Electronic Data Capture in Clinical Trials
Does the emerging world still lag behind in EDC adoption?
In early 1990s, the clinical research industry was more dependent upon paper-based systems for collection of patient data, leading to increased cost and time for trial completion. With the growth of the clinical research industry and its extension into emerging countries, many clinical research organizations (CROs) are approaching global electronic data capture (EDC) in an effort to improve the competence and accuracy of patient data collection methods. Although there are several advantages to move on to a paperless system, there are several key factors that impede the success of EDC systems. Many organizations are still at the early development stage and real tangible benefits have yet to be realized with eClinical systems.
The pharmaceutical industry is at an important crossroads in medical innovation,1 and the competitive pressures of today's marketplace are forcing the industry to seek ways of reducing drug development times and increasing productivity. Setting up the businesses in emerging countries like India and China and curbing the clinical trial lifecycle by collecting quality data more quickly and accelerating the processing of available data are just a few solutions. This has led to the growth of EDC, which has its origins in software called Remote Data Entry (RDE) that surfaced in the life sciences market in the late 1980s and early 1990s.
Today nearly half of all new clinical trials are initiated using EDC. Industry analysis predicts that investments in EDC solutions will increase at a 14.7% compound annual growth rate and total more than $3.1 billion.2 Similarly, the integration of EDC software with other types of software in the eClinical spectrum (randomization, supply management, adverse event reporting, coding, submissions, etc.) systems is increasingly feasible and could prove beneficial.
However, the use of EDC systems for clinical trials in developing regions has been affected by a number of practical, technical, and technological issues, which are not limited to the natural workflow of healthcare professionals, costing, limited IT infrastructure, inadequate training, language barriers, etc. Interim reports from a recent survey conducted by the eClinical Forum show that the use of paper case report forms (CRFs) is rising even as EDC adoption is increasing.3 Thus, drug developers must seize the opportunities and use advanced tools to find more efficient and scalable ways to use EDC systems in emergent markets.
Natural workflow of healthcare professionals
Although technology is in the forefront of drug development, many doctors working in rising countries prefer things the old-fashioned way. For example, Indian clinicians find that EDC is impractical, often hindering their work because they are used to keeping notes on paper. Similarly, many healthcare professionals follow the practice of capturing study data by hand while in front of a patient. Such aversion to keyboard-based entry during patient contact is a common practice, not just in emerging regions. In one survey, almost 60% of healthcare professionals said they thought it was never appropriate to enter data into an EDC system in front of a patient, and 17% said it was appropriate only in rare circumstances. The ClinPage report mentioned above also noted that, in 2001 and in 2009 when the survey was conducted, 16% and 26% of respondents respectively said study data was initially entered from a paper CRF into an EDC system. Such type of workflow affects the EDC systems naturally, which may not have the trial data until 48 hours to a week—or longer—after it is written down or collected in some other system, despite contractual obligations to provide the data entry within shorter time windows.
For the reticent then, it appears there is a need to accommodate the pen-on-paper-based workflow and integrate it with the data repository and management function of an EDC. In recent years several technologies have been developed that could serve as a good complement for EDC systems. These are point-of-contact data collection systems using devices such as the digital pen, tablet PCs, and more. These devices allow the user to input data using a natural pen-based workflow.
Cost a major concern
Although the implementation of an EDC system looks to be an upward path for the foreseeable future of trials in emerging regions, much of the nature and intent of the activity is changing below the surface. Use of EDC for trials in such regions is a relatively new concept and has created the need to develop the system, training, time spent on problem resolution, etc., which has naturally increased cost. These functional difficulties that increase the expenditure are highlighted in Table 1. However, companies have reported that EDC has actually increased costs in some regions. Although the majority of western companies conducting trials in China use EDC, most Chinese companies do not. One of the main reasons for this is the cost of adopting EDC technology versus the low cost of Chinese labor.4 Companies that believe EDC implementation in developing countries saves money may use EDC for all in-house managed trials. In addition, without suitable incentives and technology, there is the likelihood that investigative sites won't transfer data from paper records days or even weeks after the patient visit—thereby negating many of the potential benefits of EDC and adding more cost.
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Although the cost savings for paper-based systems versus EDC has been well known, there is the parallel problem that paper-based methods are well-established in poor countries, and that these costs are no longer examined. However, to know the actual cost of any project, the real-time comparison of cost required for EDC and paper-based system is necessary.
Lack of technological infrastructure
Participation in global clinical trials requires an updated infrastructure and facilities.5 The lack of quality and IT infrastructure support for EDC is another area of concern for a number of countries. For example, between 10% and 14% of trial sites in China require computers be supplied compared to 1% and 2% of sites in the United States.6 The majority of trials in the West that use EDC rely heavily on Internet access—something that is not always available in India and other under-developed countries, particularly in remote areas. For instance, Internet access in Asia and Africa is less widespread than in the West (Figure 1). Another concern for companies is whether or not the EDC they choose will integrate with other eClinical products they are using such as clinical trial management systems, interactive voice or web response and electronic patient reported outcomes solutions. And while the CDISC data interchange makes interoperability between vendors products easier, most people in India use Excel spreadsheets or CSV files for the import of external data. Furthermore, affordability to build complex web-based solutions and consistency of Internet services in different regions are some of the major hurdles for use of EDC in India and other similar countries.
Training
As EDC is comparatively new to the clinical trial industry in emergent regions, healthcare professionals are not very well acquainted with it, and people may require appropriate training in operating the software. But, the emerging countries lack the number of available trainers for this purpose and those available are IT experts having limited knowledge about trial-specific medical parameters, which creates delays in operational activities.
Training to ensure an acceptable level of self-sufficiency is essential for an EDC trial. Training, either standard or custom, must be scheduled at convenient locations and conducted in the local language to ensure that all trial staff understand the application and are comfortable in the use of the technology. If the design of the trial necessitates a unique skill, custom courseware should be developed for that specific functionality.
Study site issues
Although, many global sponsors generally prefer to use EDC for data capturing in nascent countries, local study site issues can affect it. For example, many local sponsors and investigators in India are not ready to use EDC for trials; for them it is more complex.7 They often complain about some systems being too slow to use, unsuitable for use in a busy clinic environment, impossible to use to capture data with a patient in front of them, additional workload, and overall data-entry burden. Like other investigative sites, emerging countries generally have common site staff to handle different trials from different sponsors, with unique software packages for each.
Clinical trials in emerging regions span the healthcare delivery system from local or regional hospitals, to rural care. While working in rural areas, study sites usually suffer from multiple problems such as slow speed of Internet connection, non-availability of dial-up, difficulties in using LAN connection to access EDC websites and existing portability issues that affects data entry directly into the EDC.
Wireless EDC systems have been extremely successful, with the technology showing much promise for running clinical trials in developing countries and areas that lack reliable Internet access. The best way to use fixed telephone lines and cellular phone networks to solve the problem, but the issue of EDC connectivity in regard to reliability remains.
Language and cultural barriers
Extension of clinical trials in emerging countries has been affected by language and cultural disparities such as lack of unifying translation standards, significant structural differences between languages, and vast linguistic and cultural differences among patients. Culture has a significant impact on the behavior and perception of individuals not only in each country, but also within a specific community. Thus a clear understanding of any cultural aspects that can interfere with the patient's or investigative site staff's comprehension is necessary. A clinical study conducted in various states of India may require knowing several communities including Hindi, Punjabi, Marathi, Malayalam, Telugu, Kannada, and Gujarati. To date, the majority of EDC systems are English-based and many languages into which materials must be translated are quite unrelated to English. As a result, identifying language equivalents can be particularly challenging. Chinese uses characters rather than letters and is composed of two separate character sets. Unlike English, a single character typically represents multiple grammatical forms (for example treat, treating, and treatment). Thus, a sentence constructed in Chinese may be considerably different from the English one. Another example is that abbreviations do not exist in Chinese, and thus each word must be translated first into Chinese and then abbreviated.6
Implementation of technical support in any given language and translation of user manuals, web-based interfaces, and automated materials for the collection of patient data, patient questionnaires, and patient diaries into required native languages can overcome the language barriers. Similarly, patient-generated or reported data requires a clear understanding of any cultural aspects that can interfere with patient comprehension. However, familiarity with the specific factors that affect the transmission of correct information, patient comprehension, and the accuracy of patient data is also essential. Thus it becomes very important to enlist the help of individuals who can make the difference and act as "cultural experts."8
Regulatory issues
Regulatory authorities in evolving countries need more comprehensive understanding of EDC and may require more time and support resources. For example, today India is considered a hub for clinical research and IT solutions, still the regulatory authority (DCGI) heavily relies on paper-based data. This may be because verification of data is necessary to confirm the participation of subjects and to detect omissions, transcription errors, alterations in data, or falsification of data, and when paper documents are available it can be performed easily.
Regulatory authorities need to be more updated to match with the existing technologies and international standards and develop a common approach for eSource documentation. FDA has set standards for electronic records (21 CFR Part 11) and also have prepared draft guidance for industry on capturing, using, and archiving eSource data in FDA-regulated clinical investigations in December 2010. Other regulators should take such initiative for successful adaptation of EDC in trials.
Privacy and data protection
Privacy and data protection is a worldwide issue for any type of electronic data and at times it can be difficult to maintain it while using an EDC system. Identification of trial patients can be possible from, for example, facial characteristics identified in a computed tomography scan.9 Similarly, the increasing affordability of genomic information, and its consequent incorporation into clinical trials, adds to the difficulty of ensuring privacy; it has been estimated that it may be possible to identify an individual from no more than 75 to 100 single-nucleotide polymorphisms.9 Although, Western companies have strong security systems for data protection, this issue still exists for them. Privacy and data protection requires strong laws, and India has recently passed the cyber crime law for protection from Internet hacking.
CRO perspective
Many CROs focusing on data management tools have business models in developing countries based on paper-based structure. Likewise, set-up of clinical trials, protocol writing, trial planning, design of case report forms, monitoring, etc., are reliant on the paper model. However, to address the challenges of the eClinical environment in these countries, CROs need to become eCROs, where technology drives process efficiencies.
In the current emerging market, very few CROs have an interactive voice response system and an interactive web response system in place for record tracking,7 and in-house EDC system design and development experts. They rely on other vendors for EDC technology; furthermore not all vendors provide end-to-end services to support drug development, and others will not provide services like clinical data management, medical coding, etc. They are contingent on the client to take responsibility for these areas, either themselves or through a CRO. Translation services are cumbersome and lack the comfort level associated with support needs to be available in the site's local time zone—having the help desk agent communicate with the clinician in his or her native language, both to secure the details of the incident as well as communicate the solution is ideal.10 In short, CROs are dependent on the service provider for EDC software, and larger CROs can have relationships with several vendors depending upon the study and requirement of the sponsor.
Identifying and categorizing potential solution providers, involving the right players, learning from experiences, narrowing the playing field, evaluating candidate solutions in a real-world setting, and ultimately selecting the right partner to meet the company's needs may help for proper vendor selection but "one-size-fits-all" could be a key solution for better vendor management.
Real-world EDC verity
Everyone in contact with the EDC system has different needs, which raises the concerns and reduces the usability of an EDC system (Table 2). On the other hand, the number of data sources including standard laboratory data (hematology, biochemistry, and safety data), specialist laboratory data (biomarkers), echocardiogram (ECG) data, images from various types of medical scanning (computed tomography (CT) scans), positron emission tomography (PET) scans, etc., has dramatically increased in the last few years and are used along with CRFs. Acquiring, storing, transmitting, merging, validating, and checking all the associated data and metadata from these sources often reduces speed, requires more diverse systems, and causes quality issues.
Conclusion
The promise of increased efficiencies stemming from EDC has existed for years. However, use of EDC as a standard clinical trial tool in emerging countries is slower than expected; the prerequisite for this is the limited adoption of EDC with very little technological and technical support to adapt to future trends. With EDC, technology is not the solution, but the enabler. In order for any technology to be effective, it cannot be implemented without consideration of the context in which it will be used, the processes it will be used alongside, and the results required.
These deliberations include nationwide initiatives for implementation of health information structures; strict adherence to standards for data interoperability; software solutions based on open and public standards not on proprietary technology; changes in the attitudes of doctors and patients; intensive training to site before implementation of such a system; and better cooperation between patient, physician, investigator, and other trial participants, etc. Eventually it has to be ensured that regulatory requirements are thoroughly considered and met before using EDC systems. An upfront detailed definition of requirements and their continuous follow up may avoid complications. The procedure of recording of source data in e-trials has to be defined for each site up front. Similarly, placing excellent service delivery at the heart of all innovation will ensure that any introduction of new technology will deliver value to the industry. Then emerging countries will also welcome the EDC and can undeniably articulate that the time to move to the EDC system for clinical trials has come.
Editor's note: All opinions expressed herewith are those of the authors and do not reflect the views of their organization.
Sunil Shewale, B.Pharm, PGDCTM, MBA, is a Clinical Research Associate, e-mail: [email protected], and Sameer Parekh, BHMS, MBA, CCRP, is Manager Clinical Trials, e-mail: .
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