugs, biologics and medical devices while increasing patient access to safe and effective drugs across therapeutic areas.

21st Century Cures presented a draft bill in January 2015 that would affect several regulatory procedures at agencies like the FDA. Included in the various proposals are reforms to the regulation of adaptive clinical trials and the use of Bayesian methods, and expedited approval processes for breakthrough therapies and medical devices. The landmark legislation also incentives improvements to Phase 2 trial design for certain therapeutic areas.   

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


Data-Driven Trial Planning: An Interview with Pfizer's Chris Conklin

Posted by Cytel

Feb 12, 2015 2:59:00 PM


Data driven decision-making can ensure that every feasibility team achieves its enrollment milestones. By transforming how pharmaceutical companies and CROs conduct feasibility studies, new techniques in recruitment planning are affecting every aspect of trial planning and clinical development strategy.

We sat down with Chris Conklin, the Director of the Feasibility Center for Excellence at Pfizer (pictured below) to discuss innovative ways to think about enrollment factors, and how he uses high-precision forecasting tools like Cytel’s EnForeSys®.

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Topics: Clinical Development Strategy, feasibility studies, patient enrollment


How to Shorten a Cardiovascular Outcome Trial By Two Years

Posted by Esha Senchaudhuri

Feb 10, 2015 5:28:00 PM

Cardiovascular outcome trials (CVOTs) have earned the reputation of being the untamable behemoths of the clinical world. Needless to say these trials are long and require extremely large sample-sizes. The Contrave LIGHT study required 8900 patients. The SAVOR TIMI trial enrolled 16,492 patients. Even the EXAMINE trial, which benefited from a promising zone design, required 650 patients. 

However, since the explosive controversy over the FDA’s conditional approval of anti-obesity drug Contrave four years ago, there is much we have learned about how to make these trials shorter while also diminishing the financial risks of investing in them. For example, one of our clients managed to shorten the expected study length of an a CVOT by two years using a four point MACE Assessment (see below). 

In this post, we explore some of the lessons we have learned when designing these large-scale clinical trials.  

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Topics: Cyrus Mehta, Promising Zone, Cytel Strategic Consulting, Interim Analyses, Program and Portfolio Optimization, Cardiovascular, Clinical Development Strategy, Adaptive Clinical Trials


3 Key Trends in Clinical Trial Enrollment Forecasting

Posted by Esha Senchaudhuri

Feb 5, 2015 4:50:00 PM

Every clinical trial requires some manner of trial forecasting, normally for feasibility and patient enrollment. However, studies reveal that more than 50% of clinical trials fail to meet enrollment targets, and that enrollment is the most commonly cited reason for Phase 3 trial discontinuation [1].

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Topics: feasibility studies, patient enrollment


Clinical Development & Statistical Methodology for Cardiovascular Risk Assessment

Posted by Cytel

Feb 3, 2015 2:00:00 PM

A new publication co-authored by Cytel Co-Founder and President Cyrus Mehta considers a range of clinical development methods for cardiovascular outcome trials. Cardiovascular outcome trials, (often referred to as CVOTs), reflect safety standards implemented by the FDA and EMA to determine whether or not new drugs impose undue cardiovascular risk on patients. CVOTs typically occur after Phase 3 trials, and often make up for the slow rate of observed events by enrolling thousands of patients. This adds substantial delay in getting a drug to market.

In this paper, Cyrus and his co-authors explore how adaptive and group sequential methods might shorten this process without compromising the quality of the trial. In particular they consider increases in sample size and early stopping boundaries. They consider the possible benefits of unblinded sample size re-estimation (also known as the Promising Zone Design) in CVOT trials. 

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Topics: Cardiovascular, Group Sequential, Adaptive Clinical Trials


Adaptive Design and Bayesian Statistics: 5 Years Later (Podcast)

Posted by Esha Senchaudhuri

Jan 29, 2015 4:00:00 PM

February 2015 marks the five year anniversary of the FDA’s Guidance on Adaptive Design Clinical Trials for Drug and Biologics, as well as the FDA’s Guidance on the Use of Bayesian Statistics in Medical Device Clinical Trials. In honor of the five year anniversary of both sets of guidance, the DIA will hold a special joint conference between its Adaptive Design working group and its working group on Bayesian Statistics.

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Topics: Bayesian Methods, Adaptive Clinical Trials


How to Take Control of Your Enrollment Woes

Posted by Esha Senchaudhuri

Jan 27, 2015 4:01:00 PM

Last week we released an infographic on why Phase 3 trials fail. The numbers, while eye-opening, did not capture a related and equally important issue: Why are so many late stage clinical trials discontinued?

Nearly 50% of all Phase 3 trials that are submitted to the FDA fail upon first submission [1]. However, 25% of all trials that begin are never even submitted for review [2].  According to a 2014 JAMA study, nearly 40% of these discontinuations cite poor enrollment as the primary reason for stopping a trial. Needless to say, the costs of discontinuity are significant.

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Topics: feasibility studies, patient enrollment, trial planning


Adaptive Clinical Trial Strategies for the Limited Early Phase Budget

Posted by Esha Senchaudhuri

Jan 22, 2015 9:00:00 AM

 

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The Journal of the American Medical Association recently published an article entitled ‘The Anatomy of Medical Research: US and International Comparisons.’ The stated objective of the study was to “quantify total public and private investment and personnel (economic inputs) and to evaluate resulting patents, publications, drug and device approvals, and value created (economic outputs)“ [1]

Amongst the many findings of this comprehensive study, a vital observation is the reduction of early phase spending by about 4% per year from 2004 to 2012. One attribution for this decline involves the financial constraints placed upon proof-of-concept trials, particularly when compared to the expected financial benefits of Phase 3 trials and medical devices. According to the authors, “Many new basic discoveries that have probable clinical value are stymied by financial constraints at the critical proof-of-concept stage, where utility in humans is demonstrated.” [1] They add that the number of new discoveries that will be underfunded at the proof-of-concept stage is expected to increase.

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Topics: Dose-Finding, Early Phase Trials, Proof-of-Concept, Case Study, Adaptive Clinical Trials


Why Drugs Fail in Phase 3: A Cytel Infographic

Posted by Esha Senchaudhuri

Jan 20, 2015 10:30:03 AM

According to a recent Cytel Whitepaper on Adaptive Clinical Trials, 50% of Phase 3 trials eventually fail. This new Cytel Infographicoffers a breakdown of why so many drugs fail in Phase 3.

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Topics: Early Phase Trials, Clinical Development Strategy, Phase 3, Adaptive Clinical Trials


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


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