Its important to take a strategic approach to clinical development in order to minimize the potential for Phase 3 attrition. The below infographic, previously published on the blog highlights some of the approvability and economic reasons cited for Phase 3 failure , and the clinical development issues which may have had an impact.
Oct 11, 2016 9:31:00 AM
Oct 7, 2016 8:29:00 AM
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 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 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
Sep 27, 2016 9:24:00 AM
The Lung-MAP trial is an innovative biomarker driven 'precision medicine' study which evaluates five novel agents for the treatment of patients with advanced squamous cell carcinoma of the lung. As well as exploring therapeutic options for this indication, it also aims to improve the drug development process.
At a Cytel seminar earlier in the year, Antje Hoering of CRAB presented to delegates on some of the practical challenges of the Lung-MAP study.
Sep 20, 2016 9:42:00 AM
Drug development is an expensive and risky business. To maximize a compound’s ultimate chances of commercial as well as regulatory success it’s imperative that sponsors are building up a strong understanding of its characteristics relative to competitors. This knowledge can support critical decisions along the development path, such as optimizing dosing, and selecting the best active control. Importantly, it also ensures the sponsor can build a body of evidence and quantify the benefits of the compound in the context of other treatment options. This knowledge can streamline the path to drug approval and support the drug’s chances of commercial success when it reaches the market.
Model based meta- analysis (MBMA) is becoming an increasingly utilized strategy to conduct this competitive benchmarking.
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 7, 2016 8:00:00 AM
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.
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.
Aug 2, 2016 10:30:00 AM
Editor's note( this blog was refreshed in April 2018)
As CDISC compliant submissions become increasingly expected, biopharmaceutical companies are considering how to approach the issue of data standards governance. Standards governance is a lynchpin in the management of CDISC compliance and is important for promoting standards awareness within organizations. It’s also an acknowledged hot topic in the industry.
It has traditionally been common practice for biopharma companies to outsource their CDISC conversion of legacy data for the purpose of publications and submissions to expert CROs. While large biopharma organizations may have dedicated in-house teams deployed to the management of standards governance, the dynamic nature of CDISC requirements means companies can struggle to find the resources to keep up to date and provide the best interpretation of the documentation. Outsourcing can be an option to ensure dedicated staff are available to manage and monitor these aspects and ensure companies remain submission ready.
Jul 28, 2016 10:06:00 AM
To close a clinical database right the first time you have to begin with study start-up. Clearly, you can’t close a database if the data is not cleaned and you can’t have clean data unless you know what is most important for analysis. It’s imperative that data management works closely with the statistics group during CRF/ eCRF design to ensure data is being collected and data checks are being written in a meaningful fashion. But that’s still not enough. The data should be cleaned on a regular basis and forms locked as soon as the data has been SDVd and reviewed. Even then, it will be important to have your statistics team run listings and tables early on to catch anything unexpected. If the data is cleaned and locked by the time the last patient visit comes around then getting Principal Investigator sign-off and ultimately closing the database can run much more smoothly and quickly.
Database lock is a significant milestone in the clinical trial, upon which further data analysis and reporting timelines depend. The Clinical Data Manager is responsible for steering the data management process to ensure that the database is locked on time, and correctly. In this blog we lay out the 6 steps to database lock success.
Jul 25, 2016 12:00:00 PM
Statistical programmers are in high demand within the biopharmaceutical industry, and within the dynamic world of clinical trials the part they play is ever evolving. In this blog, we take a look at 5 trends which are shaping their roles in 2016 and beyond.
Jul 21, 2016 6:30:00 AM
Did you miss our webinar on Single and Dual Agent Dose escalation designs earlier in the year? In this blog we have made the replay available for your review, and also take the opportunity to recap key reasons why you should consider a model based design for your dose escalation study.
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.