ORIGINAL ARTICLE
Site Organization and Management Douglas C. Wolf, MD,* Seymour Katz, MD, FACP, MACG,† Michael A. Safdi, MD, FACP, FACG,‡ Robert S. Sandler, MD, MPH,§ and James D. Lewis, MD, MSCEk
Abstract: The principal investigator is responsible for everything involved in the conduct of a clinical research study. Prior to the initiation of any clinical trial, an investigator must become acquainted with the material requirements, personnel needs, and best practices involved in the conduct of the trial. Commitment to a clinical trial should not be taken lightly because even a simple study may require a major investment of staff, space, and time. Standard operating procedures help to standardize staff training and improve regulatory compliance. Reasons for participation in clinical research may differ between community and academic gastroenterologists, but responsibility for patient care, regulatory requirements, and assumption of accountability are identical. Careful attention to the details of site organization, administrative requirements, and patient recruitment and retention all contribute to the successful performance of clinical research. Key Words: clinical research, FDA Form 1572, informed consent, patient recruitment, site management, standard operating procedure
PERSPECTIVE Community Gastroenterologist Practice For the community gastroenterologist, the decision to conduct inflammatory bowel disease (IBD) clinical research may be motivated by a variety of factors, the most fundamental of which is the opportunity to offer patients with IBD new therapeutic options. Whereas clinical research adds complexity to a community practice, it also provides additional structure and knowledge, which can elevate the level of patient care. Performing clinical research can be one of the most satisfying aspects of medical practice; however, there are important differences between clinical practice and clinical research (Table 1). Performing clinical research can be one of the most satisfying aspects of medical practice.
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linical research is an exacting science, and its associated regulatory requirements impose a substantial burden on clinical investigators. Whereas the task of undertaking a research study can appear daunting, an understanding of the material requirements, personnel needs, and best practices can streamline the process. This article will review the fundamentals of conducting a clinical trial, describe how and why to get started, and identify some of the practical considerations that should be reviewed before making the commitment.
Received for publication August 17, 2005; accepted August 26, 2005. From the *Atlanta Gastroenterology Associates, Atlanta, Georgia; †Long Island Clinical Gastroenterology Associates, Great Neck, New York; ‡Greater Cincinnati Gastroenterology Associates, Cincinnati, Ohio; §University of North Carolina, Chapel Hill, North Carolina; and kUniversity of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Reprints: Marjorie Merrick, Vice President of Research and Scientific Programs, Crohn’s & Colitis Foundation of America, 386 Park Avenue South, 17th Floor, New York, New York 10016 (e-mail:
[email protected]) Copyright Ó 2005 by Lippincott Williams & Wilkins
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Commitment to a clinical trial should not be taken lightly because even the simplest study requires major staff and time commitments (Table 2). To be successful, the investigator must have the necessary time, appropriate qualified staff and other resources, and interest in the scientific aspects of the trial. In addition, the investigator should have the ability to meet recruitment targets. For most physicians, the initial experience with clinical research occurs during residency or fellowship. While it is possible to begin without any additional training, it is advisable to receive formal instruction regarding the benefits, responsibilities, and regulations associated with clinical research. Several commercial and university-based programs are available to provide an overview of clinical research study conduct. While the scientific aspect of clinical research may be exciting and performing clinical work may seem intuitive, the regulations are significant and require a thorough understanding of both Good Clinical Practice (GCP) and the sections of the Code of Federal Regulations (CFR) that govern GCP. There are 3 typical methods used by the community practitioner when getting started in clinical research. The easiest method is to work as a sub-investigator with a Site Management Organization (SRO), a centralized, commercial
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TABLE 1. Differences Between Clinical Practice and Clinical Research Clinical Practice
Clinical Research
Many patients Art of medicine Different approaches to the same problem Individualized care
Fewer patients Science of medicine Same approach each time
Algorithm/SOP useful
Standardized care/protocol compliance Algorithm/SOP necessary
entity that the sponsoring organization contracts to perform clinical research. Partnering with a more experienced clinician is another model that provides the opportunity to share space and personnel. The most difficult method is to establish a research practice and over time, develop the site from within. On a practical level, the average profit margin for a typical clinical research study is small, but costs should be covered over time through payments from the clinical research sponsor. The study budget should parallel the complexity and length of the study. It is important to evaluate the cost factors associated with space, equipment, personnel, and time, and to be especially aware that reporting unexpected serious adverse events (SAEs) can be time-consuming. TABLE 2. Life Cycle of a Clinical Trial
Initial inquiry Site qualification visit Site acceptance Initiation visit Screening visit Baseline/randomization visit Interval visits Final study visit Safety follow-up visit Data presentation Record retention
Academic Gastroenterology Practice There are numerous reasons why an academic physician would choose to participate in clinical trials: interest in advancing the field; providing patients access to cutting edge medical therapy; learning about clinical care and translational research from opinion leaders in the field; new referrals; and collecting ‘‘academic currency’’ (i.e., publications, reputation, and financial support, etc.). What Studies To Do? A critical criterion for success in clinical research is to identify trials that meet personal and institutional needs. These studies should:
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Ask a question for which the investigators have clinical equipoise. The concept of clinical equipoise implies that the investigator is uncertain which arm of a randomized trial is superior. It is clinical equipoise that makes randomization ethical. In the absence of clinical equipoise, the clinician should recommend what they know to be the optimal therapy for their patient. However, if it is unknown which of 2 or more approaches (even placebo therapy) is superior, randomization is an acceptable method to choose a therapy. Present a good therapeutic option to study participants. It is important for an investigator to choose studies they can confidently recommend to their patients without compromising their belief that they are providing optimal care for their patients. The inclusion criteria should describe patients who are represented in the investigator’s clinical practice. It is a waste of everyone’s time and money to get involved in a study where you cannot enroll patients. Provide sufficient resources to support the necessary personnel and space resources available within the institution. Whether research is conducted in a community or academic setting, the time requirements for the investigator remain the same (Table 3). While research in an academic setting allows for reliance on fellows and house staff for some aspects of patient care, the ultimate responsibility for the conduct of the trial remains with the clinical investigator. The last point adds another stressor to an already hectic life but does come with gratifying rewards for appropriate individuals. The difficulty is deciding if you are willing to do the extra work and accept the extra responsibility.
TABLE 3. Time Requirements for a Clinical Investigator Provide patient care (office, hospital, endoscopy, emergencies) Provide research patient time; clinic visits, procedures, emergencies Identify and screen suitable subjects Meet with, evaluate, and manage subjects properly Meet and discuss issues regularly (daily) with coordinators Meet and discuss issues with the sponsor(s) and monitor(s) Attend investigator meetings Participate in conference calls Supervise quality assurance (GCP), monitor visits, and audits
PRACTICAL CONSIDERATIONS Regulatory Regulatory requirements are identical whether the study is conducted in a community or academic setting. FDA Form 1572 is a legal document that binds the investigator to compliance with the federal requirements for performing clinical research. These obligations include: protection of q 2005 Lippincott Williams & Wilkins
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human subjects; administration by an institutional review board (IRB); Investigational New Drug application (IND); record keeping and retention; reporting requirements (adverse events [AEs]); and inspection of investigator’s records and reports. Below are 10 of the most common pitfalls encountered when conducting clinical research: 1. Corrections. Corrections made to any study-related document including source documentation, the case report form (CRF), and the informed consent form must be standardized. The incorrect entry should be neatly crossed out with a single line and the correct entry should be written alongside, initialed, and dated. Do not use erasers, correction fluid, or other correction marks! 2. Archiving Study Records. Archiving study records is a major challenge and responsibility. Study sponsors and regulatory agencies expect investigators to retain all study documentation for 2 years. This rule is specified in the Code of Federal Regulations (GCP and International Conference on Harmonization [ICH]) as follows: ‘‘An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.’’1 It is best to check with the sponsor before disposing of any study records. Certain sponsors require record retention for up to 15 years. These records can be retained in appropriate off-site storage after study close-out. 3. Subject Eligibility. The investigator is responsible for reviewing the inclusion/exclusion criteria and confirming that each subject enrolled in the study meets all criteria. 4. Source Documentation. All recorded study data including patient history, exams, telephone communications, and any other relevant information must be recorded in a source document (i.e., the patient chart). 5. Drug Accountability. Drug accountability is rated ‘‘poor’’ in 11% of FDA audits.2 To comply with the regulations, the investigator must: keep detailed records of medications received from the sponsor fulfill storage requirements allocate medications per protocol instruct subjects to return unused medication at each visit record drug allocations and returns at each subject visit record missing or damaged medications verify the reliability of any external pharmacy used in the study q 2005 Lippincott Williams & Wilkins
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6. AE Identification and Reporting. Suspected or confirmed AEs should be identified by the investigator and study coordinator and tracked at each visit until resolution. Serious adverse events (SAEs) must be reported to the sponsor within 24 hours of recognition or occurrence and to the responsible IRB according to their requirements. See Ethical Issues, Safety, and Data Integrity in Clinical Trials in this supplement for information on SAE criteria. 7. Monitor Visits. A study monitor designated by the sponsor will visit the study site to review compliance to the protocol. These visits usually occur before, at selected intervals during, and at the close of each clinical study. Ideally within 2 weeks of initial patient randomization, the study monitor will review all informed consents, source documentation, CRFs, and drug accountability documents. 8. Audits. Site audits may be conducted either by the sponsor or by the FDA. Sponsor audits are often conducted at sites with high patient enrollment (in anticipation of an FDA audit) or sites where monitoring visits have exposed previous difficulties. Sponsor audits commonly include review and assessment of: the physical site including record storage; the quality and quantity of site monitor visits; the level and quality of sponsor support; the integrity of the informed consent process; adherence to the informed consent process; the role of each site participant versus the Delegation of Duties Log; and a sampling of patient charts and CRFs. FDA audits are usually conducted for the primary (pivotal) study of a new product. The FDA will evaluate the consent process and clinical operations, review all completed consents and regulatory documents, and examine at least a representative sampling of, if not all, patient charts and CRFs. The most common findings of an FDA audit include informed consent errors, protocol noncompliance, record-keeping deficiencies, and mistakes in source documentation. 9. Informed Consent. FDA audit findings often relate to the informed consent process or practice. In a 2000 FDA Division of Safety Inspection analysis, informed consent noncompliance occurred 10% of the time.2 Informed consent documents may be revised several times during the course of a study. The investigator must be certain that each study subject properly signs and dates the correct version. 10. Principal Investigator (PI) Responsibility. The principal investigator is ultimately responsible for EVERYTHING involved in the conduct of a clinical research study. Specific duties may be assigned to other individuals, but the responsibility is never abdicated.
Personnel and Space Whenever possible, research space should be maintained in a central office. Some tasks may need special
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accommodation, such as secure temperature-controlled storage for study drugs. Study charts, source documents, and CRFs must be kept in a secured area. An infusion suite may be required for IBD studies. Most decisions regarding people and space will be dictated partially by the organizational structure of the research unit. Questions that should be considered include: Will the clinical trial operation be a division of the practice or a separate company? Will it be in the same location or separate? Does the investigator want to do single- or multispecialty research?
Standard Operating Procedures (SOPs) SOPs as defined by the ICH are detailed written instructions to achieve uniformity in performance of a specific function. In practice, SOPs should encompass the spectrum of clinical research activities, including the ‘‘who, what, when, where, how, and why’’ of a clinical research operation and should be detailed enough so that a trained individual can perform the procedure without supervision after a single training session. SOPs help standardize staff training, improve regulatory compliance, decrease errors, reduce supervisory management time and operational expense, and may provide an advantage in site selection. Each individual SOP is a step-by-step outline addressing one aspect or activity of a clinical research study. Therefore, it may be necessary to have as many as 20 to 40 SOPs to achieve the operational uniformity needed for consistency in clinical research. As noted above in the section on FDA audits, perhaps the most important SOP describes the informed
TABLE 4. Recommended SOPs3 Visits
Site evaluation Initiation visit Monitoring visit Close-out visit
Study management
Informed consent Delegation of authority Source documentation General correspondence CRF completion Clinical trial material management AE reporting SAE reporting
Audits and inspections
Sponsor-initiated site audit FDA inspection
IRB
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IRB approvals IRB correspondence Protocol amendments Advertisements
consent process. A list of suggested SOPs for the conduct of clinical research is included in Table 4.
Data Management Data management requirements vary from study to study. The investigator can typically manage clinical data in a small, single-center trial. Medium-sized, multicenter trials usually require greater data management capacity (e.g., the Data Management Center of the CCFA Clinical Alliance). Since large, FDA registration trials require special expertise, data are not managed at the investigator level; instead, the commercial sponsors will typically use a Contract Research Organization (CRO) with data management expertise. High-quality research demands high-quality data management methods.
However, the basic requirements of data management strategy are identical regardless of trial size. High-quality research demands high-quality data management methods. The data management team or a Data Management Center can help the investigator refine the elements of the study protocol to make it operational. The protocol must provide a detailed ‘‘roadmap’’ for patient recruitment, eligibility, and study procedures, as well as a statistical plan and a list of relevant forms. Flow charts and schema are useful tools for managing critical steps in the trial. A structured approach to development of the CRFs reduces data elements to only those necessary for completion of the trial. CRFs should be clean, clear, and complete, and should be pilot-tested before implementation. The physical structure of the data collection form (paper, scanned, web-based) dictates how data will be submitted and entered. Quality control functions including methods for tracking outstanding forms, missed visits, and study status help to establish a consistent and acceptable level of data quality. Each data element should be range- and logic-checked and all revisions documented. Data must be stored in a secure manner and electronic data should be backed up regularly.
Recruitment and Retention of Study Subjects Developing trust among the physician, the study coordinator, and the patient is the key to successful recruitment in clinical trials. It is especially important in IBD trials because typically the patient is informed yet apprehensive of a physician who may not understand his/her specific needs or who is not familiar with available therapies. Communication with the referring physician is critical. It is important to emphasize that the clinical trial will not take patients away from the referring physician, but instead offers a new therapeutic option that is otherwise unavailable to the q 2005 Lippincott Williams & Wilkins
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patient. Mailings and communication are often unsuccessful unless they are done personally. Lecture and discussion groups have some value, but require significant question-and-answer periods preferably on a one-on-one basis. Mailings on the physician’s personal stationery with a personal note to the patient regarding the trial have proved to be effective in some practices. Radio advertisements have also been successful for some studies; however, these announcements should be broadcasted during the workday to provide immediate access to study coordinators. Consultation with potential study subjects should include the role of placebo and the potential side effects of the study drug. In addition, the physician should emphasize that the patient is not a ‘‘guinea pig’’ but an active participant in the investigation of a potentially new therapy. A follow-up telephone call on the same day following this discussion is essential and should include the benefits of trial participation, including the possibility of continuing therapy under an open-label/compassionate arm (if offered by the sponsor) or participating in another clinical trial. Patient understanding of the commitment to the clinical trial (i.e., schedule of visits, laboratory tests and procedures, etc.) is critical to retention of enrolled subjects. The clinical site should be a nurturing, friendly environment. Easy access to the investigator and coordinator through telephone or e-mail is also crucial. Optimally, the physician should plan to see the patient at each visit. For patients who must travel a long distance, a modest honorarium or the provision of lunch or transportation may be required. Other recommendations include providing reminder cards to the patient at the conclusion of each visit, confirming all patient appointments 24 hours in advance, and reaffirming the procedures scheduled for the next visit. It is important to articulate the role each patient plays in advancing the study and to emphasize that the current ‘‘stable’’ of medications are now available based on similar clinical trials. Overall, praise for reliable, adherent patients will go a long way to keeping their interest and cooperation. It may also encourage patients to look forward to participating in other studies or spreading the word in their CCFA groups.
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CONCLUSION Clinical research, regardless of the size of the study, is a complex and highly regulated process. Each decision regarding protocol development and implementation can impact the ultimate approval of a new product. A thorough understanding of the regulatory environment governing clinical research is essential to the safe and legal conduct of any clinical trial. Careful attention to the details of site organization, administrative requirements, and patient recruitment and retention all contribute to the successful performance of clinical research. REFERENCES 1. The Code of Federal Regulations. GCP/ICH Guidelines. Washington, DC: GMP Publications; 2004. 2. Miskin BM, Neuer A. How to Grow Your Investigative Site: A Guide to Operating and Expanding a Successful Clinical Research Center. CenterWatch. Stamford, CT: Thomson Healthcare; 2002. 3. Colon L, Richardson B, Palmer L, et al. Development of Effective Standard Operating Procedures (SOPs) for Clinical Research Sites. Anaheim, CA: ACRP; 1998.
ADDITIONAL RESOURCES Anderson DL. Community, physician and consumer outreach strategies to meet recruitment goals. In: A Guide to Patient Recruitment and Retention. Dallas, TX: D Anderson & Co; 2004:179–197. Gamache V. Minimizing Volunteer Dropout. CenterWatch. Stamford, CT: Thomson Healthcare; 2002:19(Issue 12). Getz KA. Study Volunteer Behaviors and Attitudes in Industry-Sponsored Clinical Trials. Presented at the Institute of Medicine’s Clinical Research Roundtable, Washington, DC, September 25, 2000. Getz KA. Benchmarking patient recruitment and retention in clinical trials. In: A Guide to Patient Recruitment and Retention. Dallas, TX: D Anderson & Co; 2004:25–44. Good PI. A Manager’s Guide to the Design and Conduct of Clinical Trials. New York, NY: Wiley-Liss; 2002. Needham J. The importance of retention. In: A Guide to Patient Recruitment and Retention. Dallas, TX: D Anderson & Co; 2004;167–177. Neuer A. Treating Study Volunteers as Customers. CenterWatch. Stamford, CT: Thomson Healthcare; 2003. Norris D. Clinical Research Coordinator Handbook. 3rd ed. Medford, NJ: Plexus Publishing; 2004. The Center for Clinical Research Practice. GCP education, training, and SOP templates. http://www.ccrp.com Woolley M. Research! American Poll Data on Attitudes toward Medical Research. Presented at the Institute of Medicine’s Clinical Research Roundtable, Washington, DC, September 15, 2000.
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