In this blog we turn to some reading matter, and interview Gautier Paux and Alex Dmitrienko about the recent book 'Clinical Trial Optimization with R'.  The book explores a unified and broadly applicable framework for optimizing decision making and strategy selection in clinical development, through a series of examples and case studies. To learn more, read on for Paux and Dmitrienko's insights.

 In this blog we are excited to unveil a new project which we have been hard at work on over the last few months. 

2017 marks a very special milestone for Cytel – our 30th anniversary.  Cyrus Mehta and Nitin Patel founded Cytel in 1987 with an initial objective to solve a specific problem in computational statistics.

Single ascending dose (SAD) and multiple ascending dose (MAD) studies are typically the first in human studies.  They seek to gain information on safety and tolerability, general pharmacokinetic (PK) and pharmacodynamic ( PD)  characteristics, and of course identify the maximum tolerated dose (MTD).

Conventionally, SAD  and MAD studies were conducted separately, but increasingly are combined into an ‘umbrella’ protocol which addresses both SAD and MAD objectives.

As a group, Cytel had over 40 successful regulatory interactions last year, many of which supported approvals for innovative trial design approaches.  In this blog we look at some of the key success factors for regulatory interactions regarding adaptive designs.

 Francois Beckers, Global Head of Biostatistics & Epidemiology at Merck KGaA joined us at the East User Group Meeting in March and presented case studies of Merck KGaA’s experiences with Blinded Sample Size Re-estimation in early phase studies, more specifically in the context of biosimilar studies.

On March 16th and 17th the 5th East User Group Meeting took place in London.  This very successful 2 days saw a variety of talks on aspects of clinical trial design innovation.  Over the next couple of weeks, we will be reviewing some of the key topics which were addressed during the meeting.

In this post, we'll take a look at Paul Frewer of Astrazeneca's presentation on Decision Making in Early Phase Clinical Development.  This talk was very well received by the delegates and prompted plenty of discussion afterwards. 

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.

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. 

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. 

We are often asked how statistical consultants can add value to the clinical development process. What do they contribute to a winning strategy, and how do they optimize business decisions? 

Statistical consultants often have decades of experience in multiple aspects of clinical development, including trial design, portfolio optimization, and regulation. Having a broad and yet nuanced feel for the industry enables statistical consultants to generate novel solutions to an array of challenges faced while navigating clinical development.

If you are thinking of hiring a statistical consultant to your team, you should be aware of the many roles that they can play. Here are some of our consultants' favorite recent projects. 

Guest blogger Laurie Halloran is the President and CEO of Halloran Consulting Group, a management consulting firm for the life-sciences industry. Here she offers her take on the importance of accountability, obligation and 'ownership' in consulting for pharmaceuticals and medical device companies.

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." 

An FDA Industry Statistics Workshop on September 23 will feature a panel on seamless adaptive designs. Seamless adaptive designs are studies which are able to combine two stages of a clinical trial into one adaptive study, thereby cuting trial costs and reducing study length. The panel will feature Cytel Statistician Lingyun Liu,Lisa Kammerman of AstraZeneca, and Joshua Chen of Merck. The FDA's Sue-Jane Wang will be the featured discussant.

Photos leaked from JSM 2014 appear to show the Reverend Bayes partying with his entourage at the Cytel Cocktail Hour, held at Boston’s Seaport Hotel on August 4, 2014. Bayes is, of course, one of the stars of Cytel’s East 6.3, a modular software package driving drug development through high quality trial design and simulations. Bayes's contributions to the East ESCALATE and East PREDICT modules are posited to transform early phase dose-escalation and interim decision-making. The Reverend has also made scene-stealing cameo appearances in a number of projects with Cytel Consulting.

PROCYSBI, the first drug to receive FDA approval after following an adaptive population re-assessment design, was one of Cytel's most exciting success stories. Could your drug be next?

It has become popular to rave about the many regulatory, statistical and financial benefits of adaptive designs when compared to the inflexibility of conventional trials. However, the reality is that not every trial benefits from such designs. While many trials gain considerable improvement to clinical utility with the choice of an adaptive method, others perform just as well with more conventional study designs. 

Pantelis Vlachos, PhD, is a Director at Cytel Consulting. He works with a team of experts who regularly assist clinical study teams with the design and implementation of Bayesian methods. In this blog post, Pantelis describes key benefits of Bayesian analyses for clinical trials.

Cytel Consulting's Zoran Antonijevic

The key focus of precision medicine is identification of patients who would most benefit from a treatment. Proper enrichment of patient population greatly improves the probability of regulatory approval as well as product differentiation through improved efficacy and safety. Greater product differentiation leads to greater market access, as reimbursement is now a key driver to commercial success.

Here at Cytel we firmly believe that if you don’t get the design of a clinical program right, then nothing else matters. A study recently published by the Journal of the American Medical Association, once again confirms the vital importance of proper trial design for the timely approval of a new drug. The article reports that nearly half of all submitted NME applications fail upon first submission, and only half of those that fail are eventually approved. The median approval delay is a costly 435 days. At least 53.6% of the trials eventually approved would have benefitted from improved study design: 24 of the unsuccessful first-time applications (15.9%) resulted from uncertainties related to dose selection; 20 of the rejections (13.2%) were due to choice of study end points that failed to display a clinically meaningful effect; 20 of the rejections (13.2%) were a consequence of inconsistent results when different end points were tested; and 17 (11.3%) demonstrated inconsistent results when different trials or study sites were compared. Moreover, 89 (58.9 %) showed inadequate efficacy, raising a question about whether the dose had been selected properly.

Cytel has biostatisticians with broad experience in clinical trial and clinical development program design, including adaptive designs and designs for efficient dose-finding. We are eager to collaborate on your clinical programs to enhance their probabilities of success.