With an increasing interest in platform designs and other innovative designs that involve multiple comparisons over multiple stages, the importance of Multi-Arm Multi-Stage ( MAMS) designs is set to rise.

Topics: Adaptive Clinical Trials, Multi-Arm Studies, Multi-Arm Multi-Stage Studies, biostatistics, adaptive designs

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.

Topics: Cytel Strategic Consulting, Cytel Consulting, Statistical Programming, Phase 1, Dose-Finding, Compass, Phase I, biostatistics, adaptive designs, adaptive trials

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.

Topics: Cytel Strategic Consulting, Cytel Consulting, Regulation, biostatistics, adaptive designs, adaptive trials

 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.

Topics: Cyrus Mehta, Cardiovascular, Cytel Events, biostatistics, adaptive designs, adaptive trials

 

As we prepare to say 'so long, farewell'  to 2016, we'd like to take the opportunity to thank all our blog readers and subscribers.  Read on for a  round up of our most read topics from the year.... 

Topics: Clinical Data, EDC, database build, data manager, CDISC, SDTM, adaptive designs, adaptive trials

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.

Topics: biostatistics, adaptive designs, adaptive trials

While adaptive designs can deliver significant benefits to clinical development-  including ethical benefits for patients, reduced costs, and improved likelihood of trial success- they are not suitable for every clinical trial.  In making the assessment of whether or not to choose an adaptive design, trial planners need to weigh the strategic benefits against the practical implications. 

We have previously discussed on the blog, the 10 steps proposed by Jim Bolognese and Ranganath Nayak to assist sponsors in making this decision. In this blog, we are delighted to share a simple infographic outlining the process. 

Topics: Clinical Research Services, Interim Analyses, Clinical Development Strategy, trial planning, adaptive designs, adaptive trials, DMC, infographic

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. 

Topics: Data Management, Clinical Development Strategy, Clinical Data, Adaptive Clinical Trials, EDC, data manager, adaptive designs, adaptive trials

 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. 

Topics: Clinical Research Services, psychiatry and neuroscience, biostatistics, adaptive designs, adaptive trials

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

In the 2010 draft FDA ‘Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics',  the agency makes an important distinction between ‘well understood’ and ‘less well understood’ adaptive designs.

‘Well understood” adaptive designs may include such approaches as adaptation of eligibility criteria, adaptation for stopping early and adaptations to maintain study power based on blinded interim analyses of aggregate data. For these 'well-understood designs', there is little concern from the FDA about their potential to be implemented in adequate and well-controlled trials.  On the other hand, at the time of the drafting of the guidance at least, ‘ less well understood designs' (which include such approaches as adaptations for dose selection studies, adaptation of patient population based on treatment-effect estimates,  and adaptation for end-point selection based on interim estimates of treatment effect) gave greater concern. Interestingly, the FDA  Adaptive Designs for Medical Device Clinical Studies : Guidance for Industry and Food and Drug Administration Staff does not adopt this distinction. 

A recent article, Addressing Challenges and Opportunities of “Less Well-Understood” Adaptive Designs (He et al 2016) (1) takes a look at some of the perceived challenges of these designs and ways in which they may be overcome.  The publication is the result of work by a best practice sub-team formed by the DIA Adaptive Design Scientific Working group in January 2014. Cytel's Yannis Jemiai is a member of this group, and one of the co-authors of the article. 

In this blog, we take a look at a few of the challenges outlined and some of the suggested mitigations.  One aspect covered in the publication is seamless designs- and given the scope we'll devote a separate blog to this area. 

Topics: sample size re-estimation, Clinical Research Services, type 1 error, Software Simulations, patient enrollment, adaptive designs, adaptive trials, DMC

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.

Topics: East, Dose-Escalation, Dose-Finding, Compass, biostatistics, adaptive designs, adaptive trials

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. 

Topics: Cyrus Mehta, Promising Zone, biostatistics, adaptive designs, adaptive trials

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. 

Topics: Oncology, Clinical Research Services, Regulation, ACES, biostatistics, adaptive designs, adaptive trials, DMC

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. 

Topics: sample size re-estimation, Phase 3, Adaptive Clinical Trials, phase 2, biostatistics, adaptive designs, Seamless designs

 Predicting the course of a clinical trial is something which people will always want to do-whether for statistical reasons, planning reasons or business reasons. In this blog we look at examples of where prediction goes off course, and how we can resolve these issues.  We also share valuable video and slidedeck resources from our VP Consulting and Software, Yannis Jemiai.

Topics: East, East PREDICT, Interim Analyses, Cytel Videos, Cytel Events, clinical development, EAST 6.4, adaptive designs, adaptive trials, DMC

A number of the Cytel team were in Berlin 22nd- 25th May  for the PSI Annual conference.  The PSI Conference is an important forum for statisticians and we found this year's event to be energetic, technically interesting and well attended.  In this blog, we’ll summarise some of the particular highlights from the sessions that our team members attended.

Topics: Clinical Data, biostatistics, adaptive designs, adaptive trials, PSI Conference

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.

Topics: Group Sequential, Adaptive Clinical Trials, adaptive sample size re-estimation, adaptive designs, adaptive trials