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Ten Commandments of Successful Trial Management
27, 84–92 (1998) PM970243
PREVENTIVE MEDICINE ARTICLE NO.
Ten Commandments of Successful Trial Management1 Susan E. Margitic´, M.S.,2 and Nancy L. Miles, M.S.N. Department of Public Health Sciences, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1063; and Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee 38105-9664
literature. Although a triad of key textbooks do offer some discussion on this topic [1–3], few journal reports, to our knowledge, focus on trial management [4–6]. Operations and management of a trial clinic may not represent ‘‘rocket science,’’ but lack of their consideration could contribute to the failure of a well thought out, soundly designed study. Poor management can have tremendous repercussions on recruitment efforts (leading to unexpected study extensions [7] or premature trial closure [8]), and can potentially compromise data quality as well as impede an investigator’s efforts to compete for future research awards. In Hunninghake’s article on recruitment in clinical trials [9], the ramifications of facing a prolonged recruitment period are discussed. These same consequences could be cited for a poorly managed trial clinic: ‘‘. . . prolonged duration of the trial, increased costs, morale problems for both participants and staff, and possible alteration of the study results.’’ This report focuses on key management and operational issues with which experienced trial personnel are very likely familiar, but which have not been comprehensively addressed in the literature. These issues, formulated as ten commandments for successful trial management, could prove useful to those new to clinical trials and could perhaps serve as worthwhile reminders to those already involved in trial clinic operations. Although the information offered is based primarily on the multicenter clinical trial experience of the authors, these directives are relevant to singlecenter trial clinics as well.
A well-designed, adequately funded clinical trial based on sound science and conducted by experienced investigators and staff can falter if participating trial clinics are not managed well. Ten commandments for successful trial clinic management address key organizational and operational issues.
● Commandment I: Thou shalt know and follow thy rules. ● Commandment II: Thou shalt know and fulfill thy roles. ● Commandment III: Thou shalt meet thy commitments. ● Commandment IV: Thou shalt collaborate. ● Commandment V: Thou shalt communicate. ● Commandment VI: Thou shalt document. ● Commandment VII: Thou shalt honor thy participants. ● Commandment VIII: Thou shalt keep thy participants’ secrets. ● Commandment IX: Thou shalt revere thy data. ● Commandment X: Thou shalt know and accept thy limitations. This report puts these commandments into context by providing concrete examples in the clinical trial setting. These commandments could serve as guidelines to the spectrum of personnel involved in the operations of a trial clinic, namely, principal investigators and co-investigators, trial coordinators, data managers, technicians, administrators, and support staff. © 1998 Academic Press Key Words: clinical trial; management; organization; communications; trial management communications.
TEN COMMANDMENTS OF SUCCESSFUL TRIAL MANAGEMENT
INTRODUCTION Commandment I: Thou Shalt Know and Follow Thy Rules
Clinical trial management issues have not received a great deal of attention in the clinical trial or medical
Whether a study is multicenter based or a single research clinic, standardization and consistency are imperative for the collection of highly credible data. Trial staff and study investigators should have a working knowledge of the study protocol and the more detailed Manual of Procedures (MOP) that elaborates on protocol procedures. Local training and certification/
1 Adapted from a lecture given in the Clinical Trials Management Workshop I at Bowman Gray School of Medicine. 2 To whom reprint requests should be addressed at Public Health Sciences, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1063. Fax: (910) 716-5425. E-mail: [email protected].
84 0091-7435/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
TEN COMMANDMENTS OF TRIAL MANAGEMENT
recertification for protocol-related procedures help to maintain the theoretical and practical knowledge needed by trial personnel. Procedural revisions in study conduct (usually originating from the sponsor or study coordinating center) should be relayed promptly to trial personnel so that appropriate changes can be implemented. Regular contact between the sponsor or coordinating center and the trial coordinators can facilitate procedural changes and clarify evolving issues. Trial recruitment can present special challenges in terms of complying with study regulations and policies. Temptations to ‘‘bend’’ the eligibility rules must be resisted. This can prove especially difficult when recruitment is not going well [1]. Clinic personnel must adhere rigorously to the protocol inclusion/exclusion criteria and must also remain keenly aware that randomization of a participant into a trial is usually considered an irreversible process (in terms of participant follow-up and, if appropriate, continued treatment). Study staff and investigators need to understand and abide by the intention-to-treat principle (once randomized, always analyzed), which, in many respects, guides trial conduct during both the recruitment and the follow-up phases of a study (in terms of randomization, adherence, and retention). Trial personnel also face conflicts in adhering to the principle of trial blinding. Although one can appreciate the importance of blinding as a strategy to minimize a host of biases in clinical trials [1], some may perceive this approach to be a hindrance to honest and open communications with participants, which remain a key component to the successful clinician–patient relationship. All trial personnel must understand and be willing to honor the rules of blinding. Equally important is the appreciation of and willingness to abide by the conditions dictating unblinding (for example, when needed to evaluate and treat severe adverse events). In addition to knowledge of and adherence to trialwide rules, regulations, and guidelines, there needs to be awareness of and compliance with (1) local institutional policies [(a) Institutional Review Board (IRB) guidelines such as proper procurement and documentation of informed consent and securing IRB approval for revisions to the approved protocol or the informed consent document, (b) Occupational Safety and Health Administration regulations, and (c) handling/ accountability/disposal of study drugs] and (2) sponsor and government policies [(a) National Institutes of Health and (b) Food and Drug Administration (FDA) rules and regulations]. Commandment II: Thou Shalt Know and Fulfill Thy Roles
All clinical trial personnel need to be aware of their expected roles, which should be defined clearly during the interview or orientation process. Key personnel involved in running a trial clinic include clinicians, clinic coordinators, data collectors, data coordinators, re-
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cruitment coordinators, technicians, and support staff, as well as specialized personnel who are unique to the intervention being evaluated (e.g., dietitians involved in a dietary intervention). Personnel configuration will vary from site to site, depending, in great part, on available resources. However, two prominent players generally remain as ‘‘constants’’ in clinical research studies [5]: the trial coordinator and the principal investigator. Their activities, which can influence all aspects of trial conduct and operations, are discussed below (Tables 1 and 2 summarize these roles). A. Roles of the Trial Coordinator Sometimes referred to as the clinic coordinator, clinic manager, program manager, or project manager, the role of the trial coordinator has been described in a number of reports [10–14]. Trial coordinators may or may not be clinicians involved in direct participant health care; however, all should be considered research professionals who make significant contributions to human research studies [5]. This position involves numerous administrative responsibilities, such as coordinating IRB documents (consent forms and annual IRB reports), reporting adverse events to the sponsor or to the study coordinating center, overseeing drug accountability, and expediting paperwork for clinic participants/staff and clinic operations. Trial coordinators, in some scenarios, may have to assume the role of fiscal specialist, attending to clinic budgets and interacting with the trial sponsor as well as the local institution to address fiscal matters that are critical to continued study operations. Another critical role is recruitment coordinator. Even when sufficient funds are available to hire other personnel to recruit participants into a study, the trial coordinator usually oversees recruitment efforts to ensure that target recruitment goals are met on time. The trial coordinator also frequently serves as the primary liaison [regularly communicating with the principal investigator (PI), sponsor representatives, trial staff, participants, participants’ families, and physicians], team TABLE 1 General Responsibilities of the Trial Coordinator • • • • • • • • • • • •
Clinician Research professional Administrator Fiscal specialist Recruitment coordinator Liaison Team leader Educator Counselor and confidante Strategic planner Arbitrator Resource person
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TABLE 2 General Responsibilities of the Principal Investigator To the trial • • • • • • •
Design Management Leadership Meeting recruitment goal Scientific integrity Conflicts of interest Dissemination
To trial participants • Communication • Accessibility • Medical management • • • • •
To trial personnel Accountability Familiarity with clinic operations Accessibility Support, direction, and mediation Delegation with authority
To the medical community • Information about trial • Regular contact with participants’ physicians • Promote team approach
leader, and clinic educator (coordinating training and certifying/recertifying staff on protocol-related activities and ensuring staff compliance with national and institutional regulations). Clinic education also entails instructing participants about intervention and compliance issues. Since the trial coordinator, by definition, coordinates trial operations, certain responsibilities should be considered mandatory for this position. These would include functioning as a counselor and confidante (to staff and participants), strategic planner (facilitating clinic flow, being sensitive to staff burden, participating in short- and long-term planning efforts), arbitrator (addressing personnel conflicts, participant adherence problems), and primary resource person (who is intimately familiar with the study protocol and MOP and who can advise both staff and participants on trialrelated matters). As the primary resource person in the clinic, the trial coordinator should be familiar with all aspects of trial operations, for backup purposes as well as to be better able to appreciate and advise staff, to gain their respect, and to enhance professional credibility. Trial coordinators need to examine their strengths and weaknesses in the above-noted roles so that they can perhaps delegate some of these responsibilities to other colleagues who may have greater expertise in particular areas. Whether they assume all or some of these roles, trial coordinators often face new challenges that call for creativity and flexibility to find solutions that remain within the guidelines of the study protocol.
B. Roles of the Principal Investigator There is very little in the clinical trial literature about the role of the trial investigator [15] or the PI [4,5]. This is unfortunate, because many trial investigators have minimal experience in the administration and management of research trials [16]. Principal investigator responsibilities formulated in this paper are based on our experience and interaction with a number of PIs who fulfill all the roles listed below. Some of these roles relate to nonmanagement topics, but in offering descriptions of these roles, we felt that a more comprehensive overview would be relevant. These responsibilities relate to the trial itself, to trial participants, to trial personnel, and to the medical community. 1. PI responsibilities to the trial. The trial PI ideally has input into the design of a clinical trial since he or she should accept substantial responsibility for the conduct and findings of the study. In assuming this role, the PI implicitly agrees to provide good management of the study clinic and effective study leadership. An example of the former includes assuming a proactive role during the planning phase of the trial (securing adequate clinic space, making contact with other medical investigators/facilities to be included in the trial, etc.). The serious commitment of meeting the clinic’s recruitment goal is not to be taken lightly. Preliminary enthusiasm and optimism can wane as the rigors of recruitment become all too real [17,18]. Failure to recruit participants in a timely fashion could be interpreted as a lack of commitment to the trial. Principal investigators also should be willing to vouch for the scientific integrity of the study (including ethical conduct as well as data integrity), should disclose any potential conflicts of interest (holding stock in or receiving consulting fees from the company producing the drug/device that is being evaluated) [19], and should participate in the dissemination of study results (active involvement in the preparation of the primary outcome paper and other trial-related manuscripts and presentation of trial findings at scientific meetings). Efforts to maintain the scientific integrity of the study should include communicating to all trial investigators and staff the reasons for random (and often blinded) allocation of treatment assignments and the importance of ensuring that randomization does indeed remain a random process [20]. Faculty level clinicians and researchers who are considering the prospect of serving as clinical trial PIs are very likely more interested in the scientific rather than the management aspects of trial participation. This is, in part, a reflection of the premium placed on scientific (as opposed to management) expertise in academia. A successful PI is one who appreciates the intimate relationship between good science and good management.
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2. PI responsibilities to participants. Although not all PIs have direct and frequent contact with study participants, PIs should be willing to communicate with participants when the need arises (perhaps to discuss a safety issue that is of concern to a participant or to facilitate compliance) [21]. Toward this end, the PI should be accessible to the participant. In accepting the role of principal investigator, the PI should also assume responsibility for appropriate medical management of the participant. (See also No. 4 of this section). 3. PI responsibilities to trial personnel. The PI should be held accountable for trial clinic conduct and operations. This accountability should encompass investigator and staff adherence to good clinical practice policies and to the study protocol. In multicenter clinical trials, management problems at one site can affect the entire study. In trials that we have been involved in, the sponsor—and study investigators at other sites—turn to the PI when problems materialize in his/ her clinic. Within the context of accountability is the expectation that the PI will have a working knowledge of the study protocol as well as familiarity with all aspects of clinic operations. Several reports [22,23] have confirmed that investigator unavailability and lack of involvement in a trial represent significant sources of frustration for trial coordinators. PI accessibility to study staff is critical. This may entail not only meeting regularly with staff, but being available on an ‘‘as needed’’ basis to provide support, direction, and, if necessary, mediation. Although trial operations in a particular trial clinic may represent just one piece of a PI’s professional pie, trial staff usually have a much greater time commitment to the study. PI attentiveness, encouragement, praise, and willingness to advise and troubleshoot demonstrate a commitment to the trial and to the trial staff. Finally, the often frequent removal of PIs from day-today clinic operations mandates that the PI delegate with authority to that person coordinating clinic activity [2]. This could be a study co-investigator or the trial coordinator. 4. PI responsibilities to the medical community. The medical community should be informed about an upcoming clinical trial that may enroll patients of local physicians [9,24,25]. The PI should be involved actively in ‘‘priming’’ the medical community via letters to physicians and presentations to local medical organizations. Community physicians should be informed that patient involvement in the trial will not include primary care, but that patient welfare and safety remain a primary concern for those enrolled in the study (see Commandment V, Section B, for additional safety information to be communicated to study participants’ physicians). The PI should ‘‘reach out’’ to physicians of
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enrolled (or potentially enrolled) participants [26] through early and regular contact to enlist their cooperation and support. This, in turn, can promote a team approach between trial staff and the personal physician that may facilitate participant trial compliance. The authors of this report acknowledge that the roles described above are not all inclusive and will, especially for the trial coordinator, vary with the type of trial, the available funding, the personnel configuration of the trial clinic, and the individual expertise of those assuming these roles. Commandment III: Thou Shalt Meet Thy Commitments
Being part of a trial clinic implies making certain commitments, such as agreeing to abide by the study protocol, being willing to put forth the enormous effort and extra time to screen and randomize a predetermined number of participants, fulfilling assigned trial roles, and working as a team to accomplish mutual goals. During the interviewing process, prospective trial employees should be made aware of the responsibilities they will assume and the corresponding commitments expected of them. These should be discussed in the context of the environment in which they will be working. The implications of working in a trial clinic as opposed to a regular clinical practice should be conveyed, since the activities and goals of these two different work settings vary considerably [12]. For example, trial clinic patient management focuses on protocol-related outcomes and adverse events, with more general patient care being channeled back to the primary physician. Clinicians working in a study clinic must also be willing to accept more rigorous training, more routine quality control monitoring, and less flexibility in practicing medicine than if they were working in a regular medical practice. Often, the goals and commitments of a study change as the study evolves. New tests/procedures may be required without the benefit of additional funding or unexpected budget cuts may be encountered. This calls for exercising flexibility and finding creative solutions to meet new commitments (enlisting services of volunteers, obtaining contributions in goods and services from local businesses, etc.). Commandment IV: Thou Shalt Collaborate
Although managing a trial clinic involves division of labor, successful trial operations depend on group and individual efforts. No one person can conduct even the smallest trial single-handedly. Collaboration, therefore is a primary factor in successful trial clinic operations. Collaborative activities involved in running a trial clinic include: ● trial coordination (managing and coordinating clinic activities),
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● recruitment coordination (committed to screening and recruitment), ● retention/adherence monitoring (committed to participant retention in the trial and adherence to the assigned treatment regimen), ● data collection (interviewing participants and completing the data collection forms), ● data coordination (editing the forms, keying the collected data into the study database, correcting data errors), ● clinician responsibilities (performing physical exams and medical tests, interpreting diagnostic procedures), ● technician responsibilities (drawing and processing blood, performing blood pressure and other measurements), ● outcomes surveillance (verifying primary and secondary study endpoints), and ● support staff responsibilities (preparing written documents, providing phone support, scheduling appointments, etc.). Unfortunately, we live in a fiscal climate dictated by budget constraints [27] and controlled staffing patterns, compelling investigators to make difficult decisions concerning staff configuration. One solution to this problem involves hiring individuals to assume multiple roles: the trial coordinator may be the study clinician, support staff could be trained to do data entry, and the recruitment coordinator could later focus on retention/adherence activities. Investigators need to prioritize staff positions, then determine which multiple responsibilities could be assumed by one person. Factors affecting these decisions include the level of funding, the size of the trial, the level of expertise among trial staff, and the personal preferences of the PI and the trial coordinator. An important downside to this approach is the greater probability for staff burnout among those individuals who do perform multiple trial activities. The advantages of this tactic relate to cross training (which should be implemented in all trial clinics to allow for backup of key personnel) and greater job satisfaction and commitment for those individuals who enjoy the challenge and diversity associated with assuming multiple job responsibilities. Another dimension of trial collaboration relates to collaboratively written clinical trial reports. Investigators should be aware that nonfaculty study personnel such as trial coordinators may be just as eager to participate in the publication process as their faculty/ investigator counterparts. Opportunities should be available for key trial employees to become engaged in and receive credit for publication efforts. Commandment V: Thou Shalt Communicate
Good communication is the cornerstone of collaboration. Effective (and reciprocal) communication is one of
the most essential components of multicenter clinical trials [16]. Three primary modes of communication in the clinical trial setting include communication among clinical staff, communicating with participants’ physicians, and clinic communications with the coordinating center and/or trial sponsor (communications with study participants is discussed under Commandment VII). Table 3 provides a summary of communications in a clinical trial. A. Communications among Clinical Staff Regular and frequent staff meetings provide forums for discussion of logistical issues such as problems with clinic flow and recruitment and compliance. These meetings also provide opportunities to build staff morale, reinforce team building, and allow staff to air grievances that may be shared by their colleagues. To channel such interactions in a productive direction, the person conducting these meetings in the absence of the PI needs to have good delegation of authority from the PI. Communication also involves resolving conflicts that may arise among staff or between staff members and participants, briefing the PI on appropriate issues, and ensuring that the PI briefs trial staff on policy or protocol changes. Successful communications with the PI implies PI accessibility to his/her staff. TABLE 3 Communications in the Clinical Trial Setting • • • • • • • •
Communications among trial staff Regular and frequent staff meetings Good delegation of authority Resolving conflicts Briefing the PI PI briefs staff PI accessibility Encourage comments from co-workers Hierarchy of communication
• • • • • •
Communications with participants’ physicians Establish early contact Provide information Reassure physicians’ roles as primary caregivers Forward appropriate and pertinent participant data Refer participants back to physicians Promote team approach
• • • • • • • •
Communications with participants High priority to informed consent Quick follow-up on inquiries Timely provision of appropriate clinical data Good clinic phone coverage Uniform information from staff and investigators Convey sincerity, patience, sensitivity, and recognition Accommodate participant needs Maintain professional integrity/appearance
Communications with coordinating center or sponsor • Routine issues • Safety issues • Clarification
TEN COMMANDMENTS OF TRIAL MANAGEMENT
The clinic supervisor (usually the trial coordinator or a study co-investigator) should encourage comments and suggestions from co-workers. These can provide fresh perspectives that may lead to improved operations, and they demonstrate appreciation for and recognition of trial employees. Finally, a hierarchy of communication needs to be established so that staff members know to whom they should report and with whom they could consult about particular issues. B. Communications with Participants’ Physicians As noted under Commandment II, Section B4, trial clinic personnel should establish early contact with participants’ physicians (usually through a letter signed by the PI) to inform physicians of their patients’ involvement in the trial; to provide information about the trial goals, interventions, risks, benefits, length of follow-up, frequency of follow-up visits, tests, and procedures; and to reassure physicians that they will remain the primary health care providers for their patients. Also to be communicated to participants’ physicians are promises to forward appropriate and pertinent participant data in a timely fashion (routine test findings, pathology reports, etc.) and to refer participants back to their physicians should unexpected findings emerge in the trial clinic. These communications, though time-consuming for clinic staff, can promote a team approach between the trial clinic and the personal physician. Potential participants should be encouraged to discuss trial enrollment with their personal physicians [28]. Continued support for the trial from a participant’s health care provider can facilitate participant trial compliance. C. Communications with the Coordinating Center and/or the Trial Sponsor Communications with the coordinating center and/or the trial sponsor could be classified into three categories: routine, safety related, and clarification. Examples of routine communications include regularly scheduled conference calls [16] (during which information is shared between sites and protocol issues and problems are discussed), clinic requests for central purchase of standard inventory items (blood collection supplies) or unexpected additional items not included in the original clinic budget, and discussions regarding data edits/corrections and budgetary issues. Examples of safety-related communications include reporting adverse events, questioning whether or not a study medication should be discontinued or tapered, requesting an emergency unblinding of a participant, and providing information regarding the death of a study subject. Clarification issues often refer to interpretation of the protocol, questions about study eligibility, administra-
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tion of the intervention, exceeding the permitted window of time surrounding a screening or follow-up visit, etc. Commandment VI: Thou Shalt Document
Proper study documentation involves accurate completion of the data collection forms in conjunction with interviewing participants and retaining datarelated source documents (lab slips, pathology or ECG reports, etc.). Examples of critical documents to be stored and updated on site include IRB approval letters and communications, protocol amendments and MOP revisions, FDA 1572 Forms for investigational drug trials (to be completed for original and new investigators joining the study), and investigational drug adverse event reports and accountability logs. Important written and e-mail communications should also be stored, and pertinent phone calls should be documented and filed. These could relate to protocol interpretation (for example, confirmation from the coordinating center that a participant remains eligible for enrollment despite some unusual circumstance or condition), reporting adverse events to the FDA/coordinating center/ sponsor, and relevant conversations with participants, their physicians, or study sponsor representatives. Commandment VII: Thou Shalt Honor Thy Participants
Without participants, there would be no clinical research. Respect, concern, and appreciation should be conveyed to all potential and randomized participants, in conjunction with providing comprehensive yet understandable information about the trial. Information giving begins during the informed consent process. Despite receiving informed consent, there are indications that participants remain ignorant about important aspects of a trial in both the short term [29,30] and the long term [31]. Trial staff and investigators should give high priority to the informed consent process so that participants understand what is involved in trial participation. Providing pertinent information about the trial and trial-related issues should be an ongoing process that spans the duration of the study. Study newsletters can greatly facilitate this information-giving process [16]. Investigators and staff should maintain regular contact with study participants throughout the trial to reinforce enthusiasm for the study and to promote adherence [1]. Immediate attention to participant adverse events, whether self-reported or measured, is essential. Quick follow-up on participant concerns and inquiries reflects staff/investigator dependability, credibility, and concern, as does the timely provision of appropriate clinical data (for example, certain diagnostic test results). Since participants communicate regularly with trial staff by phone, good clinic phone coverage is essential. Uniform information from clinic staff/investigators implies that all trial personnel are familiar with clinic operations, the study protocol, and the MOP, so that
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participants receive consistent directions, advice, and responses to their questions. Conveying sincerity, patience, sensitivity, and recognition may require extra effort and time; however, these attributes may enhance compliance and retention. Another measure to improve participant compliance and retention relates to communicating staff willingness to accommodate participant needs (for example, scheduling clinic visits in the evenings or on the weekends) [28]. Trial personnel should also maintain good professional integrity and professional appearance, which can lead to greater participant confidence in the staff and in the study. Table 3 summarizes these communication strategies. Commandment VIII: Thou Shalt Keep Thy Participants’ Secrets
Participant confidentiality must be maintained during and after a clinical trial [2]. Efforts to ensure participant confidentiality include arranging maximal privacy for interviewing, securing participant files to guard against their unauthorized use (participant files should never be left in undesignated areas of the clinic where other participants or nontrial employees could look through them), and having restricted access to the study database (only authorized personnel with proper passwords should be able to log on to the clinic computer). Finally, participant identifiers (name, photograph, identification or social security number) should never be included in trial publications or presentations, unless preapproved by the participant [2]. Commandment IX: Thou Shalt Revere Thy Data
Given the daily grind and bureaucracy involved in running a trial clinic, staff and investigators should be reminded occasionally that one of their primary goals is the collection of high-quality data, which will allow the study to answer an important medical question that could contribute to improved health care. This begins with proper training, certification, and standardization [32]; scrupulous data collection [33]; transcription and source documentation, and awareness of and involvement in quality control efforts. Those coordinating clinic operations should build in personnel time and effort to review the data collection forms for completeness, consistency, and accuracy before their timely entry into the study database. Responses to coordinating center inquiries about questionable data should be prompt. Backups of the local database should be performed daily, and, if distributed data entry is not utilized, data should be downloaded and forwarded to the coordinating center according to the study-dictated schedule. Training, certification, and recertification of staff (and sometimes investigators) are laborious but necessary to maximize the likelihood of obtaining consistent measures within and between trial staff. Clinics utilizing the services of a local outside facility
for study purposes (laboratory analyses, mammogram, or bone scan site) should work closely with facility staff to promote adherence to protocol guidelines (performing standardized procedures/measurements, proper completion of the data collection forms, etc.). Quality assurance efforts cover a spectrum of activities in a trial clinic. These include, but are not limited to, assuring: (1) the safety of study participants (for example, training staff to properly monitor and document adverse and clinical events that may or may not be related to study participation); (2) the integrity of the informed consent process, randomization, and blinding; (3) protocol-dictated delivery of and adherence to the intervention, including timely participant follow-up visits and primary/secondary outcome measures; and (4) systematic monitoring of study data (data editing, correction, and analysis). Commandment X: Thou Shalt Know and Accept Thy Limitations
Trial coordinators (as well as other clinic personnel) are at risk for burnout, because, in great part, such demanding positions attract dedicated and hardworking individuals who place many demands on themselves. There is also the broad spectrum of coordinator duties that can be especially overwhelming to those new to this position [16]. Conducting a clinical trial is a collaborative effort that implies shared responsibility in its operation and management. No one individual, not even the trial coordinator, should be expected to perform an unrealistic number of tasks. Cross training and back-up strategies can partially guard against staff burnout. However, study investigators need to be sensitive to this looming threat, which can significantly slow down trial progress if burnout leads to job resignation. Arrangements should be made for trial staff and investigators to occasionally meet socially in and out of the clinic. Earned vacations should be taken at mutually agreed upon times. Staff incentives (e.g., closing the clinic for one day when interim recruitment goals are attained) can prove to be real motivators. Personnel should be encouraged to vent their work-related frustrations by discussing their concerns with their supervisors. CONCLUSION
Although we have tried to cover major points related to clinical trial management, the topics discussed and the examples given are not all-inclusive. We do feel that the ten commandments addressed in this report have relevance to other types of epidemiological investigations beyond clinical trials, such as observational studies. The information and recommendations provided in this paper are based on the multicenter clinical trial experience of the authors, who have been involved in
TEN COMMANDMENTS OF TRIAL MANAGEMENT
Phase III clinical trials conducted in an academic environment. We therefore cannot address other types of research settings, such as earlier phase trials or pharmacokinetic studies, nor can we offer advice specific to those working in a contract research organization, which conducts trials sponsored by industry. Although we feel certain that the ten commandments discussed would apply to these settings, it would be very useful for those working in these environments to put forward their own experiences and recommendations concerning how best to manage a clinical trial. Some examples cited in this report fall under more than one commandment (communications with participant physicians are described under Commandments II and V). Although this leads to some redundancy, we felt that these topics merited discussion under the two different categories. If one were to highlight the major challenges and sources of frustration encountered in managing a trial clinic, the list would probably include the heroic efforts needed to achieve the recruitment goal [22,25,28,34], insufficient funding, the constant and demanding burden of paperwork [22] and documentation, the unending vigilance needed to maintain participant and staff compliance with the protocol, challenges faced in retaining participants in the study, and personnel turnover (more of a threat to longer running trials). Personnel turnover may be due to frustrations originating from inadequate staffing to get the job done, lack of PI support and involvement, insufficient autonomy, misguided expectations, unrealized salary expectations, lack of job security, and personnel conflict (for example, troublesome colleagues who either fail to contribute their expected workload or bring conflict rather than collaboration to the work setting). Staff turnover can impede trial progress, whether it occurs during the early [35] or later stages of a trial. Principal investigators and clinic supervisory staff should do everything possible to make job conditions as reasonably pleasant, harmonious, productive, and efficient as possible. This too can be a daunting challenge, given today’s budgetary constraints. Maintaining a good sense of humor (no costs involved) can prove to be especially valuable as a stress reliever. The positive aspects of working in a trial clinic should be emphasized. These include collaboration, contribution to science and improved public health, patient contact, intellectual stimulation, job diversity, publication, and sometimes travel opportunities. Expecting the unexpected could be considered a positive factor for creative individuals who enjoy new challenges. The day-to-day problems faced in managing a clinical trial can obscure the reasons for initially becoming involved in medical research. The following excerpted quote by D. S. Fredrickson [36] sums up the frustrations faced and ultimate ‘‘raison d’etre’’ for performing
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human research studies (referred to as ‘‘field trials’’ in his article). [Field trials] . . . lack glamour; they strain our resources and patience, and they protract to excruciating limits the moment of truth. Still, they are among the most challenging tests of our skills . . . I have no doubt that when the problem is well chosen, the study is appropriately designed, and all the population concerned made aware of the route and the goal, the reward can be commensurate with the effort. If, in major medical dilemmas, the alternative is to pay the cost of perpetual uncertainty, have we really any choice? ACKNOWLEDGMENT The authors thank Dr. Roger Anderson, Dr. Walter Ettinger, Ms. Beate Griffin, Ms. Patricia Hogan, and Dr. Electra Paskett for their willingness to review the manuscript and to provide valuable comments, which have enriched the paper. REFERENCES 1. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 3rd ed. Littleton, MA: PSG Pub., 1996. 2. Meinert CL. Clinical trials: design, conduct and analysis. In: Monographs in epidemiology and biostatistics, Vol. 8. New York/ Oxford: Oxford Univ. Press, 1986. 3. Spilker B. A guide to clinical trials. New York: Raven Press, 1992. 4. Warlow C. How to do it: organise a multicentre trial. Br Med J 1990;300:180–3. 5. Eaton T, Pratt CM. A clinic’s perspective on screening, recruitment and data collection. Stat Med 1990;9:137–44. 6. Probstfield JL, Russel ML, Silvers A, Goodwin DL, Insull W. Clinical trials methods and the practice of medicine. Controlled Clin Trials 1984;5:321–7. 7. Benedict GW. LRC coronary prevention trial: Baltimore. Clin Pharmacol Ther 1979;25:685–7. 8. Collins JF, Williford WO, Weiss DG, Bingham SF, Klett CJ. Planning patient recruitment: fantasy and reality. Stat Med 1984;3:435–43. 9. Hunninghake DB, Darby CA, Probstfield JL. Recruitment experience in clinical trials: literature summary and annotated bibliography. Controlled Clin Trials 1987;8:6S–30S. 10. The DCCT Research Group. The Diabetes Control and Complications Trial (DCCT): the trial coordinator perspective. Diabetes Educ 1989;15:236–41. 11. Mullin SM, Warwick S, Akers M, Beecher P, Helminger K, Moses B, et al. and the MILIS Study Group. An acute intervention trial: the research nurse coordinator’s role, Controlled Clin Trials 1984;5:141–56. 12. Chadwick LR. Professional nursing with a new focus: staff nurse to research coordinator. J Neurosci Nurs 1992;24:170–5. 13. Barnes G. A nurse’s experience in the MRC’s hypertension trial. Br Med J 1982;285:1625–7. 14. White-Hershey D, Nevidjon B. Fundamentals for oncology nurse/data managers—preparing for a new role. Oncol Nurs Forum 1990;17:371–7. 15. Dobkin B. Testing time. Discover 1990 May. 16. Naydek BL, Sutton-Tyrrell K, Burek K, Sopko GS. Organizational structure and communication strategies of the Bypass Angioplasty Revascularization Investigation: a multicenter clinical trial. Controlled Clin Trials 1996;17:226–34. 17. Tognoni G, Alli C, Avanzini F, Bettelli G, Columbo F, Corso R, et al. Randomised clinical trials in general practice: lessons from a failure. Br Med J 1991;303:969–71.
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18. Greenburg G. Clinical trials in general practice. Br Med J 1991; 303:940. 19. Agnew B. Coming: a user-friendly code on conflict of interest. J Natl Inst Health Res 1994;6:29–30. 20. Martyn C. Commentary: not quite as random as I pretended. Lancet 1996;347:70. 21. Cramer JA, Russell ML. Strategies to enhance adherence to a medical regimen. In: Schmidt D and Leppik IE, editors. Compliance in epilepsy (Epilepsy Res. Suppl. 1). Amsterdam: Elsevier (Biomedical Division), 1988. 22. Kellen JC, Schron EB, McBride R, Hale C, Campion J, Handshaw K, et al. A survey of clinical trial coordinators: factors influencing job satisfaction and turnover. Cardiovasc Nurs 1994; 30:25–31. 23. Hewson S, Weston J, Hannah M. TERMPROM coordinator survey. Controlled Clin Trials 1995;16:36S. 24. Baines CJ. Impediments to recruitment in the Canadian National Breast Screening Study: response and resolution. Controlled Clin Trials 1984;5:129–40. 25. Petrovitch H, Byington R, Bailey G, Borhani P, Carmody S, Goodwin L, et al. Systolic Hypertension in the Elderly Program (SHEP). Pt 2. Screening and recruitment. Hypertension 1991;17 Suppl II:16–23. 26. Gorkin L, Goldstein MG, Follick MJ, Lefebvre RC. Strategies for enhancing adherence in clinical trials. In: Shumaker SA, Schron EB, Ockene JK, editors. The handbook of health behavior change. New York: Springer, 1990.
27. Meinert CL. Multicenter clinical trials and travel: luxury or necessity? Controlled Clin Trials 1990;11:399–401. 28. Trottier D, Kochar MS. Overcoming obstacles to recruitment and retention of subjects in clinical studies. J Clin Res Drug Dev 1994;8:49–54. 29. Bergler JH, Pennington AC, Metcalfe M, Freis E. Informed consent: how much does the patient understand? Pharmacol Ther 1980;27:435–40. 30. Miller C, Searight H, Grable D, Schwartz R, Sowell C, Barbarash R. Comprehension and recall of the informational content of the informed consent document: an evaluation of 168 patients in a controlled clinical trial. J Clin Res Drug Dev 1994;8:237–48. 31. Taub HA. Comprehension of informed consent for research: issues and directions for future study. IRB 1986;8:7–10. 32. Gassman JJ, Owen WW, Kuntz TE, Martin JP, Amoroso WP. Data quality assurance, monitoring, and reporting. Controlled Clin Trials 1995;16:104S–36S. 33. Hosking JD, Newhouse MM, Bagniewska A, Hawkins BS. Data collection and transcription. Controlled Clin Trials 1995;16:66S– 103S. 34. Ederer F. Practical problems in collaborative clinical trials. Am J Epidemiol 1975;102:111–8. 35. Margitic´ SE, Byington RP. Problems in initiating recruitment in a clinical trial. Controlled Clin Trials 1990;11:289. 36. Fredrickson DS. The field trial: some thoughts on the indispensable ordeal. Bull N Y Acad Med 1968;44:985–93.
PREVENTIVE MEDICINE ARTICLE NO.
Ten Commandments of Successful Trial Management1 Susan E. Margitic´, M.S.,2 and Nancy L. Miles, M.S.N. Department of Public Health Sciences, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1063; and Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee 38105-9664
literature. Although a triad of key textbooks do offer some discussion on this topic [1–3], few journal reports, to our knowledge, focus on trial management [4–6]. Operations and management of a trial clinic may not represent ‘‘rocket science,’’ but lack of their consideration could contribute to the failure of a well thought out, soundly designed study. Poor management can have tremendous repercussions on recruitment efforts (leading to unexpected study extensions [7] or premature trial closure [8]), and can potentially compromise data quality as well as impede an investigator’s efforts to compete for future research awards. In Hunninghake’s article on recruitment in clinical trials [9], the ramifications of facing a prolonged recruitment period are discussed. These same consequences could be cited for a poorly managed trial clinic: ‘‘. . . prolonged duration of the trial, increased costs, morale problems for both participants and staff, and possible alteration of the study results.’’ This report focuses on key management and operational issues with which experienced trial personnel are very likely familiar, but which have not been comprehensively addressed in the literature. These issues, formulated as ten commandments for successful trial management, could prove useful to those new to clinical trials and could perhaps serve as worthwhile reminders to those already involved in trial clinic operations. Although the information offered is based primarily on the multicenter clinical trial experience of the authors, these directives are relevant to singlecenter trial clinics as well.
A well-designed, adequately funded clinical trial based on sound science and conducted by experienced investigators and staff can falter if participating trial clinics are not managed well. Ten commandments for successful trial clinic management address key organizational and operational issues.
● Commandment I: Thou shalt know and follow thy rules. ● Commandment II: Thou shalt know and fulfill thy roles. ● Commandment III: Thou shalt meet thy commitments. ● Commandment IV: Thou shalt collaborate. ● Commandment V: Thou shalt communicate. ● Commandment VI: Thou shalt document. ● Commandment VII: Thou shalt honor thy participants. ● Commandment VIII: Thou shalt keep thy participants’ secrets. ● Commandment IX: Thou shalt revere thy data. ● Commandment X: Thou shalt know and accept thy limitations. This report puts these commandments into context by providing concrete examples in the clinical trial setting. These commandments could serve as guidelines to the spectrum of personnel involved in the operations of a trial clinic, namely, principal investigators and co-investigators, trial coordinators, data managers, technicians, administrators, and support staff. © 1998 Academic Press Key Words: clinical trial; management; organization; communications; trial management communications.
TEN COMMANDMENTS OF SUCCESSFUL TRIAL MANAGEMENT
INTRODUCTION Commandment I: Thou Shalt Know and Follow Thy Rules
Clinical trial management issues have not received a great deal of attention in the clinical trial or medical
Whether a study is multicenter based or a single research clinic, standardization and consistency are imperative for the collection of highly credible data. Trial staff and study investigators should have a working knowledge of the study protocol and the more detailed Manual of Procedures (MOP) that elaborates on protocol procedures. Local training and certification/
1 Adapted from a lecture given in the Clinical Trials Management Workshop I at Bowman Gray School of Medicine. 2 To whom reprint requests should be addressed at Public Health Sciences, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1063. Fax: (910) 716-5425. E-mail: [email protected].
84 0091-7435/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
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recertification for protocol-related procedures help to maintain the theoretical and practical knowledge needed by trial personnel. Procedural revisions in study conduct (usually originating from the sponsor or study coordinating center) should be relayed promptly to trial personnel so that appropriate changes can be implemented. Regular contact between the sponsor or coordinating center and the trial coordinators can facilitate procedural changes and clarify evolving issues. Trial recruitment can present special challenges in terms of complying with study regulations and policies. Temptations to ‘‘bend’’ the eligibility rules must be resisted. This can prove especially difficult when recruitment is not going well [1]. Clinic personnel must adhere rigorously to the protocol inclusion/exclusion criteria and must also remain keenly aware that randomization of a participant into a trial is usually considered an irreversible process (in terms of participant follow-up and, if appropriate, continued treatment). Study staff and investigators need to understand and abide by the intention-to-treat principle (once randomized, always analyzed), which, in many respects, guides trial conduct during both the recruitment and the follow-up phases of a study (in terms of randomization, adherence, and retention). Trial personnel also face conflicts in adhering to the principle of trial blinding. Although one can appreciate the importance of blinding as a strategy to minimize a host of biases in clinical trials [1], some may perceive this approach to be a hindrance to honest and open communications with participants, which remain a key component to the successful clinician–patient relationship. All trial personnel must understand and be willing to honor the rules of blinding. Equally important is the appreciation of and willingness to abide by the conditions dictating unblinding (for example, when needed to evaluate and treat severe adverse events). In addition to knowledge of and adherence to trialwide rules, regulations, and guidelines, there needs to be awareness of and compliance with (1) local institutional policies [(a) Institutional Review Board (IRB) guidelines such as proper procurement and documentation of informed consent and securing IRB approval for revisions to the approved protocol or the informed consent document, (b) Occupational Safety and Health Administration regulations, and (c) handling/ accountability/disposal of study drugs] and (2) sponsor and government policies [(a) National Institutes of Health and (b) Food and Drug Administration (FDA) rules and regulations]. Commandment II: Thou Shalt Know and Fulfill Thy Roles
All clinical trial personnel need to be aware of their expected roles, which should be defined clearly during the interview or orientation process. Key personnel involved in running a trial clinic include clinicians, clinic coordinators, data collectors, data coordinators, re-
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cruitment coordinators, technicians, and support staff, as well as specialized personnel who are unique to the intervention being evaluated (e.g., dietitians involved in a dietary intervention). Personnel configuration will vary from site to site, depending, in great part, on available resources. However, two prominent players generally remain as ‘‘constants’’ in clinical research studies [5]: the trial coordinator and the principal investigator. Their activities, which can influence all aspects of trial conduct and operations, are discussed below (Tables 1 and 2 summarize these roles). A. Roles of the Trial Coordinator Sometimes referred to as the clinic coordinator, clinic manager, program manager, or project manager, the role of the trial coordinator has been described in a number of reports [10–14]. Trial coordinators may or may not be clinicians involved in direct participant health care; however, all should be considered research professionals who make significant contributions to human research studies [5]. This position involves numerous administrative responsibilities, such as coordinating IRB documents (consent forms and annual IRB reports), reporting adverse events to the sponsor or to the study coordinating center, overseeing drug accountability, and expediting paperwork for clinic participants/staff and clinic operations. Trial coordinators, in some scenarios, may have to assume the role of fiscal specialist, attending to clinic budgets and interacting with the trial sponsor as well as the local institution to address fiscal matters that are critical to continued study operations. Another critical role is recruitment coordinator. Even when sufficient funds are available to hire other personnel to recruit participants into a study, the trial coordinator usually oversees recruitment efforts to ensure that target recruitment goals are met on time. The trial coordinator also frequently serves as the primary liaison [regularly communicating with the principal investigator (PI), sponsor representatives, trial staff, participants, participants’ families, and physicians], team TABLE 1 General Responsibilities of the Trial Coordinator • • • • • • • • • • • •
Clinician Research professional Administrator Fiscal specialist Recruitment coordinator Liaison Team leader Educator Counselor and confidante Strategic planner Arbitrator Resource person
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TABLE 2 General Responsibilities of the Principal Investigator To the trial • • • • • • •
Design Management Leadership Meeting recruitment goal Scientific integrity Conflicts of interest Dissemination
To trial participants • Communication • Accessibility • Medical management • • • • •
To trial personnel Accountability Familiarity with clinic operations Accessibility Support, direction, and mediation Delegation with authority
To the medical community • Information about trial • Regular contact with participants’ physicians • Promote team approach
leader, and clinic educator (coordinating training and certifying/recertifying staff on protocol-related activities and ensuring staff compliance with national and institutional regulations). Clinic education also entails instructing participants about intervention and compliance issues. Since the trial coordinator, by definition, coordinates trial operations, certain responsibilities should be considered mandatory for this position. These would include functioning as a counselor and confidante (to staff and participants), strategic planner (facilitating clinic flow, being sensitive to staff burden, participating in short- and long-term planning efforts), arbitrator (addressing personnel conflicts, participant adherence problems), and primary resource person (who is intimately familiar with the study protocol and MOP and who can advise both staff and participants on trialrelated matters). As the primary resource person in the clinic, the trial coordinator should be familiar with all aspects of trial operations, for backup purposes as well as to be better able to appreciate and advise staff, to gain their respect, and to enhance professional credibility. Trial coordinators need to examine their strengths and weaknesses in the above-noted roles so that they can perhaps delegate some of these responsibilities to other colleagues who may have greater expertise in particular areas. Whether they assume all or some of these roles, trial coordinators often face new challenges that call for creativity and flexibility to find solutions that remain within the guidelines of the study protocol.
B. Roles of the Principal Investigator There is very little in the clinical trial literature about the role of the trial investigator [15] or the PI [4,5]. This is unfortunate, because many trial investigators have minimal experience in the administration and management of research trials [16]. Principal investigator responsibilities formulated in this paper are based on our experience and interaction with a number of PIs who fulfill all the roles listed below. Some of these roles relate to nonmanagement topics, but in offering descriptions of these roles, we felt that a more comprehensive overview would be relevant. These responsibilities relate to the trial itself, to trial participants, to trial personnel, and to the medical community. 1. PI responsibilities to the trial. The trial PI ideally has input into the design of a clinical trial since he or she should accept substantial responsibility for the conduct and findings of the study. In assuming this role, the PI implicitly agrees to provide good management of the study clinic and effective study leadership. An example of the former includes assuming a proactive role during the planning phase of the trial (securing adequate clinic space, making contact with other medical investigators/facilities to be included in the trial, etc.). The serious commitment of meeting the clinic’s recruitment goal is not to be taken lightly. Preliminary enthusiasm and optimism can wane as the rigors of recruitment become all too real [17,18]. Failure to recruit participants in a timely fashion could be interpreted as a lack of commitment to the trial. Principal investigators also should be willing to vouch for the scientific integrity of the study (including ethical conduct as well as data integrity), should disclose any potential conflicts of interest (holding stock in or receiving consulting fees from the company producing the drug/device that is being evaluated) [19], and should participate in the dissemination of study results (active involvement in the preparation of the primary outcome paper and other trial-related manuscripts and presentation of trial findings at scientific meetings). Efforts to maintain the scientific integrity of the study should include communicating to all trial investigators and staff the reasons for random (and often blinded) allocation of treatment assignments and the importance of ensuring that randomization does indeed remain a random process [20]. Faculty level clinicians and researchers who are considering the prospect of serving as clinical trial PIs are very likely more interested in the scientific rather than the management aspects of trial participation. This is, in part, a reflection of the premium placed on scientific (as opposed to management) expertise in academia. A successful PI is one who appreciates the intimate relationship between good science and good management.
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2. PI responsibilities to participants. Although not all PIs have direct and frequent contact with study participants, PIs should be willing to communicate with participants when the need arises (perhaps to discuss a safety issue that is of concern to a participant or to facilitate compliance) [21]. Toward this end, the PI should be accessible to the participant. In accepting the role of principal investigator, the PI should also assume responsibility for appropriate medical management of the participant. (See also No. 4 of this section). 3. PI responsibilities to trial personnel. The PI should be held accountable for trial clinic conduct and operations. This accountability should encompass investigator and staff adherence to good clinical practice policies and to the study protocol. In multicenter clinical trials, management problems at one site can affect the entire study. In trials that we have been involved in, the sponsor—and study investigators at other sites—turn to the PI when problems materialize in his/ her clinic. Within the context of accountability is the expectation that the PI will have a working knowledge of the study protocol as well as familiarity with all aspects of clinic operations. Several reports [22,23] have confirmed that investigator unavailability and lack of involvement in a trial represent significant sources of frustration for trial coordinators. PI accessibility to study staff is critical. This may entail not only meeting regularly with staff, but being available on an ‘‘as needed’’ basis to provide support, direction, and, if necessary, mediation. Although trial operations in a particular trial clinic may represent just one piece of a PI’s professional pie, trial staff usually have a much greater time commitment to the study. PI attentiveness, encouragement, praise, and willingness to advise and troubleshoot demonstrate a commitment to the trial and to the trial staff. Finally, the often frequent removal of PIs from day-today clinic operations mandates that the PI delegate with authority to that person coordinating clinic activity [2]. This could be a study co-investigator or the trial coordinator. 4. PI responsibilities to the medical community. The medical community should be informed about an upcoming clinical trial that may enroll patients of local physicians [9,24,25]. The PI should be involved actively in ‘‘priming’’ the medical community via letters to physicians and presentations to local medical organizations. Community physicians should be informed that patient involvement in the trial will not include primary care, but that patient welfare and safety remain a primary concern for those enrolled in the study (see Commandment V, Section B, for additional safety information to be communicated to study participants’ physicians). The PI should ‘‘reach out’’ to physicians of
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enrolled (or potentially enrolled) participants [26] through early and regular contact to enlist their cooperation and support. This, in turn, can promote a team approach between trial staff and the personal physician that may facilitate participant trial compliance. The authors of this report acknowledge that the roles described above are not all inclusive and will, especially for the trial coordinator, vary with the type of trial, the available funding, the personnel configuration of the trial clinic, and the individual expertise of those assuming these roles. Commandment III: Thou Shalt Meet Thy Commitments
Being part of a trial clinic implies making certain commitments, such as agreeing to abide by the study protocol, being willing to put forth the enormous effort and extra time to screen and randomize a predetermined number of participants, fulfilling assigned trial roles, and working as a team to accomplish mutual goals. During the interviewing process, prospective trial employees should be made aware of the responsibilities they will assume and the corresponding commitments expected of them. These should be discussed in the context of the environment in which they will be working. The implications of working in a trial clinic as opposed to a regular clinical practice should be conveyed, since the activities and goals of these two different work settings vary considerably [12]. For example, trial clinic patient management focuses on protocol-related outcomes and adverse events, with more general patient care being channeled back to the primary physician. Clinicians working in a study clinic must also be willing to accept more rigorous training, more routine quality control monitoring, and less flexibility in practicing medicine than if they were working in a regular medical practice. Often, the goals and commitments of a study change as the study evolves. New tests/procedures may be required without the benefit of additional funding or unexpected budget cuts may be encountered. This calls for exercising flexibility and finding creative solutions to meet new commitments (enlisting services of volunteers, obtaining contributions in goods and services from local businesses, etc.). Commandment IV: Thou Shalt Collaborate
Although managing a trial clinic involves division of labor, successful trial operations depend on group and individual efforts. No one person can conduct even the smallest trial single-handedly. Collaboration, therefore is a primary factor in successful trial clinic operations. Collaborative activities involved in running a trial clinic include: ● trial coordination (managing and coordinating clinic activities),
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● recruitment coordination (committed to screening and recruitment), ● retention/adherence monitoring (committed to participant retention in the trial and adherence to the assigned treatment regimen), ● data collection (interviewing participants and completing the data collection forms), ● data coordination (editing the forms, keying the collected data into the study database, correcting data errors), ● clinician responsibilities (performing physical exams and medical tests, interpreting diagnostic procedures), ● technician responsibilities (drawing and processing blood, performing blood pressure and other measurements), ● outcomes surveillance (verifying primary and secondary study endpoints), and ● support staff responsibilities (preparing written documents, providing phone support, scheduling appointments, etc.). Unfortunately, we live in a fiscal climate dictated by budget constraints [27] and controlled staffing patterns, compelling investigators to make difficult decisions concerning staff configuration. One solution to this problem involves hiring individuals to assume multiple roles: the trial coordinator may be the study clinician, support staff could be trained to do data entry, and the recruitment coordinator could later focus on retention/adherence activities. Investigators need to prioritize staff positions, then determine which multiple responsibilities could be assumed by one person. Factors affecting these decisions include the level of funding, the size of the trial, the level of expertise among trial staff, and the personal preferences of the PI and the trial coordinator. An important downside to this approach is the greater probability for staff burnout among those individuals who do perform multiple trial activities. The advantages of this tactic relate to cross training (which should be implemented in all trial clinics to allow for backup of key personnel) and greater job satisfaction and commitment for those individuals who enjoy the challenge and diversity associated with assuming multiple job responsibilities. Another dimension of trial collaboration relates to collaboratively written clinical trial reports. Investigators should be aware that nonfaculty study personnel such as trial coordinators may be just as eager to participate in the publication process as their faculty/ investigator counterparts. Opportunities should be available for key trial employees to become engaged in and receive credit for publication efforts. Commandment V: Thou Shalt Communicate
Good communication is the cornerstone of collaboration. Effective (and reciprocal) communication is one of
the most essential components of multicenter clinical trials [16]. Three primary modes of communication in the clinical trial setting include communication among clinical staff, communicating with participants’ physicians, and clinic communications with the coordinating center and/or trial sponsor (communications with study participants is discussed under Commandment VII). Table 3 provides a summary of communications in a clinical trial. A. Communications among Clinical Staff Regular and frequent staff meetings provide forums for discussion of logistical issues such as problems with clinic flow and recruitment and compliance. These meetings also provide opportunities to build staff morale, reinforce team building, and allow staff to air grievances that may be shared by their colleagues. To channel such interactions in a productive direction, the person conducting these meetings in the absence of the PI needs to have good delegation of authority from the PI. Communication also involves resolving conflicts that may arise among staff or between staff members and participants, briefing the PI on appropriate issues, and ensuring that the PI briefs trial staff on policy or protocol changes. Successful communications with the PI implies PI accessibility to his/her staff. TABLE 3 Communications in the Clinical Trial Setting • • • • • • • •
Communications among trial staff Regular and frequent staff meetings Good delegation of authority Resolving conflicts Briefing the PI PI briefs staff PI accessibility Encourage comments from co-workers Hierarchy of communication
• • • • • •
Communications with participants’ physicians Establish early contact Provide information Reassure physicians’ roles as primary caregivers Forward appropriate and pertinent participant data Refer participants back to physicians Promote team approach
• • • • • • • •
Communications with participants High priority to informed consent Quick follow-up on inquiries Timely provision of appropriate clinical data Good clinic phone coverage Uniform information from staff and investigators Convey sincerity, patience, sensitivity, and recognition Accommodate participant needs Maintain professional integrity/appearance
Communications with coordinating center or sponsor • Routine issues • Safety issues • Clarification
TEN COMMANDMENTS OF TRIAL MANAGEMENT
The clinic supervisor (usually the trial coordinator or a study co-investigator) should encourage comments and suggestions from co-workers. These can provide fresh perspectives that may lead to improved operations, and they demonstrate appreciation for and recognition of trial employees. Finally, a hierarchy of communication needs to be established so that staff members know to whom they should report and with whom they could consult about particular issues. B. Communications with Participants’ Physicians As noted under Commandment II, Section B4, trial clinic personnel should establish early contact with participants’ physicians (usually through a letter signed by the PI) to inform physicians of their patients’ involvement in the trial; to provide information about the trial goals, interventions, risks, benefits, length of follow-up, frequency of follow-up visits, tests, and procedures; and to reassure physicians that they will remain the primary health care providers for their patients. Also to be communicated to participants’ physicians are promises to forward appropriate and pertinent participant data in a timely fashion (routine test findings, pathology reports, etc.) and to refer participants back to their physicians should unexpected findings emerge in the trial clinic. These communications, though time-consuming for clinic staff, can promote a team approach between the trial clinic and the personal physician. Potential participants should be encouraged to discuss trial enrollment with their personal physicians [28]. Continued support for the trial from a participant’s health care provider can facilitate participant trial compliance. C. Communications with the Coordinating Center and/or the Trial Sponsor Communications with the coordinating center and/or the trial sponsor could be classified into three categories: routine, safety related, and clarification. Examples of routine communications include regularly scheduled conference calls [16] (during which information is shared between sites and protocol issues and problems are discussed), clinic requests for central purchase of standard inventory items (blood collection supplies) or unexpected additional items not included in the original clinic budget, and discussions regarding data edits/corrections and budgetary issues. Examples of safety-related communications include reporting adverse events, questioning whether or not a study medication should be discontinued or tapered, requesting an emergency unblinding of a participant, and providing information regarding the death of a study subject. Clarification issues often refer to interpretation of the protocol, questions about study eligibility, administra-
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tion of the intervention, exceeding the permitted window of time surrounding a screening or follow-up visit, etc. Commandment VI: Thou Shalt Document
Proper study documentation involves accurate completion of the data collection forms in conjunction with interviewing participants and retaining datarelated source documents (lab slips, pathology or ECG reports, etc.). Examples of critical documents to be stored and updated on site include IRB approval letters and communications, protocol amendments and MOP revisions, FDA 1572 Forms for investigational drug trials (to be completed for original and new investigators joining the study), and investigational drug adverse event reports and accountability logs. Important written and e-mail communications should also be stored, and pertinent phone calls should be documented and filed. These could relate to protocol interpretation (for example, confirmation from the coordinating center that a participant remains eligible for enrollment despite some unusual circumstance or condition), reporting adverse events to the FDA/coordinating center/ sponsor, and relevant conversations with participants, their physicians, or study sponsor representatives. Commandment VII: Thou Shalt Honor Thy Participants
Without participants, there would be no clinical research. Respect, concern, and appreciation should be conveyed to all potential and randomized participants, in conjunction with providing comprehensive yet understandable information about the trial. Information giving begins during the informed consent process. Despite receiving informed consent, there are indications that participants remain ignorant about important aspects of a trial in both the short term [29,30] and the long term [31]. Trial staff and investigators should give high priority to the informed consent process so that participants understand what is involved in trial participation. Providing pertinent information about the trial and trial-related issues should be an ongoing process that spans the duration of the study. Study newsletters can greatly facilitate this information-giving process [16]. Investigators and staff should maintain regular contact with study participants throughout the trial to reinforce enthusiasm for the study and to promote adherence [1]. Immediate attention to participant adverse events, whether self-reported or measured, is essential. Quick follow-up on participant concerns and inquiries reflects staff/investigator dependability, credibility, and concern, as does the timely provision of appropriate clinical data (for example, certain diagnostic test results). Since participants communicate regularly with trial staff by phone, good clinic phone coverage is essential. Uniform information from clinic staff/investigators implies that all trial personnel are familiar with clinic operations, the study protocol, and the MOP, so that
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participants receive consistent directions, advice, and responses to their questions. Conveying sincerity, patience, sensitivity, and recognition may require extra effort and time; however, these attributes may enhance compliance and retention. Another measure to improve participant compliance and retention relates to communicating staff willingness to accommodate participant needs (for example, scheduling clinic visits in the evenings or on the weekends) [28]. Trial personnel should also maintain good professional integrity and professional appearance, which can lead to greater participant confidence in the staff and in the study. Table 3 summarizes these communication strategies. Commandment VIII: Thou Shalt Keep Thy Participants’ Secrets
Participant confidentiality must be maintained during and after a clinical trial [2]. Efforts to ensure participant confidentiality include arranging maximal privacy for interviewing, securing participant files to guard against their unauthorized use (participant files should never be left in undesignated areas of the clinic where other participants or nontrial employees could look through them), and having restricted access to the study database (only authorized personnel with proper passwords should be able to log on to the clinic computer). Finally, participant identifiers (name, photograph, identification or social security number) should never be included in trial publications or presentations, unless preapproved by the participant [2]. Commandment IX: Thou Shalt Revere Thy Data
Given the daily grind and bureaucracy involved in running a trial clinic, staff and investigators should be reminded occasionally that one of their primary goals is the collection of high-quality data, which will allow the study to answer an important medical question that could contribute to improved health care. This begins with proper training, certification, and standardization [32]; scrupulous data collection [33]; transcription and source documentation, and awareness of and involvement in quality control efforts. Those coordinating clinic operations should build in personnel time and effort to review the data collection forms for completeness, consistency, and accuracy before their timely entry into the study database. Responses to coordinating center inquiries about questionable data should be prompt. Backups of the local database should be performed daily, and, if distributed data entry is not utilized, data should be downloaded and forwarded to the coordinating center according to the study-dictated schedule. Training, certification, and recertification of staff (and sometimes investigators) are laborious but necessary to maximize the likelihood of obtaining consistent measures within and between trial staff. Clinics utilizing the services of a local outside facility
for study purposes (laboratory analyses, mammogram, or bone scan site) should work closely with facility staff to promote adherence to protocol guidelines (performing standardized procedures/measurements, proper completion of the data collection forms, etc.). Quality assurance efforts cover a spectrum of activities in a trial clinic. These include, but are not limited to, assuring: (1) the safety of study participants (for example, training staff to properly monitor and document adverse and clinical events that may or may not be related to study participation); (2) the integrity of the informed consent process, randomization, and blinding; (3) protocol-dictated delivery of and adherence to the intervention, including timely participant follow-up visits and primary/secondary outcome measures; and (4) systematic monitoring of study data (data editing, correction, and analysis). Commandment X: Thou Shalt Know and Accept Thy Limitations
Trial coordinators (as well as other clinic personnel) are at risk for burnout, because, in great part, such demanding positions attract dedicated and hardworking individuals who place many demands on themselves. There is also the broad spectrum of coordinator duties that can be especially overwhelming to those new to this position [16]. Conducting a clinical trial is a collaborative effort that implies shared responsibility in its operation and management. No one individual, not even the trial coordinator, should be expected to perform an unrealistic number of tasks. Cross training and back-up strategies can partially guard against staff burnout. However, study investigators need to be sensitive to this looming threat, which can significantly slow down trial progress if burnout leads to job resignation. Arrangements should be made for trial staff and investigators to occasionally meet socially in and out of the clinic. Earned vacations should be taken at mutually agreed upon times. Staff incentives (e.g., closing the clinic for one day when interim recruitment goals are attained) can prove to be real motivators. Personnel should be encouraged to vent their work-related frustrations by discussing their concerns with their supervisors. CONCLUSION
Although we have tried to cover major points related to clinical trial management, the topics discussed and the examples given are not all-inclusive. We do feel that the ten commandments addressed in this report have relevance to other types of epidemiological investigations beyond clinical trials, such as observational studies. The information and recommendations provided in this paper are based on the multicenter clinical trial experience of the authors, who have been involved in
TEN COMMANDMENTS OF TRIAL MANAGEMENT
Phase III clinical trials conducted in an academic environment. We therefore cannot address other types of research settings, such as earlier phase trials or pharmacokinetic studies, nor can we offer advice specific to those working in a contract research organization, which conducts trials sponsored by industry. Although we feel certain that the ten commandments discussed would apply to these settings, it would be very useful for those working in these environments to put forward their own experiences and recommendations concerning how best to manage a clinical trial. Some examples cited in this report fall under more than one commandment (communications with participant physicians are described under Commandments II and V). Although this leads to some redundancy, we felt that these topics merited discussion under the two different categories. If one were to highlight the major challenges and sources of frustration encountered in managing a trial clinic, the list would probably include the heroic efforts needed to achieve the recruitment goal [22,25,28,34], insufficient funding, the constant and demanding burden of paperwork [22] and documentation, the unending vigilance needed to maintain participant and staff compliance with the protocol, challenges faced in retaining participants in the study, and personnel turnover (more of a threat to longer running trials). Personnel turnover may be due to frustrations originating from inadequate staffing to get the job done, lack of PI support and involvement, insufficient autonomy, misguided expectations, unrealized salary expectations, lack of job security, and personnel conflict (for example, troublesome colleagues who either fail to contribute their expected workload or bring conflict rather than collaboration to the work setting). Staff turnover can impede trial progress, whether it occurs during the early [35] or later stages of a trial. Principal investigators and clinic supervisory staff should do everything possible to make job conditions as reasonably pleasant, harmonious, productive, and efficient as possible. This too can be a daunting challenge, given today’s budgetary constraints. Maintaining a good sense of humor (no costs involved) can prove to be especially valuable as a stress reliever. The positive aspects of working in a trial clinic should be emphasized. These include collaboration, contribution to science and improved public health, patient contact, intellectual stimulation, job diversity, publication, and sometimes travel opportunities. Expecting the unexpected could be considered a positive factor for creative individuals who enjoy new challenges. The day-to-day problems faced in managing a clinical trial can obscure the reasons for initially becoming involved in medical research. The following excerpted quote by D. S. Fredrickson [36] sums up the frustrations faced and ultimate ‘‘raison d’etre’’ for performing
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human research studies (referred to as ‘‘field trials’’ in his article). [Field trials] . . . lack glamour; they strain our resources and patience, and they protract to excruciating limits the moment of truth. Still, they are among the most challenging tests of our skills . . . I have no doubt that when the problem is well chosen, the study is appropriately designed, and all the population concerned made aware of the route and the goal, the reward can be commensurate with the effort. If, in major medical dilemmas, the alternative is to pay the cost of perpetual uncertainty, have we really any choice? ACKNOWLEDGMENT The authors thank Dr. Roger Anderson, Dr. Walter Ettinger, Ms. Beate Griffin, Ms. Patricia Hogan, and Dr. Electra Paskett for their willingness to review the manuscript and to provide valuable comments, which have enriched the paper. REFERENCES 1. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 3rd ed. Littleton, MA: PSG Pub., 1996. 2. Meinert CL. Clinical trials: design, conduct and analysis. In: Monographs in epidemiology and biostatistics, Vol. 8. New York/ Oxford: Oxford Univ. Press, 1986. 3. Spilker B. A guide to clinical trials. New York: Raven Press, 1992. 4. Warlow C. How to do it: organise a multicentre trial. Br Med J 1990;300:180–3. 5. Eaton T, Pratt CM. A clinic’s perspective on screening, recruitment and data collection. Stat Med 1990;9:137–44. 6. Probstfield JL, Russel ML, Silvers A, Goodwin DL, Insull W. Clinical trials methods and the practice of medicine. Controlled Clin Trials 1984;5:321–7. 7. Benedict GW. LRC coronary prevention trial: Baltimore. Clin Pharmacol Ther 1979;25:685–7. 8. Collins JF, Williford WO, Weiss DG, Bingham SF, Klett CJ. Planning patient recruitment: fantasy and reality. Stat Med 1984;3:435–43. 9. Hunninghake DB, Darby CA, Probstfield JL. Recruitment experience in clinical trials: literature summary and annotated bibliography. Controlled Clin Trials 1987;8:6S–30S. 10. The DCCT Research Group. The Diabetes Control and Complications Trial (DCCT): the trial coordinator perspective. Diabetes Educ 1989;15:236–41. 11. Mullin SM, Warwick S, Akers M, Beecher P, Helminger K, Moses B, et al. and the MILIS Study Group. An acute intervention trial: the research nurse coordinator’s role, Controlled Clin Trials 1984;5:141–56. 12. Chadwick LR. Professional nursing with a new focus: staff nurse to research coordinator. J Neurosci Nurs 1992;24:170–5. 13. Barnes G. A nurse’s experience in the MRC’s hypertension trial. Br Med J 1982;285:1625–7. 14. White-Hershey D, Nevidjon B. Fundamentals for oncology nurse/data managers—preparing for a new role. Oncol Nurs Forum 1990;17:371–7. 15. Dobkin B. Testing time. Discover 1990 May. 16. Naydek BL, Sutton-Tyrrell K, Burek K, Sopko GS. Organizational structure and communication strategies of the Bypass Angioplasty Revascularization Investigation: a multicenter clinical trial. Controlled Clin Trials 1996;17:226–34. 17. Tognoni G, Alli C, Avanzini F, Bettelli G, Columbo F, Corso R, et al. Randomised clinical trials in general practice: lessons from a failure. Br Med J 1991;303:969–71.
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