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A Hemophilia Clinical Trial Case Study

Utilizing Biostatistical support for CDISC ADaM Standards in an FSP Model

Quanticate successfully worked on a Hemophilia clinical trial where we delivered biostatistical and programming support via an FSP model. There was a focus on CDISC Standards, especially ADaM standards due to the unique nature of the trial and ensuring that the reporting of hemophilia specific data was possible, Quanticate overcame the challenges felt by our client and provided solutions so that the trials tight deadlines were met with the trial database being locked on time for reporting to commence.

 

Study Introduction

Quanticate has been providing functional service provider (FSP) support for this Top 20 pharmaceutical company since 2015. Initially the contract agreement was for two full-time equivalents (FTEs), one statistician and one programmer, however in four months this was increased to six; in 2018 this was increased to 15 FTEs across both statistics and programming, working across three departments and covering both lead roles (trial statistician and trial programmer) and support roles across a wide range of studies. Over this time the relationship between Quanticate and the sponsor has strengthened along with the sponsor’s trust in Quanticate; the sponsor now classifies Quanticate as a preferred supplier.

One of the key trials Quanticate has been working on is a multicentre, single-armed open label phase 3b clinical trial essential for the sponsor’s submission for their recombinant FVIII replacement therapy into a new regulatory region. This trial collected data from approximately 70 patients with severe hemophilia A ranging from young pediatric patients (0-<6 years) through to adults (≥18 years); recruiting them into both preventative and on demand treatments, 25% of whom additionally took part in pharmacokinetic (PK) analyses.

The trial consisted of a main phase and an extension phase, currently only the main phase has been completed (that is, DBL achieved and the study report finalized). The primary objective of this trial was to assess the effectiveness of the drug in the treatment of bleeding events. This trial was the first study in the product development program being conducted following CDISC standards.

Haemophilia Clinical Trial Case Study

The Challenge

The sponsor needed the resources from Quanticate as this follows the sponsor’s resourcing strategy, allowing the sponsor to have flexibility in its resourcing but still allowing access to a greater number of FTE’s when required.

There was an abundance of challenges in this trial; one of the largest challenges was, as mentioned before, this trial was the first CDISC trial for this product development program. This meant that the systems to ensure a smooth movement of data from source to ADaM were not present at the start of the trial and required setting up and fine tuning throughout the trial. Additionally, the sponsor’s team was not as familiar with the ADaM standards (SDTM dataset were not produced by the statistics and programming team) and the process of ensuring the dataset structures were in the most efficient form for representing and reporting hemophilia specific data resulted in these structures being variable and liable to change as the study progressed.

This challenge was compounded by a hard deadline due to the trial containing pediatric patients, requiring the sponsor to inform the European Medicines Agency (EMA) of the results 6 months after last patient last visit (LPLV).

In this trial the Quanticate team was involved in the production and/or review of all the ADaM datasets and the production and/or review of 97% of the efficacy outputs and 78% of the non-efficacy outputs. In addition, Quanticate was involved in the review of the CTR report written by the sponsor. In this trial the SDTM programming was handled by the sponsor, however Quanticate is experienced in SDTM and does offer support on creating SDTM datasets.

CDISC ADaM Case Study

The Solution

Quanticate provided the sponsor with a dedicated team, with each member having over a year’s experience with the sponsor and similar studies within this therapeutic area. This team assisted in the production of ADaM datasets by proactively applying CDISC standards to existing company standard as well as the production and/or review of said datasets.

The team members had regular catch-up meeting, both internally and with the sponsor’s team, to discuss issues and come up with solutions; feeding this information back to the sponsor with appropriate suggestions. In addition to working on the datasets the same team members worked on the production or review of outputs derived from these datasets; reducing learning time as the members were already familiar with these datasets, even after recent dataset restructuring.

Whilst working on the datasets and output the Quanticate team was also constantly looking for any data issues, in both generic data (age consistency, visit date and visit order, etc) and hemophilia specific data (bleed start/end timings and treatments, treatment pattern checking, target joint definitions, re-bleed definitions, Annualized bleeding rate [ABR] duration calculations, etc); proactively feeding these issues back to the sponsor’s team and clinical data management (CDM) or SDTM programmers as appropriate.

 

The Outcome

The process of preparing the SDTM dataset to a point where that they were ready for use in ADaM datasets turned out to be very lengthy; causing delays in both starting and finalizing ADaM datasets. However, despite these setbacks and other complications, data base lock (DBL) was reached on time and the EMA reporting requirement was satisfied.

During the dry runs the sponsor was impressed with the level of quality of the outputs; in spite of all the data issues. As a result, one of the Quanticate team has been given the role of trial statistician for the extension part of the trial.

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