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Case Study: Bayesian Decision-Making in a Phase 3 Oncology Design

Posted by Cytel

Mar 2, 2017 8:45:00 AM

We continue our case study series with this example of a Phase 3 design that uses Bayesian decision making combined with frequentist final analysis.

Clinical Development Background

Our biopharmaceutical client’s lead drug candidate is a late clinical-stage cancer immunotherapy for treatment of a rare oncology indication.  Clinical development of therapies in this indication faces inherent challenges of patient recruitment and scarcity of data.

Sponsor Challenge

The sponsor had previously conducted a randomized, double-blind, placebo-controlled Phase 2 study. Moving into a confirmatory clinical trial setting, they came to Cytel for support with a trial design to address their key questions:

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Topics: Oncology, Bayesian Methods, Phase 3, adaptive sample size re-estimation, biostatistics, adaptive trials, Bayesian


Estimands 101: Interview with Mouna Akacha

Posted by Cytel

Feb 27, 2017 7:39:00 AM

 

It’s been hard to miss the prevalence of estimand-related discussions in the last year.  This is a topic which is very much at the forefront of statistics discussions right now.  We are lucky enough to welcome Mouna Akacha to the blog to give us the lowdown on estimands and the problems and opportunities they represent for the global biopharma industry. 

Mouna is a Consultant in the Statistical Methodology Group of Novartis Pharma AG, based in Basel, Switzerland. She has a wide range of research interests including topics on missing data, longitudinal data and recurrent event data and is an active participant in the current estimand discussions.

Read on to find out everything you ever wanted to know about estimands but were afraid to ask…..

 

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Topics: Regulation, clinical development, biostatistics


Syntax and Variables in R: A Primer

Posted by Cytel

Feb 21, 2017 9:39:07 AM

 

 In a previous blog, we provided an overview of basic data structures in R.  In this follow up piece, we will provide a snapshot of basic syntax in R for programmers who want to get up to speed in this increasingly important programming language. 

 

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Topics: Statistical Programming, biostatistics, SAS, R


Outsourcing success for emerging biopharma

Posted by Cytel

Feb 15, 2017 9:33:05 AM

Outsourcing solutions should never be a one size fits all process, and smaller and emerging biopharma companies may  have different priorities and processes when working with external vendors to larger pharmaceutical organizations.

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Topics: outsourcing, Clinical Data, data manager, biostatistics, Biometrics, RFP


The Making of a CDISC Trainer

Posted by Cytel

Feb 6, 2017 9:10:00 AM

 

CDISC is a global, nonprofit charitable organization whose mission is ‘to inform patient care and safety through higher quality medical research’.  The organization delivers this mission through the development of data standards designed to streamline clinical research- these standard formats are increasingly expected for use in data submissions by regulatory authorities. Importantly, data standardization also brings significant benefits to the industry- in the CDISC 2014 Business Case (1),  it is noted that:

 “For those developing regulatory eSubmissions, using updated baseline numbers for the time and cost of getting a drug to market, it can be found that ~ $180M can be saved per submission (18% of the total cost). An average of two years can be saved off of an average 12-year clinical development program lifecycle – just by standardizing data”.

It’s therefore critical that the biopharma and CRO industries develop the next generation of data managers, statisticians and programmers with strong knowledge of the CDISC standards.


Angelo Tinazzi has more than 20 years’ experience in data-management and statistical programming and is Director of Clinical Data Standards and Data Submission at Cytel.  He has been a member of the European CDISC Committee since 2015 and is a member of the CDISC ADaM team. Taking the next step in his journey as a data standards expert, Angelo is now a "candidate trainer" with CDISC –working towards becoming an “Authorized CDISC Instructor”.  In this blog we find out more from Angelo about his experiences and the role of the CDISC trainer.

 

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Topics: Statistical Programming, Training and Education, Clinical Data, CDISC, SDTM, ADaM, Biometrics, CDASH


Accelerating development with combined SAD/MAD approach

Posted by Cytel

Jan 30, 2017 9:50:24 AM

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.

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


How to get the regulatory green light for your adaptive design?

Posted by Cytel

Jan 23, 2017 10:35:00 AM

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.

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


Data Structures in R: A Primer

Posted by Cytel

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.  

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Topics: Statistical Programming, biostatistics, SAS, Rstats, R


Adaptive Design Approaches from Cardiovascular Clinical Trialists Forum

Posted by Cytel

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.

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


SAS and NONMEM - a marriage made in heaven?

Posted by Cytel

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. 

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Topics: pharmacometrics, biostatistics, SAS, pharmacology, NONMEM


Our readers' choice : Top Blog posts from 2016

Posted by Cytel

Dec 23, 2016 8:21:00 AM

 

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.... 

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


CDISC submissions- are you up to speed?

Posted by Cytel

Dec 21, 2016 9:45:00 AM

 

December 18th 2016 was a significant date for the pharmaceutical industry and regulatory submissions. For trials which commence after this date, the FDA will no longer accept non-CDISC data submissions for new drug applications ( NDAs) , certain investigational new drug applications, abbreviated new drug applications (ANDAs)  and certain biologics license applications (BLAs).

 The FDA guidance Providing Regulatory Submissions  In Electronic Format —  Standardized Study Data (1)  also notes that the requirement will include ‘all subsequent submissions, including amendments, supplements, and reports’  to the submission types.

With regard to other regulatory agencies position on CDISC, the Japanese Pharmaceuticals and Medical Devices agency ( PMDA) will now request CDISC compliant submissions after October 2016 with a certain transitional period. This will be fully mandatory by 2018. While the European Medicines Agency (EMA)  is adopting a top-down approach and therefore more focused on topics such as data transparency, issues of data integration and interoperability will also form part of the EMA’s future plans.  

With this in mind, any sponsor planning an NDA, BLA or other regulatory submission needs to make sure they are observing best practice with regards to CDISC.  In this blog, we outline some of the key issues to bear in mind as you prepare for your data submission.

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Topics: Regulation, Clinical Data, data manager, CDISC, SDTM, CDASH


How do CDASH standards build data quality?

Posted by Cytel

Dec 20, 2016 9:21:00 AM

 

Data Standards play a crucial role in structuring and promoting long term value of clinical data.

Clinical Data Acquisitions Standards Harmonization or CDASH was developed with participation from all three ICH regions (US, Europe and Japan) with recommended data collection fields for 16 domains-> DEMOG, AE etc. It also includes  implementation guidelines, best practice recommendations, and regulatory references.  There is sometimes a misconception that CDASH defines the layout of the CRF and eCRF.  This is not the case.  The function of CDASH is to define the naming conventions for the clinical database, and outline how variables are mapped to SDTM. It defines how questions should be formulated for data collection within the CRF and eCRF making use of standard CDISC controlled terminology. In this blog, we will provide an example of CDASH implementation. 

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Topics: Clinical Data, data manager, CDISC, SDTM, CDASH


Adaptive Design CONSORT Extension Project: The Inside Scoop

Posted by Cytel

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.

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Topics: biostatistics, adaptive designs, adaptive trials


Ensuring quality data no matter the phase: data management considerations

Posted by Cytel

Dec 6, 2016 10:18:00 AM

The management of quality clinical data collection is built on a number of core essentials- including project management, timeline management, understanding of the deliverables, alignment with statistics and selection of the right technologies.  However, clinical development is a complex business and clinical data management approaches must be tailored to meet the specific needs of the trial.  In this blog, we take a look at some of the key considerations to be addressed by data management across the different clinical development phases.

 

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Topics: Clinical Data, EDC, database build, data manager


Innovative Phase 3 Adaptive Enrichment Design in Oncology

Posted by Cytel

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.

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Topics: Oncology, Enrichment, Cytel Strategic Consulting, Phase 3, patient enrollment, biostatistics, adaptive trials, personalized medicine


Infographic: 10 steps to consider before choosing an adaptive design

Posted by Cytel

Nov 21, 2016 11:42:00 AM

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. 

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


Case Study: Dose-response modeling informs Phase 2 ulcerative colitis study design

Posted by Cytel

Nov 18, 2016 10:04:00 AM

 

Challenge

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?

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Topics: Cytel Strategic Consulting, Case Study, pharmacometrics, biostatistics, PK/PD


Infographic: 9 Do's and Don'ts to Ensure Independence of QC in Statistical Programming

Posted by Cytel

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.  

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Topics: Statistical Programming, biostatistics, SDTM, ADaM


How to ensure independence of QC in statistical programming 

Posted by Cytel

Nov 11, 2016 10:05:14 AM

A solid and robust QC process is one vital component of ensuring quality programming delivery. Angelo Tinazzi and Cedric Marchand presented at the PhUSE conference recently on the topic of ‘What Auditors want’. As part of this well received presentation, the duo discussed the question of independence of QC and how to make sure this is fully observed.

In this blog we’ll walk through their recommendations to ensure independence of QC in programming.

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Topics: Trial Quality, Statistical Programming, Statistical Analysis, CDM


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