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The Transformation of Clinical Research at BIOS

Much has been written about the escalating costs, slowing cycle times, and long time-to-publication for clinical trials.[1][2] Despite significant effort to harmonize regulations, develop sophisticated data systems and rethink outmoded practices, transformation in clinical research has been much slower than in other industries.[3]

The first off-the-shelf electronic data capture (EDC) systems emerged in the late 1990’s. Despite demonstrated tangible benefits [4], it took more than 10 years before EDC was widely adopted in the pharmaceutical industry; adoption in academic trials has been even slower.[5]  On the site startup side, some 30% of pharmaceutical and medical device companies, as reported in a 2013 NextDocs survey, were still using paper-based files and only 24% were using a dedicated electronic trial master file (eTMF) system.[6] Adoption of centralized (risk-based) monitoring, adaptive designs and similar business and technological innovations has also been painfully slow.

Certainly, a number of factors come into play, but a core obstacle may be that, by definition, clinical trials involve large numbers of people — and people (or their institutions!) can be highly resistant to change. In an informal 2009 clinical site survey by ClinPage, 26% of 629 respondents, 71% being study coordinators, said EDC data were being initially entered from a paper CRF rather than direct data collection. This is surprisingly worse than the 21% in their earlier 2001 survey. Whether this reflects human cultural hesitation, growing institutional fears (over HIPPA, European Data Directive, etc.), or just the ever increasing complexity of studies, much of the value of an EDC system is lost if its implementation does little more than transfer the task of entering intermediary paper case forms (“data collection worksheets”) from the sponsor to the investigator.[7]

BIOS’ experience with the MISTIE clinical development program is a good example of how transformational technology and business process change can reduce time and cost while improving quality. But, more importantly, it serves as an example of how innovation, to be successful, must be implemented in the context of a well-designed plan executed by a skill project management team.

 Charting new territory

The BIOS-led MISTIE consortium has been on a decade-long quest to develop and validate a treatment for intracerebral hemorrhage (ICH). The culminating international, 500-patient, 100-site, Phase III trial was launched in 2013 and, if early findings hold up, its publication has the potential to dramatically change how ICH is treated around the world, finally bringing a critically needed treatment to the hemorrhagic stoke patient.

After preliminary development work to obtain an Investigational New Drug (IND) exemption, BIOS assembled the consortium in August 2005 to conduct a small sixty-patient trial called ‘MISTIE Phase 2 Stage 1 (“M2S1”). This was an early-phase dose-ranging study of an off-label thrombolytic in the seemingly illogical context of bleeding within the brain. Innovative indeed!b2ap3_thumbnail_M2S1_enrollment.png

Data was collected from the 12 sites using Microsoft Access but otherwise the trial was largely paper-based. With no track record upon which to base projections and no knowledge of how the sites (or their IRBs) might accept such a novel off-label use of this drug, the MISTIE team was, understandably, optimistic in their ability to quickly initiate sites and recruit patients. Patient recruitment took 12 months longer (+40%) than initially planned which, unfortunately, is not atypical in an industry where 55% of trials fail to complete on schedule.[8]

Changing the Culture

The next study, ‘MISTIE Phase 2 Stage 2’ (M2S2), would be the selected-dose pilot for a planned definitive phase-III trial and a chance to implement innovation and process change with the goal of improving upon this initial performance. The team correctly recognized, however, that innovation alone would not suffice. They were working in specialized, high-intensity areas (neurosurgery and neuro-intensive care) where large-scale, rigorously controlled multicenter trials are relatively rare. For many coordinators this might be their first exposure to EDC and, for some of the ICU and surgical nurses, this might even be their first multicenter trial. BIOS needed to systematically change the slow-moving academic culture to one more focused on efficiency and performance while introducing new and potentially intimidating processes.

First, BIOS established a strategic relationship with Emissary International, a commercial contract research organization (CRO). This academic-commercial collaboration brought industry-leading expertise in two critical areas: eClinical Systems (EDC, eTMF, CTMS) and in independent, risk-based (“central/remote”) monitoring. Emissary introduced the team to Prelude Dynamics, which had an EDC system (VISION) with one of the lowest learning curves in the industry.

The EDC system was introduced in mid- 2008 during a hold for re-approval of a dosage change. It was a big change but it was followed by a 55% improvement in the enrollment rate.b2ap3_thumbnail_M2_enrollment.png

Transformative Change: Electronic Data Capture (EDC)

Result: 38% faster enrollment rate post-implementation

Several innovations were made possible by this newly implemented EDC. Among the most notable was the Electronic Trial Master File (eTMF). This innovation not only eliminated the need for both the sponsor and site to maintain paper-based regulatory files but also to reduce the burden to collect, process and track essential documents. This capability of collecting/tracking documentation and, most importantly ensuring the confidentiality of patient-identifying information, was also a critical requirement for implementing remote monitoring, which by reducing expensive travel and burdensome site visits, significantly reduced both time and cost. 

Transformative Change: Electronic Trial Master File

Result: Greater regulatory compliance; Ability to implement remote monitoring

Not all innovations are technology-based. Dan Hanley, Karen Lane and the BIOS management staff implemented a number of initiatives designed to streamline operations, and, importantly, to focus the team and the clinical sites on well defined performance goals: from simple things like monthly webinars to friendly competitions to gain everyone’s buy-in on a project goals. 

For example, BIOS compiled a set of key performance metrics and instituted a program whereby site managers would review these metrics with each clinical site on a quarterly basis. The QAP Program ensured investigators and coordinators were kept informed of their site standings. Later in the CLEAR trial, BIOS implemented a modified version of the QAP program, this time as a friendly competition called the World Cup. In this contest, sites compete for the best performance as measured by metrics with an award, the “Hanley Cup,” going to the top sites in various categories. 

b2ap3_thumbnail_AVERT_data_flow.pngRecently, BIOS has created an entirely new means of collecting clinical trial data. For the AVERT study, the team developed middleware that integrates a tablet-based system (Creoso Corporatation's Digivey kiosk system) with the VISION EDC system. This allows data to be collected OFFLINE at the patient bedside in a one-question-per-screen format while still retaining the regulatory compliance and data workflow capabilities of a traditional EDC system.


Overall, as shown on the table below, BIOS has implemented almost 50 innovations and business process changes since the start of the MISTIE program.

Although it is difficult to demonstrate an unarguable cause & effect relationship with any particular one, over time the overall result of these transformative changes is plainly evident in the enrollment curves for the three studies in the MISTIE program. Much of the credit goes to the clinical site coordinators and investigators who rose to the challenge and recognized the importance of transforming clinical research, not just for MISTIE but across the entire medical research industry. Together, the MISTIE consortium has literally changed the world!



Business Process/Technological Innovation


VISION eClinical Software Platform

A commercial electronic data capture (EDC) platform developed by Prelude Dynamics of Austin, Texas used for EDC and as clinical trial management system (CTMS) (compiling performance/quality metrics, managing study supplies, generating/tracking site invoices, etc.). The platform upon which many of our other technologies have been built.

Mar 2008

Integrated Lab Normals/Abnormal Flagging

Lab reference ranges are collected for each site as part of study startup. These high/low ranges (and unit descriptors) are then automatically copied to the individual patient case forms as needed, eliminating the need for coordinators to enter ranges on each lab report as well supporting automated high/low value notifications.

Mar 2008

Electronic Trial Master File / Patient Source Documents (eTMF)

Regulatory document management integrated into the VISION platform that allows for paperless trials.

Sep 2008

Risk-based (“Remote”) Monitoring

Quality Systems approach in compliance with FDA guidance and Clinical Trials Transformation Initiative (CTTI).

Sep 2008

Dedicated Site Manager Team

Organizational re-engineering to better focus on REAL-TIME patient enrollment and site motivation.

Jan 2009

Web Content Management System & Upgraded Study Website

Database-driven web content management system (CMS) allowing secure exchange of information. This full-featured, interactive website is used as a repository for downloadable documents, as a communications tool (blogging & article publishing system), and as a social platform for teambuilding purposes (discussion groups, photo sharing, etc.).

Mar 2009

Dedicated Site Startup Team

Organization role created to expedite the site startup process (selection, qualification, essential docs)

May 2009

Emissary College

Full-featured online courseware product used for site training and certification.

May 2009

Automated Deviation Tracking

Specialized EDC programming that automates many of the data quality checks that monitors did manually.

Aug 2009

Blinded Pharmacist Randomization Notification System

Programming & workflow to confidentially send randomization code to hospital pharmacists via fax or email.

Aug 2009

Surgical Telementoring

Dedicated team to mentor and certify new surgical investigators, review I/E in REAL-TIME and monitor surgical data

Sep 2009

Auto-coded Drug/Procedure/AE Dictionaries

EDC programming for auto-coding of AEs, procedures & ConMeds; dictionaries coded to MedDRA, SnoMed, RXNav

Sep 2009

Quality Systems Approach

Multitiered quality-by-design approach designed to build-in REAL-TIME quality (rather than inspect-in afterwards). Replicates and establishes responsibility for quality across all departments.

Sep 2009

Electronic Screening Log

EDC programming to eliminate paper-based screening logs and enhance demographic and site performance data.

Sep 2009

Integrated coordinator/monitor guidance in EDC

Extensive EDC programming/web form designs that “walk-thru” the protocol to enhance protocol compliance.

Sep 2009

Cross-reference verification functionality in EDC

EDC programming allowing cross-referencing across forms. For example, matching AEs to specific catheter insertions.

Sep 2009

Near-Real-Time CT Reading

Re-engineered process to collect dicoms and measure clot sizes PRIOR to randomization; enhances compliance.

Sep 2009

Centralized Modified Rankin Scoring System

Process to confidentially upload patient interview videos to blinded central reviewers, then retrieve back scores.

Oct 2009

Quarterly Assessment of Performance (QAP) Program

Site management procedure & associated software to provide sites and management with graphical status reports.

Mar 2010

Executive QAP Report

Quarterly status report for executive committee analyzing the QAP metrics; used for project management.


Safety & Endpoint Adjudication

EDC forms and associated workflow process allowing efficient medical monitoring and endpoint adjudication.

Mar 2010

Adaptive Randomization

Statistically-developed algorithms and validation tools to implement REAL-TIME covariate-adaptive randomization

Nov 2010

Outcomes Tracking

Process & EDC report programming allowing management of outcomes data without breaking the blind.


Quarterly Refreshers

A condensed version of the Investigator Meeting (site initiation) training given quarterly for new/re-training of sites.

Mar 2011

Webcasting and the Featured-Speaker Webinar Series

Monthly investigator & coordinator featured-topic live webinars, available via web and iTunes podcasts.

Jun 2011

Coordinator of the Year Award Program

Annual competition for the best site coordinator, based on a series of data quality, timeliness and enrollment metrics

Jul 2011

Website Social Groups/Member Profiles/Community Features

Series of social tools which enhance camaraderie and support group/teams (e.g., German Site Social Group, Case Form Feedback Team)

Oct 2011

Calendar Synchronization

iCal-compliant synchronization service that will update staff & site users’ personal Outlook (etc.) calendars

Feb 2012

Mobile Study Apps

Study and protocol information on a mobile app.


Mar 2012

Tripartite Metrics Report

Periodic report compiling by-site metrics on quality and compliance. Ex. %Patients Meeting Surgical Goal.

May 2012

World Cup Site Performance Competition

A trial-long friendly competition to be rated the best site based on data quality, timeliness & enrollment metrics. Annual winning team/site receives the “Hanley Cup” award

Jul 2012

Integration with NINDS’ RPMS Enrollment Tracking System

EDC backend programming to pass enrollment information to NINDS for cross-study site-level performance tracking.

Jul 2013

The Mount Everest Summit Challenge

A contest for coordinators to motivate sites toward faster completion of startup activities. Used in MISTIE-III

Oct 2013

Advanced Site Qualification Process

A series of survey tools for better site selection. Includes collecting hospital census and prior site experience, a detailed assessment of and written commitment to enrollment plan, facility survey, and a personal interview between project leader and key site staff to make final determination on site suitability.

Feb 2014

Dual Field Naming to Support Common Data Elements

Capability added to EDC supporting two variable names for each field: longer (more readable) names used in reports and shorter (more cryptic) CDISC or NIH CDE variable names for data analysis purposes. Also includes EDC programming to reformat/reclassify certain data to better support standardization while retaining functionality.

Feb 2014

Dicom Tracking System

Live report in the EDC and associated workflow to better manage the collection/reading of imaging data

Mar 2014

CME Credit for Online Training Courses

Obtained accreditation from Accreditation Council for Continuing Medical Education proving 9 hours of AMA PRA Category 1 Credits™ for completing the MISTIE III online training course for investigators.

Jun 2014

Site Dashboard

One-page LIVE report of key performance indicators for each site. Replaced the QAP program with real-time report.

Aug 2014

Mobile Registry

A stroke treatment registry run exclusively on a mobile platform (http://braininjuryoutcomes.com/studies/registry).

Feb 2015

Site Closeout Checklist

An EDC-supported workflow with electronic signatures for ensuring all close-out activities are complete.

Mar 2015

Quarterly Safety Forums

Periodic webinar series targeting surgeons and addressing best-practices for patient management/monitoring

Jun 2014

Digivey Kiosk Software Bridge

Direct integration of Creoso Corporation’s Digivey tablet system with the VISION EDC platform. Digivey allows rapid kiosk-style offline data collection on a mobile platform at patient bedside. Server-to-server integration allows the data to be transferred to VISION for compilation, live reporting and specialized functionality to support randomization and monitoring.

Jun 2015

Deviation Adjudication System

Enhanced EDC-based system for compiling protocol deviations and reviewing them for impact on the study objectives. Aids DSMB and biostatical reviews, improves management information and allows faster corrective action.

Aug 2015



[1] Ross JS et al. Publication of NIH funded trials registered in ClinicalTrials.gov: Cross sectional analysis. BMJ. 2012 Jan 3; 344: d7292.

[2] Per-Patient Clinical Trial Costs Rise 70% in Three Years. Cutting Edge Information website. http://www.cuttingedgeinfo.com/2011/per-patient-clinical-trial-costs/. July 2011. Accessed Aug. 18, 2015.

[3] Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020: Workshop Summary. http://www.ncbi.nlm.nih.gov/books/NBK114667/. Accessed Aug. 18, 2015.

[4] eClinical Trends: Challenges and benefits of EDC adoption. http://www.clinovo.com/blog/challenges-and-benefits-of-edc-adoption/ Clinovo website. Apr 26, 2013. Accessed Aug. 18, 2015.

[5] El Emam K et. Al. The use of electronic data capture tools in clinical trials: Web-survey of 259 Canadian Trials. J Med Internet Res. 2009 Mar 9;11(1):e8. doi: 10.2196/jmir.1120. PubMed: 19275984.

[6] State of Trial Master Files (TMF): Survey Results-2013. NextDocs. As quoted in PRNewswire press release, http://www.prnewswire.com/news-releases/survey-reveals-technology-gap-in-managing-clinical-trial-documentation-227049571.html. Accessed Aug. 18, 2015.

[7] Redfearn, S. More Paper, More Burden? ClinPage, (2009), http://www.clinpage.com/article/more_paper_more_burden/C5.

[8] Data from Delphi Pharma’s database of 1300 trials tabulated through third quarter 2009, compiled in Clinical Trial Recruitment Strategies, Business Insights Limited, http://store.business-insights.com/Product/clinical_trial_recruitment_strategies?productid=BI00025-018 Accessed via a presentation on Optum.com’s website, https://www.qualitymetric.com/Portals/0/Uploads/Documents/Public/SCOPEGwinn_2-5-2012_ForWebsite.pdf

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