Standard Operating Procedures For Clinical Research Coordinators
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( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ Standard operating procedures for clinical research coordinators Fries, Ruth Ann Clinical research coordinators are specially trained professionals who oversee and manage research trials, ensuring that rigorous standards of the Food and Drug Administration, Office of Human Research Protection, and industry are met. Standard operating procedure manuals are rapidly becoming an industry requirement. Although developing a comprehensive manual is demanding and labor-intensive, it provides structured guidelines for clinical research coordinators implementing clinical trials. A model standard operating procedure manual for clinical research coordinators is presented that addresses many issues and roles common to coordinators. Industry criteria and applicable federal regulations that impact the informed consent process, institutional review boards, and drug and device studies were utilized to develop the manual. This draft provides a framework that can be formatted to meet the specific requirements of individual institutions. Key Words: Clinical research coordinators; Standard operating procedures; Manual; Clinical trials; Processes INTRODUCTION ADOPTING WRITTEN STANDARD operating procedures (SOPs) is rapidly becoming a standard requirement when contract research organizations and sponsors select sites for clinical trials. Often, well-established processes are in place; however, they may not have been reduced to writing. Clinical research coordinators may find that allocating time for development of a procedure manual is difficult as they frequently are hard-pressed to fulfill other responsibilities. That clinical research coordinators function in multiple roles only increases the challenge. Yet, having an SOP manual provides benefit to coordinators, especially when they are training new personnel. A model SOP manual for clinical research coordinators was developed. This manual provides a working framework for institutions drafting their own SOPs. MATERIAL AND METHODS Sponsor criteria and applicable federal regulations were utilized to develop the manual. These federal regulations included those impacting the informed consent process (21 CFR, Part 50 [1] and 45 CFR Part 46 [2]); institutional review boards (21 CFR, Part 56 [3] and 45 CFR Part 46); Investigational New Drugs (21 CFR, Part 312 [4]); and significant/ nonsignificant risk devices (21 CFR, Part 812[5]).
MODEL STANDARD OPERATING PROCEDURES MANUAL This manual was designed to assist clinical research coordinators (CRCs) in the performance of
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ their duties. It is not a substitute for professional education, training, and experience. The clinical research coordinators should be available for consultation, as needed. I. Clinical Research Coordinator A. Definition A CRC is an individual with expertise in clinical research trial management. Typically, the CRC is a registered nurse, medical technologist, pharmacist, or other individual with equivalent scientific/clinical background and research experience. B. Roles and Responsibilities The CRC assists the principal investigator (PI) (usually a physician) and subinvestigators (usually physicians, physician assistants, nurse practitioners, and/or pharmacists) with all aspects of study implementation. Although the CRC is responsible for coordinating all activities related to clinical trial implementation, the CRC can only perform those procedures for which he/she is qualified by training and/or licensure. Responsibilities include: ·
Identifying research opportunities and contacting potential sponsors,
·
Negotiating budget and contract,
·
Completing regulatory documents,
·
Facilitating peer review, administrative review, and approval,
·
Applying for institutional review board (IRB) review,
·
Interacting with the sponsor, research team, pharmacy, IRB, finance, and other departments impacted by the research,
·
Developing study processes,
·
Developing study documents,
·
Educating staff,
·
Recruiting, screening, and enrolling subjects,
·
Implementing and adhering to the protocol,
·
Accounting for study funds,
·
Reporting adverse events, and
·
Providing continuing and final IRB reports.
II. Initial Sponsor Contact:
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ A. Nondisclosure (Confidentiality) Agreement Investigators are provided with clinical trial opportunities through several sources including pharmaceutical companies or device manufacturers, clinical research organizations (CROs), and site maintenance organizations (SMOs), hereafter referred to as the "sponsor." Networking with off-site investigators or coordinators may also afford research opportunities. Before substantial research information is disclosed by the sponsor, a Nondisclosure (Confidentiality) Agreement is signed by the principal investigator (PI). This agreement defines the nature and extent to which confidentiality must be maintained by the PI and study team. At a mimimum, a nondisclosure agreement should include: ·
Definition of confidential information (limited to written disclosures),
·
Disclosure restrictions (what can be disclosed and to whom), and
·
Termination of certain obligations (a description of circumstances that nullify the agreement). Examples include information that was: 1) in the public domain when revealed to the investigator; 2) entered the public domain after disclosure to the investigator without any fault on the part of the investigator; 3) known to the investigator free of any obligation of confidentiality as evidenced by written records; 4) required by law to be disclosed; and 5) received from a third party with no confidential obligation.
·
Termination of the agreement (usually three to five years),
·
Choice of state laws governing the agreement, and
·
A statement that the entire agreement is embodied in the nondisclosure document. The Nondisclosure (Confidentiality) Agreement may be forwarded to legal counsel for review. A copy (or second original) of the signed Nondisclosure (Confidentiality) Agreement should be filed in the CRC study notebook.
B. Research Contract All contracts should receive legal review. Modifications will be forwarded to the CRC and incorporated after investigator review and approval. The contract may not be executed until all necessary approvals are obtained (ie, peer review, administrative approval, IRB, etc.). An original copy of the signed research contract must be filed in the CRC study notebook. C. Research Budget To evaluate the adequacy of the proposed study budget, the coordinator must first review the protocol and identify study-related procedures versus standard of care. All study-related procedures and tests should be reimbursed by the sponsor at a rate comparable to third-party payer reimbursement. Also, compensation should be provided for physician fees, coordinator time, pharmacy charges, overhead, IRB review, and other study-related expenses. Personnel in finance, the physician's office, and other affiliated entities (for example, special procedure billing) may need to be contacted to determine the adequacy of proposed monetary reimbursement. Another. consideration is the reimbursement schedule. Although each budget is
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ unique, a payment of 10% to 20% of the entire grant is usually made soon after the contract is executed. This payment is followed by additional compensation as patients are enrolled and progress through the study. A unique research account can be initiated through finance and assigned to the grant. This ensures that study funds remain separate from the institution's operating account. A copy of the research budget should be filed in the accounting section of the CRC study notebook. D. Site Selection Visit The site selection visit is critical because it represents the first personal contact between the sponsor and the study staff. Once the investigator expresses an interest in a particular project, the sponsor further evaluates the commitment, capabilities, and resources of the study personnel. This is accomplished at the site selection visit by the company representative who gathers information and meets with key research personnel. The coordinator provides the requested information and facilitates the site selection visit. This includes arranging the date, time, and place; notifying all parties; distributing study information; and providing refreshments. Commonly requested information includes: ·
Curriculum vitae and licenses of key study staff,
·
Disclosure of prior research experience (caveat: keep the information general, previous confidentiality agreements are still binding),
·
Estimated number of patients with the pertinent diagnosis,
·
Estimated number of patients who will meet study criteria,
·
Potential patient recruitment strategies, and
·
IRB deadlines.
This information may be provided before or during the visit. Typically, company representatives will request a tour of the facilities. The CRC accompanies the company representative and answers questions. III. Institutional Review Board (IRB) A. Submission When a study is submitted for IRB review, a request for approval of a clinical investigation form must be completed, a consent document developed, and administrative, peer, and service line approval (if appropriate) obtained. The coordinator often prepares these documents; however, the PI must review and sign the appropriate forms before submission. Once written administrative and IRB approval is obtained for the study, the research contract may be signed and the site initiation visit scheduled. Although the coordinator can assist the PI with the consent process, a physician obtains consent for experimental drug and device studies. This can be dependent on state law and should be determined for each state. To eliminate any perception of coercion, the witness should be someone other than a study team member.
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ B. Adverse Events An adverse event is any untoward medical event that occurs while a patient is enrolled in a research protocol, regardless of whether it is related to the study. All onsite adverse events must be reported to the IRB and sponsor. Also, the sponsor will report serious and/or unexpected adverse events that occurred off-site to the PI who must then forward them to the IRB. The CRC often assists the PI by submitting the necessary paperwork to the IRB. If the adverse event necessitates a change in the protocol and/or consent, these modifications must be submitted to the IRB for review and approval. C. Protocol/Consent Modifications The coordinator ensures strict adherence to the IRB-approved research protocol. Any changes in the protocol or consent must be submitted to the IRB for review and approval before they can be implemented. The only exception to this rule is when a change is necessary to eliminate or reduce the risk to human subjects. If a minor protocol deviation inadvertently occurs, the CRC will report this to the IRB at the next continuing review and to the sponsor at the next monitoring visit. If modifications are approved, the coordinator notifies the study personnel and other appropriate individuals of the change and updates the study document and study process accordingly. If modifications affect patients, those currently enrolled in the study will be notified in writing and a consent addendum signed. This requires IRB approval and revision of the original consent. D. Advertisements/Media Releases/Recruitment Materials Any material distributed to or reviewed by patients or the general public must receive review and approval by the IRB and the sponsor. When drafting advertisements, the coordinator should follow FDA guidelines. A script should be utilized when responding to phone calls from potential study patients. Letters to physicians requesting referrals or releases for physician publications need not receive prior IRB review. E. Continuing Review All studies that initially receive quorum or expedited review are subject to periodic review by the IRB. Continuing review is usually performed annually and requires a summary of the investigator's experience with the study. The CRC is typically responsible for completing the continuing review form, forwarding it to the PI for review and signature, and submitting it to the IRB. F. Final Review All research must have a final review to formally terminate the study. A study may be closed to enrollment, but the final review may only occur after the follow-up on the last patient is complete. The coordinator is usually responsible for completing the final review form, forwarding it to the PI for review and signature, and submitting it to the IRB. This should include results, if available.
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ IV. Study Implementation A. Good Clinical Practice and Federal Regulations In keeping with Good Clinical Practice (GCP), the CRC will assist the investigator in complying with all applicable federal regulations regarding informed consent (21 CFR, Part 50 and 45 CFR Part 46); the institutional review board (21 CFR, Part 56 and 45 CFR Part 46 ); Investigational New Drugs (21 CFR, Part 312); and significant/ nonsignificant risk devices (21 CFR, Part 812). CRCs will also help ensure compliance with all IRB and hospital research policies. B. Key Study Personnel 1. Principal Investigator The PI is the leader of the research team and responsible for all aspects of conducting the clinical trial. The PI ensures that the study is performed according to the IRB-approved protocol, the test article is appropriately stored and administered, and informed consent is properly obtained from each study subject or legal representative. Although the PI is usually a physician, in certain circumstances other qualified individuals perform this function. (This may be determined by state law, hospital policy, or IRB policy.) 2. Subinvestigator The subinvestigator is a member of the research team who assists the PI with clinical trial implementation. Subinvestigators may include physicians, physician assistants, nurse practitioners, and pharmacists. 3. Clinical Research Coordinator The CRC manages the implementation and coordination of the clinical trial under the direction of the PI. C. The Study Document Clinical trial data are recorded both in the traditional medical record (ie, patient chart in the physician's office, hospital, rehabilitation center) and the study document. The medical record provides information regarding the patient treatment, progress notes, drug administration, laboratory testing, and other procedure results. The study document is created by the coordinator to capture all protocol-specific data and to guide the investigator and other study/office/medical center personnel through the research process. The study document includes: ·
A copy of the study summary chart (ie, a listing of all study procedures),
·
Instructions for key personnel in pertinent departments (emergency department, nursing, radiology, laboratory, etc.),
·
Two copies of the IRB-approved consent form (one will be given to the patient),
·
Space to record all information required by the sponsor (this may be a copy of the case
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ report form pages, worksheets provided by the sponsor, or flowsheets developed by the CRC), ·
A checklist of procedures to occur at relevant time points,
·
An educational packet for staff, and
·
Information regarding the test article and its administration.
The study document captures all necessary information throughout the course of the patient's participation. Indexing the study document according to preset time points (ie, baseline visit, one week, one month, etc.) is advisable. If the study document is placed in another department to facilitate patient enrollment, the coordinator should periodically check it for completeness. Also, the study document needs to be updated when the IRB and sponsor approve modifications. D. Study Process To develop the study process, the coordinator must first carefully evaluate the protocol. Occasionally, sponsors provide a study implementation manual that assists with process development. Once the protocol has been evaluated, the CRC contacts key personnel, reviews the protocol with them, and seeks input regarding the best way to integrate study procedures into routine departmental processes. The study process comprises three main components: 1. The Process Outline is a step-by-step guide for enrolling and following patients throughout the study. This outline should contain sufficient information to allow a second coordinator who is less familiar with a specific protocol to implement study activities and procedures. 2. Preprinted Standing Orders include: ·
All hospital-related testing associated with the protocol (ie, nursing, laboratory, EKG, radiology orders),
·
Information regarding study drug administration and dosage, and
·
An order for special study procedures, monitoring, and documentation.
3. The Study Document (See Section IV.C. of this manual). E. Test Article (Study Drug or Device) The CRC or pharmacist, if applicable, will be responsible for test article accountability. This documentation includes the date and quantity of the initial shipment, condition of the test article upon arrival, identification numbers, expiration date, and other information as required by the sponsor. As drug is dispensed, the following information should be recorded: patient initials and study number, test article identification number, date and amount dispensed, date and amount returned, and pharmacist's initials for all transactions. F. Site Initiation Visit
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ The site initiation visit will occur after the contract is finalized and IRB/administrative approval has been obtained. The CRC arranges a meeting between the sponsor and the study staff. The site initiation visit is the final step before patient enrollment may begin and consists of a thorough review of the protocol and case report forms (CRF), review of the investigator's role and responsibilities, discussion of Good Clinical Practices (GCPs), and monitoring of the test article. This visit allows the CRC to discuss protocol/process questions with a company representative, ask advice regarding implementation of unusual aspects of the protocol, and establish a good working relationship with the sponsor/CRO/SMO. G. Education Before patients are enrolled in the protocol, the pertinent study and medical center staff must be inserviced. For study personnel, a summary of the entire study process, as well as their specific duties, should be presented. Study personnel must fully understand the protocol and implementation process, as well as unique elements of the research. For medical center staff, a study summary is presented that includes: research purpose, inclusion/exclusion criteria, test article administration/implantation, potential side effects, specific responsibilities, required documentation, and an overview of study implementation. The CRC arranges the time, place, agenda, handouts, refreshments, and notification of educational inservices. H. Study Documentation The CRC is responsible for maintaining all study documents. A notebook, known as the investigator or regulatory binder, is usually provided by the sponsor and will contain information related to the clinical trial including: ·
Protocol,
·
Amendments,
·
Investigator brochure,
·
IRB correspondence,
·
IRB approvals,
·
Sponsor correspondence,
·
IND safety and serious adverse event (SAE) reports
·
FDA1572 (if applicable),
·
Study personnel curriculum vitaes,
·
Monitoring log,
·
Screening log,
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ ·
Lab certifications and normal values, and
·
Study drug/device records.
The coordinator should also maintain a CRC study notebook that contains: ·
Internal correspondence,
·
Research contract,
·
Nondisclosure agreement,
·
Study accounting,
·
Physician communication, and
·
Other site-specific study documentation.
The CRC is also responsible for recording all data in the sponsor case report form. When recording data, the coordinator should: ·
Review and follow sponsor instructions,
·
Use a black ballpoint pen,
·
Write legibly, and
·
Correct errors by striking through them with a single, horizontal line, dating and initialing the error, and recording the correct information.
The pharmacy may require that the CRC develop a notebook regarding the study and study drug. Essential elements of the pharmacy notebook include: ·
Study protocol,
·
IRB-approved consent form,
·
Drug receipt form,
·
Drug dispensing form,
·
Drug profile,
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Instructions regarding pharmacy's role,
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Patient randomization,
·
Nursing inservice packet, and
·
Nursing synopsis (a single sheet of information that accompanies study drug and
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ includes: dosage, administration, special handling, drug interactions, side effects, patient inclusion/exclusion criteria, and study purpose). I. Accounting The coordinator monitors and records the receipt and distribution of grant funds. These funds are deposited in an account established with the finance department. This is accomplished by completing a check receipt form indicating the study account, dollar amount, and deposit location. The grant check is copied on the bottom half of this form and the check receipt form is signed by the senior staff accountant. A copy is placed in the CRC study notebook, accounting section. All transactions (deposits and payments) are recorded on the accounting form. A copy of the signed check request and related invoice for payments should be copied and filed in the CRC study notebook, accounting section. J. Sponsor Monitoring The sponsor will periodically monitor study conduct and documentation. Monitoring is usually frequent as the first few patients are enrolled and then is scheduled periodically. Monitors often request a brief meeting with the PI to discuss problems and answer questions. To prepare for the visit, the CRC should: ·
Request an agenda from the monitor,
·
Clear his/her schedule for the day(s),
·
Review documentation in the investigator/regulatory binder and CRFs (have another CRC review it also),
·
Request patient charts be placed in the medical records audit room, and
·
Review test article documentation.
Investigator/Regulatory Binder. The monitor will review the binder and ensure that: ·
All versions of the protocol and consent are on file,
·
IRB/investigator correspondence is complete,
·
All serious adverse events have been reported to the IRB, and
·
Sponsor correspondence is filed.
Case Report Forms. The monitor will ascertain whether: ·
Data are complete,
·
CRF data correspond with documentation in the patient chart and study document, and
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ ·
All adverse events have been identified, recorded, and reported appropriately
Test Article. The monitor will ensure: ·
Proper storage,
·
Adequate inventory,
·
Complete documentation, and
·
The release of used study kits for disposal/destruction.
K. Sponsor Communication The CRC will: ·
Address any discrepancies/deficiencies identified by the monitor,
·
Document all contacts with the sponsor, and
·
Follow-up on other issues identified by the monitor or sponsor.
The coordinator should feel free to contact his/her monitor at any time regarding questions or concerns. L. Quality Assurance After enrolling the first patient, the CRC reviews the entire study implementation process, identifies problems, and develops a corrective action plan, as needed. The adequacy of the corrective action plan must be evaluated after the second patient is enrolled. This process will be repeated as needed. To ensure accurate documentation on case report forms, a second CRC will randomly select data in the source document to compare with CRF records. If more than 10 documentation errors are identified, the coordinator will review the entire case report form and compare it with the medical record and source document. All discrepancies will be reviewed and resolved. M. Record Retention Investigators shall retain records for two years following the date a marketing application is approved for the drug for the indication for which it is being investigated. If no application is to be filed, or if the application is not approved for such an indication, the records are retained for two years after the investigation is discontinued and FDA is notified (21 CFR 312.62c). Ideally, study records, which include the case report forms, study document, medical records, investigator/regulatory binder, etc., should be maintained indefinitely. A research contract may require that records be kept longer than specified in FDA regulations. The sponsor should be contacted before study records are destroyed. V. Study Completion
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ A. Sponsor Closeout Visit Once all patients have completed participation at the site, the sponsor will officially close the study during a closeout visit. At this visit, the sponsor will: ·
Review and retrieve all data not previously submitted,
·
Review the investigator/regulatory binder for completeness,
·
Prepare study drug for return to the company,
·
Instruct the CRC regarding disposition of study supplies, and
·
Request a final study report.
B. Final Report to the IRB The coordinator will notify the IRB both when the study is closed to future enrollment and when follow-up on all patients is complete. The CRC will submit a final report to the IRB that has been reviewed and signed by the PI. DISCUSSION An SOP manual provides structured guidelines for coordinators implementing clinical trials. Although developing this document can be a time-consuming endeavor, one principle benefit is that the research site becomes more attractive to sponsors. The model presented addresses many issues and roles common to CRCs, yet can be formatted for the specific requirements of individual institutions. The coordinator may wish to add appendices to the manual that include IRB policies and forms, pertinent administrative policies, a model informed consent document, and FDA/Office of Human Research Protection regulations. By personalizing the SOP manual, it becomes a vital, working document. REFERENCES 1. Title 21 Code of Federal Regulations. Part 50. Washington, DC: US Government Printing Office; 1997. 2. Title 45 Code of Federal Regulations. Part 46. Washington, DC: US Government Printing Office; 1999. 3. Title 21 Code of Federal Regulations. Part 56. Washington, DC: US Government Printing Office; 1997. 4. Title 21 Code of Federal Regulations. Part 312. Washington, DC: US Government Printing Office; 1997. 5. Title 21 Code of Federal Regulations. Part 812. Washington, DC: US Government Printing Office; 1997.
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ RUTH ANN FRIES, BS, CIP Clinical Research Coordinator, Hamot Research Center, Erie, Pennsylvania Reprint address: Ruth Fries, BS, CIP, Hamot Research Center, 104 E. 2nd St., Erie, PA 16507. E-mail: Ruth.Fries @Hamot.org. Copyright Drug Information Association Apr-Jun 2002 Provided by ProQuest Information and Learning Company. All rights Reserved By Abigail Gagara Kriger Research Center
MODEL STANDARD OPERATING PROCEDURES MANUAL This manual was designed to assist clinical research coordinators (CRCs) in the performance of
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ their duties. It is not a substitute for professional education, training, and experience. The clinical research coordinators should be available for consultation, as needed. I. Clinical Research Coordinator A. Definition A CRC is an individual with expertise in clinical research trial management. Typically, the CRC is a registered nurse, medical technologist, pharmacist, or other individual with equivalent scientific/clinical background and research experience. B. Roles and Responsibilities The CRC assists the principal investigator (PI) (usually a physician) and subinvestigators (usually physicians, physician assistants, nurse practitioners, and/or pharmacists) with all aspects of study implementation. Although the CRC is responsible for coordinating all activities related to clinical trial implementation, the CRC can only perform those procedures for which he/she is qualified by training and/or licensure. Responsibilities include: ·
Identifying research opportunities and contacting potential sponsors,
·
Negotiating budget and contract,
·
Completing regulatory documents,
·
Facilitating peer review, administrative review, and approval,
·
Applying for institutional review board (IRB) review,
·
Interacting with the sponsor, research team, pharmacy, IRB, finance, and other departments impacted by the research,
·
Developing study processes,
·
Developing study documents,
·
Educating staff,
·
Recruiting, screening, and enrolling subjects,
·
Implementing and adhering to the protocol,
·
Accounting for study funds,
·
Reporting adverse events, and
·
Providing continuing and final IRB reports.
II. Initial Sponsor Contact:
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ A. Nondisclosure (Confidentiality) Agreement Investigators are provided with clinical trial opportunities through several sources including pharmaceutical companies or device manufacturers, clinical research organizations (CROs), and site maintenance organizations (SMOs), hereafter referred to as the "sponsor." Networking with off-site investigators or coordinators may also afford research opportunities. Before substantial research information is disclosed by the sponsor, a Nondisclosure (Confidentiality) Agreement is signed by the principal investigator (PI). This agreement defines the nature and extent to which confidentiality must be maintained by the PI and study team. At a mimimum, a nondisclosure agreement should include: ·
Definition of confidential information (limited to written disclosures),
·
Disclosure restrictions (what can be disclosed and to whom), and
·
Termination of certain obligations (a description of circumstances that nullify the agreement). Examples include information that was: 1) in the public domain when revealed to the investigator; 2) entered the public domain after disclosure to the investigator without any fault on the part of the investigator; 3) known to the investigator free of any obligation of confidentiality as evidenced by written records; 4) required by law to be disclosed; and 5) received from a third party with no confidential obligation.
·
Termination of the agreement (usually three to five years),
·
Choice of state laws governing the agreement, and
·
A statement that the entire agreement is embodied in the nondisclosure document. The Nondisclosure (Confidentiality) Agreement may be forwarded to legal counsel for review. A copy (or second original) of the signed Nondisclosure (Confidentiality) Agreement should be filed in the CRC study notebook.
B. Research Contract All contracts should receive legal review. Modifications will be forwarded to the CRC and incorporated after investigator review and approval. The contract may not be executed until all necessary approvals are obtained (ie, peer review, administrative approval, IRB, etc.). An original copy of the signed research contract must be filed in the CRC study notebook. C. Research Budget To evaluate the adequacy of the proposed study budget, the coordinator must first review the protocol and identify study-related procedures versus standard of care. All study-related procedures and tests should be reimbursed by the sponsor at a rate comparable to third-party payer reimbursement. Also, compensation should be provided for physician fees, coordinator time, pharmacy charges, overhead, IRB review, and other study-related expenses. Personnel in finance, the physician's office, and other affiliated entities (for example, special procedure billing) may need to be contacted to determine the adequacy of proposed monetary reimbursement. Another. consideration is the reimbursement schedule. Although each budget is
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ unique, a payment of 10% to 20% of the entire grant is usually made soon after the contract is executed. This payment is followed by additional compensation as patients are enrolled and progress through the study. A unique research account can be initiated through finance and assigned to the grant. This ensures that study funds remain separate from the institution's operating account. A copy of the research budget should be filed in the accounting section of the CRC study notebook. D. Site Selection Visit The site selection visit is critical because it represents the first personal contact between the sponsor and the study staff. Once the investigator expresses an interest in a particular project, the sponsor further evaluates the commitment, capabilities, and resources of the study personnel. This is accomplished at the site selection visit by the company representative who gathers information and meets with key research personnel. The coordinator provides the requested information and facilitates the site selection visit. This includes arranging the date, time, and place; notifying all parties; distributing study information; and providing refreshments. Commonly requested information includes: ·
Curriculum vitae and licenses of key study staff,
·
Disclosure of prior research experience (caveat: keep the information general, previous confidentiality agreements are still binding),
·
Estimated number of patients with the pertinent diagnosis,
·
Estimated number of patients who will meet study criteria,
·
Potential patient recruitment strategies, and
·
IRB deadlines.
This information may be provided before or during the visit. Typically, company representatives will request a tour of the facilities. The CRC accompanies the company representative and answers questions. III. Institutional Review Board (IRB) A. Submission When a study is submitted for IRB review, a request for approval of a clinical investigation form must be completed, a consent document developed, and administrative, peer, and service line approval (if appropriate) obtained. The coordinator often prepares these documents; however, the PI must review and sign the appropriate forms before submission. Once written administrative and IRB approval is obtained for the study, the research contract may be signed and the site initiation visit scheduled. Although the coordinator can assist the PI with the consent process, a physician obtains consent for experimental drug and device studies. This can be dependent on state law and should be determined for each state. To eliminate any perception of coercion, the witness should be someone other than a study team member.
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ B. Adverse Events An adverse event is any untoward medical event that occurs while a patient is enrolled in a research protocol, regardless of whether it is related to the study. All onsite adverse events must be reported to the IRB and sponsor. Also, the sponsor will report serious and/or unexpected adverse events that occurred off-site to the PI who must then forward them to the IRB. The CRC often assists the PI by submitting the necessary paperwork to the IRB. If the adverse event necessitates a change in the protocol and/or consent, these modifications must be submitted to the IRB for review and approval. C. Protocol/Consent Modifications The coordinator ensures strict adherence to the IRB-approved research protocol. Any changes in the protocol or consent must be submitted to the IRB for review and approval before they can be implemented. The only exception to this rule is when a change is necessary to eliminate or reduce the risk to human subjects. If a minor protocol deviation inadvertently occurs, the CRC will report this to the IRB at the next continuing review and to the sponsor at the next monitoring visit. If modifications are approved, the coordinator notifies the study personnel and other appropriate individuals of the change and updates the study document and study process accordingly. If modifications affect patients, those currently enrolled in the study will be notified in writing and a consent addendum signed. This requires IRB approval and revision of the original consent. D. Advertisements/Media Releases/Recruitment Materials Any material distributed to or reviewed by patients or the general public must receive review and approval by the IRB and the sponsor. When drafting advertisements, the coordinator should follow FDA guidelines. A script should be utilized when responding to phone calls from potential study patients. Letters to physicians requesting referrals or releases for physician publications need not receive prior IRB review. E. Continuing Review All studies that initially receive quorum or expedited review are subject to periodic review by the IRB. Continuing review is usually performed annually and requires a summary of the investigator's experience with the study. The CRC is typically responsible for completing the continuing review form, forwarding it to the PI for review and signature, and submitting it to the IRB. F. Final Review All research must have a final review to formally terminate the study. A study may be closed to enrollment, but the final review may only occur after the follow-up on the last patient is complete. The coordinator is usually responsible for completing the final review form, forwarding it to the PI for review and signature, and submitting it to the IRB. This should include results, if available.
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ IV. Study Implementation A. Good Clinical Practice and Federal Regulations In keeping with Good Clinical Practice (GCP), the CRC will assist the investigator in complying with all applicable federal regulations regarding informed consent (21 CFR, Part 50 and 45 CFR Part 46); the institutional review board (21 CFR, Part 56 and 45 CFR Part 46 ); Investigational New Drugs (21 CFR, Part 312); and significant/ nonsignificant risk devices (21 CFR, Part 812). CRCs will also help ensure compliance with all IRB and hospital research policies. B. Key Study Personnel 1. Principal Investigator The PI is the leader of the research team and responsible for all aspects of conducting the clinical trial. The PI ensures that the study is performed according to the IRB-approved protocol, the test article is appropriately stored and administered, and informed consent is properly obtained from each study subject or legal representative. Although the PI is usually a physician, in certain circumstances other qualified individuals perform this function. (This may be determined by state law, hospital policy, or IRB policy.) 2. Subinvestigator The subinvestigator is a member of the research team who assists the PI with clinical trial implementation. Subinvestigators may include physicians, physician assistants, nurse practitioners, and pharmacists. 3. Clinical Research Coordinator The CRC manages the implementation and coordination of the clinical trial under the direction of the PI. C. The Study Document Clinical trial data are recorded both in the traditional medical record (ie, patient chart in the physician's office, hospital, rehabilitation center) and the study document. The medical record provides information regarding the patient treatment, progress notes, drug administration, laboratory testing, and other procedure results. The study document is created by the coordinator to capture all protocol-specific data and to guide the investigator and other study/office/medical center personnel through the research process. The study document includes: ·
A copy of the study summary chart (ie, a listing of all study procedures),
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Instructions for key personnel in pertinent departments (emergency department, nursing, radiology, laboratory, etc.),
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Two copies of the IRB-approved consent form (one will be given to the patient),
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Space to record all information required by the sponsor (this may be a copy of the case
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ report form pages, worksheets provided by the sponsor, or flowsheets developed by the CRC), ·
A checklist of procedures to occur at relevant time points,
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An educational packet for staff, and
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Information regarding the test article and its administration.
The study document captures all necessary information throughout the course of the patient's participation. Indexing the study document according to preset time points (ie, baseline visit, one week, one month, etc.) is advisable. If the study document is placed in another department to facilitate patient enrollment, the coordinator should periodically check it for completeness. Also, the study document needs to be updated when the IRB and sponsor approve modifications. D. Study Process To develop the study process, the coordinator must first carefully evaluate the protocol. Occasionally, sponsors provide a study implementation manual that assists with process development. Once the protocol has been evaluated, the CRC contacts key personnel, reviews the protocol with them, and seeks input regarding the best way to integrate study procedures into routine departmental processes. The study process comprises three main components: 1. The Process Outline is a step-by-step guide for enrolling and following patients throughout the study. This outline should contain sufficient information to allow a second coordinator who is less familiar with a specific protocol to implement study activities and procedures. 2. Preprinted Standing Orders include: ·
All hospital-related testing associated with the protocol (ie, nursing, laboratory, EKG, radiology orders),
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Information regarding study drug administration and dosage, and
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An order for special study procedures, monitoring, and documentation.
3. The Study Document (See Section IV.C. of this manual). E. Test Article (Study Drug or Device) The CRC or pharmacist, if applicable, will be responsible for test article accountability. This documentation includes the date and quantity of the initial shipment, condition of the test article upon arrival, identification numbers, expiration date, and other information as required by the sponsor. As drug is dispensed, the following information should be recorded: patient initials and study number, test article identification number, date and amount dispensed, date and amount returned, and pharmacist's initials for all transactions. F. Site Initiation Visit
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ The site initiation visit will occur after the contract is finalized and IRB/administrative approval has been obtained. The CRC arranges a meeting between the sponsor and the study staff. The site initiation visit is the final step before patient enrollment may begin and consists of a thorough review of the protocol and case report forms (CRF), review of the investigator's role and responsibilities, discussion of Good Clinical Practices (GCPs), and monitoring of the test article. This visit allows the CRC to discuss protocol/process questions with a company representative, ask advice regarding implementation of unusual aspects of the protocol, and establish a good working relationship with the sponsor/CRO/SMO. G. Education Before patients are enrolled in the protocol, the pertinent study and medical center staff must be inserviced. For study personnel, a summary of the entire study process, as well as their specific duties, should be presented. Study personnel must fully understand the protocol and implementation process, as well as unique elements of the research. For medical center staff, a study summary is presented that includes: research purpose, inclusion/exclusion criteria, test article administration/implantation, potential side effects, specific responsibilities, required documentation, and an overview of study implementation. The CRC arranges the time, place, agenda, handouts, refreshments, and notification of educational inservices. H. Study Documentation The CRC is responsible for maintaining all study documents. A notebook, known as the investigator or regulatory binder, is usually provided by the sponsor and will contain information related to the clinical trial including: ·
Protocol,
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Amendments,
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Investigator brochure,
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IRB correspondence,
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IRB approvals,
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Sponsor correspondence,
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IND safety and serious adverse event (SAE) reports
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FDA1572 (if applicable),
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Study personnel curriculum vitaes,
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Monitoring log,
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Screening log,
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ ·
Lab certifications and normal values, and
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Study drug/device records.
The coordinator should also maintain a CRC study notebook that contains: ·
Internal correspondence,
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Research contract,
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Nondisclosure agreement,
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Study accounting,
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Physician communication, and
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Other site-specific study documentation.
The CRC is also responsible for recording all data in the sponsor case report form. When recording data, the coordinator should: ·
Review and follow sponsor instructions,
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Use a black ballpoint pen,
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Write legibly, and
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Correct errors by striking through them with a single, horizontal line, dating and initialing the error, and recording the correct information.
The pharmacy may require that the CRC develop a notebook regarding the study and study drug. Essential elements of the pharmacy notebook include: ·
Study protocol,
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IRB-approved consent form,
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Drug receipt form,
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Drug dispensing form,
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Drug profile,
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Instructions regarding pharmacy's role,
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Patient randomization,
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Nursing inservice packet, and
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Nursing synopsis (a single sheet of information that accompanies study drug and
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ includes: dosage, administration, special handling, drug interactions, side effects, patient inclusion/exclusion criteria, and study purpose). I. Accounting The coordinator monitors and records the receipt and distribution of grant funds. These funds are deposited in an account established with the finance department. This is accomplished by completing a check receipt form indicating the study account, dollar amount, and deposit location. The grant check is copied on the bottom half of this form and the check receipt form is signed by the senior staff accountant. A copy is placed in the CRC study notebook, accounting section. All transactions (deposits and payments) are recorded on the accounting form. A copy of the signed check request and related invoice for payments should be copied and filed in the CRC study notebook, accounting section. J. Sponsor Monitoring The sponsor will periodically monitor study conduct and documentation. Monitoring is usually frequent as the first few patients are enrolled and then is scheduled periodically. Monitors often request a brief meeting with the PI to discuss problems and answer questions. To prepare for the visit, the CRC should: ·
Request an agenda from the monitor,
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Clear his/her schedule for the day(s),
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Review documentation in the investigator/regulatory binder and CRFs (have another CRC review it also),
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Request patient charts be placed in the medical records audit room, and
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Review test article documentation.
Investigator/Regulatory Binder. The monitor will review the binder and ensure that: ·
All versions of the protocol and consent are on file,
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IRB/investigator correspondence is complete,
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All serious adverse events have been reported to the IRB, and
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Sponsor correspondence is filed.
Case Report Forms. The monitor will ascertain whether: ·
Data are complete,
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CRF data correspond with documentation in the patient chart and study document, and
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ ·
All adverse events have been identified, recorded, and reported appropriately
Test Article. The monitor will ensure: ·
Proper storage,
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Adequate inventory,
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Complete documentation, and
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The release of used study kits for disposal/destruction.
K. Sponsor Communication The CRC will: ·
Address any discrepancies/deficiencies identified by the monitor,
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Document all contacts with the sponsor, and
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Follow-up on other issues identified by the monitor or sponsor.
The coordinator should feel free to contact his/her monitor at any time regarding questions or concerns. L. Quality Assurance After enrolling the first patient, the CRC reviews the entire study implementation process, identifies problems, and develops a corrective action plan, as needed. The adequacy of the corrective action plan must be evaluated after the second patient is enrolled. This process will be repeated as needed. To ensure accurate documentation on case report forms, a second CRC will randomly select data in the source document to compare with CRF records. If more than 10 documentation errors are identified, the coordinator will review the entire case report form and compare it with the medical record and source document. All discrepancies will be reviewed and resolved. M. Record Retention Investigators shall retain records for two years following the date a marketing application is approved for the drug for the indication for which it is being investigated. If no application is to be filed, or if the application is not approved for such an indication, the records are retained for two years after the investigation is discontinued and FDA is notified (21 CFR 312.62c). Ideally, study records, which include the case report forms, study document, medical records, investigator/regulatory binder, etc., should be maintained indefinitely. A research contract may require that records be kept longer than specified in FDA regulations. The sponsor should be contacted before study records are destroyed. V. Study Completion
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ A. Sponsor Closeout Visit Once all patients have completed participation at the site, the sponsor will officially close the study during a closeout visit. At this visit, the sponsor will: ·
Review and retrieve all data not previously submitted,
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Review the investigator/regulatory binder for completeness,
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Prepare study drug for return to the company,
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Instruct the CRC regarding disposition of study supplies, and
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Request a final study report.
B. Final Report to the IRB The coordinator will notify the IRB both when the study is closed to future enrollment and when follow-up on all patients is complete. The CRC will submit a final report to the IRB that has been reviewed and signed by the PI. DISCUSSION An SOP manual provides structured guidelines for coordinators implementing clinical trials. Although developing this document can be a time-consuming endeavor, one principle benefit is that the research site becomes more attractive to sponsors. The model presented addresses many issues and roles common to CRCs, yet can be formatted for the specific requirements of individual institutions. The coordinator may wish to add appendices to the manual that include IRB policies and forms, pertinent administrative policies, a model informed consent document, and FDA/Office of Human Research Protection regulations. By personalizing the SOP manual, it becomes a vital, working document. REFERENCES 1. Title 21 Code of Federal Regulations. Part 50. Washington, DC: US Government Printing Office; 1997. 2. Title 45 Code of Federal Regulations. Part 46. Washington, DC: US Government Printing Office; 1999. 3. Title 21 Code of Federal Regulations. Part 56. Washington, DC: US Government Printing Office; 1997. 4. Title 21 Code of Federal Regulations. Part 312. Washington, DC: US Government Printing Office; 1997. 5. Title 21 Code of Federal Regulations. Part 812. Washington, DC: US Government Printing Office; 1997.
( Word to PDF - Unregistered ) http://www.word-to-pdf.abdio.com/ RUTH ANN FRIES, BS, CIP Clinical Research Coordinator, Hamot Research Center, Erie, Pennsylvania Reprint address: Ruth Fries, BS, CIP, Hamot Research Center, 104 E. 2nd St., Erie, PA 16507. E-mail: Ruth.Fries @Hamot.org. Copyright Drug Information Association Apr-Jun 2002 Provided by ProQuest Information and Learning Company. All rights Reserved By Abigail Gagara Kriger Research Center
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