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Applied Clinical Trials
How one large academic trial adopted a coordinating center model-helping drive early-model RBM gains
Managing large-scale, multi-center clinical trials poses many challenges. In addition to trial design, selecting an organizational and management plan is critical to a study’s success. An administrative coordinator responsible for monitoring the conduct of the trial at sites that share a common bond (e.g., geographic location or institutional affiliation) may be a highly efficient way of meeting the challenges posed in the recruitment and follow-up periods. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive trial ever conducted, with 42,418 participants distributed among 623 clinical sites in the U.S., Canada, Puerto Rico, and the U.S. Virgin Islands, a “hub and spoke” regional coordinating center model was developed in an effort to better oversee the conduct of the trial at these widely dispersed clinical sites. Regional coordinator and physician positions led each region and bore responsibility for training, protocol adherence, and quality monitoring at multiple clinical sites within the region.
This was the second NHLBI-sponsored cardiovascular “large, simple trial” to utilize a regional plan; the Digitalis Investigation Group (DIG) trial successfully implemented four regional centers to coordinate site activity in its geographically widespread and culturally diverse subset of Canadian sites.1 This system was believed to be at least partly responsible for the success of the Canadian clinical sites in the DIG trial, and its design was subsequently implemented at a larger scale in ALLHAT. In all phases of the trial, regional coordinators served in roles similar to traditional study monitors, but also assumed responsibilities of affiliated regional coordinating centers for their respective region or network of sites while working closely with the trial’s central coordinating center.1, 2, 3, 4
The Clinical Trials Center (CTC) was responsible for the overall management and coordination of the ALLHAT trial, served as the data-coordinating center, and had fiscal responsibility for the majority of regional teams, support centers, and clinical sites. Nine regional teams were established over a three-year period to provide support, training, and oversight to the 623 clinical sites. Eight of the regions were created based upon relative geographic proximity of the sites to each other; the ninth region was composed of the 70 Department of Veterans’
Affairs sites, unrelated geographically but commonly funded through an Inter Agency Agreement between the NHLBI and the Department of Veterans Affairs.4
A regional coordinating team consisted of one to two part-time physician coordinators and between a two-thirds time and three full-time equivalent regional coordinators.4 Additional regional teams and regional coordinator positions were added during the trial as the roles expanded to accommodate the growing number of clinical sites and responsibilities added by the CTC. The physician coordinators were physicians experienced in conducting multi-center clinical trials. Regional coordinators typically had a BSN or relevant master’s degree and experience as research study coordinators or project managers. Regional coordinators worked closely with the CTC and NHLBI Project Office in the development of all operational tools utilized during the trial. Both the antihypertensive and lipid-lowering components of the study were under the supervision of the regional teams.
To meet the ambitious recruitment goals and enhance reproducibility of trial results, practice-based physicians were solicited, evaluated, and selected for participation by the CTC4. Initially, it was planned that 270 sites would recruit 150 participants each; to reach the ALLHAT recruitment goal of a total of 40,000 participants.4 Only 12% of the ALLHAT centers met the original recruitment goal.7 Multiple factors contributed to the inability of most sites to recruit 150 participants, including limited funding, insufficient funding for full-time study site personnel; the unexpected lack of interested managed care organizations and large group practices; and in some large group practices that were recruited, the investigators’ lack of success in gaining colleagues’ support of the trial due to concerns about whether some of the randomized treatments conformed to current community standards of treatment.7
When it became apparent that many sites would not meet this ambitious goal, the regional coordinators began to participate in site selection to identify additional sites. The main objectives of early regional coordinator involvement in the site selection process were to select sites that: (1) would be able to meet recruitment goals, (2) understand their requirements in the study, and, (3) have a high likelihood of obtaining regulatory approval and begin prompt participant recruitment.9
Once a site was approved for ALLHAT, regional coordinators guided sites through the regulatory process (e.g. institutional review board approval, letter of agreement). Early in the recruitment period, regional coordinators conducted visits to review the site’s recruitment plan and progress, assure protocol adherence, and observe overall clinic performance.
Clinic staff training presented multiple challenges. The experience level of study staff ranged from experienced, university-based research personnel to research-naïve, private practice office staff. Initial staff trainings were conducted centrally by the regional coordinators, CTC staff, and support centers staff (laboratory, ECG, drug distribution). As more sites were added, regional and individual site trainings were conducted. Regional coordinators and CTC also collaborated on the development of a training manual for new regional coordinators, to ensure consistency in the messages and methods of managing the clinical sites in all regions. ALLHAT investigator/study coordinator meetings were held every 18 months and incorporated a variety of training sessions on key topics; the regional coordinators had an integral role in planning and executing group training and regional breakout sessions, at which site coordinators could share concerns, exchange ideas, and participate in training and motivational activities. The regional coordinators maintained records of all trainings, including trainings and recertifications for use of the sphygmomanometer. Proper site record keeping, including those required by regulatory bodies, and all study procedures (e.g., drug ordering and distribution, laboratory draws and transmission to the central laboratory for analysis, EKG management) were continually reinforced by the regional coordinators.
During the trial, there was a 46% turnover in clinic study personnel. This necessitated an increase in on-site training visits and additional training materials. A subcommittee of regional coordinators and CTC representatives streamlined the training manual into a self-training program. An adherence-oriented guide, the Adherence Survival Kit7 was created by compiling a variety of tools into a single reference source to help sites develop skills for addressing retention and adherence issues.
Participant recruitment and retention
Participant recruitment, which included a six-month internal pilot phase, started in February 1994 and was projected to end July 1996. Following two extensions for lower-than-expected participant accrual, the recruitment period successfully ended on Jan. 31, 1998.8 Attaining participant recruitment goals is frequently one of the most difficult tasks facing clinical trial investigator/coordinator teams, and for many trials is insurmountable.9 Common recruitment challenges fall into several key categories: protocol complexity, site issues, weak referral interest or support, communication, participant motivation, funding and reimbursement.10
ALLHAT made several significant changes to address its recruitment challenges including: 1) changes to the protocol (i.e., amendments to the entry criteria and increasing the number and region of sites), 2) extending the recruitment period, 3) implementing a nation-wide publicity campaign and 4) increasing clinic reimbursement and adding a fund for extra staff based on recruitment potential and staffing needs.8 While strong administrative oversight cannot overcome all recruitment challenges, the involvement of the regional coordinators and respective teams focused on site organization and preparedness, improving communication with sites and institutions, educating and recruiting support from referring physicians, and enhancing participant recruitment with detailed plans and targeted strategies.
In ALLHAT, regional coordinators helped sites develop participant recruitment plans and provided on-going site support to ensure that recruitment goals were met. Weekly communications, monthly progress reports, and occasional incentive programs were developed and utilized by regional coordinators to enhance recruitment and acknowledge site efforts. For example, the region covering the western and northwestern states developed a themed “Salmon Run” competition, a 16-week competition for recruitment which recognized the five sites each week with the most participants recruited; at the end of the 16 weeks awards were given to the sites with the best weekly and overall recruitment, with one “grand prize” winning site. A recruitment and eligibility subcommittee, including regional team members as well as representatives from the project office, steering committee and CTC held weekly teleconferences during the recruitment period. To increase participant recruitment, regional coordinators participated in organizing a publicity campaign in targeted geographical areas. In response to an opportunity to provide supplemental funding for part-time staff to bolster recruitment efforts, the regional coordinators identified qualifying sites with good participant recruitment and retention potential, set specific recruitment and follows up goals, facilitated the funding process, and monitored recruitment performance.8
While the ALLHAT and DIG trials share some commonalities in regional design and experiences, comparison with many other clinical trials with markedly fewer participants and clinical sites (including some with limited or no research experience), and lacking two separate treatment protocols and extended follow-up, is difficult.2,8 Some strategies (e.g., centralized recruitment, home visits) employed in current clinical trials were either not practically or financially feasible or not available (e.g., remote monitoring, Internet access for both patients and sites).
When the recruitment phase was completed, efforts were increased to minimize the number of participants who were lost-to-follow-up or who declined to remain in the study. A retention and adherence subcommittee developed easy-to-use adherence tools (e.g., Adherence Survival Kit) for presentation during site visits, regional dinner meetings, and teleconferences. Participant transfer and “out-of-town visit” procedures were developed to maintain visit adherence and regional teams worked with the sites to customize plans (e.g., appropriate drug combinations, drug selection for compelling indications, simplify regimens) for improving and maintaining participant medication adherence. In the latter phase of the trial, an intensive lost-to-follow-up/participant refusal initiative was developed and launched by the CTC.
In the months prior to one annual investigator/coordinator meeting, which occurred approximately half-way through the active trial, a competition between sites was held, which looked at improvement in such data and performance quality areas as “participants missing two or more successive visits,” “participants not taking Step 1 study medication,” and “incomplete event documentation.” Regional coordinators were available to assist each site throughout the contest, and each site winning a given category was eligible for a grand prize drawing. During the trial closeout phase, regional coordinators provided guidance and training to the sites on methods, consistent with IRB guidelines, of locating participants. Once participants were located, regional coordinators worked with sites to develop strategies to reestablish contact with these participants.
Quality control and site visits
The regional coordinators served as the principal study representatives for conducting quality controls, retraining, and technical assistance site visits. Routine QC visits were conducted at each site at least every other year and focused on data verification, protocol adherence, regulatory compliance, drug accountability, and site-specific problems. Periodically, QC site visits were customized to also include items requested by study leadership. Frequent staff turnover and the need for additional assistance at some sites led to the creation of the technical assistance site visit, a precursor to risk-based monitoring (RBM), to troubleshoot organizational issues, address specific protocol or site problems, provide training, or introduce special initiatives such as the Adherence Survival Kit and study closeout plan. The agenda for a technical assistance visit was site-specific.
At a typical QC visit, case report form (CRF) data were reconciled with source documentation from the medical charts of 20 CTC randomly selected participants. Using CTC-generated site-specific data reports, site performance in key areas such as visit and medication adherence, blood pressure control, and participant retention were reviewed with the principal investigator and staff. Priority was given to searches for unreported endpoints. Regional coordinators would also provide guidance on securing appropriate event documentation to facilitate timely adjudication. When indicated, a team approach was used to develop a plan for improvement and/or additional technical assistance or training. Follow-up continued until all issues were resolved.
Following the site visit, a summary letter, copy of the official site report, and a list of action items to be addressed were generated by the regional coordinators and sent to the site and the CTC for their review. A QC subcommittee randomly audited 10% of the site visit reports for consistency and completeness, and feedback was provided to the regional coordinators.10
Participant and site close-out
A well-planned and executed closeout is an important element of a large scale clinical trial and can be as critical in determining a trial’s success as any of its other phases. The regional coordinator, as the primary liaison between the study and the clinical sites, was in a unique position to articulate and communicate both the needs of the study and the clinical sites in developing a detailed closeout plan. The regional coordinators were involved in nearly every aspect of the ALLHAT closeout, including outlining the procedures and timeline; preparing necessary staff and participant materials; training site personnel; assisting with the ascertainment of vital status, study events, and other data; and providing guidance on assuring continuity of patient care. The regional coordinator was also the primary member of the regional team responsible for monitoring the proper and timely site completion of the operational aspects of the closeout and prompt data submission to the CTC.
Unanticipated events in clinical trials
As with other clinical trials, ALLHAT had its share of challenges. In February 2000, the doxazosin arm of the trial was terminated early.5,11,12 The study entered a transition phase, closing one arm of the trial while the remainder of the antihypertensive and the lipid lowering continued. Although only a few members of the regional personnel were selected for the transitional planning team, this early and partial closure of an aspect of the trial presented the entire study with both an unexpected challenge and an opportunity for planning and executing a study closeout.
Because of the urgency implied with an early study termination, the transition team drafted the necessary plans and materials for the partial closeout. After finalization with input from the remainder of the study leadership, the regional teams were then trained on the transition materials, procedures, and timeline, with instruction to conduct similar training for their sites. The regional coordinators, principals for coordinating this level of training, used a variety of communication tools, including site visits, emails, and phone calls to customize the necessary training, completion of the transition visits, and data submission within the abbreviated timeframe. This abrupt closure of one arm of the study provided an advanced opportunity to identify and prioritize necessary steps in closing a study, implementing and evaluating closeout tools and materials, and provided lessons for enhancing the final closeout experience for all involved.6
Site personnel closeout training was scheduled for a face-to-face meeting in September 2001. Incorporating our experience and lessons learned from the doxazosin closeout, plans and materials for the final study closeout were fully developed and prepared for a standardized presentation and an opportunity for study-wide interaction and exchange. Unfortunately, this planned meeting was canceled because of the events of September 11, 2001, one day prior to the meeting.
The careful planning, organized preparation, and experience gained from the doxazosin termination provided us a unique benefit when confronted with untimely events and unprecedented challenges. The training blueprint and materials were established and available. The challenges were: 1) to assure effective closeout training to encompass the remaining arms of the study; and 2) to flex the venue in a manner that would assure timely, standardized, and
complete training for the key site personnel. With a well-defined timeline, this required an expeditious and creative approach to addressing the study training needs. The regional coordinators customized the training platform by hosting individual or groups of sites at face-to-face meetings or site visits, where geographically possible, and conducting conference calls. Group training presentations, preferred for efficiency, also preserved the element of a standardized message and the ability for collective interaction. Individual calls and/or visits were also made to clarify or reenforce information or address the needs of an absentee employee. ALLHAT completed a successful closeout phase initiated during a turbulent time using the aforementioned alternate training sessions. Closing a large clinical trial requires commitment, a keen sense of organization and attention to detail, and careful planning. When unexpected challenges threaten the process, it is critically important to have creative and flexible team members who can assess, prioritize, and execute the essential elements of the closeout plan. The regional coordinators were an integral part of the ALLHAT team in performing these duties, thus contributing to a successful study closeout.
Several subcommittees that were developed to facilitate the conduct of the trial remained active during all phases of the study. The regional coordinators, keenly aware of site issues, were essential to successful subcommittee discussion and function. Generally, subcommittees met as often as weekly during recruitment and monthly during the follow-up phase of the trial, as well as face-to-face during the steering committee and investigators’ meetings. The regional coordinator maintained representation and active participation on the operations, regional coordinator recruitment and eligibility, retention and adherence, medical management, endpoints, publications and ancillary studies, newsletter, and quality control subcommittees.
With regional coordinators dispersed across the U.S., Puerto Rico, U.S. Virgin Islands, and Canada, maintaining effective and ongoing communication with respective site principal investigator and staff was crucial. Study staff was encouraged to contact their regional coordinator with protocol questions and problems. Regional coordinators initiated contact with their sites at least monthly to discuss site performance, review staffing issues related to time and effort spent on the study, motivate staff, and when necessary, problem solve. During the recruitment phase, contact was more frequent to encourage participant enrollment.
Site performance reports co-developed by the regional coordinators and CTC were used to evaluate sites and provide appropriate feedback on progress. Monthly monitoring tools (i.e., site performance profiles, reports of needed and accomplished form edits) were distributed to the regional coordinators to assist with identifying clinic problem areas and improve monitoring efforts. Teleconferences, regional dinner meetings, and breakout meetings during investigator/study coordinator meetings were important for communicating with sites regarding specific regional issues, maintaining their motivation and nurturing the regional coordinator-site relationship. Regional coordinators collaborated with the CTC, steering vommittee, and other subcommittees on the development of trial forms, procedures, written communication, and incentive programs.
The regional coordinator position in ALLHAT’s management structure was essential to the trial’s successful site management, participant recruitment and retention, protocol adherence, and endpoint ascertainment. Employing regional coordinators, versus in-house coordinators or contract research organizations (CROs) in administrative, consultative and monitoring roles was a novel idea, deemed to be the best and most cost conscientious decision given the projected design and size of the study. At the time, CROs were more commonly involved in small, short-term pharmaceutical industry trials. Evidence regarding best approaches for clinical trial management and monitoring and respective cost efficacy in long term event trials was lacking. Without pre-existing benchmark comparators, the success of the model would be reflected in the quality of the study results achieved. The majority of the ALLHAT regional coordinators worked within the geographic area of the sites or had an institutional affiliation in common with the sites within their region; this proved to be invaluable for site management and monitoring and in the case of geographic proximity to sites reduced travel costs for local site visits.
Given the scientific advantages of a large, multi-center trial design, the ongoing need for cost control, and the increasing needs and demands for detailed study monitoring and documentation, it is likely that the regional coordinator template will continue to be implemented in clinical trials. Whether designing large clinical trials such as ALLHAT or smaller trials, consideration should be given to the lessons learned from this large multi-center trial and the contributions of experienced regional coordinators. Academic and industry models for clinical trial monitoring may each hold advantages in specific circumstances. However, the literature remains devoid of evidence describing the pros and cons and comparisons of various models of site management and monitoring.
The regional coordinator model was successfully replicated in the NHLBI-sponsored Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Systolic Blood Pressure Intervention Trial (SPRINT) Trials.13,14 These trials, as with ALLHAT, faced recruitment challenges, yet ultimately surpassed their recruitment targets and achieved high participant retention rates.13,14 Although a similar model has not been reported in industry-sponsored trials, these successes suggest it may be useful.
Therese S. Geraci, MSN, with University of Mississippi; Lillian Carroll, with Albert Einstein College of Medicine; Connie Kingry, RN, BSN, and Janice M. Johnson, SMC, both with University of Washington; Debra Egan, MSc, MPH, with National Heart, Lung, and Blood Institute; Jeffrey Probstfield, MD, with University of Washington; Sara M. Pressel, MS, and Linda B. Piller, MD, MPH, both with University of Texas School of Public Health; all for the ALLHAT Collaborative Research Group
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2. Egan, D., Geller, N., et al. Lessons learned from the DIG trial. Control Clin Trials. 2003;24:316-326.
3. Davis BR, Cutler JA, Gordon DJ, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996;9(4 Pt 1):342-360.
4. Wright JT,Jr, Cushman WC, Davis BR, et al. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): clinical center recruitment experience. Control Clin Trials. 2001;22(6):659-673.
5. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283(15):1967-1975.
6. Pressel SL, Davis BR, Wright JT,Jr, et al. Operational aspects of terminating the doxazosin arm of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Control Clin Trials. 2001;22(1):29-41.
7. Lusk CM, Bettencourt J, Carroll L, et al. The Adherence Survival Kit. Appl Clin Trials. 2004;13(10):40-48.
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9. Davis JM, Sandgren AJ, Manley AR, Daleo MA, Smith SS. Enhancing trial enrollment methods through “goal programming”. Appl Clin Trials. 2014;23(6-7):46-50.
10. Institute of Medicine (US). Public Engagement and Clinical Trials: New Models and Disruptive Technologies: Workshop Summary. Washington (DC): National Academies Press (US); 2012. 3, Recruitment Challenges in Clinical Trials for Different Diseases and Conditions.
11. Pressel S, Lucente T, Carroll L, Bettencourt J. Quality control site visits in large, simple trials – The ALLHAT experience. Control Clin Trials. 2000;21:120S-120S.
12. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertens. 2003;42(3):239-246.
13. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59
14. SPRINT Study Research Group. A randomized trial of intensive versus standard blood pressure control. N Engl J Med. 2015;373:2103–2116