In today's cost-conscious environment, healthcare providers and payers are increasingly demanding that novel products demonstrate an ability to reduce treatment costs, improve medical outcomes, or provide some other tangible benefit over existing therapies if they are to be placed on formularies, approved for reimbursement, and added to therapeutic guidelines. To attain optimal market success, new therapies must be supported by data-driven evidence that demonstrates greater value than the currently accepted standard therapy, a concept that encompasses safety, cost, convenience, treatment outcomes, and quality of life, as well as meeting regulatory requirements for efficacy.
To meet the growing requirements for data from evidence-based health outcomes research, biopharma companies need information about their products that is not available from most Phase III trials. This data can be gathered from a variety of studies, including peri- and post-approval (Phase IIIb and IV) clinical trials, patient registries and retrospective/prospective observational studies using administrative or electronic health records.
These later-phase studies present challenges beyond those experienced by researchers conducting Phase I-III trials. The most significant challenge is the need for data from a substantially larger numbers of patients and sites than is typical for a Phase III trial in order to detect safety signals that do not occur at lower frequencies. While a Phase III trial might include as few as 1,500 patients and less than 100 sites, a late-phase comparative study could encompass 50,000 or more patients at thousands of sites. In addition, late-phase or registry studies looking at patient outcomes can run for five years or more, compared with 12-18 months for typical Phase III trials.
Another major challenge is the fact that late-phase studies may need to collect data from a range of patients who are representative of those who take the product. To gather that data, the studies may need to include a larger and more diverse range of physicians, including practicing physicians who may have little or no prior experience with clinical research or the protocols of gathering and reporting clinical data. If a study calls for the recruitment of patients in multiple countries around the world - a common requirement in today's global marketplace - sponsors face additional challenges involving language and regulatory differences that can impact both investigators and patients.
Given the size and scope of most late-phase studies, greater efficiency in logistics, recruitment, site operations and information processing is absolutely essential to control costs and handle the huge volume of data. Leveraging eClinical technologies such as Electronic Data Capture (EDC), Clinical Trial Management Systems (CTMS), and Interactive Voice and Web Response Systems (IVRS/IWRS) is essential to improve efficiency, reduce costs and maintain data quality in large late-phase studies. Newer technologies such as web-based physician/site recruitment platforms and data mining from electronic health records have the potential to bring additional benefits that can further enhance the gathering of "real world" patient data to support evidence-based medicine. The key for biopharma companies is to select the right combination of technologies that can handle the required data volumes while also accommodating the unique characteristics of late-phase studies.
Selecting the Right Technology
Any technology tool in the clinical enterprise must support and enhance the key business and research needs of the trial process, as well as meet the specific technological requirements of late-phase studies. Primary business needs that can be addressed by clinical technology include effective site management, enhanced patient recruitment, enrollment, and retention, improved clinical data gathering and reporting, and greater efficiency in the management of logistics and trial supplies. Technology can also enable and enhance important research processes, such as improving regulatory compliance, streamlining the trial process, increasing data quality and reducing data entry redundancies. The need to improve data integration across the clinical enterprise is another important consideration when evaluating clinical technology solutions.
The key for trial sponsors is to select technology solutions that provide the right combination of productivity, cost-efficiency and flexibility that is essential for these larger studies. Some of the essential characteristics for late-stage study technologies would include:
-Ability to handle large numbers of sites and patients
-Support for multiple regional requirements, including local languages
-A simple user interface that provides a positive experience for research-na�ve physicians
-Fast start-up and cost-effective implementation across numerous sites and countries
-Flexibility to accommodate change over a potentially lengthy study, such as amendments to protocols, study adaptations and software upgrades
-Capacity to handle multiple/hybrid data entry methods - such as a combination of electronic and paper CRFs - with the ability to easily customize the technology to match different site needs and capabilities
-Robust remote site/study monitoring tools
-Support for data sharing among site physicians, where appropriate
-Strong, 24/7 technical support network and easily accessible on-line training and documentation
Each major category of eClinical technology - EDC, CTMS, and IVRS/IWRS - offers important benefits for late-phase studies.
EDC
An EDC system is essential for capturing the large amounts of data generated by large, multi-site, late-stage trials. EDC systems also play a vital role in monitoring site performance and ensuring that trial data entry is complete and timely. While most clinicians participating in early-phase trials are familiar with EDC systems, many of the physicians involved in late-phase studies do not have the same technology experience. For EDC to work effectively in late-phase studies, it must be able to accommodate the specific needs of these sites and physicians, including:
-A simple electronic CRF design, with minimal edit checks to facilitate fast processing, and ease of use for sites
-An automated process for selecting the right CRF for each patient visit
-Dynamic calendar features for building patient-specific schedules and reminders
-Support for both paper and electronic CRFs, with easy switching between the two
-Flexibility to handle unscheduled visits
-Simple query and query-resolution processes
-Easy-to-use online help and instruction system
-Robust user support, in multiple languages, 24 hours a day
CTMS
A CTMS serves as the logistical backbone of a clinical trial by supporting a wide variety of administrative, planning, monitoring and financial processes that are critical for the efficient operation of large, late-stage studies. With the right CTMS, a sponsor has the tools and data access to track trial progress, manage to study milestones, decrease administrative costs, and improve regulatory compliance. The benefits of a robust CTMS include:
-Site inventory management
-Detailed trial progress tracking
-Effective trial management through a central database
-Alerts for missed milestones, and tools for recovery management to keep trials on schedule
-Planning and tracking of clinical and other supplies
-Uniform enforcement of quality standards across sites
-Effective workflow and tracking of associated documentation
-Regulatory compliance tracking
-Support for web-based tools, such as study portals.
IVRS/IWRS
After study sites are initiated, an IVRS/IWRS can manage many of the data requirements for investigator sites and passes trial information to other systems such as CTMS and EDC throughout the study to support efficient trial management. Key IVRS/IWRS functions include:
-Patient enrollment and randomization
-Collection of patient data
-Patient retention support (such as automated reminders for compliance and appointments)
-Real-time study metrics and reporting
-Management of clinical supplies
-Drug supply forecasting, distribution and management
With the global scope and large number of research-na�ve physicians involved in late-phase studies, it is no surprise that the telephone remains the most common IVRS technology. However, the telephone clearly has severe limitations as a data-entry tool. Given the data entry requirements of a large, late-phase study, sponsors are increasingly selecting study sites based on their ability to utilize more advanced technology, such as IWRS, to perform these functions.
The Importance of Data Integration
One of the biggest challenges of leveraging technology for late-phase studies is the need for interchangeability and integration of data between the CTMS, IVRS, EDC and other technologies being used in the studies. Data integration is vital for late-phase studies because of the volume of data generated. This integrated data allows sponsors to more closely monitor site progress, improve trial analysis and make better-informed decisions across the suite of tools and sources of information. It also provides a more comprehensive overview of trial results that can be critical for understanding drug safety and avoiding undue risk for patients.
From a data-handling perspective, integration reduces redundancies and improves consistent data quality through less human interaction. Even if the systems themselves cannot be fully integrated, the implementation of a centralized data warehouse or a clinical technology integration platform (CTIP) that aggregates selected data from each system and facilitates communications between the technologies can deliver important benefits that improve the efficiency and quality of late-phase trials.
Whatever integration approach is used, the nature and size of most late-phase studies make it imperative that the selected solution can be implemented quickly and efficiently, within a relatively short period of time to avoid trial delays.
Web-Based Technology Improves Recruitment and Study Start-Up
One recent development that is significantly improving the efficiency of late-stage trial start-ups is the use of self-guided web-based platforms to recruit and register physicians who want to participate in these trials. Targeted e-mails and other promotional tools are used to direct prospective physicians to a customized website, where they can learn more about a specific study and its requirements. If they are interested in participating, an intelligent user interface guides them through the entire process of determining eligibility and registering for a study. The prospect can choose a preferred language, and all subsequent web pages and documents are shown in that language. Equally important, the prospect's location determines the specific documents (such as regulatory forms) and training requirements (such as GCP certification) that are required for participants in that country.
Throughout the registration process, the web platform automatically takes the physician through the correct workflow and monitors the prospect's progress by tracking the steps that are completed or pending. After prospects are approved and registered, they have access to complete study information through the web platform. They also become part of the "community" of sites registered for the study, allowing them to share information, insights and best practices during the study via the website.
This automated, self-guided approach to site registration is particularly valuable for large post-marketing studies, where thousands of sites must be screened. Such a web-based platform helps filter and pre-qualify sites and significantly speeds up the activation process for those who qualify. It also improves the quality of the business processes by ensuring that all of the required documents are filled out in the proper order and are accessible electronically.
A web platform also makes it much easier for investigators to find out about and become involved in clinical trials. The self-service nature of the web platform - in conjunction with its language- and country-specific flexibility - encourages participation by physicians new to clinical trials and bolsters participation by simplifying the entire enrollment process. This is particularly important for late-phase trials designed to gather data from real patients in a variety of community settings to support evidence-driven health outcomes research. Site satisfaction and interest are also maintained by simplified access to all systems, on-going web-based communications, and support for the study community.
Sponsors and CROs also derive significant benefits from this approach. Greater efficiency in the site enrollment process can substantially reduce start-up times and costs. Simply eliminating the use of conventional mail to exchange documents with potential sites around the world could shave several weeks off site activation times. The automated monitoring of document completion and site progress through the registration process also increases business process efficiency and quality, while also allowing sponsors to monitor and support sites that have not completed required training or documentation. The tracking of responses and successful registrations - as well as the participation of targeted thought leaders - is valuable for refining future recruitment efforts and fine-tuning features of the web platform.
Leveraging Electronic Health Data
Another emerging application of technology in late-phase trials is the use of existing electronic health records (EHR) - including prescription data and electronic medical records (EMR) - as a source of real-world clinical data about how physicians and patients are using marketed products, as well as information on health outcomes and safety. The ability to extract health data from computerized medical records has the potential to substantially reduce the time and cost of collecting certain types of post-marketing clinical data, and is already technically feasible. The widespread use of data from EHR for clinical research awaits only the resolution of critical - but solvable - issues such as what data will be available, how the data will be accessed via common standards, and how patient privacy will be protected.
EHR adoption is rising steadily around the world. The Nordic countries have long been leaders in the adoption of EHR, and the UK has enrolled more than 1.2 million patients in its Summary of Care EHR system, with the goal of capturing 50 million records in total. In the U.S. the HITECH Act - part of the 2009 ARRA Stimulus Package - mandates incentive payments to organizations that invest in EHR systems, and also imposes penalties via the Medicare reimbursement system for those who do not take up "meaningful use of certified EHRs" by 2015. Consolidation of private practices and major healthcare providers in the U.S. - combined with linking of EHR systems via Health Information Exchanges and other organizations - means that health data is theoretically accessible on a much wider basis. It is this inter-connectedness that makes EHR system data so useful for healthcare providers, insurers and biopharma companies.
The use of EHR for clinical research offers a number of intriguing possibilities for reducing the cost of clinical studies:
Feasibility testing and patient targeting - The purpose of using of EHR for study feasibility would be to test a potential study protocol against a database of patients with the targeted indication in specific geographies to determine the likelihood of recruiting the desired number of patients for the study. This would allow a sponsor or CRO to run "what if?" scenarios to test assumptions and refine the protocol enrollment criteria. The use of EHR data to test the incidence of patients that meet the protocol requirements would support the development of protocols that are aligned with real-world disease patterns and standards of care, allowing sponsors to avoid unnecessary costs and delays by maximizing the chances of recruiting success.
Investigator and patient recruitment - Once a study protocol is established, EHR data could be queried to search for investigator sites that meet the required criteria (e.g. geographic location, number of patients that meet the studycriteria). Sites meeting the criteria would be flagged as potential participants and contacted about their interest in participating. It might also be possible to use the EHR system to automate the contact process and direct interested physicians to a source of additional information (such as the webplatform discussed above). This approach has the potentialto substantially improve recruitment success and speed-up trial initiation.
Observational studies - In addition to the use of EHRsystems for long-term prospective observational studies, access to EHR records could be used to perform retrospective observational studies, testing the validity of hypothesesrelated to patient medication and treatment patterns against EHR data.
Pharmacovigilance and risk mitigation studies - With increasing regulatory requirements for long-term safety monitoring of marketed products, EHR databases could provide a highly efficient way to gather vital safety information about product usage in real-world settings without the cost of a long-term post-marketing clinical study. With appropriate statistical methods and a large enough patient database, it might also be possible to detect safety signals more quickly. The EHR systems could also potentially be used to efficiently notify patients, if necessary.
Health outcomes studies - EHR systems could be an important source of evidence-based treatment data being demanded by healthcare providers and payers to demonstrate product value.
Centralizing data entry to the clinical database can be achieved when EDC vendors provide Request Form Data (RFD) capabilities. This enables data to be electronically retrieved from an EHR system and entered into CRF pages for a study. Because EHR data is not always comprehensive, and may not include the exact data elements required for a specific clinical study, RFD would enable partially automated data collection through a standards-based interface.
Although the use EHR data offers tremendous possibilities for late-phase trials, there are issues that must be addressed before sponsors can take full advantage of that potential. It is vital that sponsors participate in the debate surrounding EHR data and invest in resources to help them understand the issues and impact the outcome.
Meeting the Late-PhaseTechnology Challenge
With the growing importance and size of late-phase studies, greater use of eClinical technology is essential to increase the efficiency of data gathering and reduce trial costs. The biggest challenge for sponsors is to understand the differences in the physicians, sites, and patients involved in these studies, and select technologies that balance ease of use, cost considerations and efficiency.
Choosing the right technology path for late-phase studies can also be a challenge. A wide array of solutions is available, and eClinical technology continues to evolve rapidly. The requirements for evidence-based data are also constantly changing. The key to making the best decision is to select experienced partners with the right combination ofclinical and technological expertise with a proven abilityto deliver the greatest benefits for the unique requirementsof large, late-phase trials. A partner with the ability to integrate various technologies to maximize effectiveness isalso critical.
Despite the difficulties and challenges of the current environment, biopharmaceutical companies have no choice but to keep moving forward and invest in technologies that will help them improve their late-stage trial performance and reduce their costs if they are to meet the growing global demands for late-phase study data.
Kate Trainor is vice president, PACE Operations at PAREXEL International, she can be reached at kate.trainor@parexel.com.