iii) Elements of GCP and Compliance
The Clinical Research Support Office works closely with the Clinical Translational Research Facilitation Office, other hospital departments, and elements of the Human Research Protection Program to address our goal of meeting or exceeding all of the requirements specified under Good Clinical Practice (GCP). The resources available through the CTSA allow us to build in redundancy and automatic checks of compliance. We use a customized version of iRIS (iMEDRIS) software for protocol writing and IRB management that interfaces with existing applications. This integration enhances our ability to provide assistance to research teams in fulfilling documentation requirements in compliance with GCP, and fulfilling the routine data entry and other key functions required to achieve Patient Safety and Regulatory Management and Compliance.
Highlights of the means by which the interdisciplinary programs in place serve to assure fulfillment of GCP include:
- Human Subjects Protections and Good Clinical Practices (GCP) training. All investigators, research team members and research nurses are required to complete training and receive certification in both Human Subjects Protections, and in Good Clinical Practices through the CITIprogram before they may conduct human research. Certification must be renewed every three years.
- iRIS, an Integrated Electronic Protocol Development, Review, and Conduct Platform. This electronic platform for IRB review, study management and subject management, was customized by Rockefeller to incorporate an integrated protocol development tool that contains step-by-step instructions incorporating elements of GCP as they relate to specific aspects of the protocol under development, along with links to the other documents and guidance. It provides a platform for mentored or self-guided education in rigorous protocol development.
- Regulatory documentation required of the Principal Investigator, including IRB and FDA correspondence, is tracked by both the IRB and the Investigator. iRIS supports reporting of deviation, violations and adverse events and its reporting functions enable early identification of trends or patterns. Investigators are provided with guidance prior to protocol start-up by CCTS support staff and offered a library of recommended logs and tool templates and guidance available through the IRB webpage. The iRIS application serves as a secure, transparent platform for document sharing among the research team and oversight personnel. The resources on the Program of IND Assistance provide a streamlined portal to the relevant FDA guidance for investigators preparing documentation for IND/IDE applications. The ability to automate timetables for milestones, filing deadlines, and renewals, and to structure reminders as well as audit trails of the timelines of compliance, will be extremely valuable in generating metrics, and assisting in and supporting compliance.
- Documentation required of the IRB: The electronic clinical research management system upgrade (iRIS) supports a customized IRB database with customized workflow. All correspondence, submission, and IRB actions are captured. The software enhancements place all this information in a single database accessible to IRB, CRSO and investigators as appropriate, simplifying work flow and documentation, and facilitating a significant portion of reporting.
- Subject recruitment practices of Investigators and the Clinical Research Recruitment Outreach Support Services (CRROSS) are overseen by the IRB and the Clinical Research Support Office. The recruitment expertise, call center services, advertising, data management, and IRB-approved Research Volunteer Repository have served to enhance recruitment etiquette, standardize recruitment approaches, and enhance the diversity of the participant population. Some of the enhancements to recruitment and outreach, include:
- Integration of health literacy and foreign language services;
- Web-based resources and coordinated links to internal programs and policies;
- Accurate analysis of the demographics, and of screening and enrollment successes and failures;
- Expansion of targeted recruitment strategies and services to minority populations,
- Research to assess retention strategies and provide comprehensive services to all investigators,
- Appropriate analyses of cost-effectiveness of efforts,
- Creation of an IRB-approved Research Volunteer Repository through which interested volunteers may be recontacted for future research
The Informed Consent process is enhanced by the requirements for demonstrated competence (through training of experience) before investigators can administer informed consent, standard operating procedures for conducting consent in various circumstances (e.g. with adults, with minors, over the telephone), and standard IRB-approved templates for the creation of the informed consent and assent forms. The Clinical and Translational Research Facilitation Office conducts an Informed Consent Tutorial to train new research team members how to administer and obtain informed consent from research participants. The tutorial must be completed before a research team member may independently conduct an informed consent discussion. Assistance in authoring Informed Consent forms in Plain Language is offered through the Research Facilitation Office and the use of widely available text readability applications.
As research participants often do not have a full understanding of the protocol or the elements of informed consent (Sugarman et al.1998), investigators are instructed during the Informed Consent Tutorial to use the Teach Back method when conducting the informed consent discussion. The "Teach Back" method (Schillinger et. al., 2003), endorsed by numerous health literacy initiatives, involves educating staff to ask healthcare recipients to teach back to the health care worker the concepts and directions that the healthcare worker has attempted to convey to the patient. In the clinical research setting, Teach Back involves asking research participants to "teach back" information over and above that imparted in routine healthcare, and for the research team to assess comprehension and retention of protocol requirements, adverse event information, risks and benefits, and the subject's rights described in the Informed Consent process. Teach Back principles are also emphasized through Nursing education, GCP training, and in Protection of Human Subjects Training for all staff.
- Documentation of the appropriate inclusion/exclusion criteria is required of investigators using an Enrollment Note in the medical record, per published Institutional Review Board procedures. The iRIS system affords creation of detailed inclusion/exclusion checklists. This capability, combined with appropriate policies from the IRB and Medical Staff Executive Committee, and IRB-approved template language, enhances compliance with these standards. Internal monitoring and periodic audits are quality assurance activities to assure the proper implementation and documentation of inclusion/exclusion criteria.
- Adverse event reporting of SAEs and UAEs at Rockefeller University Hospital is greatly advantaged by the institution's compact size, the multidisciplinary nature of the research teams, and the broad participation of personnel in weekly Interdisciplinary Rounds. All SAEs and UAEs are reported to the IRB in accord with IRB Policy and to the FDA and other regulatory bodies in accord with 21 CFR, the requirements of Sponsors, and applicable regulations. The Clinical Research Support Office reviews SAEs and UAEs in real time, and audits reported AEs against protocol records and source documents to verify accuracy. All non-serious AEs are reported to the IRB at least annually. The electronic integration of study management functions into the electronic clinical research system allows creation of a single on-line AE database accessible to both the research teams and the oversight bodies. The ability to query and resolve AE entries on-line with a documented audit trail greatly facilitates this work.
- The Drug/Device accountability requirements of GCP are met at the RUH pharmacy through the detailed standard operating procedures (SOPs) of the research pharmacist and reinforced by practices and audits of the industry sponsor in cases of an investigational agent with an industry held IND according to ICH GCP. Investigator-Sponsors have an additional resource for assistance meeting GCP through the Program of IND Assistance (PIA) modeled after the IND Assistance Program offered at University of Minnesota, and reported by Arbit and Paller, 2006. Implementation of the comprehensive Program of IND Assistance, recently streamlined as part of the Translational Research Protocol Navigation process, offers investigators the following services:
- A CRSO staff member, the Clinical Research Specialist, has specific experience relevant to IND/IDE applications
- A Program of IND Assistance (PIA) website, providing links to all the services listed below.
- Overview of investigational new drug (IND) and investigational device exemption (IDE) regulations,
- Explanation of obligations and responsibilities of IND/IDE sponsors and investigators;
- Review and assistance in the determination and documentation regarding the need to file an IND/IDE application;
- Information regarding the contents of the IND/IDE application and assistance in its preparation;
- Assistance drafting the clinical protocol to comply with Good Clinical Practices guidelines (through Navigation service),
- Assistance preparing forms and communications to the FDA regarding protocol amendments, additional co-investigators, process changes, and adverse event reports;
- Template SOPs for clinical trial monitoring;
- Review of IND/IDE documentation to assure compliance with FDA regulations and Rockefeller University policy;
- Assistance with registration of study with ClinicalTrials.gov;
The goal of the comprehensive Program of IND Assistance is to support the investigator so as to reduce the regulatory burden, improve efficiency, and address the risk management aspects of the IND, while maintaining the investigator's direct responsibility for the integrity of the IND itself, regulatory compliance, and the safety of the participants. PIA services are integrated with the other clinical research support services routinely offered by other CCTS cores.
- Case Report Forms are routinely provided by industry sponsors for their studies. For investigator-initiated studies, data collection worksheets are developed to organize the collection of clinical data that is not required as part of the medical record. Investigators are encouraged to meet with a member of the Research Facilitation Office, or the Clinical Research Specialists of the CRSO for assistance in designing these tools and to ensure that all required elements are captured. The Department of Research Nursing coordinates the data collection elements of the protocol in the Clinical Protocol Pathway which serves as a medical record and source document. The new electronic clinical research management system 'Forms Wizard" facilitates generation of case report forms and templates. Systematic use of CRFs will assist in orderly workflow, reduce duplication of effort and documentation, and help to ensure compliance with GCP.
- Formal allocation of responsibilities in each research protocol must be filed by the Principal Investigator in the form of a Delegation of Authority Log according to IRB policy. The Delegation of Authority Log, as part of the IRB-approved protocol, is available to the nursing service on a web-based platform via the intranet and is used as a real-time reference in clinical research care to confirm that research personnel are qualified and approved to perform specific research procedures in the Hospital. In the electronic clinical research management system upgrade, the Delegation of Authority submissions will be automatically verified at the time of protocol submission, against a central database containing the credentials of staff including medical licensure, credentials for specific procedures, Human Subjects Protection training certification, Informed consent process training and other qualifications. If verification cannot be confirmed, the system, and the IRB will generate a timely notification to the investigator prior to IRB review. IRB review and periodic CRSO audits are additional opportunities to assure that delegation of tasks is appropriate and effective.
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Schillinger D, Piette J, Grumbach K, et al. "Closing the loop: physician communication with diabetic patients who have low health literacy." Arch Intern Med. 2003;163:83-90.
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