The Monitor – Association of Clinical Research Professionals
September, 2010 - As target recruitment timelines continue to tighten, a pandemic of missed enrollment deadlines is delaying the availability of new pharmaceutical and medical products to patients with virtually every health condition. Enrollment rates in the U.S. have dipped significantly within the past decade—from 75% to 59% of target goals, with retention rates slipping from 69% to 48%. According to a 2009 CenterWatch survey of U.S. investigative sites, studies enrolled according to schedule only 10% of the time; 22% experienced delays of up to a month, and 68% experienced even longer delays. The situation is somewhat better outside the U.S., although not by much; studies in other regions of the world enrolled according to schedule only 14–17% of the time.
Given the statistics, careful analysis and reflection should be important precursors to a contract research organization’s (CRO’s) committing itself to enrollment deadlines, especially for studies with accelerated timelines.
As described in this article, a recent Phase II study of a new universal flu vaccine candidate was at high risk for joining the 90% of U.S. studies that fall behind in enrollment. The CRO/sponsor contract was signed in early April, and enrollment and dosing had to be completed by the end of June— in less than 10 weeks and only four weeks after the first investigative site initiation. This timeline, compounded by the sponsor’s need for continuous and immediate reactogenicity updates (meaning a vaccine’s potential to cause adverse reactions in patients), posed a unique set of challenges to the clinical research team.
A Study with High Stakes
Influenza viruses cause pandemics that can kill tens of millions of people, and each year brings seasonal flu epidemics that take between 250,000 and 500,000 lives around the world—approximately 40,000 in the U.S. alone. Fortunately, the 2009 influenza A/H1N1 pandemic caused lower mortality than the widespread outbreak of most flu strains, but it served as a grim reminder of the almost annually recurring danger.
Influenza viruses evolve rapidly and acquire genes from infections in multiple species. Each year, epidemiologists attempt to predict which viral strains will predominate the coming flu season, and a reformulated vaccine is produced in a race to combat the viruses’ global spread. Current production methods—which involve targeting each new strain and growing the target virus in millions of fertilized chicken eggs or vats of animal cells— can take up to nine months.
The universal flu vaccine candidate, on the other hand, could be produced in great volume within weeks using a breakthrough development method, with the hope that it will demonstrate efficacy against a wide variety of strains. [NOTE: Due to the confidential nature of this ongoing study, information regarding the expected capabilities of the product candidate, as well as the sponsor company’s prior clinical research experiences, is sourced solely from the author’s experience on the project.] The candidate targets the protein antigen common to all influenza A viruses that is most resistant to mutation and reassortment. Thus, while conventional methods struggle to produce enough doses based on shaky annual prognostications, the universal vaccine could significantly increase access for low-income regions, erase the need for yearly flu shots, and prevent deadly, unpredictable global pandemics.
“The universal [vaccine] would completely change the way flu vaccination would be done,” said Sarah C. Gilbert, a vaccine expert at the University of Oxford. “The sooner we have a universal vaccine the better, because we can stop worrying about what the next pandemic will be.”
The economic stakes for producing the first market-approved vaccine of this kind are high. With demand for the product expected from public health systems around the globe, the competition between vaccine developers to become the initial and primary supplier is intense. It is no surprise, then, that the study dealt with here was under tremendous incentive to avoid delays, complete on time, and move toward marketing approval as early as possible.
Major Sponsor Concerns
The June deadline for the Phase II study’s enrollment and dosing was set for only four weeks following the first site initiation and presented no room for flexibility. The comparator was the previous year’s standard flu vaccine, which expired June 30. If the study had not enrolled, scheduled, and administered doses to its target population of 80 subjects by that date, the results would be invalid; the sponsor would have to conduct a new study, which could not begin until the next year’s standard flu vaccine became available. Clearly, this would substantially delay the entire development program.
Enrollment and dosing were not the only issues challenging the study timeline. It was imperative that the sponsor receive immediate, up-to-date reactogenicity data, so that any potential adverse effects could be identified and addressed with minimal response time and dose-halting decisions could be made quickly. This was important not only for the obvious protection of the subjects’ well-being, but also to ensure that no faulty or fluke occurrences would lead either to an unnecessary dosing suspension or to the devaluation of study findings.
If an adverse effect was detected, even a single, minimal delay in the availability of reactogenicity data could have a strong negative impact on the research team’s ability to manage the problem in a timely fashion. Likewise, if a reaction was isolated to a single subject’s unknown, pre-existing medical condition, the study team would need to be alerted right away in order to enroll and dose a replacement subject before the June 30 cutoff. In either case, a lag in the availability of safety data would push the deadline out of reach—a compounding factor to the existing timeline pressures.
In previous studies, the sponsor reported waiting six to eight weeks for access to reactogenicity data—a period exceeding the entire enrollment and dosing timeline of the study at hand, not to mention the remaining lifespan of the comparator vaccine. Even if the program schedule could absorb a delay of this magnitude, the lag in accessibility of important safety information would introduce major risks affecting data quality, the validity of the study’s findings, and the well-being of subjects who could have suffered unnecessarily prolonged exposure to any serious adverse effects that could have occurred.
In operational terms, the study had no margin for error; any and all problems had to be identified, understood, and resolved as immediately as possible if the study was to avoid failure.
Preventing Enrollment Delays
Simplifying Patient Handling and Dosing
Both the sponsor and the CRO study team recognized that success or failure to meet the fast-approaching deadline hung primarily with the investigative sites. They also realized that the sites—tasked with enrolling subjects, administering doses, and handling data first-hand—were less likely to meet the goal if the study imposed burdensome, time-consuming processes. Therefore, the CRO made every effort to simplify data capture and patient visit steps.
To eliminate the common burdens of keying patient data and transcribing between multiple formats, sites were equipped with a digital pen-and-paper system. The system—as permitted by the study protocol—enabled investigators to capture and submit source data (original records of clinical findings, required for Food and Drug Administration and Good Clinical Practice compliance) without the cumbersome accumulation, organization, and physical transportation of separate source document files.
Investigators still enjoyed the convenience and flexibility of being able to record patient data and take notes by hand (versus computer-based electronic data capture [EDC]), but unlike other data-capture methods, neither manual data entry nor the collection and page-by-page review of hardcopy binders was required to complete the process. Instead, investigators recorded patient information by filling out special paper case report forms (CRFs) mapped with complex grids of tiny, invisible receptors. To write on these CRFs, investigators used pens equipped with an electronic mechanism that “reads” the marks being made by sensing the pen’s movements against the CRF’s receptor patterns. These pens contain built-in memory chips to store data, which were transmitted to the CRO automatically, immediately, and securely via a basic Internet connection when investigators “docked” the pen at their personal computers (Figure 1).
Figure 1. Digital Pen-and-Paper System. The study investigators reported that using the digital pen was far more convenient than entering data either directly to a web form using a personal computer keyboard, or to a paper form later transcribed to a web form. This reaffirms findings of independent studies comparing data capture methods in clinical trials. 
Thus, the digital renderings of handwritten patient documents were deemed legitimate source data, combining the simplicity and flexibility of pen-and-paper with the speed and accuracy of EDC, without the disadvantages of either approach. The digital pen’s compactness and portability also facilitated an efficient, multistation approach to patient visits that helped sites work more quickly and accurately, and with less tedium. Subjects moved through a series of stations in which they were enrolled in the study, reported their medical histories, had their vital signs recorded, and were administered dosing.
Sites had the option to assign pens either to each station (recording a complete set of specific data points across all subjects) or to patients (recording all data fields for each individual subject). This empowered sites with the flexibility to work within their established routines, and also provided the procedural structure and tools to streamline the activities most crucial to the study’s timeline.
Watching the Right Metrics
The research team ensured that investigators shared the sponsor’s deadline concerns by establishing open, transparent communication channels between sites and monitors. To make sure sites were performing at full capacity and that operational issues were identified and resolved before they could grow into last-minute, timeline-threatening problems, the team tracked and monitored the following key performance metrics:
- Patients screened
- Referral source
- Time from referral to initial screening
- Screen failures
- Patients enrolled
- Percent of target achieved
- How many active at each stage
- How many completing each study visit or milestone
- Patient dropout and loss to follow-up
- How many
Captured automatically in conjunction with patient data via the digital pen system, these metrics were compiled and updated on an immediate and rolling basis. Reports were made available to both the CRO and sponsor study teams in two secure, customized formats for added ease-of-use and transparency. For a thorough, detailed account of up-to-the-minute progress, the custom study website provided comprehensive enrollment information broken down by investigative site. Desktop widget reports presented more top-level, scorecard-type tabs on key study information, making nearreal time updates available to the sponsor at a glance (Figure 2 at right). These complimentary perspectives made it easy for the team to track trends and preempt the development of issues potentially affecting both deadline and data quality.
Almost immediately after enrollment began, the reports alerted the study team to lagging performance at one of the sites. The quick, preemptive attention of the study manager revealed that the site had underestimated the frequency of appointment changes and cancellations, and was distributing enrollment across the four-week timeline. By reeducating the problem site on the need to enroll, schedule, and complete dosing of all patients as early as possible to prevent a last-minute shortage of subjects, site performance was optimized across the board.
The result of all these efforts was that the study not only met its enrollment deadline, it achieved its goal within 13 business days, or a full week and 25% ahead of schedule.
Providing Rapid Access to Reactogenicity Data
Investigative sites were required to dock the digital pens no later than end-of-day for each patient visit. This was an easy mandate for the research team to enforce, since the data capture system required minimal time and trouble on behalf of investigators.
The ability to work with the electronic representations of handwritten documents as source rendered data verification and validation a faster, more accurate process. Once transmitted to the CRO, each data point—including safety data—was processed immediately upon receipt by the CRO’s data management function. Some fields were first scrubbed automatically by proprietary data management software, and all data were thoroughly cleaned by the data management team.
Custom reports (Table 1) made the freshly cleaned reactogenicity data available to the sponsor within 24 hours of patient visit. There were no weeks of waiting for interim database locks or reports on patient response. Instead, the flow of clean reactogenicity data was continuous and the access was rapid. The sponsor and study team received daily assurance that no emergent safety patterns were jeopardizing the study’s completion. This was key to making informed decisions about the trial’s progress, ensuring meticulous adherence to protocol, and achieving the accelerated timeline with full accountability for patient safety data.
Finding Other Opportunities to Affect Enrollment
The same techniques for harnessing a continuous flow of information to manage enrollment deadlines, transparency, and data quality have been successfully applied to clinical studies of various sizes, patient populations, and therapeutic areas. The specific metrics and data points of crucial concern are unique to each study, but every trial relies on access to timely information for its ability to adjust and optimize performance. For example, when the sponsor of an oncology study wanted to use only U.S. sites, despite the reluctance of U.S. cancer patients to participate in clinical studies, the solution was a tiered enrollment strategy including prequalified backup sites outside the U.S. By closely monitoring the insufficient enrollment metrics of the U.S. sites, the sponsor made an educated decision to expand the study to additional countries.
Another simple, yet surprising, instance of meeting enrollment challenges by knowing where to look for telling information occurred in a study of sexually transmitted diseases. With the tracking ability to identify one site that was far outperforming others, the research team could isolate the cause—in this case, posting patient recruitment notices in nightclub restrooms—and institute it across other sites. Neither the sponsor, nor the research team, nor the other sites had considered this strategy, but once it was adopted across the study, enrollment rates picked up and the target deadline was met, despite a slow start at most sites.
The global spread of both flu viruses and missed clinical trial enrollment deadlines threatens world health—the former by direct infection of the world’s population, the latter by delayed access to new treatments. The correct response to both pandemics is immunization against the causative agent. The availability of a universal flu vaccine represents a major advance in the fight against viral epidemics and pandemics. Although such a vaccine is becoming larger on the horizon, the agent for immunization against delays in clinical studies is here now. Timely information, including both patient data and performance metrics, can safeguard medical progress by immunizing drug development against needless, expensive setbacks.
Writing and editing support was provided by Kate Hendrick (firstname.lastname@example.org) and Phillip Lemmons (email@example.com). We would like to acknowledge and thank the CRO and sponsor study teams, as well as the investigational site staff, for their commitment to this study and its patients, their contributions to the operational benchmarks documented here, and their shared drive to improve global health and well-being.
- Quoted in Borfitz D. 2010. A social approach to patient recruitment. Bio-IT World, May 18, 2010.
- Kaitin K. 2008. Growing protocol design complexity stresses investigators, volunteers. Tufts CSDD Impact Report 10(1).
- CenterWatch Surveys of U.S. 2009. (n=950) investigative sites.
- CenterWatch Surveys of Asian (2006, n=156), Latin American (2005, n=317), and European and Canadian (2006, n=356) investigative sites.
- World Health Organization. April 2009. Influenza (seasonal).
- Dushoff J, Plotkin JB, Viboud C, Earn DJ, Simonsen L. 2006. Mortality due to influenza in the United States—an annualized regression approach using multiple-cause mortality data. American Journal of Epidemiology163(2): 181–7.
- H1N1 Flu Vaccine – Why the Delay? CDC Featured Podcasts, National Center for Immunization and Respiratory Diseases (NCIRD). November 5, 2009.
- Quoted in Pollack A. 2009. A long search for a universal flu vaccine. The New York Times. May 18, 2009.
- Estellat C, Tubach F, Costa Y, Hoffmann I, Mantz J, Ravaud P. 2008. Data capture by digital pen in clinical trials: a qualitative and quantitative study. Contemporary Clinical Trials 29: 314–23.
- Cole E, Pisano ED, Clary GJ, Zeng D, Koomen M, Kuzmiak CM, Seo BK, Lee Y, Pavic D. 2006. A comparative study of mobile electronic data entry systems for clinical trials data collection. International Journal of Medical Informatics 75: 722-9.
- Kolata G. 2009. Lack of study volunteers hobbles cancer fight. The New York Times, August 2, 2009.
- Rosenberg, M. 2009. Enrollment: situation difficult but manageable. Life Science Leader. September 2009.
- Rosenberg M. 2009. Operations and the future of adaptive research. The Monitor 23(7): 34–7.
Daniel Cormican, of Health Decisions, a full-service global CRO based in the Research Triangle Park region of North Carolina, has more than nine years of experience in clinical research, five in lead project management roles for domestic and global studies of medical devices and drugs in Phases II–IV. His specialties include multifunctional team leadership, development and management of study timelines, regulatory documentation, vendor relationship management, clinical monitoring, and clinical staff training. His primary areas of therapeutic expertise include central nervous system, exocrine disorders, infectious disease, vaccines, and women’s health. He holds a bachelor’s of science degree from Delaware Valley College and can be reached at firstname.lastname@example.org.