Adaptive designs have the potential to accelerate clinical development, and improve the probability of trial success. While the principle is simple- to reduce the uncertainty in clinical development by obtaining additional information from the ongoing trial- the statistical methodologies can be complex, and expert support is often required to conduct the clinical trial design. There's also complexity in the data collection itself, so knowledgable data management support is needed to successfully execute an innovative trial design. In this blog, we take a look at 5 top considerations for successful adaptive trial data management.
Oct 7, 2016 8:29:00 AM
Sep 29, 2016 9:28:14 AM
A paper "Best practices case studies for 'less well-understood' Adaptive designs", has been published by the DIA Scientific Working Group on Adaptive Designs as a twin document to the previously discussed "Challenges and Opportunities of 'Less Well Understood' Adaptive Designs". This publication furthers understanding by reviewing 10 important case studies and sharing details on their design and operational characteristics, as well as related regulatory interactions.
To read an abstract and details of the full publication click here.
In this blog we'll take a look at some of the case studies under discussion.
Topics: Rare Disease, Clinical Development Strategy, Adaptive Clinical Trials, Multi-Arm Studies, adaptive sample size re-estimation, Multi-Arm Multi-Stage Studies, EAST 6.4, adaptive designs, adaptive trials, Seamless designs
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.
Apr 28, 2016 12:30:00 PM
Adaptive Designs in Practice: Interview with NIHR Research Fellow Munya Dimairo
NIHR and University of Sheffield researchers recently published a paper, ‘Adaptive designs undertaken in clinical research: a review of registered clinical trials’(Hatfield et al) which explores the current state of adaptive designs in practice. In this blog we catch up with Munya Dimairo, NIHR Research fellow and one of the paper’s co-authors to find out more.
Apr 22, 2016 9:30:00 AM
FDA draft guidance on “Co development of two or more unmarketed investigational drugs for use in combination” notes that:
“Combination therapy is an important treatment modality in many disease settings, including cancer, cardio-vascular disease, and infectious diseases. Recent scientific advances have increased our understanding of the pathophysiological processes that underlie these and other complex diseases. This increased understanding has provided further impetus for new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets to improve treatment response or minimize development of resistance.” In this setting, it’s important to be able to design dose escalation studies which can identify the synergistic activity of compounds, and less toxic combinations.
Mar 11, 2016 12:30:00 PM
There has been increasing interest in multi-arm multi-stage trials with treatment selection and sample size re-estimation at interim analysis. The East 6.4 release incorporates new Multi-Arm Multi-Stage (MAMS) module to support statisticians designing these studies. In this blog, we take a high level look at some of the features and advantages of this approach.
Mar 3, 2016 3:00:00 PM
'The aim of a discussion should not be victory but progress.'
This principle, expressed by the French essayist Joseph Joubert, applies effectively to the spirit of scientific debate. More specifically, within the clinical development space, the field of adaptive designs has seen its fair share of both discussion and progress. In this blog we’ll take a look at one debated area- the efficiency of Adaptive SSR designs.
Oct 1, 2015 5:22:00 PM
This week marks the sixth annual American Conference on Pharmacometrics, held this year in Crystal City, VA. Situated at the intersection of mathematical modeling, simulation and big data, the field of pharmacometrics is delivering on its promise to revolutionize clinical research and by extension clinical development.
No wonder then that biostatisticians are now fully engaged with the enterprise.
Inference on Confidence Intervals for Adaptive Designs: The Latest Breed of Adaptive Clinical Trials
Sep 17, 2015 3:51:00 PM
Most people familiar with adaptive clinical trial designs are familiar with those statistical designs that reject the null hypothesis. These include now familiar designs like the promising zone design and the adaptive switch design.
A newer breed of adaptive designs, however, aims to apply adaptation techniques to confidence intervals.
Sep 15, 2015 3:56:42 PM
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:
Why You Should Not Power for Superiority Upfront: Promising Zone Clinical Trials with "Adaptive Switch"
Jun 26, 2015 12:00:06 PM
Powering a trial for superiority can be financially risky. In some instances it may also prove unnecessary.
Jun 11, 2015 5:21:09 PM
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 . CVOTs are typically designed as massive time-to-event trials that need to enroll several thousands of patients to establish safety . 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?
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 . 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.
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.
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.
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 .
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.
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 .
We have spoken in some depth about how thorough planning and room for flexible decision-making can avoid some of these potential difficulties   . However, sometimes the specter of trial discontinuity arises anyway. Here is a scenario which recently confronted the Cytel Consulting Team.
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 . 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.