Linda B. Piller, MD

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.

 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.

	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.

	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.

 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.

 Only 12% of the ALLHAT centers met the original recruitment goal.

 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.

	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.

	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 Kit

 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, 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.

 Attaining participant recruitment goals is frequently one of the most difficult tasks facing clinical trial investigator/coordinator teams, and for many trials is insurmountable.

 Common recruitment challenges fall into several key categories: protocol complexity, site issues, weak referral interest or support, communication, participant motivation, funding and reimbursement.

	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.

 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.

	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.

 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.

	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.

	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.

	As with other clinical trials, ALLHAT had its share of challenges. In February 2000, the doxazosin arm of the trial was terminated early.

 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.

	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.

 These trials, as with ALLHAT, faced recruitment challenges, yet ultimately surpassed their recruitment targets and achieved high participant retention rates.

 Although a similar model has not been reported in industry-sponsored trials, these successes suggest it may be useful. 

, with Albert Einstein College of Medicine; 

, SMC, both with University of Washington; 

, MSc, MPH, with National Heart, Lung, and Blood Institute; 

 MD, MPH, both with University of Texas School of Public Health; all for the ALLHAT Collaborative Research Group  

	1. Collins JF et al. The use of regional coordinating centers in large clinical trials: the DIG trial. 

	2. Egan, D., Geller, N., et al. Lessons learned from the DIG trial. 

	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). 

	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. 

	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). 

	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. 

	8. Pressel S, Davis BR, Louis GT, et al. Participant recruitment in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Control 

	9. Davis JM, Sandgren AJ, Manley AR, Daleo MA, Smith SS. Enhancing trial enrollment methods through “goal programming”. 

	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. 

	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). 

	13. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. 

	14. SPRINT Study Research Group. A randomized trial of intensive versus standard blood pressure control. 

Articles

How one large academic trial adopted a coordinating center model-helping drive early-model RBM gains

Exploring the Role of the Regional Coordinator

How one large academic trial changed its clinical trial monitoring model, gaining early-model RBM advantages

	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.

	The scope of the regional coordinators’ responsibilities encompassed several key areas in the trial, all of which will be outlined in this report, along with details of the rationale, implementation, and evaluation of these duties. Recommendations and suggestions for incorporating the role of regional coordinator into the management structure of future clinical trials will also be provided.

	The organizational scheme of the ALLHAT trial is depicted in 

. The Clinical Trials Center (CTC) was responsible for the overall management and coordination of the 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.

 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. The physician coordinators and regional coordinators also employed a cohesive team approach to clinic monitoring and problem-solving. 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 CTC

. 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.

	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. 

	Participant recruitment, which included a six-month internal pilot phase, started February 1994 and was projected to end July 1996. Following two extensions for lower-than-expected participant accrual, the recruitment period successfully ended on January 31, 1998.

	Attaining participant recruitment goals is frequently one of the most difficult tasks facing clinical trial investigator/coordinator teams, and for many trials is insurmountable.

 Common recruitment challenges fall into in several key categories: protocol complexity, site issues, weak referral interest or support, communication, participant motivation, funding and reimbursement.

	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.

 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.

 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). ALLHAT’s successful recruitment was realized through creative team thinking, judicious planning and the comprehensive efforts and unwavering support of the study leadership, regional teams and clinical 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, consisting of regional coordinators and representatives from the Project Office, Steering Committee, and CTC, 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 efforts to improve adherence, additional incentives, similar to those used during recruitment were initiated. 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 re-establish contact with these participants. To maintain motivation and performance at sites, ALLHAT regional coordinators developed and implemented strategies such as contests, incentives, and award programs. 

	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, 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. Numbers and types of ALLHAT regional coordinators site visits from the beginning of participant enrollment through March 2000, are shown in 

	At a typical QC visit, case report form 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. General agenda items for QC site visits are provided in 

	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, comprising members from the Project Office, CTC, and regional coordinators, randomly audited 10% of the site visit reports for consistency and completeness, and feedback was provided to the regional coordinators to assure quality reporting was maintained.

	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. A strong collegial and collaborative effort among the study leadership and regional teams fostered an environment that contributed to and supported our successful closeout despite some unexpected challenges along the way.

	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 and unexpected 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.

	ALLHAT was scheduled to complete the remaining participant follow-up in March 2002. Site personnel closeout training for the remainder of the 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 before the meeting was scheduled to begin.

	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 re-enforce 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.

	Maintaining effective and ongoing communication with the site principal investigator and staff was an important part of the ALLHAT regional coordinator role. Frequent telephone calls, fax, and email with those sites that possessed the technology and were comfortable with its use, and periodic regional newsletters and mailings were all utilized. 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. The level of research experience at the site often determined the amount of contact necessary.

	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. 

	Communication among the regional coordinators, CTC, and Project Office was critical to ensure cohesive trial management. As regional coordinators were dispersed across the United States, Puerto Rico, U.S. Virgin Islands, and Canada, there was a strong need to maintain regular communication for support and shared problem solving among the various study organizational groups and the clinical sites. For this purpose, an regional coordinators subcommittee met by monthly teleconference and at biannual meetings. Regional coordinators collaborated with the CTC, Steering Committee, and other subcommittees on the development of trial forms, procedures, written communication, and incentive programs. Regional office evaluation conferences were conducted three to four times per year via teleconference and meetings with the RPCs, regional coordinators, Project Office, and CTC. The RPCs and regional coordinators from one other region were present at this evaluation in order to contribute ideas and offer suggestions as to the handling of specific issues, and to learn from the experiences of the group being evaluated.

	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 clinical 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. 

	Extensive clinical trial experience and strong communication skills, along with flexibility, creativity, and adaptability are imperative for a successful regional coordinator. As early as possible in trial planning and throughout the trial, the regional coordinators should be actively engaged in all aspects of protocol development, study implementation, and closeout planning. 

	A regional coordinator or equivalent position within a multi-center clinical trial may assume or participate in a variety of roles. Many of the major regional coordinator responsibilities, though not an exclusive list, are provided in 

. 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 coordinators played an important role in ALLHAT’s success. Having a designated coordinator to oversee operational aspects of the trial as an advisor and consultant to the clinical sites on issues related to recruitment, follow-up, event ascertainment, and closeout enhanced the success of these critical trial elements. Decentralizing the trial management into regional teams with the regional coordinators as the primary liaison to the clinics re-enforced attention to clinic-level operational details that were essential to the trial’s successful completion and, thus, scientific achievements. Development and “field-testing” of this unique organizational scheme in a trial the size of ALLHAT provided an important and innovative example of trial management for future clinical trials. 

	This model was successfully replicated in the NHLBI-sponsored Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Systolic Blood Pressure Intervention Trial (SPRINT) Trials.

 Although a similar model has not been reported in industry-sponsored trials, these successes suggest it may be useful. Identifying and comparing common parameters in clinical trial monitoring in large industry-sponsored trials with non-industry-sponsored trials which utilize the regional model may identify advantages and disadvantages of this model for each, allowing for a more informed decision when selecting management and monitoring designs for future clinical trials.

	To evaluate the most appropriate use and circumstances for the academic and industry models, it may be best to identify common parameters in clinical trial monitoring that could be examined for comparable performance between the two. 

	The authors thank Dr. Ellen Breckenridge and Ms. Kara Elam, The University of Texas School of Public Health, for editorial assistance in the preparation of this manuscript.

	This research was supported by contracts NO1-HC-35130 and HHSN268201100036C from the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril) and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer, Inc.

	The authors have no financial interests to disclose. Debra Egan is a contractor for NHLBI.  The views expressed in this manuscript are those of the authors and do not necessarily represent those of NHLBI.  No specific funding was allocated for this work.

	ALLHAT was a randomized multicenter clinical outcome trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with participation of the Department of Veterans Affairs, and additional support from pharmaceutical companies. The antihypertensive trial (AHT) component was a double-blind, comparative trial of three newer antihypertensive drug agents (the calcium antagonist, amlodipine; the angiotensin-converting enzyme inhibitor, lisinopril; and the alpha-antagonist, doxazosin), each compared to the diuretic chlorthalidone, in 42,418 high-risk hypertensive men and women, age 55 years and older. A subset lipid-lowering trial (LLT) consisting of 10,355 participants compared the open-label agent pravastatin to usual care.

 The 623 clinical sites randomized 42,418 participants in a variety of practice settings between February, 1994 and January, 1998. Participants were seen three to four times per year during the follow-up phase. Follow-up for the AHT averaged six years (excluding 6,868 participants from the doxazosin arm, which was terminated early

) and the active trial ended in March 2002.

, for the ALLHAT Collaborative Research Group

Albert Einstein College of Medicine, Bronx, NY 10461; 

University of Washington, Seattle, WA 98102; 

National Heart, Lung, and Blood Institute, Bethesda, MD 20892; 

The University of Texas School of Public Health, Houston, TX 77030; For a complete list of members of the ALLHAT Collaborative Research Group, see 

	University of Texas School of Public Health  

The largest antihypertensive trial ever conducted throughout North America, ALLHAT, was organized using a coordinating center model for oversight. Regional coordinators played a key role in carrying this trial out.

	The ability of clinical research to produce valid conclusions depends upon successful subject recruitment.

Eighty-five percent of clinical trials are extended due to insufficient recruitment.

Consequently, study costs increase due to loss of study time and lead to delay in drug approval and presentation of important results.

Compared to exclusively academic clinical trials, community-based clinical trial outcomes have the potential to observe large-scale effects and expand generalizability to a broad population because they operate within a variety of treatment centers across wide geographical regions.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive trial ever conducted by any public or private sponsor, was a randomized, double-blind, active-controlled trial which adopted the community-based approach by including 42,418 high-risk participants recruited largely by their own treating physicians. ALLHAT successfully recruited large numbers of women (47%), African-Americans (36%), Hispanic Americans (19%), and persons with type II diabetes (36%).

Such underrepresented populations were previously reported as difficult to recruit in community-based cardiovascular trials.

	Although study coordinators (SCs) exert an essential role in the clinical trial recruitment process, in community practice-based clinical trials, physician investigators, whose attitudes and characteristics define the clinic environment, also exert a strong influence on recruitment. Several physician-related variables tied to clinical trial participant recruitment have been identified: Bell-Syer and Moffett

found investigators and practices recruited to primary care clinical trials early were more successful in enrolling study participants. Ramirez et al.

looked at physician barriers to recruitment in multiethnic oncology trials in Texas and found no major difference in demographic factors between good and poor recruiters. However, several studies have noted that investigators who believe a clinical trial presents an undue burden to their work, fails to provide personal benefits, or has too complex a protocol tend to be poor recruiters.

In addition, physicians who want to participate in clinical trials may not enroll their eligible patients due to concerns that their patients may not receive the treatment they believe is better, thereby influencing their perceived quality of care and hampering the patient/physician relationship.

	ALLHAT investigators went to great lengths to assure that the participants they enrolled had no medical contraindications to the study medications (or, conversely, compelling indications for any one antihypertensive class), and to assure that the participants fully understood and accepted the randomized design of the study. Although the study leadership respected the rights of investigators to alter antihypertensive treatment when, in their judgment, compelling clinical issues required it, the leadership also sought to recruit investigators with study equipoise, who accepted the tenets of randomized, controlled, “intention to treat” trials.

	Previous studies have identified physician/investigator characteristics that influence recruitment.

ALLHAT, unique in its large participant population with predefined population subgroups previously underrepresented in antihypertensive trials,

successfully recruited clinics able to draw from their patient base to fulfill these recruitment goals. Here we draw from the ALLHAT experience with its large database to look at investigator characteristics that related to patient recruitment. We readily acknowledge the essential role played by SCs in recruitment and in all phases of clinical research. Many of the investigator characteristics that we describe here may apply to the SCs, especially as they assume more leadership roles in clinical research, and may serve to teach the entire research team more effective recruitment and clinical management skills. The primary objectives of this study are: 1) to describe the clinical investigator characteristics in ALLHAT, and, 2) to determine which physician/investigator characteristics were associated with successful participant recruitment.

	The rationale and design for ALLHAT have been previously published.

ALLHAT compared clinical outcomes of those assigned to one of three newer classes of antihypertensive medications-calcium channel blocker (CCB; amlodipine), angiotensin-converting enzyme inhibitor (ACE-I; lisinopril), and alpha-blocker (doxazosin)-with those assigned to the thiazide-type diuretic (chlorthalidone)-when each drug was used as first-step treatment with other drugs added to achieve a BP goal of <140/90. A

 total of 42,418 high-risk hypertensive participants, ages 55 and older, from 623 sites in the United States, Puerto Rico, Canada, and the US Virgin Islands, were randomized between 1994-1998. The sites included academic medical centers, Veterans’ Affairs Medical Centers (VAMCs), private practices, community health centers, and health maintenance organizations, and were distributed across eight geographic regions and a ninth region composed of VAMC sites. A map indicating location of ALLHAT sites along with a description of major recruitment aims is shown at right.  Each of the nine regions had one regional coordinating center (RCC) which directed 30 to 102 sites and was led by a physician-investigator and one or more regional SC (RSC), some of whom were nurses.

	The RSCs monitored participant recruitment through baseline and visit form submission, as well as weekly reports created for each site. Participant selection was initiated through examination of potential participant charts at the study sites. Two pre-randomization visits assessed participant eligibility. Once eligibility was confirmed, the participant provided written informed consent, discontinued pre-study prescribed antihypertensive drugs (unless tapering or a “wash-out” period was required), and was subsequently randomized to one of four treatment components.

The alpha-blocker arm of ALLHAT was terminated early in 2000;

results of the other two treatment group comparisons were published in 2002.

The population for this study included the 502 site principal investigators (PIs) who voluntarily completed and returned the ALLHAT investigator profile survey.

	Clinical sites were recruited from 1994-1997, and participants from 1994-1998.

An abbreviated physician orientation profile questionnaire, distributed to site physician/investigators in 2000, examined physicians’ attitudes and opinions regarding randomized controlled trials (RCTs).  The original questionnaire had been pre-tested for validity and reliability;

the abbreviated version was tested on members of the ALLHAT steering committee for acceptability, though no formal validation procedure was conducted. The survey captured characteristics in three main categories: demographics/practice type, physician’s views of RCTs, and investigator attitudes/experiences. An investigator identification number was sequentially assigned and allowed for non-identified tracking. In order to achieve an adequate response rate, if less than 50% of investigators returned the profile, a second copy was mailed to the non-responders. The investigator profiles were matched centrally with site and recruitment data.

	A frequency distribution by type, size, and geographic region for sites was conducted for site recruitment and investigator characteristic data. A chi-square analysis of the association of each characteristic with successful recruitment was performed. In these analyses, the recruitment outcome was dichotomized by comparing sites that recruited at or above the overall site recruitment median of 46 participants with those that recruited fewer than 46 participants. The statistical significance of each association was reported as a p-value for the corresponding likelihood ratio statistic. A multivariate logistic analysis was performed to recognize independent associations of characteristics with successful recruitment, when adjusting for all other variables. A univariate logistic analysis was first done for each characteristic, and those with p <0.10 were included in the multivariate model. Backward elimination technique was used to build the multivariate logistic model, and all p-values <0.05 were kept in the final model. Given the many univariate and multivariate analyses performed, statistical significance at the 0.05 level should be interpreted with caution. A STATA 12 (STATACorp LP, College Station, Texas) was used for the statistical analyses.

	Table 1 at right provides responding investigator characteristics and indicates characteristics associated with generally successful recruitment. The majority (411/497, or 83%) of the responding ALLHAT investigators were male and

 nearly 75% were between 40-59 years old. Two-thirds were Caucasian, 13% African-American, and 8% Hispanic. Sixty percent of sites were urban, 14% academic, 11% VAMC, and over half private or group practice. Seventy-four percent (28/38) of the Hispanic investigators were successful recruiters (p=0.015), as were 78% (42/54) of VAMC sites (p<0.0001). No data were collected about investigators who did not respond to the questionnaire.

	Investigator research activities are described in Table 2 below. Over half (113/204, p=0.027) of the physician/investigators who were PIs of two or more concurrent research grants were successful recruiters. The majority of successful recruiters (79% vs. 21%, p=0.002) spent less than 25% of their time in research-related activities, and most continuing medical education focused on clinical care rather than research topics. The two-thirds of investigators who 

devoted time to educating other physicians about RCTs had greater recruitment success compared to those who reported very low/no time in this activity (p=0.008).

	Investigator views on patient attitudes and rights are presented in Table 3 below. Investigators who were willing to spend additional time reviewing the consent form with a potential participant whose reaction

 warranted additional clarification or explanation had greater success in recruitment (p=0.041).

	Table 4 below describes significant characteristics among those included in the multivariate logistic model. The final model included 357 (71%) of the 502 investigators due to variation in the number who answered the respective questions. Hispanic ethnicity (odds ratio [OR], 3.698; p=0.037), urban setting (OR, 0.423; p=0.019), VAMC site (OR, 6.447; (p=0.002), more than two study staff (OR, 

1.931; p=0.022), more than 20 dedicated study coordinator hours/week (OR, 34.776; p=0.001), clinically-focused conferences (OR, 0.159; p=0.002), motivation to contribute to scientific knowledge (OR, 5.184; p=0.001), and encouraging patients to accept protocol-directed treatment when they expressed their opposition to it (OR, 1.894; p=0.032) had independent, beneficial effects on the recruitment success of ALLHAT investigators. 

	This study identified many investigator characteristics that may potentially influence participant recruitment, including physician-investigator ethnicity in relationship to the site’s potential participant pool, clinical practice type, investigator attitudes and research experience, dedicated SC time, and site characteristics. However, notwithstanding the importance of investigator and practice characteristics, in most clinical trials, the SCs and staff have the initial contact, and, typically, the most dedicated time spent with potential participants. Patient trust in the non-physician team members is mandatory.

	Beliefs and attitudes of non-physician staff that complement those of the investigator and appeal to the patient base are necessary for optimal recruitment to occur. Further, continuing development of new techniques to enhance effective communication with potential and enrolled participants is important. Yates and colleagues,

recognizing the blockade to successful clinical trials put forth by participants’ lack of clear understanding of the clinical trial rationale and protocol, urged the exploration of thoughtful and innovative means of presenting study concepts and obtaining informed consent.

	In ALLHAT, Hispanic ethnicity and site setting and type had independent effects on investigator recruitment success. One of ALLHAT’s strengths was the high representation of minority participants, including Hispanics and African-Americans. Hispanic site investigators, many located in Puerto Rico, had the best recruitment performance, followed by African-American and Caucasian investigators (Table 1). Ramirez et al.,

exploring Latino physicians’ attitudes towards clinical trials, reported that Latino (defined “as a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin without regard to race”)

physicians participate in clinical trials less often than Caucasian physicians, likely influencing the level of Latino participant recruitment. Roberson

explored reasons limiting clinical trial participation among African-American, Hispanic, and Native American patients in Buffalo, NY, and found insufficient trial information, ethnic background, and, in all three groups, mistrust of Caucasians to be important obstacles.

	Roberson further suggested that conducting a study within a minority community demonstrates commitment by the primary investigator.

Site investigators and staff should be knowledgeable and respectful of the attitudes and culture, including primary language, of the target population.

ALLHAT was unique in having 33 Puerto Rico sites, comprising 14% of the total study population.

The recruitment of active community sites led by Hispanic investigators and entire clinic staffs sensitive to the culture and attitudes of potential participants was fundamental to the ALLHAT recruitment success in Puerto Rico. Among site types, only the VAMC sites demonstrated a positive effect on the investigators’ recruitment success. Although the VA Region was limited in number of participating sites (68 of 623), each VAMC site recruited large participant numbers (average 100/site), likely attributable to the VAMCs’ longstanding emphasis on research. Further, VAMC nurses have long held active roles in the recruitment process.

	Sites located in suburban areas had significantly lower recruitment rates compared to sites in urban settings. Clinical trials may appeal to urban populations with greater need of free or low cost medical care. The greater ALLHAT success in urban compared to suburban sites may also be related to easier access, especially for the elderly and lower-to-middle income participants, and to greater need in the more densely populated areas. This urban success was beneficial for ALLHAT, which was designed to reflect hypertension treatment in the general community. ALLHAT, unlike most clinical trials, had a relatively small number of academic sites (71/623, or 11%, representing 9% of ALLHAT participants).

	Not surprisingly, the number of staff hours was important in the recruitment success of a site investigator; sites with over two staff members working on ALLHAT had almost double the odds of successful recruitment compared to those with fewer staff. The ALLHAT experience is consistent with the conclusions of other studies: site staff influences participant recruitment; staff-patient interaction and recruitment success are directly related.

Thus, more dedicated staff (i.e., time compensated by the site’s study contract) interacting with potential study participants resulted in a greater recruitment outcome.

	The ALLHAT SCs were essential to all study phases, from planning through participant closeout. Participant enrollment, randomization, retention, and data collection depended primarily upon the efforts of the SCs. Percent effort made a difference: investigators with SCs who worked more than 20 hours/week were markedly more successful in recruitment (95% CI, 3.9-307.6; OR, 34.8) compared to those with SCs working fewer hours.  SC training was a part of each annual study meeting, and SC retraining was provided periodically by the ALLHAT regional coordinator offices. Clinical trial planning must include resources to support adequate study staff time (i.e., salaries commensurate with their workload in the study), including time specifically dedicated to training and continuing education.  

	In community-based clinical trials, a physician balances dual roles: that of a clinician and that of an investigator. The conflict between the physician’s roles as researcher versus clinical care provider frequently poses a dilemma to the physician and may translate to a less-than-definitive message to potential participants and those already randomized.

suggest the possibility that investigators with difficulty in assimilating the dual role as both clinician and scientist may have difficulty recruiting participants into a clinical trial. Taylor and Kelner

also noted that physicians have difficulty differentiating their leadership role as either a physician or a scientist. Similarly, the majority of ALLHAT investigators viewed themselves as leaders in the clinical, rather than scientific, field. Yet, greater recruitment success was observed among investigators who valued their role in science, saw their primary commitment to that of future generations, and received patient referrals primarily for their research activities. The ALLHAT experience suggests that investigators who were more firmly committed to the study protocol had better recruitment rates than those less committed. It behooves clinical trial leadership to selectively seek out investigators who are knowledgeable about the current evidence, have equipoise regarding the research question, and are committed to clinical trial principles and cognizant of the potential importance of the outcomes to the community.

	Data regarding the relationship between investigator characteristics and cardiovascular clinical trial participant recruitment are extremely limited in the scientific literature. Clinical trialists need well-designed and tested tools to enhance and support recruitment efforts. ALLHAT, exceeding recruitment goals, successfully randomized 42,418 participants and ultimately observed 99% of expected person-years in the chlorthalidone, amlodipine, and lisinopril treatment groups

and 95% in the prematurely terminated doxazosin group.

This study was well positioned to identify investigator and site characteristics that strengthened participant recruitment.

	This study has several limitations. First, data were not collected on non-responding investigators; how they differed from responders is unknown. Further, several sites with more than one investigator responding to the questionnaires may have been overrepresented, as all responding investigators were counted equally in this study, and non-responding sites were not represented. While characteristics that positively impact cardiovascular clinical trial recruitment may differ in some ways from those of other clinical fields, lessons from ALLHAT may, nonetheless, be applicable to non-cardiovascular, community-based trials. Finally, it is clear that investigators alone do not determine the outcome of participant recruitment in clinical trials. It is, of necessity, a team effort, and the contributions of other members of the physician’s team are a vital component of the process.

	Inability to meet recruitment goals leading to extension of the recruitment period is costly to the sponsors and ultimately detrimental to the timely reporting of study outcomes. Predicting rates of participant recruitment requires assessment of potential site investigators’ likelihood of recruitment success.  ALLHAT provides large clinic and patient population data by which to evaluate the recruitment success of its investigators, and which can be useful for sponsors and sites interested in maximizing clinical trial participant recruitment. These same characteristics may influence participant adherence and thus maximize success in meeting other study-related goals.

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Analysis of the largest antihypertensive trial ever offers useful blueprint for sites in boosting subject enrollment.

Linda B. Piller, MD

Articles

Exploring the Role of the Regional Coordinator

Exploring the Role of the Regional Coordinator

Investigator Characteristics & Patient Recruitment in ALLHAT

Investigator Characteristics and Participant Recruitment in ALLHAT