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.
Mar 19, 2015 5:26:00 PM
Monte Carlo Simulations for Patient Enrollment: A Presentation by the Director of Pfizer's Feasibility Center for Excellence
Mar 12, 2015 5:08:00 PM
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.
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.
Mar 5, 2015 11:00:00 AM
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.
Topics: Adaptive Clinical Trials
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.
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.
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®.
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.
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 .
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.
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.
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 . However, 25% of all trials that begin are never even submitted for review . 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.
Jan 22, 2015 9:00:00 AM
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)“ 
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.”  They add that the number of new discoveries that will be underfunded at the proof-of-concept stage is expected to increase.
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.
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.
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.
Jan 8, 2015 5:24:25 PM
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.
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.
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.
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.
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.
Jan 6, 2015 4:00:00 PM
As we head into the new year, the life-sciences industry can look forward to some long awaited advances in pharmaceutical drug development. Here are our predictions for top trends to look out for in 2015.
1: The Arrival of Adaptive Financing:
Adaptive financing was an idea that was cultivated and nurtured by members and affiliates of Cytel. It is the idea that a financial strategy can be built around outcomes that are observed at certain decision points during clinical development (for example, at interim analyses.) Constructing designs with adaptive financing in mind helps provide potential investors and study sponsors with a monetary ballpark of how much innovation will cost, and how much they have the potential to save. This helps overcome one of the biggest bottlenecks in implementing safer and more efficient adaptive trials, namely the perception by many in the industry that these trials are risky.
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:
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.