iii) Elements of GCP and Compliance
The integration of information and processes afforded by the new electronic clinical research management system is critical in addressing 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. The implementation of iRIS/iMEDRIS and the anticipated interfaces with existing applications will dramatically enhance 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.
A review of the means by which GCP functions are currently met, and will be enhanced under the CTSA is summarized as follows, organized by 10 areas of GCP guidance:
- Regulatory documentation required of the Principal Investigator, including IRB and FDA correspondence is tracked by both the IRB and the Investigator. Investigators are provided with guidance prior to protocol start-up in a meeting with the Clinical Research Support Office staff who provide a suggested template for organization of the Regulatory Binder and a library of recommended logs and tool templates. Additional guidance is provided through the IRB webpage. The iRIS/iMEDRIS software system will make the filing of the required documents transparent, permit document sharing with the IRB and CRSO and support automated checklists and prestructured workflow. The development of a specific Program of IND Assistance, will provide additional assistance to Investigator-Sponsors. 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. The software enhancements will 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 the reporting.
- Subject recruitment practices of Investigators and the Patient Recruitment and Outreach Program: (PROP) are overseen by the IRB and the Clinical Research Support Office. The ability to expand recruitment and outreach, including:
- 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,
- The Informed Consent process is enhanced by investigator access to assistance from the IRB, additional expertise including informed consent form editing, informed consent education and observation from the CRSO, and new electronic document management options to track Informed Consent signature dates, generate reminders for re-consenting, and requiring explicit workflow sign off and more. These data can be audited and tracked for Quality Assurance purposes. The enhancement of Informed Consentauthoring assistance is described above.
As research participants often do not have a full understanding of the protocol or the elements of informed consent (Sugarman et al.1998). The Informed Consent process will be more directly enhanced by several initiatives: There will be broad implementation the Teach Back method with the investigative teams and Patient and Clinical Interactions Resources (PCIR) staff. 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 information, 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 will be emphasized through Nursing education, GCP training, and in Protection of Human Subjects Training for all staff. Processes to capture the conduct and results of Teach Back encounters are currently under development for assessment purposes; the results will be used to improve the education of the research team and to enhance the Informed Consent process.
- 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 electronic clinical research system upgrade will afford creation of customized Case Report Forms, including detailed inclusion/exclusion checklists. This capability, combined with appropriate policies from the IRB and Medical Staff Executive Committee, and IRB approved template language will enhance compliance with these standards. The clinical research database has the functionality to assist in monitoring the proper implementation and documentation of inclusion/exclusion criteria as well.
- 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 the 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, all AEs quarterly, and audits 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 will allow 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 GCPare 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 will have additional assistance meeting GCP at the Center with a new Program of IND Assistance (PIA) modeled after the IND Assistance Program offered at University of Minnesota, and reported by Arbit and Paller, 2006. In the first year the CRSO plans a staged implementation of a comprehensive Program of IND Assistance to investigators, offering investigators the following services:
- A CRSO staff member, the IND Specialist
- 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;
- Templates for the initial IND/IDE application, clinical monitoring activities, adverse event reporting, annual report submissions, product disposition log, study protocol, and case report forms;
- Assistance drafting the clinical protocol to comply with Good Clinical Practices guidelines,
- Assistance preparing forms and communications to the FDA regarding protocol amendments, additional co-investigators, process changes, and adverse event reports;
- Written procedures for clinical trial monitoring;
- Reminders when annual progress reports and other obligations are due;
- Review of IND/IDE documentation to assure compliance with FDA regulations and Rockefeller University policy;
- Registration of study with ClinicalTrials.gov;
- Notification of news items relevant to investigator-initiated research.
(adapted from Arbit and Paller, 2006, List 2).
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 will be supplemented by the other clinical research support services routinely offered by the CRSO.
- Currently, 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 the Clinical Research Specialists of the CRSO for assistance in designing these tools and to insure 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 insure compliance with GCP.
- The record keeping requirements of GCP have been addressed in the Program of IND Support and Regulatory Compliance above, and will be detailed in the written study conduct and monitoring standards for the IND Assistance Program and for the Monitoring program described below. Electronic databases implemented for IND-related studies will be compliant with appropriate FDA standards.
- 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 with 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.
Arbit H, Paller M. "A Program to Provide Regulatory Support for Investigator-Initiated Clinical Research." Academic Medicine, Vol. 81, No. 2 / February 2006.
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.
Sugarman J, Kass NE, Goodman SN, Perentesis P, Fernandes P, Faden RR. "What patients say about medical research." IRB 1998;20:1-7.
Sugarman J, Lavori PW, Boeger M, Cain C, Edson R, Morrison V, Yeh SS. "Evaluating the quality of informed consent." Clinical Trials 2005;2:1-8.