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.
Jan 23, 2017 10:35:00 AM
Jan 19, 2017 7:05:00 AM
R is on the rise in biopharma, and as we have previously discussed on the blog, it is now time for SAS programmers to get up to speedwith this popular and powerful programming language. Indeed, one of the advantages of R is its ability to integrate with other languages like C, C++, Python and SAS. Its strong graphical capabilities allow output in PDF, JPG, PNG, and SVG formats and table outputs for LaTeX and HTML. Importantly, as an open source resource, there is a strong community around R and extensive support for users in the form of forums like R-bloggers, StackOverflow and GitHub Repository
In this blog, we’ll provide an overview of R basic structures for programmers.
Jan 16, 2017 8:41:00 AM
The Global Cardiovascular Clinical Trialists Forum is a key event bringing together leading experts from across the spectrum of opinion leaders, clinical trialists, investigators, regulators, statisticians and practitioners to address the most pressing questions in cardiovascular clinical development today. At the December conference, eminent biostatisticians Cyrus Mehta and Stuart Pocock led a packed workshop tackling the advantages and limitations of adaptive designs within this space.
Jan 5, 2017 8:45:00 AM
Nonlinear Mixed Effects Modeling (NONMEM) is a type of population pharmacokinetics/pharmacodynamics (popPK/PD) analysis used in Clinical Pharmacology research. The population PK approach combined with pharmacodynamics modeling, allows integrated analysis, interpretation, and prediction of the drug’s safety, efficacy, dose-concentration relationship, and dosing strategy.
Dec 15, 2016 11:53:14 AM
In April, we interviewed NIHR research fellow Munya Dimairo about the paper, ‘Adaptive designs undertaken in clinical research: a review of registered clinical trials’ (Hatfield et al, 2016), for which Munya was a co-author.
During the previous interview, we discussed the barriers to uptake of adaptive designs, and the urgent need for a cross-sector discussion and work on reporting guidance of adaptive design. As a follow up to this, Munya is now Lead Investigator of the ACE project which aims to develop a consensus-driven reporting guidance tailored for Adaptive designs in the form of a CONSORT extension. The ACE Project is funded by the NIHR and is led by a multidisciplinary Steering Working Group of international experts in collaboration with the CONSORT Executive Group and the MRC HTMR Adaptive Designs Working Group. The goal is to enhance transparency, credibility, reproducibility, and replicability of adaptive trials as well as facilitate uptake of ADs in clinical trials research when appropriate.
We are delighted to welcome Munya Dimairo back to the blog to give us the inside scoop on this project.
Dec 2, 2016 9:19:10 AM
At a recent Pfizer/ Cytel seminar on rare disease and oncology development, Cytel’s Lingyun Liu presented innovative work on a patient enrichment design. In this blog, we share some design and operational considerations. This approach can help mitigate against underpowering of a clinical trial where there is uncertainty and heterogeneity of treatment effect among subpopulations.
Nov 18, 2016 10:04:00 AM
Our client had the following key questions which they wanted our pharmacometrics group to address for an upcoming phase 2 trial of their ulcerative colitis compound .
1) Can knowledge from pre-clinical and Phase 1 data inform on the optimal range of doses for an upcoming Phase 2 dose-ranging study?
2) How may the dose response observed in PD markers in Phase 1 healthy volunteers translate to the patient population?
Nov 14, 2016 8:13:29 AM
In our last blog, we shared some of Angelo Tinazzi and Cedric Marchand's recommendations on how to ensure independence of QC in statistical programming. Now, we've put together an infographic highlighting some key do's and don'ts in a handy checklist.
Oct 5, 2016 9:48:00 AM
While some progress has been made in terms of scientific development in Neuroscience and Neuropsychiatry indications, the pace of translation into more effective treatments remains elusive.
At the recent Cytel seminar co-hosted with Pfizer, Abdul J. Sankoh of Sage Therapeutics presented on some of the challenges in these therapeutic areas and discusses strategies moving forward. He bases his presentation on his broad industry experience.
Sep 13, 2016 10:15:00 AM
Exposure-response data gained from clinical studies can provide a basis for model-based analysis and simulation, helping to predict the expected relationships between exposure and response. Using this approach, it may be possible to optimize dosage regimens and to individualize treatment in specific patient subsets for which there are limited data. In this blog, we examine a case study of an exposure response modeling project conducted by our Quantitative Pharmacology and Pharmacometrics team.
Sep 9, 2016 9:24:00 AM
Our client, an emerging biotechnology company, was preparing for the next stage of development for their novel compound in a rare disease. They had two major concerns which they wanted the clinical trial design to address- an anticipated difficulty in recruiting subjects to the trial, and the cost and time investment associated with running separate phase 2 and phase 3 trials. They approached Cytel’s strategic consulting team for an innovative solution.
An inferentially seamless Phase 2/ 3 design with promising zone was proposed as a means to address the sponsor’s objectives. Because of uncertainty regarding which dose would be selected and what the effect size of the selected dose would be, the team proposed design options which allowed for adjustment of the sample size using information learned at the interim analysis. Several seamless phase 2/3 designs, with and without adaptive sample size re-estimation were evaluated through simulations using East 6.4.
The simulations evaluated various design parameters such as maximal sample size, timing of the interim analysis, size of the promising zone, and efficacy and futility boundaries. Designs were compared on the basis of overall power, average sample size, conditional power, probability of entering each interim zone, and number of overruns.
The inferentially seamless design has the potential to accelerate clinical development by removing the ‘white space’ between phases 2 and 3. Where the sample size is increased adaptively at the interim analysis by a specified percentage of the original pre-planned sample size, an overall increase in power could also be achieved. The sample size re-estimation design provided a boost to power where the interim results fell in the promising zone. The client benefited from a design which only calls for additional investment of patients and resources when this investment would meaningfully boost the chances of success.
Cytel's statistical consulting team help you decide if an adaptive approach is right for your trial. Read further examples of our work by clicking below.
Sep 2, 2016 10:30:00 AM
Aug 31, 2016 1:11:57 PM
Traditional rule-based approaches to dose escalation such as 3+3 are widely used in early clinical development. They can be appealing due to the simplicity of execution. However, estimates produced may be highly variable and the targeting of true Maximum Tolerated Dose may be poor. Bayesian dose escalation approaches in early phase trials can offer an effective alternative to determining the maximum tolerable dose of a new drug more quickly, as well as ensuring that all of the information available to trial clinicians is taken into account so that the patients enrolled in the trial receive the best possible treatment.
Aug 26, 2016 11:30:00 AM
At the recent JSM in Chicago, Cytel’s Sam Hsaio and Lingyun Liu alongside Genentech's Romeo Maciuca, presented a framework for inference in adaptive bioequivalence trials with unblinded sample size re-estimation.
In bioequivalence trials where the variance is often unknown, and the sample size small, using boundaries derived under the assumption of a normally distributed test statistic may lead to type I error inflation. This problem can be overcome with p-value combination methods, however these approaches generally do not directly provide confidence intervals for the geometric mean ratio on the scale of the original pharmacokinetic endpoint.
Aug 23, 2016 9:00:00 AM
At the recent JSM meeting in Chicago, Cytel's Jim Bolognese presented the results of work he has conducted evaluating the T-Statistic ( or T-Stat) method for adaptive dose finding of MTD. In this blog we'll provide a brief summary of Jim's findings, and share his slides with our blog readers.
Aug 17, 2016 11:57:43 AM
Following the recent publication of their review article Adaptive Designs for Clinical Trials in the New England Journal of Medicine, co-authors Cyrus Mehta ( President and Co-Founder of Cytel, and Adjunct Professor of Biostatistics at Harvard University) and Deepak L. Bhatt M.D C M.P.H. (Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center) were invited to participate in a live video discussion with the journal.
Aug 9, 2016 9:00:00 AM
At the recent JSM Meeting, Cytel’s Yannis Jemiai presented the case study of the VALOR trial which used a promising zone design. At the time of the study, existing therapy for relapsed or refractory AML was generally unsatisfactory with no approved drugs available for patients, and a very poor prognosis. Vosaroxin was a first-in-class anticancer quinolone derivative which had previously been studied in a single arm Phase 2 study. In this blog we'll take a look at the operational and regulatory considerations in the implementation of this trial, which were highlighted during Jemiai's talk.
Jul 20, 2016 8:30:00 AM
The Joint Statistical Meetings is the largest and arguably most highly respected gathering of statisticians in the world. It will bring together over 6000 statisticians for this year’s event in Chicago. As a large meeting, it can be a challenge to navigate and find the sessions which are going to be most valuable for your work. To help out, we've asked some of the leading lights of our statistical group which sessions are their top picks this year.
Jul 18, 2016 8:00:00 AM
In order for adaptive designs to reach their potential, it’s critical that knowledge is effectively dissemirnated within the medical research community – in particular detailed information about the operating and statistical characteristics of specific designs and insights as to their benefits and limitations.
Cytel recently announced the publication of an important article in the New England Journal of Medicine which takes a leap forward in promoting better understanding of adaptive designs particularly in a confirmatory setting. We'll discuss some of the highlights of the article in this blog.
Jul 7, 2016 10:30:00 AM
Why do we do what we do? At Cytel we have always been driven to deliver benefits in the service of human health, and ultimately to bring new drugs to the patients who need them. In the context of our work in statistical software, we have recently had the opportunity to support an important conservation project defined by a similar passion to make a difference.
While our core focus has always been in biostatistics, and thus in the life science industry, our StatXact statistical software is used by customers across a broad spectrum of natural and social sciences thanks to its ability to handle small sample sizes.
The Association Takh is one such customer. Takh is dedicated to the re-introduction of the world’s last wild horse, as well as conservation in Mongolia and improvement of the lives of Mongolian herders. (1) In 2004 and 2005 the association reintroduced 22 Przewalski’s horses( one of the world’s most endangered species) from Le Villaret in southern France to the buffer zone of Khar Us Nuur National Park in the Khomyn Tal herder community of western Mongolia.