2010 best practices competition clinical research category...kendle used the arx cosign digital...

2010 Best Practices Competition Clinical Trials & Research Category

Pg Nominating User Company Project Title 2 ARX, Inc. Kendle International Digital Signature integration for TrialWatch and Site

Manager CTMS 7 CRA

Solutions, Inc.

Medical Research Management

Fundamentals of Clinical Research

10 ERT Centralized Cardiac Safety 2.0 14 ERT Suicidality Monitoring 19 GlobalSubmit FDA Common Table of Contents 22 GlobalSubmit FDA Study Design Software Development 24 Image Analysis Dynamika – comprehensive platform for clinical R&D in

dynamic MRI 33 Kendle TrialEAS™: web‐based adjudication system 44 MaxisIT, Inc. Merck Research

Laboratories ADAPT Dashboard Prototype

55 Medidata Solutions

Abbott Global EDC Centralization at Abbott using Medidata Rave

59 Merck & Co, MRL Dev‐ IT Clinical Portal & Collaboration (CPAC) 62 Revolution

Computing Merck Research Laboratories

gsDesign Explorer

69 Perceptive Almirall A Complete Clinical Trial Picture: Enabling More Effective Decisions with Real‐Time Information

74 Pharma Vigilant

QuatRx rSDV experience in Phase III Trial

79 SAS MDS Pharma Services AND Daiichi Sankyo

Daiichi Sankyo / MDS Pharma Services Collaboration

85 St. Luke's Medical Center ‐ Quezon City

St. Luke's Center for Clinical Trials

87 Technion‐Israel Institute of Technology

Preservation of Ovarian function despite chemotherapy

92 University of Arkansas for Medical Sciences

Implementing a Vision for Clinical Research

250 First Avenue, Suite 300, Needham, MA 02494 | phone: 781‐972‐5400 | fax: 781‐972‐5425

Published Resources for the Life Sciences

Bio‐IT World 2010 Best Practices Awards

1. Nominating Organization (Fill this out only if you are nominating a group other than your own.)

A. Nominating Organization Organization name: ARX, Inc. Address: 855 Folsom St. Suite 939, San Francisco, CA 94107 USA

B. Nominating Contact Person Name: Gadi Aharoni Title: CEO, ARX, Inc. Tel: (415) 839 8161 Email: [email protected]

2. User Organization (Organization at which the solution was deployed/applied)

A. User Organization Organization name: Kendle International Address: 500 Carew Tower, 441 Vine Street, Suite 500 Cincinnati, OH 45202

B. User Organization Contact Person Contact #1 Name: Christopher Kaas Title: IT, Global Clinical Research Services (Site Manager Project) Tel: (513) 562‐1761 Email: [email protected] Contact #2 Name: Bill Wilson Title: IT, Global Clinical Research Services (TrialWatch Project) Tel: (513) 763‐1988 Email: [email protected]

3. Project

Project Title: Digital Signature integration for TrialWatch and Site Manager CTMS Team Leader: Chris KaaS (Site Manager application), Bill Wilson (TrialWatch application) Title: Kendle International, IT, Global Clinical Research Services



Tel: (513) 381‐5550 Email: [email protected], [email protected] Team members – name(s), title(s) and company (optional): Technology Partners: ARX: CoSign Digital Signature system Microsoft: Sharepoint web collaboration platform Perceptive Informatics: Datalabs Site Manager Clinical Trial Management system

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound‐focused research, drug safety Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource

optimization Health‐IT: ePrescribing, RHIOs, EMR/PHR Manufacturing & Bioprocessing: Mass production, continuous manufacturing

(Bio‐IT World reserves the right to re‐categorize submissions based on submission or in the event that a category is refined.) 5. Description of project (4 FIGURES MAXIMUM):

A. ABSTRACT/SUMMARY of the project and results (150 words max.) Kendle is a top 10 clinical research organization (CRO). As such, Kendle has many forms and documents that need to be authored, signed, processed and managed by internal employees (clinical research associates) as well as external partners (principal investigators, IRBs) in order to set up and conduct clinical trials at investigator sites. Once a form is filled, approved and signed, it needs to be submitted to clients (sponsors, pharmaceutical companies, etc.) within a tight deadline, and clients ultimately need to submit it to the FDA and other regulatory authorities. Additionally, since the employees are mobile and the investigators and IRBs are remote, access and signing of documents needs to be completed via a web browser. By enabling these forms to be completed electronically, Kendle is able to substantially reduce costs, speed up approvals, start studies/sites quicker, submit to sponsors electronically and enable clients to manage the signed forms more efficiently.



B. INTRODUCTION/background/objectives

Historically, CROs have been paper‐intensive in their need to set up clinical sites for a study, and report on site activities during the course of a study. Kendle recognized an opportunity to gain a competitive advantage by levering electronic forms, signatures and processes to complete and approve forms required by the pharmaceutical sponsors and FDA. They focused on two areas: 1. Kendle integrated digital signatures with their internal Clinical Trial Management System

(CTMS), TrialWatch®. This enables all of Kendle’s Clinical Research Associates (CRAs) to eliminate the costs and time associated with physically signing, manually routing, and priority shipping site‐generated documents such as Monitoring Reports, which are completed and sent following each clinical site visit. Under contract, the reports are to be submitted back to study sponsors within 10 business days after each visit. By expediting the signing process, CoSign ensures Kendle’s contractual compliance with clients, and reduces shipping and routing costs that a paper‐based workflow would necessitate.

2. Kendle also integrated digital signatures with their Site Manager™, a Microsoft® SharePoint®‐based web application provided by Perceptive Informatics. This externally facing CTMS, which is often referred to as an Investigator Portal, is designed to expedite clinical trial site initiation and is used by over 6,000 external collaborators in the Kendle clinical ecosystem, such as principal investigators and coordinators, IRBs, sponsors and Kendle project managers. The system is accessed through a web browser, without the necessity for any client‐side software, which makes it easy to set up and apply digital signatures across thousands of clinical settings. The documents being signed are FDA or EMEA Regulatory Packets, which are part of the Trial Master Files (Protocol Letter, Informed Consent Form, IRB Approval, Master Trial Agreement(s), CDA, Form 1572, Financial Disclosure Form, CV, Medical License/Certifications/References, Authorize to Handle and Drug Shipment Forms, etc.).

C. RESULTS (highlight major R&D/IT tools deployed; innovative uses of technology).

Because documents need to be trusted and verified by outside parties (the various participants in their clinical network, including sponsoring pharmaceutical companies and regulatory authorities like the FDA), Kendle was determined to use standards‐based (PKI) digital signatures.

Digital signatures are standardized electronic signatures and are being used extensively in government and the life sciences industries around the world. Unlike proprietary electronic signatures, digitally signed documents become self‐contained, portable, and sustainable electronic records that are maintained in a non‐proprietary format conforming to published standards (NIST, ISO). Hence, signed documents do not require any proprietary software to verify the signer’s identity and intent or the document’s data integrity. Recipients simply open the document in order



to verify. The electronic record is a legally defendable, signed document that provides authentication, data integrity and non‐repudiation. Kendle used the ARX CoSign digital signature system for their implementation. CoSign is established as the market leader in the FDA markets with hundreds of organizations using it today including over 25 CROs. The total cost of ownership of CoSign made the project ROI realizable and quick, and the installation, setup and validation of the system made the project deployment fast. The fact that CoSign offers a centralized server architecture and enables signing through a web browser means that no client‐side software needs to be deployed to enable end user signing.

D. ROI achieved or expected (200 words max.):

Kendle has been able to eliminate or greatly reduce the high costs of priority mailing and other paper based costs associated with site visit reporting, estimated to be well over $100,000 per year – not including the cost of people’s time. By speeding up the process for clinical sites to be on‐boarded, Kendle is able to initiate sites quicker and, consequently, expedite the clinical studies at reduced costs. Kendle is providing a greater service to their clients which results in greater satisfaction and new business opportunities and client retention.

E. CONCLUSIONS/implications for the field.

Digital signatures have provided tangible benefits for Kendle:

• By eliminating priority mailing and other costs associated with Kendle clinical research associates and project managers signing site visit monitoring reports and submitting to sponsors, Kendle is able to enjoy reduced operational costs and ensure compliance with sponsor contracts. Studies by Pitney Bowes & Xerox, as well as KPMG and RSA, have placed the cost of paper based documentation at $10‐20 per document, higher in cases where multiple copies and multiple signatures are required across wide geographies and organizations; these costs are eliminated with digital signatures and web enabling technologies.

• By allowing principal investigators and IRBs to sign regulatory packet documents and forms electronically, Kendle is able to accelerate the speed of initiating clinical sites to commence study activities, with the additional benefit of eliminating costs if the forms had been completed and signed in paper format.

• Sponsors prefer clinical documents to be submitted electronically from the CRO, hence, Kendle is supporting the sponsors’ goal of making electronic submissions to regulatory authorities. This value added service increases sponsor satisfaction with Kendle services, which ultimately results in additional business.



6. REFERENCES/testimonials/supporting internal documents (If necessary; 5 pages max.)

"From the first deployment with digital signatures we've seen significant value in our clinical operations," said Chris Kaas, Associate Director of Information Technology, GCRS Kendle International, Inc. "CoSign digital signatures have given Kendle a competitive advantage critical to our success in the CRO marketplace. Over time we have expanded our use of CoSign to additional operations and we continue to explore new areas throughout the enterprise for its applicability." "Digital signatures allows clinical trial sponsors and CROs to electronically complete, approve, sign and manage many required documents," says Zikria Syed, VP Product Management, Collaboration Solutions, DataLabs (Perceptive Informatics). "Participants can electronically sign and submit these documents in real‐time without generating a hard copy as the source document. Enhanced electronic collaboration results, increasing the efficiency and accuracy of data capture. " "CoSign digital signatures integrates seamlessly with Microsoft's Active Directory and SharePoint allowing customers in the biopharmaceutical market to move from paper‐based to electronic business processes without additional system administration," says Steve Shihadeh, General Manager, Healthcare and Life Sciences at Microsoft. "CoSign’s use of Microsoft technology enables increased user acceptance and improved efficiency, helping people to better connect and collaborate as well as make more informed business decisions." "Kendle's use of CoSign highlights the two most common applications for CROs," said Rodd Schlerf, FDA and USDA Markets Manager, ARX. “By eliminating paper in Site Monitoring Reports, Kendle can save hundreds of thousands of dollars just in priority mailing costs alone. And by enabling the investigator sites to sign the regulatory packet documents quickly and affordably, Kendle is initiating sites and studies more efficiently – which is of huge importance to Kendle’s success with their study sponsors.”


s, Inc. ron Bay Blvd., Suite 200

Nominating Organization name: CRA Solution11555 Heprings

Nominating Organization address: Nominating Organization city: Coral SNominating Organization state: FL Nominating Organization zip: 33076

Nominating Contact Person: Lisa Murphy Nominating Contact Person Title: Clinical Trial Services Managerominating Contact Person Phone: 561‐901‐1156

s.comNNominating Contact Person Email: lmurphy@cra‐solution

arc29

User Organization name: Medical ResePO Box 86prings

h Management User Organization address: User Organization city: Coral SUser Organization state: FL User Organization zip: 33075 User Organization Contact Person: Jill Matzat User Organization Contact Person Title: Founder ser Organization Contact Person Phone: 877‐633‐3322

@cra‐training.comUUser Organization Contact Person Email: jmatzat Project Title: Fundamentals of Clinical Research Project Title: Fundamentals of Clinical Research Team Leaders name: Jill Matzat Team Leaders title: President / Founder / Course Designer Team Leaders Company: Medical Research Management Team Leaders Contact Info:

jmatzat@cra‐training.com Team Members name: Team Members title: Team Members Company:

ical Trials & Research Entry Category: Clin bstract Summary:

nt will be able to: AIntroduction: The participa Part One Course Objectives:

with marketing ‐ Describe the medical product path starting with discovery and endingapproval. ‐ Identify the GCP obligations in protecting the rights of study subjects.

Investigator, Sponsor, and ‐ Distinguish the different roles and GCP obligations between the IRB. ‐ Explain the ‘ideal’ elements used in coordinating a clinical trial.

‐ Demonstrate the ability to perform monitoring and coordinating activities and deficiencies.

problem‐solving techniques in resolving GCP deficiencies.

etect GCP d‐ Choose the different Part Two Objectives: Recognizing the value of learning through repetition and application of knowledge, the "Hands‐On" Training course was created. Monitoring is a vital part of clinical research and requires a systematic approach to standardize the monitoring activities and yield quality

ng data in an efficient time frame. MRM provides 2 weeks of exposure to monitoring, applyiour "3 Step Quality Monitoring Method SM". We train on "how to" onitor, "how to" write an efficient report, and "how to" interact with sites on a regular m

basis and with difficult issues. The "Hands‐On" was designed to provide exposure to different therapeutic areas, monitoring plans, source documents, Case Report Forms (CRFs), and Standard Operating rocedure Requirements (SOPs). Students receive a protocol, monitoring plan, and CRF Pcompletion guideline. During week one, a HRT Patch Study involving three subjects and the Investigator file is monitored. During week two, an OA tablet study involving two subjects and the Investigator file is monitored. Each case study is created using sophisticated GCP eficiencies. The level of sophistication and difficulty increases with each subject, allowing dthe student to gain exposure to a broad range of GCP issues. The monitoring is followed by review and discussion, during which, deficiencies are identified. Using MRM's "Issue, Action, Follow‐up, Results SM" report writing technique, ICH GCP action plans are presented to resolve the deficiencies and prevent their reoccurrence. The content, strategies and importance of writing professional and effective reports is emphasized throughout the two week training session. Students are provided eport writing guidelines and are required to prepare a written report for review by the rinstructor. Our experienced, professional instructors, in addition to their teaching responsibilities, actively monitor and manage research studies. By sharing with the students their

n for clinical research, they bring real world commitment, experience, and passioknowledge into the classroom.

y, 9:30 am – 5:30 pm; ‐Our Nationwide Course Locations;

ay thru Fridaourse;

‐All classes: Two consecutive weeks, Mond * Comprehensive review of the Part 1 online c * Case studies simulating CRA activities; * Course examinations and pre‐exam review; * Resume evaluation and career guidance; * Prerequisite: Part 1 “Education” online course. Results: The step method developed by Medical Research Management

teaches a systematic approach to monitoring. This approach equips the clinical research professional with a methodical and efficient way to monitor trials to ensure the safety of subjects and the integrity of the data. The approach incorporates the principles of Corrective Action and Preventative Action (CAPA) to identify issues and prevent them from occurring in the future. MRM also provides its students with incredible tools to help monitors do their jobs more effectively and efficiently. he company believes in Continuous Quality Improvement (CQI) and is always seeking

better. Tways to do things ROI/Conclusions: The MRM Step Monitoring Method is a systematic approach to monitoring that significantly reduces the number of errors and oversights in monitoring because students learn to monitor the same way each time and are given specific tools to use to provide higher quality monitoring. This approach protects the integrity of the data and the safety of the subjects. It is less likely that the trial will end prematurely or be dismissed due to insufficient oversight. Subjects’ safety is protected because it is more likely that the inclusion and exclusion criteria are truly met and adverse and serious adverse events are less likely to be overlooked. Not having properly trained monitors can cost a company millions of dollars in losses.

Companies can be sure that hiring a MRM grad will give them the same quality monitoring very time regardless if it is a pharma, biotech, or medical device study. e





A. Nominating Organization Organization name: Address:

B. Nominating Contact Person Name: Title: Tel: Email:


A. User Organization Organization name: ERT Address: 1818 Market Street, Suite 1000 Philadelphia PA 19103‐3638 USA B. User Organization Contact Person Name: Amy Furlong Title: Executive VP of Cardiac Safety Operations Tel: +1 215 972 0420 Email: c/o [email protected]

3. Project

Project Title: Centralized Cardiac Safety 2.0 Team Leader Name: Amy Furlong Title: Executive VP of Cardiac Safety Operations Tel: + 1 215 9720420 Fax: +1 215972 0414 Email: c/o: [email protected] Team members – name(s), title(s) and company (optional):

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research



Drug Discovery & Development: Compound‐focused research, drug safety X Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource



A. ABSTRACT/SUMMARY of the project and results (150 words max.)

Industry regulations are under increased scrutiny to safeguard cardiac safety of new drug compounds in clinical trials. ERT has developed a new centralized cardiac safety approach to simplify operations at investigator sites and facilitate reliable identification of cardiac risk. This solution overcomes the perceived challenges associated with outsourcing ECG management in trials to a core laboratory, including data reliability and the misconception that a centralized approach is more expensive to implement. As part of the centralized cardiac safety approach, ERT has developed a solution, which substantially reduces costs associated with centralized collection and transmission of ECG data while increasing the overall consistency and timeliness of cardiac safety data. This new solution is enabled by ELI-PC, a revolutionary small, hand-held device, co-developed with Mortara Instruments, making it easier for investigators to adopt a centralized approach to cardiac safety in trials as it is significantly less expensive to ship and store and is scientifically more consistent.

B. INTRODUCTION/background/objectives Cardiac safety is the primary reason for delay or denial of regulatory approval for marketing, drug withdrawals from the market and labelling changes. Some drugs can cause serious adverse cardiovascular reactions such as arrhythmias. This has triggered the pressing need for dependable assessment of a new drug’s short- and long-term effects on the electrical functions of the heart in clinical trials. While there is no legislative mandate in relation to ECG assessment across clinical trials, the requirement to conduct a Thorough ECG Trial (TET) for new compounds has been mandated by the US Food and Drug Administration (FDA) with limited exceptions. This is as a result of the introduction of the ICH E14 guideline which was developed to assess QT/QTc prolongation in new drugs to determine cardiac safety risks. The ICH E14 guideline advocates that a TET should be performed to establish any cardiac concerns that may be raised by a drug. If any cardiac issues are found, Phase III trials will then require further intense ECG collection. Traditional methods of assessment for cardiac safety risk in the form of decentralized ECG studies are associated with data inconsistency and inaccuracies. Decentralized ECG studies are carried out across multiple investigator sites using different



instrument types, resulting in data variability. In addition, the fact that these studies involve clinician-based, and not digital, data collection methods leads to common transcription and misinterpretation errors. Utilizing ERT’s solutions has helped overcome these shortcomings, accelerating the analysis process and generating higher quality cardiac safety data. At the same time, ECG data management and analysis are greatly simplified through on-demand, real-time access to information. These benefits are of utmost importance to clinical trial sponsors and pharmaceutical companies that need to reliably detect the adverse cardiac effects of drugs early in the drug development process in order to save costs and accelerate time-to-market. Knowing that only the most consistent and regulatory-compliant data can ensure the cardiac safety of patients, ERT has developed Centralized Cardiac Safety 2.0 that offers superior data reliability in a cost effective way while alleviating the workloads of clinical trial investigators.

C. RESULTS (highlight major R&D/IT tools deployed; innovative uses of technology). To enable trial sponsors to take full advantage of the benefits offered by a centralized ECG model, ERT’s innovative Centralized Cardiac Safety 2.0 approach along with the new innovative ELI-PC (manufactured by Mortara Instruments) provides improved accuracy, reliability, convenience and cost effectiveness. ELI-PC is a small hand-held device that makes it easier for companies to adopt a centralized system as it is significantly less expensive to ship and store and affords significant benefits to the sites using this approach. The complete system includes the Wireless Acquisition Module with memory (WAM PC) with patient applied parts, a USB Transceiver Key (UTK) for sending patient demographics to the WAM PC and receiving WAM PC data, and the ELI-PC application software to collect and upload data to a third party clinical information server (CIS). Transmission of diagnostic quality 12-lead ECG to ELI-PC allows the cardiac signals to be displayed on a computer without the need for a direct connection to an ECG. The result of this quick response system ensures that the responsible investigator is immediately notified of any cardiac safety risks. Centralized Cardiac Safety 2.0 along with the new instrumentation is designed to seamlessly integrate with computer systems, enabling important information such as demographics and algorithms to be automatically downloaded in advance of a trial and thus saving staff time and costs. All data are stored centrally, allowing for information to be simply transferred to the database as required. In that way, clinical trial sponsors ensure that regulators can simultaneously access all data stored on the system and efficiently analyze data quality, thereby facilitating regulatory inspections. Utilization of this new technology incorporated with the process enhancements and reduced site and sponsor burden will result in significant and measurable cost savings. The solution also helps clinical trial investigators save demographic entry time by selecting patients from an existing patient list. This capability also reduces the risk of demographic discrepancy query. In addition, the visit name no longer needs to be entered; this is again selected from an existing list. For even more efficiency, the expected visit is selected by the application by default.

D. ROI achieved or expected:

Using ELI-PC, ERT’s Centralized Cardiac Safety 2.0 solution reduces the cost of ECG instrumentation by approximately $1,500 per machine. The system does not involve the use of receiving stations, modems and phone lines, eliminating the $76K initial and $20K per year maintenance costs. As ELI-PC is extremely small and lightweight, it is shipped to the investigator site



only once, reducing shipment costs, saving $20 x 2 (including recall) on one shipment to California. A significant 34.6 % overall cost reduction is observed, while only a minor cost of $90 incurs per ECG for queries after database lock. The TUFTS Centre for the Study of Drug Development reported on and highlighted these cost drivers and potential cost-savings. It showed 33 % of ECGs collected in clinical trials were centralized via a core laboratory and the rest collected using decentralized clinician-based methods, resulting in a total cost of $30M. ERT have determined from the results of this TUFTS analysis that sponsors who adopt the Centralized Cardiac Safety 2.0 solution across the majority of their ECG studies, can reduce their overall Cardiac Safety costs by 25% or more. Another benefit is faster transmission compared with phone-line ECG machines and elimination of machine programming because new protocols can be added to the site automatically. Previously, programming would have required 10 minutes per machine for a total of 50 machines. More time is saved, since if a receiving station was employed, this would have required a 15 min configuration per protocol.

E. CONCLUSIONS/implications for the field. As regulatory scrutiny for the cardiac safety of all new drug compounds increases, more pressure will be placed upon the pharmaceutical industry to improve the reliability and cost efficiency of cardiac safety monitoring during clinical trials. Although the ICH guideline is not currently enforced as an industry standard, it is clear that the regulatory landscape is set to grow more complex, requiring ECG studies to be performed for every new compound in drug development. It is also expected that submitting ECG data to a central digital system to facilitate regulatory inspections will become a mandatory requirement. ERT is at the forefront of providing a comprehensive, centralized cardiac safety solution, which already enables easy compliance with the anticipated regulatory requirements. New, highly compact ECG instrumentation not only provides the same industry-leading performance of conventional systems at a lower cost but more importantly enables companies to adopt a centralized system that affords better science, lower sponsor costs and more site convenience. As well as making it easier and less costly for trial sponsors to adopt an efficient centralized model, ERT is helping equip clinical trial investigators with the tools to address any forthcoming regulatory challenges.


Although the actual TUFTS report is not yet available on the website, it is mentioned as a recent project at the following link: http://csdd.tufts.edu/commission/recent_projects. For further information on this collaboration you can also contact: Kenneth Getz, Senior Research Fellow, Tufts CSDD (+1 617-636-3487)








A. User Organization Organization name: ERT Address: 1818 Market Street, Suite 1000 Philadelphia PA 19103‐3638 USA

B. User Organization Contact Person Name: Mike Federico Title: VP of ePRO Solutions Tel: +1 215 972 0420 Email: c/o: [email protected]

3. Project

Project Title: Suicidality Monitoring Team Leader Michael Federico Name: Title: Tel: + 1 215 9720420 Fax: +1 215972 0414 Email: c/o [email protected] Team members – name(s), title(s) and company (optional):

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research



Drug Discovery & Development: Compound‐focused research, drug safety X Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource




With the increasing regulatory concern over the risk of suicidal ideation and behaviours (suicidality) in patients in clinical trials. ERT has developed new solutions to reduce the burden on clinical trials investigators while reliably identifying suicidality signals from patients. ERT developed a solution using electronic Patient Reported Outcomes (ePRO) technology which sustainably improves the reliability of suicidality monitoring by overcoming challenges of traditional methods and data collection, including confidentiality since the information is collected directly from patients without the involvement of another human being, resulting in a sustainable boost to both patient and product safety. This new validated suicidality monitoring ePRO solution the e-C-SSRS uses specific algorithms to ensure that all relevant questions are asked in a consistent manner, ensuring that any changes in suicidality signals are reliably identified. This solution reduces the investigator burden and overcomes many of the challenges associated with monitoring suicidality during clinical trials.


Utilizing ERT’s solutions has helped improve business performance by increasing the reliability of patient suicidality data. The ability to do this while reducing the burden on the investigator is a key benefit to clinical trial sponsors and pharmaceutical companies in today’s challenging market where it is important for companies to get new products right first time to avoid costly retesting of drugs and overcome regulatory safety concerns. ERT has worked alongside the most eminent psychiatrists in this field who have been working with the suicidality scales for many years. Therefore, these relationships enabled the development of a solution that clinical trials sponsors can adopt quickly, creating a cost effective, reliable solution that meets regulatory needs, improves efficiency and accuracy of data collection.



Medicines previously thought to have minimal effects on the central nervous system have been shown to pose a potential suicide risk. Furthermore, with the concern over the increased risks of (suicidality) in patients taking both anti-depressants and other forms of medication has raised the urgent need for prospective monitoring of suicidality in clinical trials. The US Food and Drug Administration (FDA) commissioned researchers at Columbia University to develop a Suicide Severity Rating Scale (C-SSRS) – to conduct a semi structured clinical interview with participants during trials. Traditional methods of assessment for suicidality in the form of structured face-to-face interviews came with limitations which affect the accuracy and reliability of the data returned. Patients do not feel comfortable answering questions on suicidal thoughts and behaviours during a face-to-face situation, and consequently may not give accurate or reliable information to the clinician. Furthermore, clinicians who do not routinely work in mental health settings are also inexperienced in assessing suicidality in patient.


The use of Personal Digital Assistants (PDA) and other handheld computers as ePRO solutions is on the increase, but involve complex study logistics, a major commitment of resources and lengthy patient training processes. However, ERT’s innovative phone-based, voice response solutions offer an inexpensive, easy to use and readily available solution. ERT’s suicidality monitoring solution is designed and optimized to help facilitate the collection of clinically valid sensitive data directly from participating patients via Interactive Voice Response (IVR) interviews. IVR is an established interactive technology that uses simple telephone keypad inputs. ePRO solutions will simply and reliably identify changed in suicidality signals, which in turn increases patient safety. Incorporating comprehensive suicide assessments into clinical trials that are backed by a response system assures swift reaction to suicide concerns. Certain patient – reported answers trigger alerts to the trial site. This quick response system ensures that the responsible investigator is notified and the patient is reached immediately. The use of computers and phones to automate suicidality assessments reduces of false negatives and maximizes signal sensitivity to evaluate the true effects of new compounds and drugs. Key objectives included:

• Reduced site burden • Error checking system validates patient answers to ensure that the answers given do not contradict one another in order

to return clean accurate data • Reliability in both content and delivery • Instant suicidality reproducibility scalability • Increased patient candor in answering suicidality questions • Any patient suicide risks can immediately reported which will substantially improve the overall patient safety

throughout the duration of the clinical trial.




ERT is working with several pharmaceutical companies across multiple clinical trials which require suicidality monitoring. Utilizing ERT’s solutions has helped improve business performance by increasing the accuracy and reliability of patient suicidality data. The ability to increase the accuracy and reliability of suicidality data is a key benefit to clinical for companies to get new products right first time to avoid costly retesting of drugs and overcome regulatory safety concerns. Combining computer-automated IVR interviews with clinician judgement informed by immediate, automated feedback available through standardized reports of the patient’s responses can facilitate accurate, efficient, thorough assessment of suicide risk and provide clinicians with valuable information for evaluating and managing patient safety. When ePRO solutions are deployed effectively they eliminate issues often encountered through the use of traditional methods of assessment. Eliminating the need for face-to-face interviews in suicidality monitoring helps to boost the reliability of the resultant information from the patient as sensitive questions can be answered in a more comfortable environment.


Suicidality is notoriously difficult to assess and monitor as signals can be hard to identify, presenting a significant challenge to pharmaceutical companies. However, ERT’s innovative suicidality monitoring solutions are helping clinical trials sponsors to increase the safety of both its patients and products, by increasing the reliability of monitoring techniques, while reducing site burden. The ability to validate real-time results ensures that investigators are alerted to any slight changes in suicidality signals and patient data can be monitored if required. All interview questions are asked consistently to avoid problems associated with clinician variability. As regulatory concern mounts over the suicidality affects of new drugs, more pressure will be placed upon companies to improve the efficiency, reliability and accuracy of suicidality monitoring during clinical trials. Although, suicidality monitoring is not yet compulsory for all new drugs, increasing concerns suggest that it could become mandatory in the future. ERT is at the forefront by leading the way with a solution which already meets anticipated regulatory demands. As well as increasing patient safety, companies that adopt these new solutions, in the future, will be perfectly poised for any future changes to legislation.


Kelly Posner, PhD, Columbia University On the eC-SSRS: As primary author of the Columbia-Suicidality Severity Rating Scale(C-SSRS), I have worked with Drs. Greist, Mundt

and Gelenberg since July 2008 to develop, author and refine an interactive voice response (IVR) script and scoring algorithm for the computer-administered version, the eC-SSRS.

I believe the e-CSSRS is a faithful and accurate representation of the interview version of the C-SSRS, as it was carefully designed to produce consistent outcomes.

A salient advantage inherent in computerized administration of the eC-SSRS is significant reduction of investigator burden, while providing all necessary data and appropriate safety monitoring procedures.

The eC-SSRS has been shown to be reliable in comparisons with well-trained C-SSRS raters, supporting consistency of C-SSRS data across modalities and studies.



We have worked to develop streamlined, low-burden procedures to promote consistent and efficient C-SSRS databases, promoting consistency of C-SSRS outcomes.

The FDA Division of Psychiatry Products has indicated that C-SSRS is an acceptable prospective suicidality monitoring assessment (the only one acceptable at this time) and that computer administration is an acceptable method of obtaining C-SSRS data.

Dr. John Greist, Co-author of the eC-SSRS, on the FDA’s acceptance: The eC-SSRS is sufficiently validated, and has let other divisions know that the Division of Psychiatry Products (DPP)

has concluded, based on the results of the validation study, that the IVR version of the SSRS is an acceptable approach to administering this assessment.

Bio‐IT World 2010 Best Practices Awards Nominating Organization name: GlobalSubmit Nominating Organization address: 1880 JFK Blvd., #605 Nominating Organization city: Philadelphia Nominating Organization state: PA Nominating Organization zip: 19103 Nominating Contact Person: Sue Cole Nominating Contact Person Title: Manager. MarCom Nominating Contact Person Phone: 215‐564‐6837 Nominating Contact Person Email: [email protected] User Organization name: FDA User Organization address: 10903 New Hampshire Ave. User Organization city: Silver Spring User Organization state: MD User Organization zip: 20993 User Organization Contact Person: Randy Levin, MD User Organization Contact Person Title: Director, Director, Office of Bioinformatics, Office of the Commissioner; Associate Director, Medical Information, CDER User Organization Contact Person Phone: 240‐460‐6283 User Organization Contact Person Email: [email protected] Project Title: Common Table of Contents Team Leaders name: Jason Rock Team Leaders title: CTO Team Leaders Company: GlobalSubmit Team Leaders Contact Info: Team Members name: Team Members title: Team Members Company: Entry Category: IT & Informatics Abstract Summary: Introduction: eCTD adoption has accelerated across the industry since the CRADA was signed in 2005. When the FDA was using an internally‐developed tool, the reviewers rejected the eCTD and asked the industry to send paper submissions instead. When GlobalSubmit REVIEW was implemented at the FDA, the reviewers asked for electronic submissions again. Adoption increased exponentially from 1,000 eCTD submissions per year to 40,000 eCTD submissions per year. In January, 2008,the FDA officially announced the eCTD as the preferred format for electronic submissions. Quality electronic submissions help to drive innovation in the industry by making both pharmas and regulatory agencies more efficient. By making the FDA more efficient, the FDA can spend more time ensuring the product is safe and effective. Results: GlobalSubmit’s REVIEW allows reviewers to review eCTD

submissions for technical accuracy. Navigating the submission is much easier and reviewers are able to see all regulatory activity. Both the old FDA system and competitors’ solutions can take up to 30 minutes to open a large submission. REVIEW can open a large submission in approximately two seconds. With GlobalSubmit REVIEW, 4000 agency reviewers are able to do the work of 4400 reviewers. REVIEW is the only eCTD review software used at the FDA. who is looking into one day make the eCTD an industry standard. VALIDATE™, the validation solution that works hand‐in‐hand with REVIEW is the FDA's implemented validation tool. Again, this is the only validation tool used at FDA. Before VALIDATE, it was commonplace for submissions to have missing or duplicate information. Important documents were impossible to find. With VALIDATE, missing and duplicate information is found quickly and important information is easy to find. VALIDATE processes submissions at a rate of 1000 per hour, while other validation tools process approximately 10 submissions per hour. ROI achieved: Conclusions: References: Emily Onkka Associate Director, Regulatory Operations and Submissions CADANCE PHARMACEUTICALS "One of the things that I really like about GlobalSubmit's REVIEW™ product is the unique presentation of study files. When all of the study files in module 5 are presented in a flat list, they are very cumbersome to navigate. REVIEW’s navigation tree makes it easy to navigate to a specific study and to understand which files belong to that study. The inventory list is terrific too, because it enables reconciliation of documents contained in a sequence or study against a tracking document. At the end of the day, GlobalSubmit's products brought our eCTD submission to a level where we felt extremely confident in its quality and acceptance.” Esther Driscoll, PhD EDMS Project Manager ACTELION “When Actelion began working with Kathleen Clark of GlobalSubmit, we wished to elaborate our knowledge of electronic submissions and implement a robust document management solution. While we knew that having a great document management system was critical, we also knew that having the guidance on how best to use the system was essential to our strategy. We wanted expert direction on how best to implement our document management solution for the management of documents not only on the R&D level, but across the overall business as well. Kathleen guided us in setting up new classification schemes and consulted us on important electronic submission topics. Kathleen listened carefully to our questions and concerns and helped us to develop a logical and consistent solution for management of greatly diverse documentation. We also found that Kathleen works phenomenally fast, an invaluable trait to a growing company like ours.” Nicole Borer DRA, Documentation Group Leader, Director ACTELION “Working with GlobalSubmit proved to be a very positive experience. Their expert, Kathleen Clark, was very facilitative and helpful, even when we changed the map of how we wanted to

proceed. Because Kathleen was able to collaborate with us prior to – as well as during and after ‐‐ the seminar, the presentations delivered met the needs of each participant. That could not have happened had Kathleen not been so down to earth, straightforward and quick to respond to our changing needs. Moving forward, we will continue to work with GlobalSubmit experts to gain relevant and timely knowledge.”

Bio‐IT World 2010 Best Practices Awards Nominating Organization name: GlobalSubmit Nominating Organization address: 1880 JFK Blvd., #605 Nominating Organization city: Philadelphia Nominating Organization state: PA Nominating Organization zip: 19103 Nominating Contact Person: Sue Cole Nominating Contact Person Title: Manager. MarCom Nominating Contact Person Phone: 215‐564‐6837 Nominating Contact Person Email: [email protected] User Organization name: FDA User Organization address: 10903 New Hampshire Ave. User Organization city: Silver Spring User Organization state: MD User Organization zip: 20993 User Organization Contact Person: Randy Levin, MD User Organization Contact Person Title: Chair, Data Standard Council; Director, Office of Bioinformatics, Office of the Commissioner; Associate Director, Medical Information, CDER User Organization Contact Person Phone: 240‐460‐6283 User Organization Contact Person Email: [email protected] Project Title: Study Design Software Development Team Leaders name: Jason Rock Team Leaders title: CTO Team Leaders Company: GlobalSubmit Team Leaders Contact Info: 215‐253‐7474; [email protected] Team Members name: Team Members title: Team Members Company: Entry Category: Clinical Trials & Research Abstract Summary: Introduction: GlobalSubmit is developing software that allows FDA and industry to view, analyze and compare study design information in a unified view. Although the FDA provides guidance on what should occur within a clinical trial, they do not provide guidance on how to present that information. Currently, a significant number of study data submissions are paper‐based, making the review process tedious and time‐consuming. In addition, there is no consistent format for submitting study data, making it difficult for the FDA to perform critical evaluations such as cross‐study reviews and safety analyses in the pre/post approval phases. The new Study Design software will allow FDA to easily understand the purpose and organization of a study, then to compare what actually happened to what was supposed to happen. Right now, this is a very tedious, manual process, and often issues are not found until later. One example of how relevant information can be missed occurred

recently, when it was not determined until after a pediatric study was complete that said study had no one under the age of 18 enrolled. That Reviewers didn’t know this up‐front meant that many man‐hours were spent reviewing a study that could not, under any circumstances, progress. With a vision of making the review process exponentially more efficient, the FDA has commissioned GlobalSubmit to design and develop a commercial software application that alleviates these problems by allowing comparable views of study data to be evaluated at a single glance via one interface. Results: Before launching this project, GlobalSubmit conducted a Proof of Concept that converted two studies and 10 datasets, (each from a sponsor format), into the new Study Design software format. The result was that within seconds, a panel was able to determine the purpose of the study. Within minutes, they had determined what protocol violations had occurred. By comparison, when using the existing process, it took several hours to determine the purpose of the study, and several weeks to determine protocol violations. The Study Design Software currently under development will: o Provide broad‐overview visualization for the organization of activities in a study o Facilitate description of the entire path of activities any patient population takes over the course of a study o Clarify which sets of activities are to be directly compared The product’s workflow view will display the workflow for sets of related activities and for all patients over the course of a whole study. ROI achieved: Conclusions: References: Randy Levin, MD Chair, Data Standard Council Director, Office of Bioinformatics, Office of the Commissioner Associate Director, Medical Information, CDER Telephone: 240‐460‐6283 E‐mail: [email protected] Jonathan G. Levine, Ph.D. Senior Scientific Policy Analyst Science and Informatics FDA/Office of the Commissioner Office of Critical Path Programs Telephone: 301‐827‐7862 E‐mail: [email protected]








A. User Organization Organization name: Image Analysis Ltd Address: 7 Whitehall Waterfront, 2 Riverside Way, Leeds, LS1 4EE

B. User Organization Contact Person Name: Dr. Olga Kubassova Title: Founder and Managing Director Tel: 44 79 859 39 915 Email: [email protected]

3. Project

Project Title: Dynamika – comprehensive platform for clinical R&D in dynamic MRI Team Leader Name: Dr. Olga Kubassova Title: Founder and Managing Director Tel: 44 79 859 39 915 Email: [email protected] Team members – name(s), title(s) and company (optional):

Clinical Dirctor: Dr. Mikael Boesen, Image Analysis Ltd Senior Solutions Architect: Dr. Duncan Russell Client Relations: Jeremy Nettle 4. Category in which entry is being submitted (1 category per entry, highlight your choice)



IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies

5. Description of project (4 FIGURES MAXIMUM):

A. ABSTRACT/SUMMARY of the project and results (150 words max.) Image Analysis Ltd is a young innovative company founded in June 2007. Image Analysis provides software and services to support basic clinical practice, imaging research and imaging based clinical trials. The company’s core product Dynamika is a comprehensive unifying software platform for analysis of any dynamic MRI data. It was developed in the past 2 years in collaboration with key opinion leaders and clinicians from around the world and comprises the most recent clinical science as well as state of the art research methods. It is main advantage in automating the data analysis and therefore delivering an objective, accurate decision on treatment effect and patient progress in a speedy manner. Therefore saving consultants and research time and helping to make the right judgment. After the launch in November 2008, Dynamika is being used in 25 centers world wide and became a de facto scientific platform for 4 clinical trails. Currently, Dynamika has 2 dedicated modules for rheumatology and oncology. We plan further develop the software with building general immunology and neurology modules. The launch is planed for Oct 2010.


Background According to the UK Department of Health review, published in Sept 2009, in England in PCTs only, 91,606 people are waiting for a planned MRI scan; 137,050 are waiting for an unplanned MRI. On average a patient has to wait 2-4 weeks for an MRI and then another 2 weeks for a diagnostic decision. Using our product, a diagnostic decision can be performed in real time saving consultant time and therefore cost of MRI, increasing patient throughput and cutting running cost for PCTs, private clinics, and surgeries. Company Image Analysis’s core product – Dynamika is a result of years academic and clinical research of the company’s founder Dr. Olga Kubassova, who collaboratively with clinicians from around the word developed the first prototype of the product and set-up 1-person Image Analysis Ltd to commercialise it.

After graduation from Russian and Finland with Masters in math and IT and the University of Leeds with a PhD degree, 40 published articles and a large network of contacts, Olga Kubassova co-founded a company Image Analysis with the aim to see the results of her PhD work being used in clinical practice. In 18 months, Olga won more than £150,000 in grants, secured a multi-billion international pharmaceutical companies and MRI hardware manufactures as clients, which allowed her to employ 4 more people, increase the turnover of the company by 110%, and to transform 1-person start-up into a vibrant profitable businesses with positive cash flow and increasing customer base. Olga won countless business awards over the 2 years in recognition of her endeavours including Yorkshire



Entrepreneur of the Year 2007, University Innovation 2007, Investor Quest for Business Acumen, and most recently a Spin-out Company of the Year 2009.

The company was setup in October 2007 with the help of a micro grant from a local development agency, which helped to finish the product and to get the first customers in Oct 2008. Since then, Dynamika was installed in 25 hospitals, used as a de facto scientific platform in 4 clinical trials, and its benefits were acknowledged in more then 15 scientific articles written by the users. IA increased revenues by 100% and employed 4 more people. We recently won ‘Spin Out of the Year’ in UK Excellence in Business Awards (Oct 2009) and nominated as ‘Entrepreneur of the Year’ in UK national StartUps awards (Nov 2009). Vision We see Dynamika gradually becoming a de facto software platform for clinical practice and clinical research in rheumatology, oncology and immunology. Due to the unique algorithmic configuration behind the software, Dynamika is easily expandable across imaging modalities (MRI, Ultrasound, X-ray) and across application (various cancers, heart conditions, etc). We envisage in 3-5 years, IA software will become one united platform for the diagnosis of patients across all modalities and for a range of the world’s most serious clinical conditions.

C. RESULTS (highlight major R&D/IT tools deployed; innovative uses of technology). The company’s core product DYNAMIKA is currently used in the diagnosis of rheumatoid arthritis (DYNAMIKA-RA) and breast imaging (DYNAMIKA-BI) The key features of the software are that it:

• automates process of reviewing MRI scans, as opposed to labour-intensive and expensive manual interpretation by clinicians

• eliminates the negative effects of mid-scan patient movement upon the data and hence

improves accuracy of diagnostic decision

• provides quantitative assessment of patient condition and treatment effect

• incorporates traditional and innovative ways of analysis. A user can choose, apply and compare various methods

Key Benefits for Hospitals/Primary Care Trusts (clinical use)



The incorporation of DYNAMIKA into the clinical workflow permits:

1. Reduction of data analysis time (by 80%) 2. Massive cost savings for PCT. Dramatically less consultant time needed to analyse data

(Consultant time £200+ per hour).

3. Reduces waiting lists for patients. On average a consultant can review 7 patient scans per day, whereas Dynamika can get through an unlimited number as automated

4. Reducing lead time between initial scan and treatment. On average the lead time is 2-3 weeks,

this would be significantly shortened, giving patients a window of opportunity to prevent destructive effects of the disease with prompt treatment.

5. Replicating the analysis always leads to the same objective result, as opposed to subjective

human analysis prone to error and varying second opinions. The current manual process tends to result in a 30% variance between clinicians on deemed severity/progression of disease or on the success of treatment. Automation of the analysis gives an opportunity to exclude human bias from evaluation of the data.

6. Gives a possibility of ‘second opinion’ to less experienced user or double check for the more

experienced.

7. Reduction of a number of times a patient has to re-scanned to get quality data Key Benefits in clinical research use (by Clinical Research Organisations and Pharmaceutical Companies) Integration of DYNAMIKA into clinical trials, allows pharmaceutical companies to:

1. Eliminate human bias from evaluation 2. Increase reliability of the results

3. Quantitatively assess drug performance, patient’s response, and disease progression at early

changes, and

4. Improve study quality control and economics. Essentially prove their drugs are working and hence increase sales



D. ROI achieved or expected (200 words max.): ROI for clinical use Our users report time saving for reading and interpretation of the data reduced by up to 80%. By adopting our products, a clinic will be able to see at least 1extra patient a week due to the reader freeing up time or not having to re-scan a patient due to poor image quality. An average scan charge is £500. With this one extra patient, an increase in annual turnover would be approx. £25,000 (estimated for one patient a week; 50 weeks a year). Currently a clinic process approximately 8 patients a day, working 6 days a week. Having one extra patient a day (9 cases, 6 working days), we conservatively expect a 12.5% increase in productivity. Using the same average patient charge, this conservative estimated improvement would net a clinic an extra £150,000 per year. With products offered at the price above, a clinic effectively pays £32 or £40 a day for RA and BI products, respectively. Given saved money and time a hospital or a research center will be able to afford to buy new equipment as well as to increase patient throughput and research spent.


Dynamika is the first software that can be used on any dynamic MRI data. Experiments and trails in rheumatology and breast imaging are being conducted. Dynamika can be used wit t Dynamika’s main application in the Phase 1, 2, 3 of clinical trails with immediate cost saving benefits:

• Phase 1: automated analysis of controls. The bulk of the data can be processed automatically generating an objective decision and saving the time

• Phase 2: bulk data processing, objective assessment of the treatment effect, sensitive and

robust analysis of imaging biomarkers. In the figure below a treatment strategy of the knee joint was assessed using Dynamika. Within day 1 we were able to depict signs of improvement. Dynamika can be used for assessment of long term and short term follow-ups and will generate 100% reproducible, robust decision (these statements are confirmed by clinical data)

• Phase 3: efficient comparison of treatment strategies, efficient analysis of follow-ups, analysis

of outliers. Because the human bias is taken out, we able to perform comprehensive and objective comparative analysis of different treatment strategies.



Quantitative analysis of treatment effect in a fully automated manner. The early signs of progress were detected and quantified, which allowed to make comprehensive conclusions about the treatment effect



Analysis of kidney in the patient imaged with DCE‐MRI



Tumor detection, precise location and quantification


In the past 2 years, Dynamika was used to produce 15 scientific papers, with at least 12 in the pipeline. It has been used in 4 clinical trails, and the results are to be published in early 2011. Below are some of the references to the scientific papers and customer testimonials.

• Comparison of traditional and automated methods for analysis of DCE-MRI (ECR 2009)

• Impact of motion correction on diagnostic accuracy (ACR 2009)

• Assessment of rheumatic diseases with computational radiology: current status and future potential., Eur J Radiol. 2009

• A computer-aided detection system for rheumatoid arthritis MRI data interpretation and quantification of synovial activity., Eur J Radiol. 2009

• Quantifying disease activity and damage by imaging in rheumatoid arthritis and osteoarthritis., Ann N Y Acad Sci. 2009

• Imaging as a follow-up tool in clinical trials and clinical practice. Best Pract Res Clin Rheumatol. 2008

• General Framework for Unsupervised Evaluation of Quality of Segmentation results. IEEE, 2008.

• Impact of Registration on Enhancement Curve Estimation in DCE-MRI Data. MICCAI 2008



“Dynamika is a fantastic tool for evaluation of our arthritis patients. This program makes up for patient movement artifacts and enhances data quality. Using the program, we were able to save significant time diagnosing each patient. Furthermore, we get a quantitative measure of the local perfusion in the joints reflecting ongoing disease”, Dr. Mikael Boesen, Medical Doctor, Head of MRI Department, Parker Institute, Denmark

250 First Avenue, Suite 300, Needham, MA 02494 | phone: 781-972-5400 | fax: 781-972-5425


Bio-IT World 2010 Best Practices Awards





A. User Organization Organization name: Address:

B. User Organization Contact Person Name: Title: Tel: Email:

3. Project

Project Title: TrialEAS™: web-based adjudication system Name: Dr Drew Kilpatrick (Team Leader) Title: Director, Global Safety and Pharmacovigilance, Europe and Asia/Pacific Tel: +44 141 222 5525 Email: [email protected] Team members – name(s), title(s) and company (optional): Russell Burt, Manager IT, Kendle

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound-focused research, drug safety Clinical Trials & Research: Trial design, eCTD



Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non-responders, biomarkers X IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource

optimization Health-IT: ePrescribing, RHIOs, EMR/PHR Manufacturing & Bioprocessing: Mass production, continuous manufacturing

(Bio-IT World reserves the right to re-categorize submissions based on submission or in the event that a category is refined.) 5. Description of project (4 FIGURES MAXIMUM): A. ABSTRACT/SUMMARY of the project and results (150 words max.)

The escalating costs of undertaking clinical studies has led to Pharma/CRO companies looking at web-based initiatives to reduce or contain clinical costs at their current level. We have developed TrialEASTM, a web-based electronic adjudication system, and integrated it with web-based portal and IVR/IWR systems. The use of this integrated system reduces the time and costs of clinical studies in the pre-registration and post registration phase. Two areas were targeted: enrollment of appropriate patients, especially in situations where diagnosis is difficult due to vague symptoms,and adjudication of endpoints in endpoint driven studies. The introduction of the integrated TrialEASTM system has led to a more homogeneous patient population being enrolled in an ongoing study and in faster adjudication at reduced costs in endpoint driven studies.

B. INTRODUCTION/background/objectives Introduction: This submission is in two parts and covers the use of the TrialEASTM system in two distinct roles: supporting investigator selection of appropriate patients to be enrolled into a clinical study and for the adjudication of clinical endpoints in endpoint driven studies. Both roles will be described in turn. B1) The enrollment of appropriate patients into clinical studies. As a result of the increasing costs associated with clinical studies, greater emphasis is being placed on cost containment and as patients are a key cost driver in any clinical study, it is imperative that the correct patients are enrolled into a study. In certain conditions/diseases, where the diagnosis is open to interpretation, the failure of a consistent diagnosis between sites can lead



to a relatively heterogeneous population being enrolled into a study with the impact not being recognized until the end of the study. The failure to enroll appropriate patients contributes to a reduced signal-to-noise ratio being observed in the primary/secondary measures of efficacy, making it more difficult to detect a statistically significant difference between treatments. The introduction of a web-based adjudication system makes it possible for external experts to review the available patient information at screening and assist the investigator at site in selecting the appropriate patients to be enrolled into the study. B2) Endpoint adjudication Regulatory authorities are increasingly requiring marketing applicants/marketing authorization holders to undertake endpoint driven studies to confirm the morbidity/mortality/safety profile of their products. Unfortunately, endpoint studies tend to be global in nature, have an uncertain duration and involve thousands of patients. In addition, endpoint studies differ from other clinical studies in that the number of patients required to be recruited into the study is unknown at the start. Therefore the key factor impacting any endpoint driven study is the time it takes for an event reported by a patient at site to be confirmed as a study endpoint as defined in the protocol. Traditionally endpoint adjudication has been undertaken using a paper-based approach. This has major implications for the time it takes to confirm the status of an event. This becomes more important toward the end of the study when only a few endpoints are required to reach the required number of endpoints for the study. For every added day taken to complete the adjudication, further patients can be enrolled into the study. Unfortunately, this has a major impact on study costs as patients are a key cost driver in any study. In a global study with more than 800 sites, surplus patients recruited into the study would have a major cost and resource impact on those undertaking the study. The introduction of a web-based adjudication system with same day adjudication minimizes the risk of over recruitment of patients and reduces other costs associated with endpoint adjudication.


c1) Appropriate patient enrollment into clinical studies We have integrated the TrialEASTM system with IVRS/IWRS to allow the seamless flow of information from the site to sponsors/external experts. As the system is web based, access can be from anywhere in the world (provided an internet is available). A patient is contacted or visits the site and if the investigator considers the patient suitable for the study will register the patient via the IVR/IWR system as outlined in Fig .1. The TrialEASTM system is notified of the patient screening number at the same time as the investigator.



Fig. 1. Integration of the TrialEASTM system with IVRS/IWRS to confirm patient eligibility The investigator provides the required screening documents to the adjudication center either by fax or via a study-specific web-based portal. The documents are uploaded into the TrialEASTM system and then allocated to external experts (including sponsor if required). Allocation is routinely carried out using a paired approach although the system will allow allocation to an unlimited number of experts at the same time. The experts log on to the system via the Internet, review the documentation and complete an electronic adjudication form. The outcome of their review; patient is not eligible or is eligible is automatically exported back to the IVRS/IWRS and the TrialEASTM system automatically sends an email to the investigator confirming the outcome. The investigator obtains the randomization number for his patient from the IVR/IWRS system. In an ongoing study, external experts have decided that approximately 50% of patients considered appropriate to enter the study by the investigators were not suitable for enrollment into the study. Thus, electronic adjudication at the screening step makes it possible to remove the decision on patient eligibility from the site to the sponsor/external experts offering the possibility of a more homogenous patient population in studies where diagnosis of conditions/diseases is open to broad interpretation. c2) Endpoint adjudication Endpoint studies have traditionally been undertaken using a paper-based approach. This approach has major limitations with regard to the time it takes from an event reported at the site until it is confirmed as an endpoint by independent adjudication. In a paper-based approach, the patient reports an event at site, the investigator completes the required documentation and either couriers the documents/images to an endpoint center or they are collected by the study monitor, reviewed and then couriered to the adjudication center (Fig. 2).



Fig. 2 Paper based approach to endpoint adjudication The event documents/images form an event dossier and when all documentation/images are available and the dossier considered complete, it is couriered to adjudicators for review. A paper adjudication form is completed and this form and the event dossier are returned to the adjudication center. If each adjudicator agrees with the outcome the endpoint is confirmed and closed. If however, the adjudicators do not agree on the outcome then the procedure is for all adjudicators to review these “mismatched” adjudicators at a face-to-face meeting with the endpoint confirmed by consensus. We identified four areas in which the introduction of a web-based approach to endpoint adjudication would have major advantages over a paper based approach. These are outlined in Table 1 and cover five key process steps. First, the integration of the TrialEASTM system with an IVRS/IWRS makes it possible to instantly know when a patient has been randomized into the study. This is important if baseline assessments are required. Through completion of the eCRF the system is instantly aware if a potential endpoint has been reported at site. This information from the IVRS/IWRS/eCRF is uploaded into the TrialEASTM system nightly, with the study, site, patient and potential endpoint automatically created in the system. The second process step addressed was the movement of endpoint documentation/images for the site to the adjudication center. We integrated the TrialEASTM system with a web-based study specific portal which allowed investigators/monitors to directly upload documents/images onto the



portal. The portal, as part of the upload process, automatically sends an email to the adjudication center. Documents/images are thus instantly available for “drag and drop” into the TrialEASTM

system. This becomes important if the adjudication center is situated in the United States and the site is located in China where it can take up to four days for the documents/images to reach the endpoint center via courier. We have retained the option of sites to use a courier if this is their preference, but otherwise, with the introduction of the TrialEASTM system, geography is no longer a barrier to efficient endpoint adjudication.

Table 1 Re engineering the endpoint adjudication process Third, we realized that one of the benefits of the portal was that it offered a solution to one of the major problems associated with global endpoint studies. In contrast to the majority of clinical studies where you can dictate the language of the CRFs, the documents received in endpoint driven studies will be in the language of the country where the patients experience the endpoint. i.e., the documents for a patient reporting an endpoint in France will be in French whereas in certain counties such as India, multiple languages are possible. We included a translation room within the portal with access granted to third party, translation agencies. A document requiring translation is “dragged and dropped” into the translation room, the system sends an email to the Translation Agency and the Translation Agency downloads the document, translates it and uploads it back into the translation room. The system automatically sends an email to the adjudication center confirming that the translated document is now available in the translation room. The translated document is “dragged and dropped” into the TrialEASTM system. Thus, with the introduction of the portal , source language is no longer a barrier to efficient endpoint adjudication.

Event notification Integration of the TrialEAS system with IVRS/IWRS/eCRF

Transmission of endpoints

Integration of the TrialEAS system with a study-specific Web portal giving instant access to documents and images

Allocation of endpoints

Simple or complex randomization module contained within the TrialEAS system

Adjudication outcome

Completion of a study-specific electronic adjudication form within the TrialEAS system. Automatic confirmation of matched/mismatched adjudications

Source language Specific translation room within the web portal to allow secure transfer of source documents and receipt of translated documents



In the paper approach to adjudication, the endpoint dossiers were couriered to all adjudicators participating in the study. In the fourth process step, we have included a randomization module within the TrialEASTM system that makes it possible to undertake paired randomization or simple allocation to all adjudicators. A benefit of the randomization list is that it makes it possible to account for periods of unavailability of a particular adjudicator. Each adjudicator updates the TrialEASTM system with periods of unavailability; the system takes this into account when it allocates endpoints for adjudication. Finally, when the TrialEASTM system allocates an endpoint for adjudication, it sends an email to the appropriate adjudicators informing them that they have an endpoint for adjudication. The adjudicator logs on to the TrialEASTM system using his/her unique log on details, reviews the documents/images from his home, office or anywhere in the world with an internet connection and completes the electronic adjudication form. This form is the “cornerstone” of the TrialEASTM

system. New study-specific adjudication forms are easily incorporated into the system and the TrialEASTM system accommodates multiple adjudication forms for the same endpoint type or for different endpoint types that require different specialists adjudicating the endpoints, i.e. cardiologists adjudicating cardiovascular endpoints and oncologists adjudicating cancer endpoints. The TrialEASTM system automatically compares the outcome recorded on the adjudication forms and either closes the endpoint if the adjudicators agree or changes the status of the endpoint to a “mismatch” if disagreement exists on the outcome reached by the adjudicators. The TrialEASTM

system has several options programmed within it to resolve mismatched adjudications. The mismatched endpoints can be flagged for future face-to-face reconciliation meetings or the endpoint can be sent to a third, independent “tie-breaker” adjudicator. The process developed to handle web-based adjudication from the patient initially reporting a potential endpoint at site through to its eventual confirmation as an endpoint (or not) is summarized in Fig 3.



Fig 3 Integrated Web-based approach to endpoint adjudication A web-based approach to endpoint adjudication makes it possible to replace paper and shorten the time taken to confirm that a potential endpoint reported at a site is an endpoint as defined by the protocol. In addition the randomization module makes it possible to undertake simple or complex allocations depending on study requirements. The feedback from our adjudicators is that they really appreciate not being overwhelmed with paper endpoint dossiers and prefer the option of logging on to the system and having access to all the documents/images that would have been provided in the paper endpoint dossier. Finally, in addition to overcoming the geographical and language issues associated with endpoint adjudication in endpoint driven studies, our Web-based approach allows faster adjudication; endpoints can be allocated and adjudicated in the same day, something that could not happen with a paper based approach. D. ROI achieved or expected (200 words max.):

Event Packet Management Randomization

Receipt & Tracking of

Event

a) Track all documents

Reporting

Web Portal

Translations

IVRSeCRF

Site

EventAdjudication

Translation Agency

a) Liaise with CRAs to obtain missing documentsb) Liaise with Translation Agency to translate documents

a) Send packet to adjudicator using randomization list

Confirmation of Endpoint by

Adjudicator

Adjudicator access Endpoint Form & documents via secure Web link

from home or office

Direct download of results to Clinical

Database

Sponsor

Courier

Global Safety/Endpoint Centre

Event

Web Portal Room



Patient eligibility The ultimate cost savings is dependent on the number of patients over recruited into a study. An average cost/patient per visit would be in the region of $1,000 taking resources and investigator costs into account. Web based versus paper adjudication. Courier costs; a) receipt of documents and b) allocation of endpoints. Study assumptions; a) 18,000 patients baseline assessments b) 1 baseline package-10% original documents to be returned, 20% with missing documents and second package c) Similar assumption for 12,000 endpoints Receipt of paper source documentsTotal baseline packages: 18,000+1,800+ 3,600= 23,400 packages Total endpoint packages: 12,000+1,200+ 2,400= 13,440 packages Assuming an average courier cost of $40, total cost of receiving documentation is $1.47 Million. Allocation of endpoints (paper approach) Assume 3 adjudicators and 12,000 dossiers; If an average courier cost is $40 per adjudication package, the total cost of sending out the endpoint packages is 12,000 x 3X $40 = $1.44 Million. In this example, if TrialEAS were used exclusively, there would be a total potential savings of $2.91 Million in a single study – and this is before accounting for the time saved by the adjudicators themselves. All costs associated with the allocation of endpoints for adjudication are eliminated by using the TrialEASTM system and our integrated approach to endpoint adjudication




The introduction of our TrialEASTM system and integrated approach to assist in the selection of appropriate patients for enrollment into a clinical study and the undoubted advantage that the web-based system has over paper-based adjudications has had a clear beneficial impact on ongoing studies. The TrialEASTM system makes it possible to remove the final decision of inclusion of a patient from the investigator without having to extend the screening period of the study. We have also been able to overcome the geographical and language barriers that are evident with a paper-based approach in endpoint driven studies. Furthermore, our web-based approach results in faster adjudication and minimizes the risk of over recruitment of patients into the study and the subsequent additional monitoring and close out activities associated with these patients. Our approach has major cost savings for those undertaking endpoint studies by potentially eliminating the courier costs associated with both the receipt of documents/images from site but also providing this information to external experts for independent adjudication. Cost containment or a reduction in the costs associated with undertaking clinical studies and developing new drugs or extending the safety profile of existing drugs on the Market is in all our long term interest.


Sample online adjudication form:

C:\Documents and Settings\dkilpatrick\Desktop\TrialEAS Sample Electronic Adjudication Form.pdf Sample of image-based adjudication:

C:\Documents and Settings\dkilpatrick\Desktop\TrialEAS CT Scan Sample.pdf

TrialEAS™ Web-based viewing andadjudication of CT/MRI scans

* Screen capture of actual CT/MRI scan



Quantify the resources expended (hours, personnel, $) Explain broader impact on the life science community/biopharma industry

Don’t Enter promotional “brochure‐ware” or rewrite press releases Make vague, unsupported qualitative claims Emphasize technology (product) features over project results—integrate the two Forget to clearly identify positive results/benefits!

ENTRY FORM Direct questions about entry criteria/process to:

Allison Proffitt, Managing Editor, 617.233.8280 or [email protected] Please email completed entry to:

Allison Proffitt, Managing Editor, [email protected] Subject: 2010 Best Practices Entry

Early bird deadline: December 18, 2009; Deadline: January 18, 2010


A. Nominating Organization Organization name: MaxisIT, Inc. Address: 203 Main Street, Metuchen, NJ 08840

B. Nominating Contact Person Name: Maulik Shah Title: Vice President Tel: 732‐494‐2005 ext.101 Email: [email protected]


A. User Organization Organization name: Merck Research Laboratories Address: 126 E. Lincoln Avenue Rahway, NJ 07065

B. User Organization Contact Person Name: Jerald S. Schindler, Dr. P.H



Title: Vice President, Biostatistics and Research Decision Sciences ‐ Late Development Statistics

Tel: 732‐594‐6903 Email: [email protected]

3. Project

Project Title: ADAPT Dashboard Prototype Team Leader Name: Weili He Title: Associate Director, Biostatistics Tel: Email: [email protected] Team members – name(s), title(s) and company (optional):

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound‐focused research, drug safety Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource




Mid‐course and on‐going decision‐making capabilities in adaptive trial represented the problem domain. The infrastructure lacked timely availability of cross‐functional, interwoven aspect of information supporting required decision‐making and also knowledge on how the decision may impact other functional areas.

(Current) Multi‐stage manual process goes through various touch‐points and disparate systems.

The entire process would involve multiple organizations, tools, various formats and individual



approaches causing loss of focus from the desired information or meaning. Delay in business critical decision‐making causes either loss of revenue or loss of investment.

The ADAPT Dashboard prototype project demonstrated ability to perform cross‐functional

decision making and model various mid‐course corrections utilizing rapid, (pre‐built) statistical analytics capabilities. Solution offered role‐based information portal and interactive reporting capability to perform various decision support analysis including trend, root‐cause, comparative, predictive and forecasting at levels ranging from a trial to a group of trials to program to portfolio to therapeutic area.


Convincing results with correct statistical inference, highest level of confidentiality and assured

consistency between the stages of the study are primary requirements for validity and integrity of adaptive designs. Successful execution of adaptive trials depends on in‐depth planning, availability of clean data, constant monitoring, rapid analysis, efficient decision‐making, and secured review.

At Merck the senior management and also the adaptive trials’ implementation team clearly

realize that the potential benefits of adaptive trials are substantial. Adaptive Clinical Trials are complex in nature and raise certain operational challenges due to its iterative nature than a sequential process. Constant monitoring and frequent decision‐making at an accelerated cycle times are critical for realizing the benefits.

Ability to derive such benefits depends on timely availability of domain specific information.

Authenticity of the decisions taken on that information depends on knowing the transcending impact of such decisions across the other functional domains. For example, if we were to make adjustments to one or more operational parameters (reduce Screen Fail rate, e.g.), then having knowledge of how that impacts to drug supply and IA trigger dates, would allow us to make informed, more convincing and scientifically acceptable decisions without causing the loss of integrity.

Various business scenarios, such as listed under, involved adaptive cross‐functional decision‐

making and raised the management eyebrow due to its non‐existence in the current infrastructure landscape.

Let’s say at 6 months in a trial following adaptive design, observed event rate is lower

than planned, which would cause interim analysis being delayed by 3 months. What can we do to pull the interim analysis back to plan?



Can we add sites? How many sites do we need to add and in which geography? Also if we add new sites, will we have enough drug supply to support the demand? Or in another scenario, let’s say the observed variance is higher than expected; to

counter that we can increase the sample size. If we increased the sample size, what would be the implication to enrollment timelines? Or what will be the impact on drug supply? Or what would be the impact on the expected interim analysis timelines?

Let’s also consider other scenarios involving mid‐course correction specific decision making:

Need to define next interim analyses schedule/s: when and how many? This required quick information availability of current enrollment rate, event rate and forecasting when enough patients will be enrolled and enough events would have occurred? After knowing that from various source systems and manual reports, we decided to increase sample or increase sites or may modify inclusion/exclusion criteria to boost enrollment and then eventually affect the interim analysis timelines. What about drug supply now?

Need to add or drop a dose: when and which dose?

This requires information on current enrollment rate, response data and variability and then predicting the probability of that future data could produce significant results. As a result we may get a range from best possible to worst possible case for future data. In case of adapting to that decision, one may definitely want to know the impact on sample size and even drug supply

Or certain operation information quest:



How close are we to triggering an Interim Analysis? …………when will the remaining Interim Analyses for this study (if any) be triggered?

Which studies amongst a group are either ahead of schedule or behind the schedule or on track for enrollment? …………how many patients are expected to be on any specific study in the future date?

What interim analyses are upcoming for this group of studies, and when are they expected to be triggered? …………when will the Interim Analyses be triggered for this study?

Management realized a serious need of getting answers to such questions and maintaining the

availability of such information at finger‐tips to enable faster, accurate and informed decisions. Also knowing the need, ability of accessing cross‐functional data, rapid statistical analysis, building displays and even performing predictive scenario modeling were inevitable. Current processes would rather delay and potentially cause loss of integrity in such pervasive decision‐making.

The decision making process must also consider its implications among several inter‐related

functions, for example, enrollment and drug‐supply or enrollment and interim‐analysis. Today, forecasting and operational decision‐making require excessive manual processing at functional domain level, and also at cross‐functional decision making level causing huge turn‐around‐time.

Moreover this cross‐functional decision making requires aggregated data, relationships and

dependencies among the cross‐functional domains. The data must be analyzed quickly and within the premises of the inter‐related functions to proactively identify the implications of potential decisions.

ADAPT Decision Support Portal called ADAPT Dashboard workstream was chartered to

formalize the ADAPT Dashboard vision. A working prototype was built to help stakeholders conceptualize the solution and also provide something tangible to build stakeholder awareness. Objectives of the project were to aggregate multiple functional area outputs (plan, actual, forecast data) into a single setting; model the relationships which exist among functional area information; allow users to subscribe dynamic reports; and also allow scenario modeling to further evaluate potential cross‐functional impacts of each decision.




Merck needed a web based, cross‐functional decision support system for all of its clinical trial programs running adaptive trial design; a single solution that can integrate with the aggregated data source providing on‐demand analytical and visualization capabilities. Solution should allow users to build various cross‐functional predictive analysis models to propose mid‐course change in the trial design and also perform impact analysis.

Goal of the solution is to effectively monitor and dynamically take decisions on controlling the

patient exposure to effective or ineffective doses. Rapid statistical analysis based on predefined validated processes, are required to enable efficient and valid review of ongoing data.

Besides its ability to integrate with the cross‐functional data layer, solution needed analytical

capabilities to define & evaluate the cross‐functional impact of potential adaptive decision scenarios. Solution is also intended to define predictive and forecasting algorithms that can be reused, and improved over time – to become more/less sensitive to certain parameters, to respond to new variables, to account for historical performance data, etc; and also to incrementally add new scenarios and algorithms (expand functional scope) with minimal impact to existing system (“plug and play” modular design).

Visualization capabilities are required to display data in meaningful graphical and tabular

formats in an interactive user interface which allows for flexible filtering criteria, dynamic drilldown to additional levels of detail, and other user cues (such as mouse‐over effects). A personalized and collaborative user interface which allows for specific views or models to be saved and/or easily accessible.

ADAPT Dashboard working prototype was tasked to show the bigger picture and increase the

awareness of such interwoven and collaborative decision making requirement in a time‐bound schedule. Prototype was subject to follow a rapid configuration/development process working on a set of representative data from different functional domains of multiple trials. Participant functional areas were enrollment, drug supply and interim analysis.

The initiative was allocated a time frame of approximately 6‐7 weeks. Tasks involved gathering

necessary functional requirements & test data, customization/configuration, building cross‐functional framework. Additionally, include or configure algorithms and statistical programs that would display a



collection of dynamic reports representing various business scenarios and allow cross‐functional adaptive decision‐making.

Decision to include MaxisIT as a software vendor and implementation partner was taken

considering its CT Renaissance™ software suite, which allows desired functionalities out‐of‐the‐box.

CT Renaissance™ suite product, eAdaptive provided information portal capable of loading large number of cross‐functional reports with top‐down navigation and cross‐functional decision making. Mid‐course adaptive scenario building, trend analysis, forecasting techniques, and impact analysis features existed out of the box and were also customizable. This role‐based information portal provided single‐sign on allowing access to all the role‐based functionalities assigned at the security level. Portal allowed drill down from therapeutic area to any specific trial level or even at any specific site level within a functional area or across the functional areas. eAdaptive comprehensively provided functional and cross‐functional reports allowing an informed & timely decision making with an ability to collaborate.

CT Renaissance™ suite product, eNalyze (Scientific Computing Environment) provided pre‐built

and customizable library of algorithms and statistical programs. Library included trend analysis, planned vs. actual vs. forecasted comparative analysis, root‐cause analysis, predictive analysis, various clinical reports and forecasting models available out‐of‐the box. eNalyze acts as a backbone to eAdaptive and offers functionalities to configure, review, schedule and publish various kinds of reports to the eAdaptive portal and scenario modeler. Its scheduling mechanism also allows event‐based and time‐based interim analysis scheduling and execution.

CT Renaissance™ Integration Layer allowed integration with the representative database

containing cross‐functional data. The ADAPT Dashboard prototype solution built on top of CT Renaissance™ suite products,

successfully demonstrated capabilities to support cross‐functional decision‐making in a timely manner and also perform various scenario modeling. Each of the reports was produced on‐demand, scheduled and published to the portal. Based on the schedules, it would auto‐refresh. User would be able to subscribe the required reports from a la carte menu options and also get further updates to it based on its schedules. Users can drill‐down from global region level to any specific site level and also from therapeutic area level to site level. Based on any specific report, user can further drill‐down and also perform scenario planning on that report in comparison to other functional‐domain specific reports. As a part of adaptive scenario modeler, multiple global and local controls were available for users to



further fine‐tune the design change. Analyzing impact of any change was simply automated and visually identified in all the cross‐functional reports. Additionally, solution demonstrated ability to load large number of reports in real‐time that are generated on‐demand from pre‐built and scheduled algorithm. The portal interface also allowed necessary customization and scalability. D. ROI achieved or expected (200 words max.):

Overall information availability for cross‐functional decision making process can be reduced

from weeks to day/s with minimum manual intervention. Moreover, such decisions allow optimal utilization of resources, early identification of potential risk or opportunity and overall time and cost benefits without losing validity or integrity of the design. Decisions linked at clinical portfolio, program, and trial levels can reduce: cycle time, number of patients per trial, and grant costs.

Proactive monitoring will help, e.g., identify variance or dropout rate to further adjust the

sample size. It also identifies (via cross‐functional impact analysis) a need to perform randomization. Built‐in interim analysis capability will allow timely decisions to either stop trial or arm due to unexpected efficacy or futility or even be able to combine phases in case of an opportunity.

In case of any midcourse corrections, knowing the requirements for such correction in a timely

manner is equally important as its implementation. Likewise, knowing the ineffective treatment arm in a timely manner and controlling the enrollment at that arm and vice versa are very important for overall trial efficiencies and costs management. Also, knowing the unsuccessful trials early on is very important to safeguard the patients and also the investments.


Adaptive designs allow the necessary adaption during the course of trial execution and offer the benefits that inspire us all.

Deciding on a change, an adaptation, within the trial causes recursive effects in the interlinked

functional areas, which is either not known or not measured effectively and timely. Such cross‐functional impact can help identify various opportunities and also raise caution on certain negatively impacted aspects.

Knowing the unknowns is important in an accurate and informed decision making but knowing

the unknowns in a timely manner with an optimal use of resources helps achieve desired benefits.



Industry has either looked into this aspects or started to adopt manual solutions or has just realized the need of one.

This revolutionary solution shows a path forward in adaptive, cross‐functional decision making

process supporting mid‐course corrections and also ongoing vigilance of adaptive clinical trials. It also accelerates turn‐around‐time of taking important decisions like removing an ineffective arm to ensure patient safety and also to seize an opportunity to combine phases in case of effective results – knowing how each decision impacts all functional areas would increase the accuracy of the decision and confidence of decision maker.




ADAPT Dashboard Prototype: Home Page



Note: Illustration does not represent real‐data.

ADAPT Dashboard Prototype: Cross‐Functional Scenario Modeling and Impact Analysis

Note: Illustration does not represent real‐data.


Celebrating Excellence in Innovation


A. Nominating Organization Organization name: Medidata Solutions Address: 79 Fifth Ave., New York, NY 10003

B. Nominating Contact Person Name: Ron Rubinstein Title: Sr. Director, Product Marketing Tel: 212.918.1806 Email: [email protected]


A. User Organization Organization name: Abbott Address: 100 Abbott Park Road, Abbott Park, IL 60064

B. User Organization Contact Person Name: Brooks W. Fowler Title: Director GPRD Clinical Systems Operations and Global EDC Project Office Tel: 847.937.8228 Email: [email protected]

3. Project

Project Title: Global EDC Centralization at Abbott using Medidata Rave Team Leader Name: Brooks W. Fowler Title: Director GPRD Clinical Systems Operations and Global EDC Project Office Tel: 847.937.8228 Email: [email protected] Team members – name(s), title(s) and company (optional):

Erik Merwitz – Senior Project Manager, Global EDC Office Teresa Oberlander – Section Manager, Clinical Data Management Lee Ann Liss – Director, Clinical Data Management Brian Gilleland – Technical Liaison, Global EDC Office Detlef Nehrdich – Director, Global Data Management and Statistics – Germany 4. Category in which entry is being submitted (1 category per entry, highlight your choice) Clinical Trials & Research: Trial design, eCTD


A. ABSTRACT/SUMMARY of the project and results: Abbott was able to significantly increase the speed at which clinical studies are designed and executed while reducing operational costs despite a growing study pipeline through an executive‐sponsored

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A. User Organization Organization name: Merck & Co, MRL Dev‐ IT Address:

B. User Organization Contact Person Name: Cathy Carfagno Title: Program Manager Tel: Black berry 610‐291‐4794 Office 275‐305‐7512 Email: [email protected]

3. Project

Project Title: Clinical Portal & Collaboration (CPAC) Team Leader: Ingrid Akerblom Name: Cathy Carfagno Title: Program Manager Tel: 610‐291‐4794 Email: [email protected] Team members – name(s), title(s) and company (optional):

Jose Rivera – Account Manager Clinical Operations Krupa Patel – Portal Business System Owner Ken Snyder – Director Business Integrations Lynne Germsheid – Director Clinical Operations Maryellen O'Donnell – Clinical Operations Support Lead



4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound‐focused research, drug safety X Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource optimization Health‐IT: ePrescribing, RHIOs, EMR/PHR Manufacturing & Bioprocessing: Mass production, continuous manufacturing


A. ABSTRACT/SUMMARY of the project and results (150 words max.) In early 2007, as part of a Clinical Trial transformation project (G2), Merck implemented a custom built role based externally facing portal solution to support clinical trials. The portal was viewed as a way to enhance the Investigator site relationship, improve communications and increase productivity by reducing clinical trial start up cycle time activities and alerts. Today, the portal has grown to include monitoring capabilities for study enrollment, study milestones, global communication distribution, training status monitoring, electronic distribution of safety reports, reporting of financial disclosure information and complete trial document exchange. The solution has proven to increase the productivity of the Merck research staff by consolidating information from multiple sources into a centralized dashboard that monitor a trial's overall state of health. It currently supports over 27,000 users, 125 Clinical Trials, 7,500 Sites. It is a pivotal hub providing a holistic Investigator Experience as a competitive advantage for Merck's pipeline goals.

B. INTRODUCTION/background/objectives Background The first phase of a Clinical Trial Portal was deployed as a part of a transformational project to streamline Merck's Clinical Trial Process. The goal was to standardize the process of clinical trial study monitoring and accelerate document exchange by creating a portal which used user roles as the basis for access and viewing information. Initial requirements centered on increasing CRA productivity and providing a collaborative tool that would manage study start up documents; monitor enrollment progress; provide event alerts and online completion of Regulatory Financial Disclosure information. Project had 2 main objectives:

• 3 days of cycle time reduction from PA to SR through faster document exchange



• 70 person hours of productivity improvements per trial, due to faster creation of document packages during study site set‐up


The portal leverages many of the clinical trial applications used at Merck. We start with data made available via our Clinical Trial Management System (CTMS); it provides all trial planning information and system target users. We leverage an in‐house built data mart (Oracle DB) which provides most of the trial metrics and data. We use TIBCO and XML to move data back and forth from the source system to our portal. Our portal is based on a customized installation of the Microsoft SharePoint platform using custom built web parts. Many "out of the box" features were used as part of the portal, such as survey, tasks and announcements. Other communication capabilities and alerts rely on the use of email. For document exchange we rely on a product called Docway which allows our Documentum based repositories to interact with users on our SharePoint portal. All these features made available via our interconnected systems improve Merck's ability to respond quickly to issues, prevent delays, cut spending and increase regulatory compliance.

D. ROI achieved or expected (200 words max.): The Merck clinical portal has managed to meet its original goal of reducing 3 days cycle time from PA to SR and saving 70 hours per trial largely by providing faster access to documents. In 2009 new enhancement to the clinical portal were made available which are expected to yield over 20,000 people hours by facilitating greater access to information and improving Merck trial monitoring capabilities. New capabilities will allow Merck to monitor site training status, deliver greater flexibility to deal with non standard documents and provide electronic delivery and monitoring capabilities of safety reports. Current ROI is estimated at over $3M per year.

E. CONCLUSIONS/implications for the field. The clinical portal was built as a first step into improving information exchange between Merck and the investigative sites. Merck has certainly learned quite a bit from the experience and we look forward to taking those learning's and combining it with new trends and technology such as social networking and presence detection as we build Merck's new generation of collaborative tools.









A. User Organization Organization name: Merck Research Laboratories Address: UG1C‐46, 351 N Sumneytown Pike, North Wales, PA 19454

B. User Organization Contact Person Name: Keaven Anderson Title: Late Development Statistics Tel: 267‐305‐7285 Email: [email protected]

3. Project

Project Title: gsDesign Explorer Team Leader Name: Bill Constantine Title: Senior Software Engineer Tel: 206‐577‐4778 x3205 Email: bill@revolution‐computing.com Team members – name(s), title(s) and company (optional): REvolution Computing

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound‐focused research, drug safety x Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies



Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource




The gsDesign Explorer graphical user interface allows analysts to instantly create, compare, and produce graphical and textual summaries of multiple group sequential clinical trial designs. Users can focus on the model parameters and their statistical and clinical implications without being burdened by technical details or programming. It is based on gsDesign—a group sequential design package for the R language. Group sequential methods allow clinic trial design with interim analyses to evaluate efficacy while controlling false positive and false negative error. Interim analyses offer opportunities for early stopping of trials, if, for example, the new treatment is demonstrably better than the standard treatment or clearly inferior. This can have benefits in many areas, from improved patient outcomes to significant savings in money and time. The software is built on established open source software tools (R and Qt Creator) to minimize development costs and maximize ease of use and extensibility.

B. INTRODUCTION/background/objectives The objective of this project was to create a graphical user interface for gsDesign (Anderson, 2009) so that statisticians could easily create and compare group sequential trial designs without programming. gsDesign is a package for the R statistical programming environment that provides a flexible set of tools for designing and analyzing group sequential trials. Group sequential methods allow clinic trial design with interim analyses to evaluate efficacy while controlling Type I error and power. Interim analyses offer opportunities for early stopping of trials, if, for example, the new treatment is demonstrably better than the standard treatment or clearly inferior. This can have benefits in many areas, from improved patient outcomes to significant savings in money and time. The purpose of the gsDesign Explorer is to enhance the appeal of the gsDesign and make it more amenable to widespread use. The development life cycle of the gsDesign package has spanned many years. The original C language routines for the underlying group sequential computations were developed by Keaven Anderson (Merck) and an initial gsDesign package was created as a summer intern project in 2006.



In December 2008, Merck and REvolution Computing collaborated in qualifying the gsDesign package for subsequent release to open source repositories. The gsDesign Explorer is an extension of that collaboration. Sequential methods in statistics have a fairly long history, but the modern theory of group sequential methods essentially begins with the papers of Pocock (1977) and O’Brien and Fleming (1979). These gave useful criteria for selecting boundaries for critical trials. Slud and Wei (1982) introduced the notion of error spending, in which the Type I error α is partitioned into probabilities π1,…,πk which sum to α, and πk represents the probability of stopping at analysis k to reject the null hypothesis when this hypothesis is true, also called the “error spent at stage k.” Lan and DeMets (1983) introduced the notion of spending functions, where Type I error is spent as a function of the observed information levels. When combined with a sampling rule aimed at continuing to a pre‐specified maximum information level, the spending function approach can satisfy a given power condition quite accurately (Jennison & Turnbull, 2000) while allowing flexibility for the number and timing of interim data analyses. The gsDesign package in R uses the spending function approach to create a flexible tool for designing and implementing group sequential clinical trials comparing two treatment groups. Among the supported spending functions are those of Lan and Demets (1983), Hwang, Shih, and DeCani (1990), Kim and DeMets (1987), and Anderson and Clark (2010). Other important features of the package include the ability to design with non‐binding futility rules and the ability to adapt designs based on changes to the timing and number of analyses performed. Group sequential designs considered are based on asymptotic normal approximations to the joint distribution of interim test statistics. The gsDesign package offers increased flexibility of design and significant reduction in the cost of ownership versus proprietary software offerings in the market such as Cytel’s EAST or Tibco’s S+ Seqtrial, which is specifically oriented toward group sequential trial design. However, gsDesign requires knowledge of programming in the R statistical programming language. Using gsDesign Explorer with gsDesign provides the ease‐of‐use of a graphical user interface (GUI) while maintaining the extensibility provided by the R language. The gsDesign Explorer GUI allows analysts to instantly create, compare, and document multiple group sequential designs. Users can focus on the model parameters and their statistical and clinical implications – without any knowledge of the underlying R syntax. The gsDesign Explorer provides graphical and textual summaries of group sequential designs that can immediately be incorporated into protocols and presentations. R code can be generated and saved to allow further customization, when needed.


The gsDesign Explorer allows statisticians to easily specify model parameters for group sequential designs and quickly view and compare the results. It provides high‐quality graphical and textual



summaries of group sequential designs that can immediately be incorporated into protocols and presentations and help the user choose, justify, and document the best combination of design options for the trial. Users can extend and modify the analysis by exporting the design to an R script that can be optionally processed by the R engine and/or written to file for subsequent manipulation by the user. The gsDesign Explorer is an open‐source R package created through a collaborative effort between Merck Research Laboratories and REvolution Computing. The GUI was built using Qt, an open‐source, cross‐platform GUI‐building toolkit. The GUI is linked to the R engine using a DLL written in C++. The code for dialogs themselves is implemented as an R package that calls Qt code. The user interface can be launched from the R command line or from R scripts on any supported R platforms (e.g., Windows, Linux [CentOS/Red Hat], and Mac OS X). The gsDesign Explorer includes several menus, a toolbar, and two main panels, one for specifying model parameters, and one for showing text or graphical output.

Figure 1: The gsDesign Explorer User Interface

At the core of the gsDesign Explorer are the dialogs in which the user can control all design parameters. Three major tabs allow simple specification of Type I error, power, interim analysis number and timing, spending functions and endpoint specification. The endpoint specification tab computes sample size for a fixed design based on standard methods for time‐to‐event endpoints commonly used in, say, cardiovascular studies or binary endpoints used in many indications. The user can also input a fixed sample size generated for a fixed design using software of their choice. The other two tabs describe the parameters for the group sequential aspects of the design.



A powerful feature of gsDesign Explorer is the ability to create multiple designs in a single interactive session, moving back and forth from one design to another to see how various modifications affect the sample size requirements and boundary characteristics. To add a design, users simply click New on the toolbar; this copies parameters from the current design to a new design. The new design can be interactively renamed and given a brief textual description to better describe the underlying study. Other toolbar buttons allow users to save or load a set of designs, delete designs, reset parameters to defaults, export designs as an R script, run the current design and display the results in an output window, and toggle between editing design specifications and plot specifications. The Plot tab can be used to create seven types of plots related to the design: test statistics at boundaries, power, treatment effect, conditional power, spending functions, expected sample size, and B‐values. All of these descriptions are useful for evaluating and comparing designs.

Figure 2: A treatment plot of a non-inferiority group

sequential design for a binomial outcome.



Help is available throughout the gsDesign Explorer through menu access to the complete manual and context‐sensitive help. To obtain help on a particular control, a user clicks the Help button in the toolbar, and then clicks the control. There are also status‐line hints in the lower left hand corner of the screen, and tooltips that pop up over each control when the mouse pointer hovers over the control.


By allowing direct comparison of competing designs, gsDesign Explorer allows the trial designer to optimize the trial design on a range of criterion; whether on number of test subjects, length of trial, or several others. This is expected to produce real and substantial savings in time, money, and patient outcomes. At Merck, group sequential designs with appropriate futility analyses may save on the order of $10 million dollars for a trial. These benefits come at the minimal cost of installation and learning how to use the intuitive and well‐documented user interface. The output provided by the package provides clear documentation of the rationale for a particular design.


The gsDesign Explorer promises to be game‐changing on several levels. As a free, open‐source project it can immediately compete with existing proprietary group sequential design tools. With its unique ability to compare designs, it promises to shorten the group sequential design process. And its visualization tools provide greater insight faster into the differences among the various trial designs. We hope to further establish open source software as a key resource for clinical trial design and analysis.


Anderson, K. M. (2009). gsDesign: An R Package for Designing Group Sequential Clinical Trials. Version 2.0 Manual. Merck Research Laboratories. http://cran.r‐project.org/web/packages/gsDesign/.

Anderson, K. M., & Clark, J. B. (2010). Fitting Spending Functions. Statistics In Medicine . To appear. Farrington, C., & Manning, G. (1990). Test statistics and sample size formulae for comparative binomial trials with null

hypothesis of non‐zero risk difference or non‐unity relative risk. Statistics in Medicine (9), 1447‐1454. Hwang, I. K., Shih, W. J., & DeCani, J. S. (1990). Group sequential designs using a family of type I error probability

spending functions. Statist. Med. , 9, 1439‐1445. Jennison, C., & Turnbull, B. W. (2000). Group Sequential Methods with Applications to Clinical Trials. Boca Raton, FL:

Chapman & Hall/CRC.



Kim, K. M., & DeMets, D. L. (1987). Design and analysis of group sequential tests based on Type I error spending rate functions. Biometrika (74), 149‐157.

Lachin, J. M., & Foulkes, M. A. (1986). Evaluation of Sample Size and Power for Analyses of Survival with Allowance for

Nonuniform Patient Entry, Losses to Follow‐up, Noncompliance, and Stratification. Biometrics (42), 507‐519. Lan, K. K., & Demets, D. L. (1983). Discrete sequential boundaries for clinical trials. Biometrika (70), 659‐663. O'Brien, P. C., & Fleming, T. R. (1979). A multiple testing procedure for clinical trials. Biometrics (40), 549‐556. Pocock, S. J. (1977). Group sequential methods in the design and analysis of clinical trials. Biometrika (64), 191‐199. Proschan, M., Lan, K., & Wittes, J. (2006). Statistical Monitoring of Cliinical Trials. A Unified Approach. New York:

Springer. Slud, E. V., & Wei, L.‐J. (1982). Two‐sample repeated significance tests based on the modified Wilcoxon statistic. J.

Amer. Statist. Assoc. (77), 862‐868.

FINAL FOR SUBMISSION 2/19/10

Bio-IT World 2010 Best Practices Awards – Celebrating Excellence in Innovation

Nominating Organization Organization name: Perceptive Informatics Address: 200 West Street, Waltham, MA 02451 Nominating Contact Person Name: Nicholas Richards Title: Senior Vice President, Product Management Tel: 888-773-0099 Email: [email protected] User Organization Organization name: Almirall, an international pharmaceutical company Address: R&D Sant Feliu de Llobregat, Laboratorios Almirall, S.A. General Mitre, 151 08022 Barcelona, Spain User Organization Contact Person Name: Estrella García, PhD Title: Head of Global Clinical Operations & Strategic Resourcing Tel: (34) 93 2913481 Email: [email protected] Project Project title: “A Complete Clinical Trial Picture: Enabling More Effective Decisions with Real-Time Information” Team leader: Estrella García, PhD Title: Head of Global Clinical Operations & Strategic Resourcing Tel: (34) 93 2913481 Email: [email protected] Category: Clinical Trials & Research: Trial design, eCTD

Description of the Project ABSTRACT/SUMMARY of the project and results (150 words max./800 characters max.) Typically, when biopharmaceutical companies are trying to coordinate data among systems, key challenges include that retrospective or delayed information provides an incomplete picture of their clinical trials. Almirall, an international pharmaceutical company, conducts complex clinical trials in the respiratory therapeutic area, and needed to gain greater visibility into its clinical trials and improve data access for faster decision-making. Through the use of optimized technology enabled processes and integrated eClinical solutions Almirall achieved its goal to make more effective decisions based on real-time information. The company was able to accelerate the clinical development process while maintaining a continued focus on innovation and goals to improve health and well-being.

INTRODUCTION/background/objectives

From a technology and data management perspective, respiratory studies with end points coming directly from spirometry devices provide several challenges for the handling and reconciliation of the collected data. One of these issues is reconciling the right patient and visit with the corresponding spirometry test. Key objectives included making it easier for Almirall to reconcile these data and to identify where queries needed to be resolved if there were discrepancies. Overall, the company was focused on creating a more sophisticated data exchange between technology solutions to improve the productivity and efficiency of their trials and gain a better integrated view of clinical trial data. An overarching goal was to enable more effective decisions based on real-time information and combined visibility of all clinical data.

RESULTS (highlight major R&D/IT tools deployed; innovative uses of technology). Through the implementation of a clinical program strategy enabled by the implementation of core, interoperable eClinical technology solutions, Almirall aimed to access data seamlessly, save time, and reach decision points faster about new compounds. Integrated eClinical solutions, including Electronic Data Capture (EDC), a Clinical Trial Management System (CTMS), and Randomization and Trial Supply Management (RTSM) technologies, were set up with these challenges in mind. The eClinical solutions provided clinical site personnel with randomization information in real-time as they entered patient information into the EDC application. For these studies, RTSM data was automatically imported into the EDC. In addition, key metrics from both the RTSM and EDC data was automatically imported into the CTMS so that Almirall had the critical information consolidated from the disparate technology applications. Thus, the study team had a true, complete picture of the study’s status at any moment in time. Almirall was able to achieve real-time randomization information directly from the EDC system, therefore eliminating the need to enter this data into the EDC. As a result, the site burden was reduced. Additionally central lab data was integrated directly into the EDC system on a daily basis whereby these data were viewable from within an eCRF. Values with clinical significance were able to be flagged to the investigator and study team for review and critical reports with the lab values were able to be combined with other patient data for a complete view of the trial data without having to wait for reconciliation. Almirall was therefore able to perform real-time randomization and dispensation activities directly from within the EDC solution, integrate critical external central lab data, access high level consolidated clinical trial metrics data drawn from the technologies to make faster decisions, and benefit from a seamless, automated exchange of data across different systems without having to modify applications on connected systems. Integration of key patient, visit, and clinical end point data among systems, providing front end processing and reconciliation of spirometry data, enabled real-time reconciliation, compared to a typical process where the bulk of reconciliation is handled at the end of the study when there is little or no time for issue resolution. Ultimately, Almirall benefitted from full visibility at any time to all key data.

ROI achieved or expected (200 words max./1000 characters max.): A 15-20% deduction in data reconciliation and reporting efforts was achievable with data available for ongoing reconciliation and interim and final analyses. Cost and time savings could be realized through an automated approach, streamlining processes and improving resource alignment. Decreased cost and processing time could be achieved by coordinating information and process flow across functions and systems. Technology streamlined workflow through system convergence enabling applications to work synergistically. A 10-25% site training reduction could be targeted due to use of one solution, enabling faster, better quality site and study performance decisions. Almirall derived value from the integrated solution and reduced set up time to go live with trials. Typically, with disparate technologies and integration challenges involved in a trial there would be a 16 week window to go live. With this integrated approach, Almirall decreased study set up and launch cycle time by several weeks. It is estimated this integrated approach reduces solution vendor contracting and management, which can contribute to a 30% cycle time reduction.

CONCLUSIONS/implications for the field (800 characters max): Pathways are being developed for trial efficiency improvement. Standalone systems to facilitate trials limit opportunity to maximally leverage technology. The challenge is being addressed through integrated, interoperable eClinical solutions aligned to accelerate development. With more complex studies, companies must access comprehensive data throughout development. Almirall took action to gain greater trial visibility and improve data access for better, faster decision making, while improving productivity and decreasing costs. Chronic respiratory diseases are a growing concern. Development issues include competition for sites with equipment to perform complex respiratory tests; recruiting patients; and seasonal effects. With advanced eClinical technology, Almirall expedited processes to achieve development goals, bringing respiratory treatments to patients sooner.

ENTRY FORM

1. Nominating Organization (Fill this out only if you are nominating a group other than your own.) A. Nominating Organization Organization name: PharmaVigilant Address: 69 Milk St. Suite 308 Westborough, MA 01581 B. Nominating Contact Person Name: Stephanie Bullis Title: Account Executive Tel: 617‐779‐1859 Email: [email protected]


A. User Organization Organization name: QuatRx Address: 777 East Eisenhower Parkway,

Suite 100 Ann Arbor, MI 48108

B. User Organization Contact Person Name: Stephanie Bullis Title: Account Executive Tel: 617‐779‐1859 Email: [email protected]

3. Project Project Title: rSDV experience in Phase III Trial Team Leader: Cathy Radovich Name: Cathy Radovich Title: Director of Clinical Development Tel: (734) 913‐9900 Email: [email protected] Team members – name(s), title(s) and company (optional): N/A

4. Category in which entry is being submitted (1 category per entry, highlight your choice) Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound‐focused research, drug safety X Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging

technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration,

resource optimization Health‐IT: ePrescribing, RHIOs, EMR/PHR Manufacturing & Bioprocessing: Mass production, continuous manufacturing

(Bio‐IT World reserves the right to re‐categorize submissions based on submission or in the event that a category is refined.)

5. Description of project (4 FIGURES MAXIMUM): A. ABSTRACT/SUMMARY of the project and results (150 words max.)

After the completion of a pivotal, U.S.‐based Phase III study, QuatRx was interested in recreating this same trial using new technologies and updated monitoring strategies to reduce costs and increase efficiencies of monitor and project management resources. To do this, QuatRx pharmaceuticals deployed PharmaVigilant’s I‐Vault Remote Source Document Verification (rSDV) technology in 2008; PharmaVigilant’s I‐Vault rSDV is the first commercially‐available rSDV solution and provides on‐going data monitoring for clinical trials independent of site visits. By implementing this technology, QuatRx experienced roughly $425,000 in cost savings compared to the previous study, drastically reduced trial delays with less sponsor trips and re‐monitoring, and received faster awareness of site issues needing investigation, ultimately increasing the overall quality of its findings.


Clinical trial sponsors are increasingly looking to technology vendors to help them conduct trials more effectively, cutting the time and costs associated with trial inefficiencies, while ensuring all study data is of the highest quality and accurately reported. Source data verification (SDV) is the only evidence available to confirm that a study was conducted in accordance with the protocol, regulations and applicable laws and procedures. With traditional SDV sponsors have little to no visibility into the site’s documenting and data handling processes, limiting their control over and access to their data. For trials using SDV, monitors are on‐site to review the data collection; however, on‐site monitoring is often one of the costliest expenses of running a trial, and monitors’ time could be spent more productively by focusing on recruitment and retention, two other major factors that often lead to budget overages and delays. According to QuatRx, “We wanted a solution that provided significant cost savings, increased efficiency and an automated approach to collection of source documents.” The Company turned to PharmaVigilant for help, specifically for its rSDV solution, which was developed to store and maintain source documents in a 21 CFR Part 11 compliant system to help sponsors increase the efficiency of their clinical trials.


Throughout the trial, QuatRx realized numerous benefits by implementing the rSDV technology. “Rather than wasting time verifying non‐clinical data points, with PharmaVigilant’s rSDV solution, site monitors were now able to focus on core responsibilities to ensure the proper progression of the trial, such as assisting in enrollment and retention and providing protocol training,” said QuatRx. Through its electronic audit trail, rSDV created increased accountability of monitors leading to higher quality data collection and a decrease in onsite rework, saving QuatRx both time and money. In addition to improved utilization of the monitors’ experience and time, rSDV also provided a faster awareness of issues needing attention prior to site visits as well as identifying potential problem sites.

D. ROI achieved or expected (200 words max.): By utilizing PharmaVigilant’s rSDV capabilities, QuatRx estimated they were able to eliminate at least 35 onsite visits resulting in a minimum savings of 120 study visit expenses (travel, food, etc.). As the hourly rate is lower for an rSDV specialist than a traditional SDV monitor and the overall rate of rSDV was roughly four times faster than onsite SDV, the number of site visits was reduced, resulting in approximate wage savings of $725 per rSDV conducted. With this being a pilot study for QuatRx’s rSDV implementation, it was difficult to forecast a reasonable target for cost savings. Through scenario planning and assumptions, it was predicted that rSDV could lead to cost savings of up to $1 million dollars, roughly eight percent of the total study budget, if implemented within a “perfect” set of circumstance. After completion of the study, it was determined that overall estimated cost savings was approximately $425,000, roughly four percent of the total study budget, but was still considered significant ROI as this was the first deployment of the technology in a QuatRx study. And at the conclusion of the study, 92 percent of sites said they would conduct another study using rSDV, indicating a high level of site satisfaction and adoption.

E. CONCLUSIONS/implications for the field. (150 words max.) rSDV, which can easily be implemented in any phase II or III study, provides sponsors with greater visibility into their data and offers substantial cost and time savings while ensuring quality and accurate data. It is assumed that for future studies with QuatRx the ROI in terms of cost savings would exceed four percent of the total study budget as QuatRx has now gained the best practices necessary to effectively utilize rSDV to its maximum potential. As a result of implementing this game‐changing technology, not only were the desired efficiencies achieved, but QuatRx also identified new efficiencies that were not initially projected. By implementing rSDV sponsors can eliminate travel expenses of monitors, reduce necessary billable hours of a traditional monitoring trip, continuously monitor data frequently and quickly, independent of site visits, and ensure monitors’ experience and time is being utilized most efficiently.


Please see attached documents which include graphical representation of data collected upon completion of this study. The data was collected by QuatRx and completed by the sites.

rSDV Simplifies Source Document Collection

• Rating: 0=Can’t Tell 1=Strongly Agree 3=Neutral 5=Strongly Disagree

• Mean = 2.81 – 78% rated answer 1-3 – 22% somewhat or strongly disagreed – 8.7% could not tell

rSDV Reduces Onsite Time for SDV


• Mean = 1.96 – 88% rated answer 1-3 – 12% somewhat or strongly disagreed – 1.4% could not tell

rSDV enabled Onsite Monitor to Focus on Issues Important to Me • Rating:

0=Can’t Tell 1=Strongly Agree 3=Neutral 5=Strongly Disagree

• Mean = 2 – 90% rated answer 1-3 – 10% somewhat or strongly disagreed – 4.3% could not tell

I would do another study that used rSDV


• Mean = 1.9 – 93% rated answer 1-3 – 7% somewhat or strongly disagreed – 3% could not tell





A. Nominating Organization Organization name: SAS Address: SAS Campus Drive, Cary, NC 27513

B. Nominating Contact Person Name: Angela Lipscomb Title: Media Relations Manager Tel: 919‐531‐2525 Email: [email protected]


A. User Organization Organization name: MDS Pharma Services 2200 Renaissance Blvd, Suite 400, King of Prussia, PA 19406 (MDS Pharma Services)

B. User Organization Contact Person Name: Charlene McGrady, Communications & PR, MDS Pharma Services Title: Senior Director, Communications & Public Relations Tel: 610‐239‐7900, ext 60231 Email: Charlene.mcgrady@MDS Pharma Servicesinc.com

A. User Organization Organization name: Daiichi Sankyo

B. User Organization Contact Person Ron Fitzmartin, Vice President Informatics and Knowledge Management Daiichi Sankyo 399 Thornall Street Edison, NJ 08837 Tel: 732 590 4337 Email: [email protected]

3. Project

Project Title: Daiichi Sankyo / MDS Pharma Services Collaboration



Team Leader: Bernd Doetskies Title: Director, Informatics Tel: 732‐590‐4332 Email: [email protected] Team members – name(s), title(s) and company (optional):

4. Category in which entry is being submitted (1 category per entry, highlight your choice)

Basic Research & Biological Research: Disease pathway research, applied and basic research Drug Discovery & Development: Compound‐focused research, drug safety Clinical Trials & Research: Trial design, eCTD Translational Medicine: Feedback loops, predictive technologies Personalized Medicine: Responders/non‐responders, biomarkers IT & Informatics: LIMS, High Performance Computing, storage, data visualization, imaging technologies Knowledge Management: Data mining, idea/expertise mining, text mining, collaboration, resource





C. RESULTS (highlight major R&D/IT tools deployed; innovative uses of technology). D. ROI achieved or expected (200 words max.):



Existing press releases

A. Abstract / Summary

Organizations across the clinical research spectrum are collaborating more than ever, but frequently rely on older, manual, processes to share information. Overnight couriers have only recently been replaced by rudimentary electronic transfer methods, and in both cases additional processing is required to ensure that what’s been delivered matches what’s been



sent. In the case of multiple transfers of similar content, the ability to confidently ensure that everyone is looking at the same version of the content is dramatically reduced.

MDS Pharma Services and Daiichi Sankyo have implemented a modern, 21st century approach to collaboration and information sharing in clinical research. This approach, which leverages SAS Drug Development as the focus of their collaboration strategy, ensures that not only are the transfers well‐controlled, automated and seamless, but that they are also fully documented to ensure the integrity of the content itself. This ability to confidently share research content enables MDS Pharma Services and Daiichi Sankyo to collaborate efficiently, effectively and at reduced costs.


Collaboration between organizations is a vital aspect of 21st century clinical research. Biopharmaceutical companies have outsourced work to CRO’s for many years, and work is frequently outsourced even further to lower cost labor markets. Each time content is transferred between organizations, that content is at risk. Whether the transfer is via digital media sent by overnight courier, or via a rudimentary digital transfer mechanism, organizations build detailed processes to ensure that what has arrived at the delivery point matches the content sent from the originator. In many cases, frequent, repeated, transfers are necessary as delivery products are updated, especially during the final stages of a project as last‐minute updates are made. These content hand‐offs support collaboration in name only, often with as much attention paid to the transfer processes as the content itself. The risk of version skew, where one company is working on one version of the content, and the second company is working off of a different version remains high. This, in turn, creates endless review cycles and even more deliveries. Given the maturity of Sponsor / CRO relationships, and the value these organizations obtain by working closely together – reduced timelines, mitigated costs and quality deliverables – it would be expected that companies would have worked already developed efficient content transfer processes. However, this is frequently not the case. Most often, Sponsors and CRO’s exchange information as shown here:



This complex process show many steps to enable the CRO both load content into the Sponsors systems, as well as read content from the Sponsors systems. In most cases, these steps are not only complex, but very manual. MDS Pharma Services and Daiichi Sankyo, however, have recognized the challenges associated with their existing collaboration practices and successfully deployed a new strategy to ensure more effective collaboration between their research organizations. This approach leverages SAS Drug Development as the enabling technology to provide 21st century collaboration between research partners.

C. RESULTS (highlight major R&D/IT tools deployed; innovative uses of technology). SAS Drug Development enables the collation and sharing of clinical research data and results within and across research organizations via a well‐managed, controlled, centralized repository. This single version of the truth enables rapid, efficient sharing of resources, data and knowledge across all stages of the clinical R&D process. Both MDS Pharma Services and Daiichi Sankyo have independently licensed SAS Drug Development, and were routinely using the solution as a core technology to manage clinical trial data, analyses, reports and associated content. As part of their ongoing collaborative discussions, they subsequently realized that each company was using the same solution to collaborate internally within their respective research organizations. The next logical step was to integrate their technology investments so that collaboration could be readily extended outside each organization. In particular, the companies’ joint goal was to minimize the typical shuttling of content between systems, and use SAS Drug Development to track, or in many cases prevent, multiple circulating copies of data and analysis content. SAS Drug Development provides key traceability and notification features, as well as various levels of content locking – each of which enables the controlled collaboration expected in a sponsor / CRO relationship. As shown in the accompanying figure, the new collaboration process is greatly streamlined. Not only is the transfer of content more straightforward, it is also automated.



One key example of this is found in the delivery of data sets, tables, listings and graphs at the conclusion of a trial. Across the industry, and true for MDS Pharma Services and Daiichi Sankyo as well, the historic process for delivering trial analysis results involved creating the results at the contract research organization, and the providing copies to the sponsor. This typically resulted in multiple revisions and versions of the deliverables, and uncertainty as to the identity of the final result. With SAS Drug Development, MDS Pharma Services and Daiichi Sankyo have implemented a more direct content delivery mechanism. Rather than having MDS Pharma Services generate and copy results to the Daiichi Sankyo, the process has been both altered and automated. SAS programs are executed within MDS Pharma Services’ instance of SAS Drug Development, and the program results are directly output to DaiichiSankyo’s instance of SAS Drug Development. Simultaneously, a copy is created on MDS Pharma Services ’ instance for maintenance and documentation purposes. By using SAS Drug Development’s intrinsic versioning ansd traceability controls, the delivery quality and confidence is dramatically increased, while at the same time reducing the effort to manage multiple cycles of delivery.

D. ROI achieved or expected (200 words max.): Formal ROI calculations are not yet available. However, a significant return is expected in both direct cost reductions, and indirect business value. From a cost reduction perspective, the integration between MDS Pharma



Services and Daiichi Sankyo’s instances of SAS Drug Development removes many manual steps – each of which would typically take non‐trivial time to complete, and introduce the opportunity to introduce quality issues. Through the technical integration, and the ensuing automation that is enabled, labor costs and reduced while quality is sustained. Importantly, and perhaps more difficult to quantify, is the value that MDS Pharma Services and Daiichi Sankyo achieve by working in a collaborative, controlled manner. All content transfers are automatically tracked between systems, and all supporting metadata and associated documentation is online and readily available. Importantly, this metadata and documentation does not rely on manual processes to be created; it is built into the business processes of the system.


Although many organizations boast about their ability to collaborate effectively, MDS Pharma Services and Daiichi Sankyo are actively demonstrating how to achieve true collaboration. Through tightly integrated, but controlled, systems, these organizations are able to share clinical trial content – data, tables, listings and graphs – such that the management of this content is automated and intelligent. Users – at either company – are automatically notified when new content is available, and the systems’ abilities to thoroughly document the history of each content object increases trust between the two organizations. There can never be a doubt about the shared content because the system fully documents not only the current version of the content, but all previous versions as well.

Bio‐IT World 2010 Best Practices Awards Nominating Organization name: St. Luke's Medical Center ‐ Quezon City Nominating Organization address: 279 E. Rodriguez Sr., Blvd., Nominating Organization city: Quezon City Nominating Organization state: NCR Nominating Organization zip: 1102 Nominating Contact Person: Miguel Martin N. Moreno II, MD Nominating Contact Person Title: Scientist Nominating Contact Person Phone: 62‐32‐727‐5540 Nominating Contact Person Email: [email protected] User Organization name: St. Luke's Medical Center ‐ Quezon City User Organization address: 279 E. Rodriguez Sr., Blvd., User Organization city: Quezon City User Organization state: NCR User Organization zip: 1102 User Organization Contact Person: Miguel Martin N. Moreno II, MD User Organization Contact Person Title: Scientist User Organization Contact Person Phone: 62‐32‐727‐5540 User Organization Contact Person Email: [email protected] Project Title: St. Luke's Center for Clinical Trials Team Leaders name: Filipinas F. Natividad, PhD Team Leaders title: VP for Research Team Leaders Company: St. Luke's Medical Center ‐ Quezon City Team Leaders Contact Info: 632‐723‐0101 Ext.4501 Team Members name: Blanquita B. De Guzman, PhD Team Members title: Scientist Team Members Company: St. Luke's Medical Center ‐ Quezon City Entry Category: Clinical Trials & Research Abstract Summary: Introduction: The clinical trial (CT) scenario in the Philippines started in the sixties and a dramatic increase in the number of clinical trials was noted in the last two decades. St. Luke’s Medical Center (SLMC) is a tertiary medical facility in the Philippines envisioned being the model for the comprehensive implementation of CTs according to global standards of excellence in Good Clinical Practice (GCP). Hence, in 1996, the Institutional Bioethics Committee, which was later renamed Institutional Ethics Review Board (IERB) was created. Its purpose was to review CT protocols by pharmaceutical companies submitted to SLMCs. The Research and Biotechnology Division served as Secretariat of the IERB, and was tasked to handle the logistics of the application process and implementation of CTs. Results: In its efforts to be the model for the comprehensive implementation of clinical trials, the St. Luke’s Center for Clinical Trials established a “one‐stop‐shop for clinical trial application process. Seeing the friendliness and accessibility of this process to the public, the center improved again on its services by creating a web portal that facilitated on‐line access and communications expansion to include all phases of a clinical trial.

Moreover, provision of additional facilities such as equipment for storage, more office space, and building of a larger reception area was done. In addition, new personnel were hired to handle various aspects of implementation of clinical trials. ROI achieved: Conclusions: References:

Bio‐IT World 2010 Best Practices Awards Nominating Organization name: Nominating Organization address: Nominating Organization city: Haifa Nominating Organization state: Israel Nominating Organization zip: 31096 Nominating Contact Person: Zeev Blumenfeld Nominating Contact Person Title: M.D., Associate Professor Nominating Contact Person Phone: 972‐4‐8542577 Nominating Contact Person Email: [email protected] User Organization name: Technion‐Israel Institute of Technology User Organization address: 8 Haalyia St, Bath‐Galim User Organization city: Haifa User Organization state: Israel User Organization zip: 31096 User Organization Contact Person: Zeev Blumenfeld User Organization Contact Person Title: M.D., Associate Professor User Organization Contact Person Phone: 972‐4‐8542577 User Organization Contact Person Email: [email protected] Project Title: Preservation of Ovarian function despite chemotherapy Team Leaders name: Zeev Blumenfeld Team Leaders title: M.D., Associate Professor Team Leaders Company: Technion‐Israel Institute of Technology Team Leaders Contact Info: Team Members name: Team Members title: Team Members Company: Entry Category: Clinical Trials & Research Abstract Summary: Introduction: The preservation of fertility and ovarian function have gained ubiquitous interest in the last decade.Invasive techniques, such as ovarian cryopreservation and other techniques, await further experience.IVF in women with orthotopically grafted ovarian tissue involves a high risk of empty follicles(29%), abnormal oocytes(38%)and low embryo transfer rates(24%).Only 7 deliveries have been reported worldwide out of over 200 estimated ovarian implantations.Ovarian autotransplantation is promising, but according to a recent report 31% of the patients died without undergoing reimplantation of their cryopreserved ovarian tissue.Autotransplantation has not been desired at all in the UK because of possible risks.Furthermore, ovarian metastases were detected in 8–55% of women younger than 40 years.There is no reliable method to detect minimal residual disease in the cryopreserved tissue, and the safety of reimplantation cannot be guaranteed yet.Meanwhile, non‐invasive techniques have attempted to minimize the gonadotoxic effect of chemotherapy, by using gonadotrophin‐releasing hormone‐analogues(GnRH‐a). Results: Our and others' studies analyzing the effect of GnRH‐a found

lower rates of premature ovarian failure (POF) in patients receiving GnRH‐a compared with controls.Recently, two prospective randomized studies and a metaanalysis reached similar results. Summarizing the studies resulted in 8‐11% incidence of POF in patients who received GnRH‐a compared with 40‐55% incidence in controls. ROI achieved: Conclusions: References: 1. Blumenfeld Z, von Wolff M. GnRH‐analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 2008;14:543–52. 2. Badawy A, Elnashar A, El‐Ashry M, Shahat M. Gonadotropin‐releasing hormone agonists for prevention of chemotherapy‐induced ovarian damage: prospective randomized study. Fertil Steril. 2009; 91: 694‐7. 3. Blumenfeld Z. Preservation of Fertility in Patients with Cancer‐Letter to the editor. New‐England J. Medicine, 2009; 360; 25: 2680‐1. 4. Blumenfeld Z, Zuckerman T. Repeated spontaneous pregnancies and successful deliveries after repeated autologous stem cell transplantation and GnRH‐agonist. The Oncologist. In‐Press 2009. 5. Blumenfeld Z, Avivi I, Eckman A, Epelbaum R, Rowe JM, Dann EJ. Gonadotropin‐releasing hormone agonist decreases chemotherapy‐induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril 2008; 89: 166‐73. 6. Blumenfeld Z. GnRH‐agonists in fertility preservation. Current Opinion in Endocrinology, Diabetes, and Obesity. 2008; 15:523‐8. 7. Blumenfeld Z. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. The Oncologist. 2007; 12: 1044‐54. Review. Selected for CME‐ Continued Medical Education. 8. Moore HC. Ovarian failure after chemotherapy for breast cancer and the role of gonadotropin‐releasing hormone analogs in protection of ovarian function. In: American Society of Clinical Oncology 2008 educational book. Alexandria (VA): American Society of Clinical Oncology, 2008: 39–42. 9. Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009. 10. Ataya K, Rao LV, Laurence E, Kimmel R. Luteinizing hormone‐releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys. Biol Reprod 1995; 52:365–72. 11. Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta‐analysis. J Womens' Health (Larchmt). 2009; 18: 311‐9. 12. Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van Langendonckt A, Pirard C. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. 2009 Aug 11. [Epub ahead of print] 13. Meirow D, Rabinovici J, Katz D, Or R, Shufaro Y, Ben‐Yehuda D. Prevention of severe menorrhagia in oncology patients with treatment‐induced thrombocytopenia by luteinizing hormone–releasing hormone agonist and depo‐medroxyprogesterone acetate. Cancer 2006; 107: 1634–41. 14. Blumenfeld Z., Benarush M, Zuckerman T. Spontaneous pregnancy and

normal delivery after repeated autologous bone marrow transplantation and GnRH‐agonist treatment. Hum Reprod. 2007; 22:2346. Epub 2007 Apr 23 15. Blumenfeld Z. Ovarian cryopreservation versus ovarian suppression by GnRH analogues: primum non‐nocere. Hum Reprod 2004; 19: 1924‐1925. 16. Blumenfeld Z. The beneficial role of gonadotropin releasing hormone agonists on fertility preservation. Pediatric Blood Cancer. 2009; 53:1159. 17. Blumenfeld Z. Ovarian Function Preservation by GnRH Agonists during Chemotherapy. J Womens Health (Larchmt). 2009 ; 18: 1471. 18. Blumenfeld Z. "It ain't necessarily so". Fertil Steril. 2009 November 5th. [Epub ahead of print].

Bio-IT World Best Practices Awards 2010

A. ABSTRACT/SUMMARY of the project and results (800 characters max.) The preservation of fertility and ovarian function has gained ubiquitous interest in the last decade. Invasive techniques, such as ovarian cryopreservation, await further experience. Recently, attempts of egg retrieval from cryopreserved implanted ovarian tissue have yielded increased rates of empty follicles, abnormal ova, and low rate of embryo transfer with no pregnancy. Only 7 deliveries have been reported worldwide out of 200 estimated ovarian implantations. Furthermore, ovarian metastases were detected in 8–55% of women younger than 40 years. We found that GnRH-a cotreatment yielded lower rates of premature ovarian failure (POF) in patients receiving GnRH-a compared to controls, similar to two recent prospective randomized studies and metaanalysis. B. INTRODUCTION/background/objectives The preservation of fertility and ovarian function have gained ubiquitous interest in the last decade. Invasive techniques, such as ovarian cryopreservation and other techniques, await further experience.IVF in women with orthotopically grafted ovarian tissue involves a high risk of empty follicles(29%), abnormal oocytes(38%)and low embryo transfer rates(24%).Only 7 deliveries have been reported worldwide out of over 200 estimated ovarian implantations. Ovarian autotransplantation is promising, but according to a recent report 31% of the patients died without undergoing reimplantation of their cryopreserved ovarian tissue. Autotransplantation has not been desired at all in the UK because of possible risks. Furthermore, ovarian metastases were detected in 8–55% of women younger than 40 years. There is no reliable method to detect minimal residual disease in the cryopreserved tissue, and the safety of reimplantation cannot be guaranteed yet. Meanwhile, non-invasive techniques have attempted to minimize the gonadotoxic effect of chemotherapy by using gonadotrophin-releasing hormone-analogues (GnRH-a).


Our and others' studies analyzing the effect of GnRH-a found lower rates of premature ovarian failure (POF) in patients receiving GnRH-a compared with controls. Recently, two prospective randomized studies and a metaanalysis reached similar results. Summarizing the studies resulted in 8-11% incidence of POF in patients who received GnRH-a compared with 40-55% incidence in controls.

D. ROI achieved or expected (1000 characters max.):

As GnRH-a has no serious side effects and can even reduce chemotherapy-induced complications, such as severe menometrorrhagia, GnRH-a are considered by many clinicians as a clinically useful co-treatment in chemotherapy. In the last decade 16 publications had similar positive results. A recent ASCO publication, similarly found the rates of POF to be 0-6% with GnRH-a vs. 32%-47% without it. Thus, there are three prospective peer reviewed studies with positive results. A recent meta-analysis has found a significant beneficial role for the agonists on both preservation of ovarian function and conception: 68% increase in the rate of preserved ovarian function (RR = 1.68, CI=1.34-2.1). Among the GnRH-a treated women, 22% achieved pregnancy compared with 14% without GnRH-a (RR = 1.65, CI=1.03-2.6). This meta-analysis concluded that women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRH-a.

E. CONCLUSIONS/implications for the field (800 characters max.)

Ovarian cryopreservation, GnRH-a administration, and follicular aspiration should be offered to all young women before gonadotoxic chemotherapy. The failure to offer GnRH-a co-treatment may possibly harm many patients who could benefit such a clinical combination, in addition to IVF and ovarian tissue cryopreservation, while waiting for the results of additional large prospective randomized studies. Furthermore, GnRH-a can effectively prevent the thrombocytopenia-associated menorrhagia in these patients.


1. Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update 2008;14:543–52.

2. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril. 2009; 91: 694-7.

3. Blumenfeld Z. Preservation of Fertility in Patients with Cancer-Letter to the editor. New-England J. Medicine, 2009; 360; 25: 2680-1.

4. Blumenfeld Z, Zuckerman T. Repeated spontaneous pregnancies and successful deliveries after repeated autologous stem cell transplantation and GnRH-agonist. The Oncologist. In-Press 2009.

5. Blumenfeld Z, Avivi I, Eckman A, Epelbaum R, Rowe JM, Dann EJ. Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma. Fertil Steril 2008; 89: 166-73.

6. Blumenfeld Z. GnRH-agonists in fertility preservation. Current Opinion in Endocrinology, Diabetes, and Obesity. 2008; 15:523-8.

7. Blumenfeld Z. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. The Oncologist. 2007; 12: 1044-54. Review. Selected for CME- Continued Medical Education.

8. Moore HC. Ovarian failure after chemotherapy for breast cancer and the role of gonadotropin-releasing hormone analogs in protection of ovarian function. In: American Society of Clinical Oncology 2008 educational book. Alexandria (VA): American Society of Clinical Oncology, 2008: 39–42.

9. Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. Published online January 20, 2009.

10. Ataya K, Rao LV, Laurence E, Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys. Biol Reprod 1995; 52:365–72.

11. Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens' Health (Larchmt). 2009; 18: 311-9.

12. Dolmans MM, Donnez J, Camboni A, Demylle D, Amorim C, Van Langendonckt A, Pirard C. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. 2009 Aug 11. [Epub ahead of print]

13. Meirow D, Rabinovici J, Katz D, Or R, Shufaro Y, Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone–releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer 2006; 107: 1634–41.

14. Blumenfeld Z., Benarush M, Zuckerman T. Spontaneous pregnancy and normal delivery after repeated autologous bone marrow transplantation and GnRH-agonist treatment. Hum Reprod. 2007; 22:2346. Epub 2007 Apr 23

15. Blumenfeld Z. Ovarian cryopreservation versus ovarian suppression by GnRH analogues: primum non-nocere. Hum Reprod 2004; 19: 1924-1925.

16. Blumenfeld Z. The beneficial role of gonadotropin releasing hormone agonists on fertility preservation. Pediatric Blood Cancer. 2009; 53:1159.

17. Blumenfeld Z. Ovarian Function Preservation by GnRH Agonists during Chemotherapy. J Womens Health (Larchmt). 2009 ; 18: 1471.

18. Blumenfeld Z. "It ain't necessarily so". Fertil Steril. 2009 November 5th. [Epub ahead of print].

Bio‐IT World 2010 Best Practices Awards Nominating Organization name: University of Arkansas for Medical Sciences Nominating Organization address: 4301 W. Markham Nominating Organization city: Little Rock Nominating Organization state: AR Nominating Organization zip: 72205 Nominating Contact Person: Cheryl Lane Nominating Contact Person Title: Director, IT Research and Development Systems Nominating Contact Person Phone: 501‐603‐1934 Nominating Contact Person Email: [email protected] User Organization name: University of Arkansas for Medical Sciences User Organization address: 4301 W. Markham User Organization city: Little Rock User Organization state: AR User Organization zip: 72205 User Organization Contact Person: Cheryl Lane User Organization Contact Person Title: Director, IT Research and Development Systems User Organization Contact Person Phone: 501‐603‐1934 User Organization Contact Person Email: [email protected] Project Title: Implementing a Vision for Clinical Research Team Leaders name: Team Leaders title: Team Leaders Company: Team Leaders Contact Info: Team Members name: Dr. Umit Topaloglu, Dr. Thomas Kieber‐Emmons, Dr. Laura Hutchins Team Members title: IT Research Technical Manager, Assoc. Director of Research Development, Professor of Medicine and Director of the Hematology/Oncology Division Team Members Company: University of Arkansas for Medical Sciences Entry Category: Clinical Trials & Research Abstract Summary: Introduction: It is the mission of the University of Arkansas for Medical Sciences (UAMS) that through discovery and research, the health, healthcare and well‐being of people in the region, the nation and the world will improve. In the past 18 months, UAMS launched a clinical research information initiative that will transform the way we conduct not only cancer research but all research at our institution. The UAMS IT research team is in the pilot phase of implementing numerous clinical research tools that support the activation and conduct of clinical research studies. Prior to this clinical research informatics initiative, UAMS clinical trails were managed independently, and data management was not centralized. Through this

initiative, proteomic, genomic, and clinical trial data identification, collection, management, and reporting will be centralized. This initiative encompasses the entire clinical research enterprise, and is not limited to cancer‐specific clinical trials and biospecimens. Results: We are in the early phases of deploying our clinical research solution which includes the following applications: caBIG C3PR (participant registry), caBIG PSC (patient study calendar), Akaza Research OpenClinica (open source Clinical Trial Data Management), ET (UAMS developed clinical trial Event Tracker), TrialSearch (UAMS developed link to and administration of Clinical Trials Search on the Web), caTISSUE (caBIG tissue bank repository tool for biospecimen inventory, tracking, and basic annotation), caARRAY (caBIG microarray data management system that allows users to submit, annotate and download microarray data) and Research Portal (a UAMS developed tool to search across the patient population providing: de‐identified demographic, diagnostic, pathologic, radiologic results; transciption notes, tissue availability, and tumor registry documentation utilizing the caBIG caTIES information extraction tool). To organize and streamline the researcher’s access to these clinical research applications, a single sign‐on dashboard was developed. The dashboard, is comprised of open source caBIG® tools (C3PR and PSC); the open source tool, OpenClinica, and internally developed tools: ET, TrialSearch, ARIA (Grant and Protocol Submission and Tracking), and CRIMSON (Protocol Budgeting and Clinical Trial Contracting). Within the dashboard infrastructure, caBIG caXchange provides fluid movement among these applications. With the forthcoming addition of caBIG tools caTissue and caArray to the dashboard, the scope will be expanded to include proteomic and genomic research data. The inclusion of our internally developed Research Portal to the dashboard will provide quick access to research information that was previously impossible for a researcher to obtain independently. UAMS is the first institution in the nation to utilize caBIG tools C3PR and PSC in conjunction with the OpenClinica application. The inclusion of OpenClinica within the caBIG framework completes an open source clinical trial data management solution for the caBIG CTMS (Clinical Trial Management System). Additionally, UAMS incorporated caTIES functionality to automate searches in its Research Portal. These innovations have been recognized by the caBIG and NCI leadership and UAMS is currently conducting presentations of this initiative across the country. Several UAMS campus champions are highly supportive of this research initiative and have partnered with the IT Research team to roll this out campus wide. This collaboration will result in a successful implementation for the enterprise. ROI achieved: Conclusions: References: Presentations and Awards

* NCI’s caBIG Clinical Trials Management System Face‐to‐Face Meeting, Memphis, 2008 * AAMC Group on Information Resources Annual Conference, 2008 * UAMS Cancer Institute Forum, November 2008 * UAMS Cancer Institute’s Senior Leadership, December 2008 * NCI’s caBIG Senior Leadership Conference, December 2008, Washington D.C. * NCI’s caBIG Clinical Trials/Imaging Face‐to‐Face Meeting, Spring 2009, Las Vegas * Drug Information Assoc. Annual Meeting, Executive Steering Committee NIH NCI caBIG, June 2009, San Diego * AAMC Group on Information Resources Annual Meeting, Spring 2009, Atlanta * UAMS Chancellor’s Cabinet, March 2009 * NCI Highlights UAMS caBIG initiative in the February 2009 LINKS publication: http://cabig.cancer.gov/media/links/Feb_09/building.asp * NCI Highlights UAMS caBIG initiative in a video, June, 2009: http://cabig.cancer.gov/action/casestudies/UAMS/ * caBIG Annual Meeting ‐ UAMS conducted a panel session, July, 2009 * caBIG Annual Meeting ‐ UAMS conducted a video conference with India, July 2009 * AAMC Group on Information Resources Annual Conference, Presenter, 2009 * UAMS caBIG Team received an award for 'Delivering Results' from NCI at the caBIG® Annual Meeting, July 2009 * UAMS received ranking of 23rd in Information Week’s annual ranking of the Top 250 Innovators, September, 2009 * National Bone Marrow Transplant Meeting, September 2009 * NIH, NCRR, CTSA Informatics Key Function Committee, Poster Presentation, Fall 2009 * Dr. Laura Hutchins and Kari Cassel, CIO presented podcasts for caBIG, January 2010 * American Association for Cancer Research, Will Present, April 2010 * BIO‐IT World Annual Conference, Will Present, April 2010 In the past six months the National Cancer Institute asked us to share our caBIG tools implementation efforts with: * Columbia University * Louisiana Cancer Center * A group of scientists from The Netherlands * the NCI Knowledge Support Center