Easy Does It

NGP. EDC has been talked about for many years. What is its current status in the pharma industry and is the promise being fulfilled?

WC. Though pharma is science and technology intensive, IT has simply not been used effectively in some areas. Clinical trials represent one such area. Trials are challenging, as the sponsor typically doesn’t have control of all technology at the sites, and training end users can further complicate deployment. Furthermore, EDC used to be thought of as just another way to get clean data, maybe faster. There were some early adopters, but a combination of unrealistic expectations and a lack of pressure to improve the management of clinical trials caused adoption to languish.

A number of developments have altered the landscape and the uptake rate for EDC is already increasing dramatically. These issues include: increasing regulatory scrutiny, escalating R&D costs, Vioxx outgrowth, financial reporting concerns, and EDC technology maturation. With improvements in technology, the need for trials of longer duration, and an increased comfort level with the commercialization of the internet, EDC is here to stay, and it’s growing. The focus of discussion has now shifted from whether sponsors should use it, to one of how they will deploy it. Success stories like JNJ’s use of EDC in Phase I demonstrate that the promise is real – not only in big studies but for the entire product lifecycle.

PB. This past year has been a very important one for EDC. The industry has begun a clear transition to a world dominated by web-based EDC, and is looking forward to the additional value that can be achieved from the process. Most major pharmaceutical and biotechnology companies have made the decision to move, albeit at different speeds, towards a data collection process dominated by EDC. This is not unlike the move to adopt email in the 1980s. Companies are no longer focused on objections or return on investment – but are trying to determine with which vendor, at what pace, and with what process to proceed. The 2004 CDISC survey suggests that 20 percent of clinical trials now use EDC, up from 15 percent the year before. This number is likely to increase steadily as EDC is integrated into the mainstream clinical trial process at growing numbers of sponsors.

ES. Several years ago I heard a conference speaker refer to EDC as a ‘perpetually emerging technology’. Today, however, after a long experimentation phase, we are nearing the tipping point of widespread adoption – to borrow from Geoffrey Moore’s popular book, EDC has crossed the chasm. The question is no longer ‘Should we adopt EDC?’ but rather, ‘How should we adopt EDC?’ Now, champions of the technology are not technologists, but the operational people charged with wringing greater productivity out of scarce clinical resources. Today’s pharma clients recognize the broader opportunities EDC enables and, most importantly, are willing to change their internal processes to realize those benefits.

AS. Pharmaceutical companies have no time to lose, and have therefore reconsidered the integration of EDC into their clinical trials and standard work flows, keeping in mind their business and economic interests. We believe an increased benefit will be achieved from the improved quality and reliability of data which EDC provides, while saving time, money and staying in compliance with the changing regulatory requirements. We have, for example, increased our EDC offerings for centralized services (eDiary, ECG, EEG, Spirometry and Sleep) and are adding centralized imaging services.

NGP. Why then is it beneficial to the drug development process – what are the key selling points of EDC?

WC. The real ‘product’ of clinical trials is information, and the objective of every trial is to produce that information as safely, accurately and rapidly as possible. Of course, acceptable cost figures into that equation as well. When a sponsor uses EDC, they get access to their study information sooner, and that access translates into so much more than simply a clean database. Faster access to the data can be used to run better, safer trials, and to improve the adaptability of the trial.

What this means is that clinical operations has better control and can therefore better manage studies, monitoring enrollment in real time. They are able to see which sites and subcontractors are doing well, and who is behind. Leading EDC systems also provide real-time alerts regarding SAEs or other events, which helps to improve patient safety. If the EDC vendor provides real-time access to the data, the sponsor can even gauge the efficacy of the treatment before the study is ended. EDC also makes it much easier to make mid-study changes to enrollment guidelines or to the eCRFs, if required.

PB. Many of the benefits of EDC focus on the most obvious reason for using an electronic data collection tool – immediate access to data. Real-time data allows monitors to ensure the quality of data early and continuously during the trial, training sites where necessary, and improving the overall quality for statistical analysis. Data validation and cleaning can be performed more efficiently, with fewer site visits, leading to reduced travel and on-site costs as well as eliminating CRF printing and shipping costs. Most importantly, faster data availability can help sponsors with decision-making from operations to interim analyses. The end result is the potential to virtually eliminate the post-accrual cleaning phase and drive clinical trial cycle times down.

In addition to these benefits, EDC is exceedingly valuable in helping to manage the clinical trial process itself. Since participants in the trial are working through an electronic process, information about their activities is also collected, and this ‘metadata’ can provide a rich source of information about the operational efficiency of a clinical trial. For example, it is possible to benchmark and compare ‘time to’ parameters to determine which sites or monitors are operating inefficiently. Since this information isn’t collected on paper, such operational reporting is only possible with EDC. This information can be used to optimize resource utilization and streamline workflows.

ES. Our customers’ primary objective is to deliver robust clinical results as cost-effectively and efficiently as possible. EDC tools do not exist in a vacuum, so often the benefits of pilot implementations have been lost amid other inefficiencies in the clinical development process. However, with the commitment to adopt new processes, EDC makes it possible to manage trial activities more effectively, readily access trial results, and make development decisions more confidently. Notice, I didn’t say EDC trials are necessarily faster or cheaper. They often are, but focusing on just those two attributes is only a small part of delivering robust clinical results.

The benefits of implementing EDC actually begin with the protocol and extend through the review and submission processes. Electronically capturing protocol content at the design stage takes weeks out of EDC set-up activities and ensures the data being collected is exactly what the protocol specified. Capturing the data electronically in a submission-ready format enables the data to be reviewed, exchanged and submitted much more efficiently. As the pharmaceutical industry is increasingly focused on productivity, EDC has emerged as the most significant leverage point within clinical development.

AS. EDC is all about improving data quality. By providing automated edit-checking functions, increasing workflow efficiencies and decreasing the so-called ‘parking lot effect’, database locks are achieved more rapidly.

Sponsors can benefit from a one-stop-shopping solution that integrates and streamlines processes to decrease the varied approaches. With increasing standardization, data accessibility will be improved greatly and information will be available in near-real time speed.

As a manufacturer of medical devices, we have married technologies with the unique requirements of clinical trials to provide reliable, user-friendly and affordable solutions, and are the first and the only provider to have combined an electronic lung function monitor with an electronic Diary. This handheld device incorporates individualized protocol driven workflows, systematically guiding the patient through the clinical trial in her/his native language. Another key element leading to our success is our capability to support international trials through global and local presence.

From our customers, we’ve learned that with the use of our EDC solutions, they are able to reduce the sample sizes without risking statistical power, due to high patient compliance and data quality.

NGP. It’s certainly starting to take off, but are there any remaining concerns with EDC systems?

WC. The key to success is acceptance of EDC within the organization. Applying old processes and methodologies to trials using EDC will undermine or negate some of the benefits, and back-ending an EDC system into archaic clinical database management systems present additional complications. However, the biggest concern anyone should have is the organizational commitment to make it work.

Part of that commitment includes a process of translating clinical trial expertise. What I mean here is that sponsors still need smart people who know how trials work and understand the data, and how to solve problems. Change can threaten some people but, if well handled, can also empower them by taking away some of the drudgery and giving them the tools and information to do their job better. Good EDC systems provide the information and tools for better control, but there still needs to be intelligence at the helm. This is so important that if a sponsor doesn’t have someone to fill that role – trained and experienced data managers or coding experts – we’ll supply the resources to make sure it’s done well.

Then there are the basic plumbing issues to address as well: Do the sites all have high-speed connectivity? Is there still a paper source? If not, how will we handle the requirement for having data available at the site? Does it make sense to have monitors do a lot of their job remotely?

PB. There are, and should always be, concerns with the implementation of any technology. Here we can learn a great deal from other industries that underwent a similar technology adoption cycle more than a decade ago. Early on in technology adoption, companies worry about functionality, buy vs. build, and the risks of immature technology. As the EDC industry matures and consolidates to a handful of vendors, most companies are making enterprise adoption decisions. Their concerns now focus on finding a financially stable vendor with long-range vision who can provide the global services and infrastructure they will require. Modern software vendors are no longer simply technology providers; they provide a complete service, are less interested in pilots, and more focused on how EDC will change their processes, and how they can take advantage of the benefits these changes can bring.

ES. My concerns with EDC primarily relate to the ‘how’ of implementation rather than the underlying technology itself. The business case for EDC extends to both upstream and downstream activities. Specifically, the ability of an EDC system to meaningfully integrate across a number of disparate systems (semantic interoperability) is more an issue of how the technology will be implemented rather than what technology will be selected. The establishment of CDISC standards certainly helps facilitate this integration, but not all companies and products are equal with respect to standards adoption.

Other key implementation issues include: defining ownership of data across systems - who can change information and what is the audit process; the allocating sufficient time for training on how the technology supports the business process, as opposed to simply explaining the use of the particular tool; and decisive leadership to clearly communicate the future vision and outline concrete steps to achieve that vision.

AS. Although there have been concerns in the past with EDC, industry and sponsors have developed ways to overcome these challenges together and will continue to do so in the future.

NGP. Just how mature is EDC as a technology and does it cross over with other technologies?

WC. EDC technology is very mature at this point. RDE systems started appearing more than 10 years ago and have morphed into EDC. PDS is in its ninth year of business and has been used in pivotal trials for a number of submissions to regulatory agencies. The technology is ready.

As for crossing over with other technologies, a good EDC solution will work satisfactorily as a replacement for paper processes and a better way to clean the data. The best EDC solutions make it easy to reuse the information captured by EDC in other systems, and to use the tools within the EDC system to consolidate and clean data from other systems. Many PDS implementations integrate with IVR, clinical trial management systems, and grant payment systems.

A typical EDC/IVR integration offers a good example of some of the benefits. Sites don’t have to double enroll participants, reconciliation effort is reduced, drug supplies for the sites can be better managed, and IVR data can be used to pre-populate the eCRF within the EDC trial and allow real-time randomization data in the EDC system. You can also run trials better, with fewer errors and full visibility.

PB. The past 10 years have witnessed a rapid maturation of development platforms for web-based software in all categories, leading to sophisticated, powerful technologies being applied to business processes in many industries. Leading EDC technologies built on these platforms provide mature, feature-rich and stable solutions that can be (and are) relied upon for mission critical clinical trials. EDC trials are now frequently used in Phase III pivotal trials used to approve key pharmaceuticals, biotech products and medical devices. Although some still wonder about regulatory issues, the FDA and other regulatory authorities have been very supportive in their acceptance of EDC data from high quality, validated systems.

They are being integrated with other data capture technologies (ePRO, IVRS, etc.) and can be an important data and metadata source for clinical trial management and other business process systems.

ES. EDC vendors are generally not pioneering radical new technologies - rather they are adopting technology that has been widely used in other industries to the specific requirements of the pharmaceutical industry. Although these systems are relatively mature, there will always be some exciting new way to collect data. The real question is where these technologies overlap with other common systems in use by pharma. The most direct linkage is to technologies designed to electronically capture protocol content at the front end and to interpret/review the collected data at the back end. As these two areas of technology become more widely implemented, the benefits of EDC become much more evident. For example, the current version of the CDISC Study Data Tabulation Model (SDTM) standards, approved by the FDA for submitting clinical trial data, includes a very important group of datasets that extends from the protocol through to analysis and review processes.

AS. Maturing standardization efforts like CDISC, for example, will help to streamline the information flow between different technologies, reducing time and resources.

NGP. So does every trial need EDC?

WC. Yes, absolutely! The best EDC solutions are economically competitive with paper for any phase trial. This allows a sponsor to invest in a fundamental set of processes, in a minimum set of technologies necessary to support those processes, and in optimizing best practices for those processes for the entire product lifecycle. This includes Phase I through Phase III and IV, and even investigator initiated studies. With commitment and focus, sponsors get better results, faster, from all of them. If the news isn’t good, it won’t change an unpromising compound into a blockbuster, but it will save you time and money to find out sooner.

PB. EDC is useful in virtually every clinical trial. It’s value can be demonstrated in large, multi-national Phase IV trials with simple CRFs, in multi-site Phase II and III clinical trials, and even in standard Phase I clinical pharmacology trials. Does every trial NEED EDC? Probably not. But almost every trial can benefit from it.

AS. Depending on the scope of the project, EDC can be the ideal choice. Sponsors and suppliers together need to develop a common understanding of the expectations and need to determine the necessity of EDC. It is important to distinguish between the individual suppliers capabilities and experiences in order to determine the best fit. Again, not every trial must use EDC, but I believe every trial would benefit from it!

Need EDC? What should you ask a potential supplier?

WC. The key questions are maybe better posed as: ‘What is my plan to replace paper?’ and ‘How quickly can I make it happen?’ rather than ‘if’.

Supplier flexibility is critical from both a technical and service perspective. First make sure that the solution is flexible enough to use for most or all of your trials or you’ll be investing in duplicate systems and processes. A basic function of every EDC system is cleaning the data: look at the supplier’s tools for sophisticated edit checks and tools to ensure that manual effort is minimized and the end user isn’t handicapped when they’re turned on. Make sure that you have real-time access to the data whenever you need it and be wary of charges to get to your data – otherwise you may not realize all of the benefits I’ve mentioned elsewhere.

Finally, take a realistic look at your organization and make sure you have the skills and resources to execute. The best suppliers have the capability to help implement processes and methodologies for EDC, not just supply the software. An EDC vendor that can augment your organization or broker best-of-breed services and identify pre-existing relationships for use in your trial is critical.

PB. I’d suggest 10 key questions to ask about a technology vendor:

1. How many EDC trials have they done, in what therapeutic areas, and with what user experience?
2. What are their global capabilities?
3. How scalable is their solution and service capacity?
4. Are they focused on demonstrable, rigorous regulatory compliance?
5. Do they have flexible deployment options from turnkey ASP to ‘hands off’ enterprise deployments?
6. What is the breadth and depth of their EDC offering. Including scope of the solution, adaptability to mid-study changes and dynamic data, and online/offline options?
7. Do they have integrated solutions for managing, reporting, and analyzing safety data?
8. What is their financial status? Is the vendor profitable? Do they have sufficient cash and resources to outlast your clinical trial?
9. Does their solution provide robust, flexible, user-defined clinical trial operational data reporting?
10. Can they show successful, large-scale enterprise deployments?

Where now for EDC?

ES. To borrow from another industry, consider how substantially Auto-CAD revolutionized the time-sensitive design and engineering processes involved in complex manufacturing environments. Capturing design specifications upfront contributed to more informed product development decisions and led to higher quality as the computerized manufacturing systems were directly linked to the design information. Ultimately, new relationships emerged among previously unrelated tasks and many existing activities were substantially redesigned.

Taking an expanded view – beginning with the protocol and extending through data capture, analysis, review and submission – a CAD/CAM approach to clinical development will yield similarly transformational results. In five years we won’t be saying EDC, but rather ECD – Electronic Clinical Development – because so many more operational activities will be conducted in fundamentally different technology enabled ways. In this future state, standards-based interoperability will facilitate new possibilities for data-rich interactions and will ultimate yield more robust clinical results far more cost effectively and efficiently than is currently possible.

Prior to joining Phoenix Data Systems in 2001, William Claypool was responsible for global clinical drug development at SmithKlineBeecham, including clinical statistics and data management. He joined SmithKlineBeecham in 1991, Rising to Senior Vice President and Director of Worldwide Clinical Development and Medical Affairs in 1998. In this role, he established EDC as the preferred platform for data management and also managed more than 34 regulatory filings and supported nearly two dozen pharmaceutical product launches.

Paul Bleicher has more than 14 years of experience in the design, implementation and analysis of clinical trials from both the sponsor and clinical investigator perspective. In the pharmaceutical industry, Paul was a director, early phase services at PAREXEL International and subsequently joined Alpha-Beta Technology, Inc. where he served as vice president, clinical affairs. Paul founded and moderated the Internet-based Clinical Trials Mailing List, is the technology columnist for Applied Clinical Trials, and serves on the editorial board of Applied Clinical Trials and the Drug Information Journal.

Ed Seguine joined Fast Track as CEO in February 2005 after serving for two years as an active Board advisor and consultant to the company. Prior to his involvement with Fast Track, he worked several years at Eli Lilly, where he was instrumental in establishing both e.Lilly and Lilly Ventures. With over a decade of experience as both an investor and entrepreneur, Seguine’s operational focus has earned him a reputation as an effective implementer and keen strategist.

In his role at VIASYS Healthcare Inc., Achim Schuelke oversees all strategic planning, contract negotiation, and customization services requirements. He is an acting senior advisor for the design and development of the VIASYS Clinical Services Product Line. Schuelke has over 20 years of experience in design and development of medical databases, as well as a decade of experience in managing global, large scale respiratory and cardiology projects in clinical trials and disease management.