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Applied Clinical Trials
Work is needed if true efficiencies are to be gained in clinical trial performance.
1. Overcoming Obstacles to Successful Clinical Trials through Open Source
2. Ins and Outs of IRB Registration
3. Personalized Medicine Development
Ensuring the quality of a clinical trial in today's challenging drug development climate hinges on several important elements, perhaps none more crucial than the start-up phase, where much of the groundwork for a product development program is built. Achieving predictability in study start-up has become a critical goal within the clinical research timeline. Until recent years, activities associated with study start-up—which include site identification and feasibility, negotiations of contracts and budgets, planning for patient recruitment, managing/tracking regulatory documents, and drug accountability—were largely executed through numerous and often cumbersome manual processes. This would frequently lead to inefficiencies in study timelines and cost. Today, with the advancement of electronic, real-time document collection and data reporting systems, along with increased efforts by biopharmaceutical companies and their contract research organization (CRO) partners to align these technologies with specialized personnel in areas such as critical path project management (CPM) and resource centralization, strides have been made in streamlining study start-up and reducing trial initiation times.
Despite this progress, there remains a strong need for the industry to evolve start-up approaches to the next level. Pursuits in data collection and analysis must now focus on the underlying dimensions unique to an individual country or site being targeted for clinical research. This is particularly important amid the rapid globalization of drug development, where access to the right intelligence during study start-up is critical.
Intelligence has evolved to go beyond the typical site-level information. It is now captured at the country level, which allows for better feasibility outcomes. Intelligence also now incorporates the regulatory environment risks; the timelines for site contracting; and budget negotiation, as well as submissions, and even time to schedule critical path visits, such as pre-study and site initiation visits. In addition, site intelligence consists of enrollment capabilities and the site's ability to meet enrollment goals. As data integration of country and site performance improves, so will the selection of the best sites available to complete the project in the shortest timeframe. The increasing integration of investigator databases with companies' already proven processes should aid these efforts.
An additional consideration involved in gathering intelligence is understanding and gathering data around the more complex clinical trials and creating relationship models across the therapeutic areas. This will result in a higher level of data integration. Such integration, however, will be difficult to achieve if best practices in study start-up are not adequately implemented. To that end, sponsors and CROs must find innovative ways to operationalize start-up activities through technology.
While recent studies have reported improved trends, sponsors and CROs continue to experience significant challenges in meeting overall clinical trial timeline demands. According to Cutting Edge Information, 72% of studies run more than one month behind schedule. Such delays can impact the bottom line, with sponsors standing to lose between $600,000 and $8 million for each day that a trial delays a product's development and launch.1 Challenges in patient recruitment and retention are considered the major cause of drug development delays, but start-up activities are key factors as well, particularly issues around site contract and budget negotiations and approval. This may be a result of increased costs of clinical trials at the site, a more competitive environment, or the result of financial pressures on sponsors to keep investigator payments low. The Tufts Center for the Study of Drug Development finds that while the majority of clinical trials globally meet their patient enrollment goals, sponsors and CROs typically need to nearly double their original timelines to reach those targets. Nevertheless, Tufts reports that 89% of clinical studies meet enrollment expectations, with site activation rates reflecting success with study start-up in particular.2
Historically, the study start-up phase has been viewed as a labor intensive, costly, and time-consuming component of the clinical trial process. Today, sites must perform a number of specific activities related to documents, submissions, contracts, and visit schedules across multiple studies with multiple sponsors. These documents include site feasibility survey forms, protocols, investigator brochures, site contracts, budget worksheets, patient recruitment plans, informed consent forms, and advertising materials. Ensuring that the most recent versions of these documents are used can be challenging if there are multiple versions and amendments.3 Heavy paper-based processes have long burdened efforts in study start-up. For instance, Form 1572, which each investigator participating in a trial must complete,4 was identified as the single most redundant paper received by the U.S. Food and Drug Administration (FDA). Manually processing each 1572 could result in weeks of elapsed time per investigator. Devoting resources to the manual routing and tracking of these forms also frequently requires the use of valuable resources that could be allocated to other more critical tasks.
Several inefficiencies and limitations continue to threaten the data-collection process during study start-up. For many global trials, there is little standardization for what data is collected, and there are typically multiple places where the information is stored. There is significant need for sites to be able to provide and update their information to a single source rather than multiple sponsor and CRO databases, all with differing criteria. Also impeding efforts in this area is a lack of industry standards regarding the terms or milestones to measure.5 Though initiatives around integration have increased, sponsors largely feature standalone databases that typically do not feed information into vendor workflow systems, making it difficult for clinical teams to measure the data. Instead, CROs usually are required to mine the database and pull out information. This can present challenges because study start-up does not just focus on metrics around what sites have conducted a particular project and how many patients they enrolled, but also involves timelines related to regulatory activities and site contracting.
Another challenge for outsourcing providers, in particular during study start-up, is the management of resources in cases where there is no global source of information regarding a development program and the window from a request for proposal to award of a study to a CRO can be as short as one month. When assigning staff, CROs must be able to predict the number of personnel and resources that will be needed within each country to assist with language and cultural barriers, as well as how to distribute and utilize those resources as efficiently as possible. With start-up staff at these organizations routinely moving in and out of projects, CROs need the necessary visibility to plan across their overall resourcing strategy. It is crucial, therefore, that technology used in study start-up be built in to allow for more proactive and effective resource planning at the country level.
Similarly, better strategies are needed to reduce any project downtime often associated with study start-up. Sponsors and CROs have traditionally functionalized start-up activities, which inevitably creates inefficient "handoffs" between the various steps in the process. This can lead to gaps in time between activities that may range from hours to days, thus slowing down overall clinical trial timelines and potentially compromising study budgets. The use of technologies allow for the seamless sharing and visibility of documents and information in real-time throughout the world that streamlines any necessary handoffs. Technologies that use workflow management systems, alerts, document collection, version control, and reporting eliminate the number of handoffs, errors, and downtime along the start-up continuum, and produce critical efficiencies in CPM and workflow design.
In the United States, activities involving local institutional review boards (IRBs) have traditionally challenged efforts to simplify study start-up. Typically, in multicenter clinical trials a site can use a central IRB or a local IRB. Central IRBs review the protocol for multiple sites. Sites that are required to use a local IRB—usually academic and institutional centers—appear to have a less efficient review process and require more time to gain approval. Each site's local IRB conducts a full review of a multicenter protocol, and this process, repeated at each site, produces very similar outcomes that add significant delays to the start-up phase.
With multicenter studies becoming increasingly more common, some have questioned whether local IRB review actually enhances the goal of protecting patients. A recent study contends that multiple reviews and differences in informed consent forms may result in differences in the way patients are treated from site to site, with no ethical justification. The report notes that the FDA and other US agencies have encouraged the use of a central IRB to improve the efficiency of trials with multiple sites, though research institutions differ in their willingness to defer to centralized IRB review.6
Studies have shown that the use of a central IRB results in a site's approval an average of 27 days sooner than when using a local IRB.5 With more pressure being placed on shortening the timeframe to start studies, site selection is becoming more competitive. Sites utilizing local IRBs can be at a greater disadvantage in cases of competitive enrollment. Central IRB sites have more resources to achieve optimal quality and performance goals as well as ensure appropriate oversight to adhere to regulatory guidelines. There has been a large trend globally for the centralization of IRBs and ethics committees. This trend will also lead to better oversight from regulatory agencies and will increase consistency and protections for study participants.
There are several therapeutic areas that pose particular challenges during the clinical trial start-up phase. For instance, in oncology, with the emergence of molecular-targeted therapy, the complexity of study protocols has increased, allowing for the inclusion of patients with a wide range of tumor types that share a common genetic mutation.7 Including diverse cancer disease types with a shared genetic mutation can lead to additional challenges for study start-up and implementation.
Trials that target central nervous system disorders may present the greatest challenge to start-up efforts. Studies in this area typically feature very complex protocols, and are largely conducted in institutional environments that utilize local IRBs or ethics committees. With disease-modifying treatments desperately sought for cognitive impairments such as Alzheimer's disease and Parkinson's disease, research institutions that specialize in CNS disorders are highly tapped for clinical trials. However, whether state run or private, these institutions generally encounter numerous challenges when initiating a study, particularly around site contracting, specialized institutional review committees, and addressing ethics committee and regulatory requirements.
Amid the growing challenges in study start-up, strategies in this area are increasingly emphasizing workflow management as opposed to simply the tracking of data. This approach allows study teams to better manage key start-up steps through process improvement techniques such as CPM and Lean Six Sigma methodologies. The goal is to create global visibility and foster better communication and understanding around issues such as when sites are available for pre-study visits, for example, or when they are qualified after pre-study visits, and then being able to perform those project handoffs on a global and much more visible basis. Workflow management also enables greater focus on certain start-up activities that may be outside a sponsor's or CRO's specific functional areas. Drug shipment to sites, for example, will be easier to manage as workflow systems continue to evolve and predictability of site activation is enhanced. Staffing of clinical research associates can benefit from these approaches as well.
Companies today are building their databases to allow sponsors and CROs to see more clearly into the future based on past project experience. Using this information to evaluate new protocols and products according to their overall design and composition can help identify risks or trouble spots that may occur along the same path. However, simply basing projected timelines on general comparisons with past trials in the same phase and indication is not sufficient. Depending on the level of complexity, there are several aspects of study start-up that require in-depth evaluation to attain predictability in start-up. Protocol design evaluated against the regulatory environment, patient population, and standard of care allows for the identification of risks that can potentially be mitigated through better selection of countries and changes to submission documentation or approach with the regulatory agencies to gain advice in advance of submission. Investigational products, concomitant medications, supplies, and laboratory exports also need to be reviewed against the regulatory environment to ensure the ability to import and export needed clinical trial products, as well as samples for evaluations at centralized laboratories. It is critical, therefore, that study teams are able to enter multiple unique parameters of a new study into the intelligence databases upfront to create plans that increase the likelihood of predictability around timelines.
During the clinical trial, measuring against performance is key to ensuring baseline timelines and plans are managed appropriately and variability is understood. Study tracking of key deliverables should be performed against a baseline plan that establishes realistic end-to-end goals at the beginning of the project. If circumstances arise that change the timeline, then a projection should be created, however, the original plan should always remain as the baseline. Staying as close as possible to the baseline plan will ensure that the appropriate data is available when measuring predictability. If there is a delay that is inevitably part of the start-up process, this approach will allow for the gathering of information that will lead to a quicker mitigation strategy.
Activities related to site identification and feasibility can benefit significantly from improved data strategies. Identifying high performing investigators and sites is essential for research outcomes because the activity directly correlates with quicker patient enrollment, the attainment of overall enrollment goals, higher quality data, fewer queries, and better subject retention.8 Poor selection of trial sites, however, remains a problem in the industry and reportedly increases the cost of clinical trials by at least 2%. Poor site selection is largely attributed to the lack of knowledge of active and relevant clinical investigators. In addition, database-driven site selection is still a relatively new option for the industry, as many sponsors continue to rely heavily on their relationships with previously-used sites to find suitable investigators.9
Typically, when recruiting sites, sponsors and CROs first identify which regions the targeted patient population is more commonly located. Next, they determine whether the protocol is appropriate for those particular regions. Access to regulatory intelligence databases can help improve the success of these decisions by applying key information to country and site feasibility assessments. Those companies able to combine information around timelines and metrics data with robust regulatory intelligence will be able to establish a strong foundational knowledge when exploring geographies to conduct trials. That should, in turn, help expand and refine their network of qualified sites and investigators.
The practice of enrollment modeling can also help improve study start-up efficiency. This method allows study teams to estimate the time needed to recruit the required number of enrolled patients using a set number of sites. Enrollment modeling has application throughout a trial, providing a plan to measure enrollment progress as the study advances. Technology in this area enables study teams to view in parallel enrollment data and intelligence regarding specific protocols, countries, and sites from an end-to-end perspective. It is important that all systems built into a clinical development program feed into the specific enrollment modeling technology being used.
Global reporting systems and technologies in clinical development have advanced considerably over the past decade, largely shifting from the tedious exercise of compiling Excel spreadsheets to technologies that allow for more real-time data and reporting. Systems today, for example, enable queries from ethical committees and regulators to sites in various countries to be shared globally in real-time. The process of communicating with investigators is becoming increasingly digital, although site adoption of web-based tools for clinical document exchange remains slow. A global survey conducted by CenterWatch in 2011 found that 73% of sites were still using traditional methods of e-mail, fax, and courier as a primary tool for exchanging clinical trial documents.10 Nevertheless, the majority of investigators, even those in developing regions, have access to smartphones, tablets, and other mobile devices. This reality puts further onus on sponsors and CROs to consider sites' needs accordingly. That could mean making sure that investigator questionnaires, for instance, can be distributed electronically, completed on a handheld device, and signed with an electronic signature. Providing investigators routine, pre-populated documents that can be quickly completed via mobile would help speed up the overall start-up process. As technology improves, the clinical trial environment will need to keep up with the demands to manage start-up in order to remain competitive and reduce timelines.
Online clinical document exchange portals are being used to simplify the task of tracking study start-up activities for multiple sites. These portals can enhance visibility into the status of a site's progress through reports generated directly from the system. Streamlined communication with sites potentially allows sponsors and CROs to track and collaborate on operational data in a more transparent, regulatory-compliant, and user-friendly manner. In addition, smart workflow technologies make it easier for study teams to provide real-time status updates to management that it can use to find process bottlenecks and optimize resources. It is important to be mindful, however, that adoption of digital portal systems is not without challenge. For sites already overburdened with work from multiple sponsors with their own systems for start-up, there may be reluctance to learn a new technology. In addition, adopting a new system requires the creation of new SOPs and a commitment to additional staff training. For sponsors and CROs, there are issues to consider such as cost of the initial investment and the potential return on investment.3
Because study start-up activities are repetitive and consistent across all clinical trials, there is increased recognition that implementing technologies that deliver process efficiencies can generate valuable time and cost savings. This realization has led to more industry collaboration around leveraging such efficiencies. For example, in September 2012, 10 big pharma companies formed a nonprofit, called TransCelerate BioPharma Inc., which is developing shared industry solutions to simplify and accelerate drug development. The collaboration has launched five pre-competitive initiatives, including a program focused on speeding up study start-up timelines through the development of standard criteria for mutual recognition of good clinical practice (GCP) training and site qualification. The program is also exploring a standard process for information requests related to site qualification, including investigator CVs, profiles, and site-specific profile information. Another TransCelerate initiative involves a cross-industry investigator portal that offers a central point of access and single sign-on for investigators and site staff.11 Also recently, three biopharmaceutical companies formed a collaboration to launch a shared investigator database aimed at eliminating certain redundant procedures in study start-up. The database contains such information as infrastructure details, GCP training records, and site capabilities.12
Although notable advances have been made in the way study start-up activities are conducted, there remains much work to be done if true efficiencies are to be gained in clinical trial performance to increase predictability in site start-up. The emergence of new approaches to streamline burdensome and time-consuming start-up procedures offer promise, but with still uneven adoption of digital document management and integrated data systems, challenges in predicting start-up timelines and identifying potential holdups will continue. Therefore, the need for companies to compile intelligence and drill deeper into the evaluation of protocols and the regulatory environment when projecting site activation is crucial.
Carolann Schimanski is Executive Director, Global Site Start-up and Regulatory, e-mail: [email protected], at INC Research, 3201 Beechleaf Court, Suite 600, Raleigh, NC. and Marie Kieronski, is Associate Director, Site Start-Up & Regulatory, e-mail: [email protected], both at INC Research, 3201 Beechleaf Court, Suite 600, Raleigh, NC.
1. PR Newswire, "Clinical Trial Delays Cost Pharmaceutical Companies," (2004), http://www.prnewswire.com/news-releases/clinical-trial-delays-cost-pharmaceutical-companies-55044607.html.
2. Tufts Center for the Study of Drug Development, "New Research from Tufts [CSDD] Characterizes Effectiveness and Variability of Patient Recruitment and Retention Practices," (2013), http://csdd.tufts.edu/news/complete_story/pr_ir_jan-feb_2013.
3. IntraLinks, "Faster Study Start-Up and Reduced Costs Through the Use of Clinical Document Exchange Portals," (2009), http://www.intralinks.com/articles/wp_faster_study_startup.pdf.
4. FDA, "Frequently Asked Questions—Statement of Investigator (Form FDA 1572)," (2010), http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm214282.pdf.
5. A. Chasse, "Site Metrics for Study Start-Up: Clinical Trials Transformation Initiative," DIA 2012 presentation, (2012), https://www.ctti-clinicaltrials.org/steering-committee/contact-information/dia-2012-presentations/Chasse_Site%20Metrics%20for%20Study%20Start%20Up.pdf.
6. K. E. Flynn, et al., "Using Central IRBs for Multicenter Clinical Trials in the United States," PLoS ONE, 8 (1) e54999 (2013).
7. S. O. Joseph, J. Wu, and F. M. Muggia, "Targeted Therapy: Its Status and Promise in Selected Solid Tumors Part II," Oncology, 26 (11) 1021-1030, 1035 (2012).
8. V. Rajadhyaksha, "Conducting Feasibilities in Clinical Trials: An Investment to Ensure a Good Study," Perspect Clin Res., 1 (3) 106–109 (2010).
9. Manufacturing Chemist, "Poor Clinical Trial Site Choices Inflate Costs by 20%," (2011), http://www.manufacturingchemist.com/news/article_page/Poor_clinical_trial_site_choices_inflate_costs_by_20/58943.
10. Bio-IT World, "IntraLinks Survey Highlights Need for e-Clinical Document Exchange Tools," (2011), http://www.bio-itworld.com/news/06/14/2011/IntraLinks-survey-need-clinical-document-exchange.html.
11. TransCelerate BioPharma Inc., "TransCelerate Initiatives," (2013), http://transceleratebiopharmainc.com/?4a17eb50
12. D. Beasley, "J&J, Lilly, Merck Plan Clinical Trial Site Database," Reuters, (2012), http://www.reuters.com/article/2012/11/15/us-pharmaceuticals-trials-idUSBRE8AE0XS20121115.