In any CRO, the choice of an EDC tool is a combination of meeting the CRO's needs and adapting to sponsor requests. There are many EDC products that sponsors prefer to use in trials. There are EDC products that CROs have acquired to promote as their own to broaden their capabilities. What it comes down to for PPD, one of the larger publicly traded CROs, is flexibility. 

"We work with large, diverse pharmaceutical, medical device, and biotechnology companies," explained Jim Streeter, executive director, EDC, for PPD. "Some have their own EDC preferences like Oracle Clinical (OC) RDC Onsite, Phase Forward's Inform, or Medidata's Rave, and PPD offers these solutions to ensure flexibility for our clients. 

While we have the capabilities and processes to work with any EDC vendor in the market, Oracle RDC Onsite is our preferred EDC system. It is hosted internally and used for a large portion of our EDC trials. When a client doesn't have an EDC preference, OC RDC Onsite is the system we use." 

To date, PPD has performed over 200 clinical trials using EDC, with over 125 using Oracle's RDC system. "PPD has used EDC in clinical trials for over six years and the Oracle RDC product for almost four years," said Streeter. 

Upgrading to Oracle's latest version—OC RDC Onsite 4.5.3—was a decision made easier by a number of factors: the look and feel of OC RDC and its Web-based interface; integrated discrepancy management; and performance and stability. PPD also uses the Siebel Clinical (now Oracle) CTMS system and Oracle's AERs. 

PPD looked at Oracle's future integration strategy and vision strategy to ensure that its current and future products are integrated. "This future integration of Oracle products was important to PPD," said Streeter. 

PPD was the first company to upgrade to the new version of OC RDC Onsite 4.5.3 and is now the largest user of it. It has deployed RDC Onsite 4.5.3 to over 8000 global users and over 30 active studies since last March. PPD is an Oracle Strategic Development Partner—one of four to take part in testing and beta testing the new version. 

"We were involved from the beginning in the development of the product, including requirements, design, and testing phases of the system development. In addition, some of our investigator sites were involved in usability testing, and they could look at the screens and offer input into the design," said Streeter. 

By being part of the beta testing, PPD knew what to expect and could plan activities and training for a successful roll out to PPD investigator sites and users. Thus, it was able to migrate investigators quickly to the upgraded system and provide on-line training with no interruption to protocol activities at investigator sites.  These sites were excited to upgrade to the new version and adapted to it very fast. 

For the PPD technology department, RDC Onsite 4.5.3 was a "true" Web-based system, and it (and PPD's sponsors) reaped the benefits of not having to install plug-ins, products, or other interfaces onto thousands of users' computer systems. In addition, there was a 30% drop in support calls and a reduction in time to resolve them, resulting in time savings for investigator sites and clinical research associates (CRAs) who call the support center. 

A key to PPD's use of Oracle's RDC Onsite is that electronic case report forms (eCRFs) can be set up to look and feel like paper CRFs. 

The new version includes features key to investigator sites. CRAs like special page views for recording adverse events in addition to key log pages and the ability to work on multiple eCRF pages. 

The change to the discrepancy management system provided a new eCRF integrated discrepancy feature, allowing investigator sites and CRAs side-by-side review of data and discrepancies, thus saving time. 

At PPD headquarters, the upgrade to OC RDC Onsite 4.5.3 was consistent with its overall strategy to make investigator sites successful with their clinical trial data acquisition and reporting by providing rapid data collection with an application that is intuitive and easy to use. This product also allowed PPD teams and its sponsors to integrate with other data sources (e.g., IVR and central labs) and provide needed reports for rapid review of progress and on-time reviews for safety and other business decisions. 

For the CRO, the results were equally satisfying. If time is money, which it is, then success speaks for itself. Using the new OC RDC Onsite system, PPD has been able to have data cleaned in real time for optimal interim trial decisions and to have it fully finalized within 10 days after the last subject visit. 

"Our sponsors and investigators have been very pleased with our approach and tools," said Streeter. The benefits of technology...realized. 

Articles

Case Study

Designing and adapting the latest technology to meet clinical trial needs and redeem the best of its multiple benefits.

The Benefits of EDC Realized

In today's technology focused world, paper-based administration is quickly becoming outdated. Despite the obvious benefits of adopting a paper free approach to data capture, the clinical trials industry continues to be apprehensive about using electronic methods. Patient reports can be the only way to reliably collect assessments pertaining to subjective information, such as the perception of pain and fatigue. It is essential that this data be captured accurately, using the most efficient instrument medium. 

 Rachael King is chief executive officer of CRF Inc.			

Approximately half of the 20-year patent protection period is spent on the drug development process. One of the largest cost and time commitments during this time is clinical trial testing and the associated data collection and reporting from the patients in the trial. On average, approximately $6 million to $11 million is spent on paper-based patient reported outcomes (PRO) capture. With regulatory costs and government levies on the rise, the industry may need to adopt a more streamlined and cost effective method of patient reporting. 

The industry is familiar with the three main methods used in clinical trials to collect the important information from patients as they progress through a trial. Interactive Voice Response (IVR), electronic PRO (ePRO), and paper-based instruments are the primary ways to capture patient reported data. Each method has its own advantages for the clinical study management team, but it is fair to argue that in terms of accuracy, compliance, and efficiency, ePRO is outperforming its main rival: the paper questionnaire. 

Last year CRF Inc. conducted a study into compliance rates when using ePRO methods. The results were unequivocal: patient compliance when using electronic diaries is more than three times that for paper-based trials. As we know, paper-based trials usually have a patient compliance rate of around 30%. Compare this to the ePRO rate of 89.5% and this alone makes the argument for using electronic capture extremely persuasive. 

So why is paper still proving more popular? The traditional argument against ePRO has been cost. Investing money into the purchase of eDiary devices from the outset can be off-putting for some. However, more and more clinical trials are moving to ePRO as sponsors begin to recognize the savings that come down the line through improved efficiency, speed, and accuracy of the data. In addition, the eDiary devices themselves can be reused for subsequent studies, lowering the effective cost of the hardware over time. 

Risk is a major factor for the clinical trial team when deciding on the medium to use for PRO instruments. The traditional reluctance in using electronic data capture (EDC) methods has been attributed to an estimate of risk, with doubt over the security and stability of using an electronic device to capture the patient data. However, the risks associated with paper are far greater, with the potential for loss, damage, and inaccuracies. 

ePRO reports can be sent to the study team in real time, removing the risk of losses in transit. All manner of accidents can happen, leading to the paper being damaged or even lost before ending up back in the hands of the study management team. ePRO also provides substantially more discretion and privacy for the patient; there is no possibility of a curious friend or relative inadvertently or intentionally browsing through a diary left lying out. 

The FDA's ALCOA (Attributable, Legible, Contemporaneous, Original, Accurate) criteria for patient data in labelling claims have helped to substantiate the argument for using ePRO, as patient data is far more accurate when collected electronically. 

The common issues raised when collecting data from paper-based instruments are that of legibility and human error when interpreting handwritten answers. The margin for error is heavily increased when the study management team must decipher someone else's writing, without also taking into account that they could be physically unwell, in pain or have a disability that affects their coordination. 

Spelling can also affect the accuracy of the data, as this can lead the team to make a possibly serious misinterpretation. With the administrative burden of typing up the handwritten responses removed, the clinical study team is free to spend this time on other aspects of the trial, such as monitoring patient safety or increasing enrollment. 

Data accuracy is called into question when patients are asked to recall complex and sensitive information retrospectively. When using a paper-based instrument, the onus is on the patient to effectively recall their details—no easy task when you consider that the paper questionnaires can be filled in some time after the symptom or pain has occurred.  

With an ePRO instrument, patients have the freedom to complete the information at the time they need to. The introduction of mobile devices means that patients now also have the flexibility to fill in their information from wherever they are, even when they're on the move. This allows the clinical team to get a real sense of the patient experience and as the patient data is captured in real time, allowing for more realistic and ultimately more accurate answers. 

Real-time access to data has even greater value for the clinical trial team. Clinical managers can get a snapshot view of their trial data, with instant visualizations of patient enrollment, compliance rates, and overall progress. When considering patient safety, this is invaluable, as potential issues can be spotted easily at any stage of the trial and the appropriate interventions can be instigated. 

This also means an end to the frustrating wait for paper-based instruments to be collected, data to be prepared for analysis, and inaccuracies and extra information to be resolved. The electronic capture allows for accurate date and time stamps on each response, something that is impossible with paper. This information ensures that the team can see their patients' responses and know that they adhere to the criteria needed for timely data collection. 

The design of the instrument on an electronic device puts the control back into the hands of the clinical trial team, as patients cannot add to their answers extraneous information. All too often a patient alters data when completing their paper instrument, adding what they feel is useful extra information, or even raising questions. These additional comments—however well intended—can actually result in a high query volume. 

The additional time spent recording and interpreting this data can be significant, further escalating costs down the line. Each query raised must be investigated and has the potential to affect the data that is issued. With an electronic capture method, the instrument can be formatted so that patients choose from a list of options, with no space to add extra and possibly confusing information. 

Clearly, the formatting and design of the electronic instrument requires time and planning at the start of the trial. Although initially this may seem to be a burden, a carefully planned electronic instrument will facilitate a smooth trial, with little administration needed at completion, as the data is captured, available, and ready to be analyzed. 

The best ePRO companies are experienced in working with the trial team during the design phase and make it a collaborative process. Trial managers need not worry that they will be left floundering with incomprehensible technology. 

The use of ePRO enables the team to design comprehensive patient questionnaires that are easy for a patient to complete. With technology infiltrating so many aspects of modern life, from mobile phones to the Internet, the world at large is much more familiar with handling and understanding electronic devices. Plus, images can be used to make the questions more accessible. Graphical and visual representations add to the instrument and also give the ability to incorporate examples of what information is needed. 

Touch screen functionality allows patients to easily enter their data in a more natural way, for example, by using the stylus or a finger to indicate on a body map where they feel pain. Navigating through an electronic questionnaire is logical, with a touch point at the end of every question, allowing patients to see just one question at a time, rather than feeling potentially overwhelmed by sheets of paper full of detail. 

Any changes that occur midstudy can be attended to when using EDC. If a change to an instrument question is needed as a result of an amendment to the study, electronic methods are better suited to cascading the updated information. 

One of the key issues when comparing electronic instruments to paper instruments is the measurement of validity. What variables affect the patient's response to the instrument? Do the amount and visibility of questions and answers, seen by the patient during data collection, have a psychological impact on the answers given? 

Many instrument authors tend to be in favor of a one question per screen approach to delivery, whilst others feel this changes the delivery of the instrument enough to affect validity. In some ways, the one question per screen approach may be superior: Many instruments assume independence between the answers given to individual questions, allowing for a more accurate assessment of inter-response correlation and variability. Easily allowing a patient to refer back to an earlier answer in the same instrument may call into question that assumption of independence. 

However, if a patient must scroll through several pages to see all of the answer options, they may not answer as they would when confronted with all options laid out on paper. To counter that, the ease of use and modern interface of an ePRO instrument may encourage a tired and ill patient to complete the questionnaire with more concentration, rather than feel overwhelmed by a long paper list. 

The user interface of an ePRO tool is an attractive feature of moving to electronic methods. The designs can be altered to make the input of data a more interesting and simple process, further encouraging patient compliance rates. 

An added benefit is that the ePRO devices are able to interface directly with other wireless devices. This is ideal when conducting a study that involves the capture of other physiological data, such as blood sugar levels. 

Seamless connection with devices such as spirometers and glucometers pave the way for more detailed studies, with less room for error when collecting information from a multitude of sources. It opens up opportunities for further technological advances, as the handheld devices can adapt quickly to software upgrades and new functionality. This will only increase in importance as the industry continues to migrate from paper to ePRO data collection. 

With all this information in mind, ePRO is emerging as not only a serious contender in the choice of capture methods but also as the way forward for the clinical trials industry. 

Although paper still seems to be the overall preference for clinical trial managers, it must be accepted that the world is embracing the digital age and that the clinical trial industry cannot afford to be the exception. Technology is no longer the sole reserve of the IT specialist. 

With every new generation becoming more and more used to technology in daily life, there will come a point in time when it is expected that an electronic device will be used. Mobile devices will be a familiar, everyday tool for patients, and this will only further increase compliance rates. 

So, how does the clinical trial manager choose which method to employ in their trial? The advice and guidance is available from the ePRO specialists. With a proven track record in improved accuracy and compliance, consultants can learn from previous trials and work in partnership with clinical study teams to design a robust and useful instrument. 

The benefits of using ePRO are numerous, with improved speed, efficiency, higher compliance rates, and greater accuracy. However, there is still a change in culture needed  among clinical study teams. This change will instigate the movement away from traditional and familiar paper-based instruments and toward ePRO technology. 

Viewpoint

Why ePRO edges out paper as the most reliable data source.

Embracing Electronic PRO

ACT Supplement Cover

While Electronic Data Capture (EDC) has been considered a technology of choice to run Phase II–III studies, the industry is now finding that EDC can be particularly effective for late-phase programs, improving the speed and even the quality of real-world postmarketing research. But just as late-phase programs are very different from Phase II–III clinical trials, the technologies to complete these studies are equally as different. 

A flexible technology is essential because postmarketing research typically is conducted in the general medical community with physicians who do not have trained site coordinators and because patients often need to answer questionnaires electronically (e.g., via electronic Patient Reported Outcomes or ePROs). Thus, it is important to have one solution that permits ultimate flexibility and ease of use by both prescribers and patients. 

Unlike clinical development sites, which are expected to adapt to the study requirements, sites involved in postapproval studies will only participate if the protocol meets their needs. In fact, the burden on site personnel can often be the biggest obstacle to recruitment and ongoing study follow-up, particularly if the protocol and data collection needs are perceived to be disruptive. These challenges are exacerbated by the fact that postapproval studies typically pay honoraria that are significantly lower than Phase II–III trials, and any perceived burden will cause investigators to decline to participate. 

A flexible EDC system that's purpose-built for postmarketing studies can address these concerns for three reasons: it's highly configurable; it includes effective communication and reporting tools to fit the needs and constraints of all study participants; and it can be customized to meet unique study needs. Specifically, EDC can facilitate postmarketing studies by supporting:  

An increase in the volume of patients at minimal cost, since today's EDC systems are considerably more cost-effective than older data collection methodologies

Streamlined enrollment, where sites are monitored in real time and participants can be stratified immediately

The capture of data from various sources (labs, physician assessments, and patient-reported outcomes) that can then be seamlessly and cost-effectively integrated

Better data quality, with less missing data and lower loss-to-follow-up rates, as well as enhanced regulatory compliance.

The following case study illustrates how EDC supported the rapid start up of a rescue study. United BioSource Corporation (UBC) was asked to replace a vendor in running a large FDA-mandated postapproval observational safety registry, taking over project management, IT, EDC, central monitoring, and data management activities. 

The primary reason cited for the move to UBC was that the previous vendor was unable to meet the requirements of the study. This was, in large part, because that vendor's EDC system was not flexible enough to allow the kind of tailoring required by the Sponsor. This resulted in below target enrollment and negative feedback from investigators who wanted a more simplified and streamlined look, feel, and function. 

Stepping into this role at the six-month mark following first subject enrollment, in a large study that anticipated a 24-month enrollment phase, UBC was asked to: 

 Develop a new EDC application, referred to as eRegistry, importing all data currently captured in the previous vendor's EDC—and complete this in three months

Handle all data management activities, including development of new data collection tools (eCRFs), mapping of data variables in SAS from the previous vendor's EDC to UBC's eRegistry, and all legacy data entry activities, and make this transition immediately

Launch a centralized Coordinating Center with dedicated points, one for subjects and one for sites, with a phased transition (participant line in two months and site line in three months) to coincide with the eRegistry release

Coordinate all transition activities and manage legal and regulatory aspects of the program takeover, from day one. 

The first steps, of course, involved defining expectations, outlining timelines, and maximizing the transfer of knowledge and study materials from the previous vendor.  To accomplish this, various meetings were held to enable teams to work in the compressed time frame. 

In addition, the UBC Coordinating Center began planning for the transition, including setting up designated telephone lines with the already established toll-free numbers, identifying dedicated program resources, and developing call schedules to cover the inflow of calls. The Coordinating Center became the primary resource for both investigator site and participant program communications. 

 At latest count, more than 37,000 subjects have been enrolled and it appears all enrollment targets will be met, albeit with a slightly expanded recruitment period (see Table 1). 

The sponsor's project director noted that the sponsor wrote the protocol without getting outside input. What he discovered was that detailed consideration must be given to every data element and how it is going to be collected in order to meet FDA requirements in the most straightforward manner possible. 

So the primary lesson learned was that the design phase of this kind of study is of critical importance to  effective utilization of EDC. Before selecting a method of data collection—and even before choosing a particular vendor—study objectives and data collection needs have to be clearly understood. 

In addition, the other vendor's EDC system (designed primarily for earlier phase clinical research) was insufficiently flexible to handle the flood of requests for study modifications—from site requests asking for changes in the flow of the CRF to sponsor requests for what seemed to them like minor changes in data ranges or field labels.  However, any change proved time consuming, costly, and ultimately too cumbersome. Moreover, it lacked the look and feel requested by the investigators. 

Further, the other system's business logic and edit-check engine were also designed for earlier phase clinical research. In postmarketing, with less experienced sites entering information, it is critical for the system to flag missing or incorrect information immediately, sometimes as the person clicks out of one field and moves to another. It is not adequate to wait until the entire form, or even the entire screen, is completed. This is even more critical when collecting data from subjects who will quickly lose interest or become frustrated and decide to drop out. Data validation must be immediate and user-friendly. 

As important, the previous vendor did not field-test the interface with the physicians and nurses. Field-testing the application with only six representative physician offices provided the sponsor and UBC with invaluable feedback that was used to extensively customize the EDC system. This fostered faster enrollment yet required limited time. 

Another benefit of this EDC system's flexibility was that we could deploy only the baseline questionnaire at go-live, then complete the system and add the follow-up questionnaires a few weeks later, providing significant time savings. 

We also relied on the system's flexibility to solve one of the most critical problems in a long-term follow-up study. The study requires an annual patient questionnaire over a 10 year period. As a result, we had to develop an easy-to-use login system and a powerful reminder system for patients. 

Finally, the system provides study-specific reports to the sponsor. As is typical with large postmarketing studies, there are multiple objectives unique to the therapeutic area and to the particular design questions. As such, standard EDC reports usually provided in clinical EDC systems prove of little value. For instance, 55 field CRAs are helping the sites with their enrollment activities. The CRAs have a dedicated portal that provides them with an environment where they can keep track of their site support and data review activities, while allowing the sponsor and CRO to track study progress on a real-time basis across the entire CRA team. 

In postapproval research—where fast results, design study flexibility, and branding opportunities are far more important than in earlier stage research, and where dedicated trained site coordinators are rare—electronic data capture can be the customizable technology of choice. Moreover, the ease of data entry, enhanced by hide/show and enable/disable logic, is translatable across global boundaries with systems that are completely internationalized and localized to embrace local languages and cultural preferences. ? 

 PhD, is senior vice president, strategy and market development, and 

 is general manager of safety, epidemiology, registries, and risk management at United BioSource Corporation, email: 

*To whom all correspondence should be addressed.

Vendor Study

Realizing the need for flexible technology when implementing EDC in late-phase research.

Supplements-03-02-2009

The Benefits of EDC Realized

Embracing Electronic PRO

ACT Supplement Cover

Adapt EDC for Postmarket