Capturing the Value of EDC

Transcription

1 Capturing the Value of EDC Medidata and other marks used herein are trademarks of Medidata Solutions, Inc. All other trademarks are the property of their respective owners. Copyright 2013 Medidata Solutions, Inc.

2 2 Introduction Over the past decade, life science companies have been migrating their clinical organizations from a paper clinical trial process to electronic, EDC-based tools and related software. Even considering the inherent advantages of electronic data capture (EDC), this conversion is slow, steady and incomplete. And because of the degree of organizational process change required, the return on investment (ROI) of these EDC systems has been difficult to measure in a consistent way. This paper looks at the evolution of EDC, the considerations and requirements of each process (paper vs. EDC) and the ROI companies can expect to see over multiple trials. It also attempts to explain reasons why some companies have yet to make the change, and delves into the future of these technologies and why making the switch is both wise and essential for all life science organizations, irrespective of size. A Shifting Landscape from Paper to Electronic In the last 10 years, the clinical trials industry has seen a dramatic shift away from paper. Where only 24 percent of 2005 trials used EDC, 75 percent of clinical trials begun in 2012 were likely to use EDC. 1 This is a year-by-year increase of 15 percent for studies using EDC vs. paper. Alongside this trend has been a wholesale shift towards complementary clinical trial systems, such as randomization and trial supply management (RTSM), electronic patient reported outcomes (epro) and clinical trial management systems (CTMS). These trends are expected to persist as the technology becomes easier to use, even for firms without a large IT support staff. Historically, it s taken some time for clinical development to start moving away from paper. For decades, the use of paper has been sufficient to run clinical trials, with the industry always focusing on the biological science and not on the latest paperless technologies. In truth, it took some time for EDC technology to mature to the point of efficiency on par with paper. Indeed, many believe that the first forms of EDC were not actually EDC at all but just a transfer of the data entry burden from the sponsor to the investigator site. Recognized now as remote data entry (RDE), sponsors would supply their investigational sites with thick client software that required local hardware to be installed and it generally came in the form of a laptop. With multiple sponsors running trials at a site, sites often had to manage and maintain multiple laptops one for each sponsor.

3 3 Back at the sponsor, the EDC software would collect data from these remote computers into a central repository. Then they d migrate the information to a clinical data management system (CDMS) a separate database designed specifically for running queries, data cleansing and data extraction. This separate system was necessary to store data in a form suitable for query and export, and as a focal point for laboratory results. At the time, EDC was promoted with these benefits: Data checks could be implemented to reduce common transcription errors in the paper process. Some immediate feedback to site staff was possible to assist data integrity. Data could be transmitted, often on a nightly basis, and provide sponsors with the ability to monitor patients and site progress. Sponsors would be able to spot safety concerns earlier with the new process. The evolution of EDC has seen many of the top life science companies committing to conducting 100 percent of their clinical studies with EDC, due to the clear advantage over paper. Though there were some clear benefits to this vision, making it work was much harder than expected. Trial setups required significant resources and financial investment up-front to train both sponsor staff and the investigator site teams on how to use the system. The hardware was expensive to deploy and support. In addition, any midstudy change needed as a consequence of a protocol amendment resulted in updates at multiple points in the process, including EDC design changes, CDMS data model and query changes, and changes to extractions and reports. Another fundamental issue that early developers did not take into account was end-user experience. Medically trained site personnel felt they spent too much time sitting in front of a laptop rather than attending to their patients. Thankfully, the EDC landscape has evolved since its early days. Today, EDC vendors are delivering software that aids their clients in every aspect of the clinical data capture process, from the initial setup, through the trial conduct and closeout, and all with end user experience in mind. Cloud-based web applications increasingly allow sponsors and sites to start using EDC almost immediately, with little to no hardware and software configuration. This evolution of EDC has seen many of the top life science companies committing to conducting 100 percent of their clinical studies with EDC, due to the clear advantage over paper. In a recent CenterWatch study, 73 percent of sites now use EDC for at least one-fourth of their trials, and an increasing percentage of sites report that they no longer use paper for the capture of case report form (CRF) data. 2 This document demonstrates that the ROI of EDC is substantial and that it exists for customers of all sizes, not just Big Pharma. It shows that moving to EDC is now a prerequisite for running an efficient, modern trial and that the industry is now focusing on a fully data-driven process, as paper is replaced at all stages of the clinical development lifecycle.

4 4 Process Improvements Inherent in EDC To better recognize the benefits of moving from paper to EDC, a good starting point is to compare the two processes. Below is a depiction of patient data collection using paper CRFs. 3 MONTHS SITE CRF CRF Assess patient medical charts Transcribe to CRF Correct CRF Answer and sign queries CRA CRF CRA document verification and review Send queries to site Return answered queries DM TRACK RECEIPTS OF CRFS Double data entry Batch validation REVIEW DISCREPANCIES & IDENTIFY QUERIES PRINT QUERY FORM Update CRF database from queries The Paper Collection Process 3 SECONDS Before the trial starts, the sponsor sends each site their blank CRFs. As patients complete their visits during the study, the trial investigator records the data collected from each patient and sends the completed ecrf EDIT CHECKS RUN SITE forms back AND to QUERIES the sponsor. This data is IDENTIFIED entered twice into the central database and screened for inconsistencies, usually Assess patient medical charts Transcribe to CRF Data submitted to the EDC database weeks later. Data issues are entered on data clarification forms (DCFs) and sent back alongside any answered queries from the sponsor. Conduct SDV & raise In CRA a Phase III study for example, monitors typically visit each site every six to ecrf queries in ecrf eight Remote monitoring weeks. After each visit, they perform source document verification (SDV) by comparing the data entered on the paper CRF to what is recorded in the patient notes. This is done before the CRF is faxed or mailed to the data management team at the sponsor. Once the sponsor receives the CRF, the data cleaning can start. ecrf DM Data review Raise queries in ecrf

5 5 The database lock (DBL) process is a demanding period of time during a clinical study, with the data management team placed under intense pressure to finalize all data entry, query resolutions and data cleansing. This process is completed during a timeframe of six to 12 weeks, from last patient, last visit (LPLV) to DBL. It often leaves the statistical analysis teams waiting anywhere from two to five months after LPLV before the final analysis can take place. And a further one to three months is required before the clinical study report can be potentially completed and submitted to the regulatory authorities. 3 Even a few missing data points will stop the statistical analysis from progressing and since all programs need to be executed on complete and final data, the speed in which the data cleaning progresses and database lock is achieved is critical to the submission timelines. An additional concern is CRF storage at both the site and sponsor. A typical Phase III study contains on average 929,203 pages. 4 No carbon required (NCR) paper copies of the CRF and any related study queries are required by law to be stored for many years in fireproof storage rooms. Although measures are taken to ensure physical security, storing these physical copies is a burden and doesn t approach the security of a fully auditable electronic archive. EDC has already gone through one redefinition, and given the continuing and natural convergence of related clinical trial applications, it may be presently going through another one. This method of data collection has worked for many years but it is far from efficient and the entire process is error prone from the outset. Clinical site staff must transcribe data multiple times in different places without any feedback on data quality. If left unidentified, data transcription errors can result in database unlocks or worse they can risk patient safety. The EDC Collection Process The investment return of EDC is primarily driven by the currency of the database. The number of steps required in capturing and processing data during a trial is dramatically reduced via EDC and includes the elimination of double data entry (DDE) and a much shorter time period between LPLV and database lock. During the EDC process, the site enters data on web-enabled electronic forms that validate the data immediately. Entry or collection mistakes are prevented or reduced through this direct feedback and the cleaning process often starts before the data manager has even seen the data. These edit checks alert the site staff to any missing or inconsistent data that could go unnoticed for many months in a paper setting. Through the use of automated edit checks, sponsors have reported significant drops in query rates compared to paper and, more importantly, database lock cycle time reductions of up to 43 percent. 5

6 CRA CRF CRA document verification and review Send queries to site 10/2013 WHITE PAPER Return answered queries 6 DM TRACK RECEIPTS OF CRFS Double data entry Batch validation REVIEW DISCREPANCIES & IDENTIFY QUERIES PRINT QUERY FORM Update CRF database from queries 3 SECONDS SITE Assess patient medical charts ecrf Transcribe to CRF EDIT CHECKS RUN AND QUERIES IDENTIFIED Data submitted to the EDC database CRA Remote monitoring Conduct SDV & raise queries in ecrf ecrf DM Data review ecrf Raise queries in ecrf Many sponsors rely heavily on contract research organization (CRO) partners, often using flexible strategies that include multiple partners on the same trials. This heightens the demands for appropriate study oversight and reporting. Creating a portal for decision making and study management is critical in these cases, and always having the latest copy of the data is essential for this to be feasible. In short, sponsors using EDC have a clearer understanding of the study progress and site performance through real-time access to the collected data. They are able to make safety decisions on that data more quickly than with paper. Monitors are able to focus on ensuring compliance by spending less time checking paper CRFs against the source and more time on other aspects of site execution such as drug supply management, site management and adherence to the clinical protocol. The Evolution of EDC The first thing to consider when assessing the potential ROI of EDC over paper is the scope of the EDC implementation. But how does one define an EDC system? The term EDC covers a mix of solutions on the market today, each offering a different level of sophistication and function. Considering the vast number of integration options, it is not surprising that firms new to EDC find the prospect of an EDC trial very complicated. But EDC has already gone through one redefinition, and given the continuing and natural convergence of related clinical trial applications, it may be presently going through another one.

7 7 Many Different Options To identify the value add of an EDC solution versus paper, the first step is to determine system scope. Products can range from point solutions to enterprise installations with extensive impacts on the overall business. EDC applications are categorized as follows: Traditional EDC software that requires a separate CDMS back-end for data queries, processing and extraction: These are rudimentary solutions that function purely as mechanisms for collecting data from the site, with most data validation and cleaning done via the CDMS. These are sometimes still referred to as RDE. Survey, academic or free and open source solutions (FOSS): These systems have extremely simple form and query capabilities, and tend to require a great deal of programming and customization before they become useful for a production study. They tend to be inexpensive for the initial purchase, have little commercial polish but can often supply the basic functions required for studies with lower complexity. Combination EDC/CDMS solutions: These solutions provide for data capture and management in a single repository. They offer greater flexibility since sponsors only need to manage a single database. They also provide comprehensive data export and integration features. Enterprise clinical trial platforms: These are EDC/CDMS solutions but include, either directly or through the integration of a product suite, additional and necessary functions to formulate and plan, start-up and conduct the trial entirely through to study close. The integrated systems can include solutions for RTSM, medical coding, training, protocol and study design, budgeting and contracting, reporting, extractions, metrics, epro, clinical portal, electronic trial master file (etmf) and more. Items to Consider There is more to take into account beyond the categories mentioned above. Over time, a set of best practices have become almost universally adopted by EDC vendors, forming the baseline functions of modern EDC solutions. The following questions are also important to consider: 1. Is the EDC solution a thin or thick client? Does the system require its users to install hardware and software locally in order to use the solution, or can the site use a standard web browser for all data entry? Are all web browser types supported? 2. Are the user interfaces intuitive and easy to use? Are existing sites familiar with the system? 3. Is there a fully functional, multilingual helpdesk available 24/7 to both sponsor and site personnel? What is the service cost associated with this support? 4. What data import capabilities exist for lab or separately collected data streams? Do conversion and migration functions exist to aid the sponsor and site? 5. What are the reporting, output and extraction capabilities of the system?

8 8 6. How much time does it typically take to complete a study build? What are the implementation requirements and resources needed? Can study designs be easily reused and controlled, and is there a central design library available? 7. What training, online help and documentation is available to support the EDC solution? 8. Is the system Software as a Service (SaaS)? Does the SaaS solution have a service level agreement (SLA)? 9. How well does the EDC system interoperate with software that may be already in place such as CTMS, clinical data warehouse (CDW) and clinical safety systems (CSS)? For integrations and outputs, does the solution comply with industry standards such as Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM), Clinical Data Acquisition Standards Harmonization (CDASH), E2B and Study Data Tabulation Model (SDTM)? 10.Is the system Good Clinical Practice (GCP) and Electronic Records and Electronic Signature (ERES) compliant? Is it pre-validated and does it provide sufficient validation to withstand a vendor audit? The selected product should follow industry best practices and have the correct fit for the intended use. If the system is planned for a portfolio of products and trials, it makes sense to strongly consider an enterprise solution. Conversely, if a single trial is required, a point solution with assistance from a partner for trial conduct probably makes the most sense. Once a sponsor has performed this due diligence, they can better understand the scope of the EDC implementation and its potential improvements. Knowing the Path, and Walking the Path EDC implementations vary. Each sponsor organization follows their own quality policies and slightly different standard operating procedures (SOPs) and these differences will determine how EDC is best applied to realize its full potential. For example, a common question that a sponsor might ask an EDC vendor is: How long will it take to set up the EDC database for each study? Many factors go into answering this question, including study complexity, edit check requirements, therapeutic area (TA), the degree of user acceptance testing (UAT) required, software flexibility, availability of a database and form design library, design reuse, and ultimately the experience of the sponsor team and EDC study builders. The key element here is sponsor up-front involvement in the database and ecrf design and delivery. Medidata Professional Services have been involved in the deployment of studies using Medidata Rave in as little as four weeks; but in practice, there is a preferred review cycle for many clients of four to eight weeks that drives the overall schedule. In actuality, it has been possible to lower the setup time for study designs and implementation down to several days for similarly constructed studies pulling from a common design template and global library. A redesign of the business process is what is truly required to achieve these incredibly short timeframes, as well as an overall commitment to quality throughout the design process.

9 9 How Moving to EDC Saves Money and Time A common oversight made when comparing EDC to paper is an overemphasis on the fixed, up-front cost of EDC instead of the total cost of ownership over time. A focus on one study at a time can motivate this kind of thinking. But since multiple studies are necessary to drive a treatment through all phases and to final marketing approval, it s critical to look at the marginal cost over many studies when making a decision, as well as the full value proposition that EDC can deliver. These efficiencies come through significant process improvements and may extend upstream to protocol development and downstream into processes such as biostatistics and regulatory operations. Moving to EDC requires fundamental changes to most jobs within the clinical team responsible for conducting the study. EDC also asks more from sites up-front, but in exchange lowers the site s effort over the length of the trial. Comparisons are sometimes made across tasks such as queries generated and average turnaround times, but many of the processes required during a paper study simply become redundant with EDC. Data entered correctly the first time leads to higher quality, which significantly improves study completion time. EDC also eliminates the physical infrastructure and cost required to publish, traffic and store hundreds of thousands of paper CRF pages. Below are the key areas that EDC improves. EDC asks more from sites up-front, but in exchange lowers the site s effort over the length of the trial. First and foremost, the use of EDC allows for the practical elimination of double data entry in a trial. Decreased Double Data Entry and SDV 30 Percent Reduction in Monitoring 6 First and foremost, the use of EDC allows for the practical elimination of DDE in a trial. Perhaps more importantly, EDC makes it possible to also potentially reduce SDV by utilizing a risk-based approach to data point verification. SDV is where the monitor verifies the data entered against the paper CRF and requires constant trips to and dedicated time spent at the site. A risk-based, centralized approach allows SDV to be reduced through a statistical analysis of error rates, as well as common sense reductions in data checks. Advantages of reducing these verifications include: Data entry and data modification responsibilities are shifted from data management to the clinical research associate (CRA) and site personnel, allowing data management to focus on more value-added activities. Data entry cost is reduced as data is entered only once by those who should know the data best (i.e., the clinical study site), and most data is cleaned as it is entered. With monitoring of data via EDC website access, travel costs are reduced and onsite monitoring costs are significantly reduced in frequency and duration, by up to 75 percent. 7 Quality is increased with constant data monitoring. A single monitor can review CRFs as they are generated from multiple sites during the same day. This can be done prior to the visit, and missing, illogical and incorrect information can be reviewed off-site and then confirmed at the time of source document review.

10 10 Less, more targeted monitoring against potential trouble spots or underperforming sites is more effective than the traditional brute force approach to SDV. This may be even more impactful in smaller organizations with less access to monitoring resources generally and where existing monitoring coverage may be lighter. Access to staff for data entry is also less of an issue with EDC. DECREASED DOUBLE DATA ENTRY 30% REDUCTION IN SITE MONITORING The use of EDC allows for the practical elimination of DDE in a trial, because the ecrf data is entered directly by the investigator site from the original source documents. Up to 75% of onsite and travel costs are eliminated, with increased data quality. Perhaps more importantly, EDC makes it possible to also potentially reduce SDV by utilizing a risk-based approach to data point verification. IMPROVED STUDY START UP 36% REDUCTION FROM DESIGN STANDARDIZATION The initial configuration of EDC should be an exercise in creating standards. Once standards are created for forms and the associated edit checks, all elements can be easily reused for other studies through a global library system. This can bring average study startup down from 12 to 8 weeks in a typical phase III trial, even across Therapeutic Areas. DATA AVAILABILITY AND ACCURACY 52.5% FEWER QUERIES PAPER ADMINISTRATIVE EXPENSES SIGNIFICANT SAVINGS REAL-TIME DATA FOR DECISION SUPPORT 22.5% IN COST REDUCTIONS The initial configuration of EDC should be an exercise in creating standards. Once standards are created for forms and the associated edit checks, all elements can be easily reused for other studies through a global library system. This can bring average study startup down from 12 to 8 weeks in a typical phase III trial, even across Therapeutic Areas. The expense of printing, scanning, trafficking, and copying paper can he quite high over the duration of the trial. The cost of circulating a DCF in response to a valid query can be as high as $80 to $120 and take as long as 8 days. A large pharmaceutical has estimated a total paper expense for all trials to be $17 million dollars for the cost of printing alone. The availability of real-time data to clinical professionals during the trial is a classic example of the kind of improvement provided by EDC that simply does not exist using paper. Decisions about an individual patient s safety, as well as the direction of the trial, can be made in a greatly expedited fashion and in a centralized way. Consistent and timely metrics are required to improve any process, and EDC provides sponsors the capability to do both. Project progress is easily seen, and CRAs can thoroughly prepare for monitoring visits and conduct data review between visits. Finally, access and dissemination of safety data is possible with immediate access to electronic data, taking central access down from weeks or days to just minutes. FASTER TIME TO DATABASE LOCK 43% TIME REDUCTION The ability for EDC to be a single source of truth for collected data greatly reduces time from LPLV to database lock: From months to weeks, or even days. Management reports may be used to drive the close out of a study by confirming when all forms are monitored and locked and automatically routing CRFs for signatures.

11 11 Improved Study Start-Up 36 Percent Reduction from Design Standardization The initial configuration of EDC should be an exercise in creating standards. Once standards are created for forms and the associated edit (validation) checks, all elements can be easily reused for other studies through a global library system. In a modern EDC system, a new study can be created by merely invoking a copy function, which effectively clones the established design to create forms for the next trial. This standardization: Can bring study design and start-up times down from 12 weeks to eight, 8 even across TAs. It also allows the clinical group to create the CRF forms and, together with data management, deploy a full EDC study in days rather than weeks or months, depending on the complexity of the study and the experience of the EDC study builders. Lowers the required programming experience level for form and data designers, allowing TA experts to create the EDC design with zero programming in a much more agile and responsive way. Provides a consistent way to capture metrics on the study build, delivering additional ongoing improvements in efficiency. The efficiencies of study reuse, global library standardization and metrics feedback varies between organizations but can lower implementation time, effectively eliminating the perceived advantage of a paper trial. Data Availability and Accuracy 52.5 Percent Fewer Queries 9 Because the data is validated as it is entered, the total number of queries goes down and the paper DCF feedback loop is no longer needed. In addition: Data is available in real time from the website allowing for immediate medical monitoring, with automated data cleaning occurring as the site enters the data. There is a significant decrease in errors left uncorrected in the EDC system, leading to a higher quality of data. The data manager can view all edit check activities and can generate queries directly to the clinical sites. This happens in real time so when it is time to lock the database, there can be a very high expectation that the data is clean. There is a reduction in the number of batch edit checks and potential queries generated by data management and clinical, reducing the overall data cleaning effort. In a 2002 paper on this subject, the number of queries per subject went down by 86 percent, with an enormous cost reduction of $53,000 for query resolution using EDC, versus an average expense of $500,000 for query resolution in a large Phase III study using paper. For smaller trials with fewer queries, this still translates to a marginal cost per query of $60 for paper versus $10 with EDC. 10

12 12 Paper Administrative Expenses Significant Savings Moving completely to paper on the sponsor side is a big part of what contributes to lower trial costs. The expense of printing, scanning, trafficking and copying paper can be quite high over the duration of the trial. In summary: No CRF and DCF printing and shipment costs are necessary. Copying, facsimile and courier costs are likewise avoided. Scanning costs are negated as well for downstream TMF and regulatory submissions. There is no need for expensive, secure and fireproof paper storage solutions. Data is stored on central servers in already secured and fireproofed data centers, with offsite backups and other data retention procedures. Likewise, the sponsor requires no archiving of paper at the end of the study, as PDF versions of final CRFs may be generated and sent to the sites alongside an electronic archive. While it is instructive to look only at costs, the improvement in patient safety due to real-time data access cannot be understated. Many electronic trials must take a hybrid approach with both paper and electronic aspects due to practical considerations at the site. Many sites still require some paper capture, with a paper record and wet signatures for inclusion in the TMF and regulatory submission. Some report that the cost of circulating a DCF in response to a valid query can be as high as $80 to $120 and take as long as eight days. This is in comparison to an instantaneous timeframe with a marginal cost of zero using EDC. 11 Similarly, in 2002 Novartis estimated total paper expense for all trials to be $17 million for the cost of printing alone. 12 Real-Time Data for Decision Support 22.5 Percent in Cost Reductions 13 The availability of real-time data to clinical professionals during the trial is a classic example of the kind of improvement provided by EDC that simply does not exist using paper. In general, decisions about an individual patient s safety, as well as the direction of the trial, can be made in a greatly expedited fashion and in a centralized way. This avoids the lack of real-time visibility that is inherent in the paper process, which can delay access to critical safety data by days if not weeks in some cases. 14 This also enables the capability to conduct an adaptive trial with the latest quality data. Data can be accessed by all project team members and not just the data manager for example, the safety and pharmacovigilance team, monitors, project management, executives and so on. Project progress, including patient recruitment, early terminators and screening failures is easily determined, greatly facilitating study and project management. Rapid ongoing study decision requirements are possible, such as dose escalation judgments, reducing white space and saving effort.

13 13 CRAs can thoroughly prepare for monitoring visits and conduct data review between visits. Site visits are ensured to be effective and focused. Consistent and timely metrics and analytics may be collected and reviewed on study execution for ongoing process improvement. Access and dissemination of safety data, including suspected unexpected serious adverse reactions (SUSARs) and signal detection, is possible with immediate access to electronic data. While it is instructive to look only at costs, the improvement in patient safety cannot be understated here. The capture and processing of adverse events, the availability of data for signal detection, the ability to make timely clinical decisions, the quick dissemination of this data to doctors, the Investigational Review Board (IRB) and regulatory agencies, and the impact on timeframes when safety reconciliation is reduced all go beyond financial considerations to potentially impact the health of trial participants. Faster Time to Database Lock 43 Percent Time Reduction 15 The ability for EDC to be a single source of truth and provide a single database for all collected data can greatly reduce time to database lock, sometimes by many months. The impact of a delayed lock can translate into lost revenue if the final study report delays the submission to the agency for a marketing approval. 16 Because EDC has an understanding of the status of all incomplete forms, management reports are used to drive the closeout of a study by confirming when all forms are monitored and locked and automatically routing CRFs for signatures. Prior to locking the data for a patient, a final check can ensure that there are no unresolved edit checks and queries. Advantages include: Drastically reduced time from LPLV to database lock in comparison to paper from months to weeks by as much as 43 percent. Extraction of clinical data directly to the biostatistics group for immediate analysis and clinical report writing. Ability to conduct interim analyses based upon real-time data.

14 14 Single Studies Versus Enterprise ROI Another way to look at the savings inherent in a move to EDC is to look at the tasks individually that are either replaced or made more efficient. Below are listed tasks and processes that are made more efficient or completely eliminated through EDC use: Cost of printing and shipping paper CRFs. Cost of producing overage CRFs, that in many cases, remain unused. Cost and time as a result of a change to the study design, including the reprint of CRFs, shipping and study delays. Cost and resource for storage of CRFs, both at site and sponsor. CRF receipt and tracking coordination resources. On-site monitoring, including monitor fees, travel cost, and time and materials to SDV. Time between visit and receipt of data within data management. DDE time and materials expense by the data entry group, along with project management and oversight of that group. Query list generation and query tracking within data management, as well as query cost and turnaround time. Project time saved from LPLV to database lock. These improved or eliminated processes apply equally to either individual study or enterprise usage of EDC. Many apply to smaller individual trials as well, with lower complexity, fewer sites and fewer participants. When making an ROI analysis of the operational benefits EDC delivers, sponsors can take a low risk approach by looking at the benefits based on a single study, or take a more exhaustive approach and look at an enterprise implementation. Most EDC vendors, particularly the modern, cloudbased ones, provide implementation services that allow sponsors to pursue either option. In fact, most recommend a toe in the water approach for the first study, particularly in the case of small to medium life science organizations. 17 The Bottom Line Clearly, there is no direct correlation between the license expense of EDC software and the expense of using paper for a clinical trial, so comparisons should never be assessed in a simplistic like for like manner. Instead, sponsors should look at the efficiencies like the ones described above as well as how those efficiencies can be further enhanced. Even without the bulk of this analysis, a savings of 25 to 30 percent is generally guaranteed by using EDC, simply by decreasing DDE and SDV budgets. 18 But the clear advantage is in the immediate availability of the data, which is tied to improved patient safety, efficient trial execution and a better understanding of the direction of the research at hand.

15 15 What s Taking So Long? It s a fair question to ask why many companies have not yet made the switch. Simple math indicates that between 15 to 25 percent of all studies started this year will still use paper for the collection of CRFs. 19 This raises the question: If EDC is so great, providing so many clear advantages over paper, why is paper still used at all? Given all these savings, wouldn t it be difficult to justify the use of paper in any trial? There are several reasons for the continued use of paper. The most obvious reason is that EDC does require additional up-front cost, configuration and implementation. At first glance, particularly for newer, emerging companies, it may seem like overkill to make the investment in EDC. With a focus on the science and the treatment, IT may not be a central concern of the clinical team, and the additional focus on a single study instead of many can exacerbate this oversight. Additionally, all the design of an EDC trial must be done prior to first patient enrollment. This means that a greater degree of organization is required before the trial begins. Hopefully the reasons provided above show that this is shortsighted and that the addition of EDC can assist the clinical team in study execution and ultimately lower trial expense. The clear advantage [of EDC] is in the immediate availability of the data, which is tied to improved patient safety, efficient trial execution and a better understanding of the direction of the research at hand. Internet connectivity is extremely important for a modern, cloud-based EDC to work properly and in the recent past many remote sites did not have it. This is becoming less common as more countries and global regions gain consistent access to the Internet. The introduction of wireless, high-speed ISP access and slow but reliable use of dial-up access in remote regions makes this less of a consideration. For many sites, the introduction of EDC can require a change in their natural workflow of patient care. The site personnel may also require a good deal of training in the use of an EDC system. 20 For these reasons, a sponsor may choose to go with the flow of what the sites are requesting, rather than attempting to force them to use EDC in a timely fashion. In this case, the responsibility of the sponsor to improve their own process must include their sites as well. This can be challenging but is a worthwhile investment for the savings outlined above. The introduction of the practices of EDC at the site is also the first step in the introduction of similar technologies such as webbased RTSM, epro and CTMS. It is now unlikely that a CRO assisting with a trial will decline to use EDC. At one point, CROs might have charged a premium for the service, but EDC has quickly become a baseline for running a modern trial and few CROs will willingly go back to paper. One of the advantages CROs can provide smaller to mid-sized life science organizations is the ability to kick-start a fully electronic trial very quickly, as they have already made the necessary software and infrastructure investments.

16 16 Finally, EDC may be more challenging to use in certain kinds of trials. A Phase I Healthy Volunteer trial, for example, requires pharmacokinetic data collection at very specific time points during each visit. This data is collected concurrently for each patient that does not lend itself to electronic data entry, unless the instruments are directly integrated with EDC. However, many EDC systems now have the capability to either collect this data efficiently or else integrate with the necessary lab equipment. Again, this requires up-front planning but can greatly decrease effort over multiple trials. Beyond EDC to an eclinical Platform Current trends in the industry continue to advance companies beyond point solutions such as EDC and towards an eclinical platform. Other systems involved in the planning and conduct of a clinical trial that have been traditionally separate are improved by EDC interoperability from better information management to an improved end user experience. These connections may be used to create clinical development efficiencies, delivering a web service platform to work with systems such as safety, central labs, RTSM, epro, etmf and data warehouse and analysis platforms. It is perhaps these efficiencies that represent the biggest potential gains to enabling an interoperable EDC solution. For example, if data is pulled first into EDC from various third-party sources (randomization, epro, etc.), integrated datasets can be extracted from EDC to another location like a clinical data repository in real time. Setting up this type of interoperable data flow can greatly reduce or nearly eliminate the need for manual reconciliation steps and provide more complete datasets and reports to all stakeholders. Wherever data is allowed to flow completely through the clinical process without reentry, better decisions can be made and quality can be maintained without extra time and effort. Additional examples include: Managing protocol amendments into ecrf forms and data migrations with robust simulation functionality; An integrated site experience for EDC, drug randomization and drug dispensation; The auto-coding of clinical data with dictionary up-versioning; Risk-based monitoring through targeted SDV right within EDC; Real-time E2B transmission of serious adverse events (SAEs) into the safety database to eliminate the need for manual reconciliations;

17 17 Streamlining investigator payments and trip reporting through CTMS integration; Simplifying monitoring tasks and reporting through EDC integration; and Study management through turnkey clinical operations analytics and reporting. Such a clinical solution built on an EDC platform has the potential to realize millions in dollars of savings per study while improving quality, ensuring compliance and speeding time to market. esource Arch. Protocol Authoring BUILD & DEPLOY ecrf Lib INTEGRATION Study Design Labs Device EPR/EHR About Medidata Medidata Solutions is the leading global provider of cloud-based solutions for clinical research in life sciences, transforming clinical development through its advanced applications and intelligent data analytics. The Medidata Clinical Cloud brings new levels of productivity and quality to the clinical testing of promising medical treatments, from study design and planning through execution, management and reporting. We are committed to advancing the competitive and scientific goals of global customers, which include over 90% of the top 25 global pharmaceutical companies; innovative biotech, diagnostic and device firms; leading academic medical centers; and contract research organizations. info@mdsol.com mdsol.com Warehouse EXTRACT & REPORT CTMS/ ERP Analysis Warehouse Datasets Metrics And Safety Clinical Data G AT E W AY Coding IVRS CAPTURE & MANAGE Medidata Clinical Cloud Cloud-based clinical research solutions Innovative technology Data-driven analytics Reduced costs Improved time to market Faster decisions Minimized risk

18 18 Endnotes 1. PAREXEL s Bio/Pharmaceutical R&D Statistical Sourcebook 2012/ "EDC Adoption in Clinical Trials: A 2008 Analysis," CenterWatch, February Electronic Data Capture (EDC) as a means for e-clinical trial success, IBM Global Services, Pharmaceutical Clinical Development, March Medidata Solutions Worldwide, The EDC Value proposition to the pharmaceutical industry. A Detailed Comparison of EDC Versus Paper Model Costs For Four Different Clinical Research Projects (Phase I IIIb), Datatrak International, Inc., July "Achieving Cost Savings using EDC Effectively," Research Dynamics Consulting Group, Ltd., November "EDC in Clinical Trials: An ROI Analysis of Medidata Rave," Health Industry Insights, June "Purdue Pharma Leverages Medidata Rave Global Library to Reduce EDC Study Build Times by 40%," Medidata Solutions, May Banik N. "Evaluation of EDC versus Paper in a Multinational Asthma Trial." Presented at the DIA European Data Management Meeting. Berlin, October C Spink, Electronic Data Capture (EDC) as a means for e-clinical trial success, IBM Global Services, Pharmaceutical Clinical Development, March Babre D. "Electronic data capture - Narrowing the gap between clinical and data management," Perspectives in Clinical Research 2011;2: Uehling, Mark D. E-source Is Coming, Experts Say, BioIT_Article.aspx?id=23122, Bio-IT World, June 24, EDC in Clinical Trials: an ROI Analysis of Medidata Rave, Health Industry Insights, June 2006

19 Bayer HealthCare Bridges the Gap Between Data Management and Pharmacovigilance with Rave Safety Gateway, Medidata Solutions, June The EDC Value proposition to the pharmaceutical industry. A Detailed Comparison of EDC Versus Paper Model Costs For Four Different Clinical Research Projects (Phase I IIIb), Datatrak International, Inc., July Lorraine D. Ellis, "Achieving Cost Savings using EDC Effectively," Research Dynamics Consulting Group, LTD "Achieving Cost Savings using EDC Effectively," Research Dynamics Consulting Group, Ltd., November J A Green, The EDC Value proposition to the pharmaceutical industry. A Detailed Comparison of EDC Versus Paper Model Costs For Four Different Clinical Research Projects (Phase I IIIb), Datatrak International, Inc., July PAREXEL Biopharmaceutical R&D Statistical Sourcebook 2012/ Clinpage. More paper, more burden. paper_more_burden/c5