In a multicenter research study, the an individual or group of individuals charged with study oversight, coordination and overall conduct need to be identified. Those responsible could be simply the study Principal Investigator or there could be a more formal study Steering Committee or Data Coordinating Center (DCC). In addition, oversight may be the responsibility of a single entity or divided between multiple organizations. For industry sponsored studies the study sponsor or their designated CRO(s) (contract research organization) are required by the FDA to provide trial oversight.
Components of Multicenter Study Oversight
The group(s) responsible for the oversight of a multicenter research study must ensure the integrity of the study as it is executed at all sites. They must ensure that all of the following considerations:
- investigators and sites are qualified by virtue or training and experience to conduct the research;
- investigators have adequate resources - space, time and potential for enrolling the requisite number of subjects - to ensure that it is feasible to conduct the study at their site;
- all sites conduct the research in the same manner by using and adhering to the same protocol and study procedures;
- all sites obtain IRB approval prior to local initiation of the study;
- if a central IRB is serving as the reviewing IRB for multiple sites, the DCC may be responsible for choosing the central IRB;
- a valid consent is obtained using an IRB-approved informed consent form that contains the required elements of consent;
- all required study materials are distributed and accounted for - including investigational test articles, case-report forms, etc.;
- the data that is collected is accurate, valid and securely stored;
- analyses are accurate and carried out in conformance to the pre-specified statistical analysis plan (as specified in the protocol);
- safety of subjects is assured by continual assessment throughout the conduct of the study;
- unanticipated problems are reported to the relevant regulatory authorities, funding agencies and all local sites;
- authorship of results is equitably apportioned to investigators in accordance to the requirements of the ICJME.
Detailing the Plan for Study Oversight
In the eIRB application, if the investigator indicates in Section 1.03(1.0) that the study is multicenter and in Section 1.04 (2.0) that the CHOP PI is responsible for one or more aspects of study oversight, then Form DCC must be completed and attached to the application. Form DCC provides the IRB with the details of how the CHOP investigator will provide oversight for the components of the study that they are responsible for. In near future, Form DCC will be integrated into the eIRB application. Form DCC covers the following areas of study oversight:
- Document Preparation and Distribution,
- Test Article and Materials Distribution,
- Site Management and Oversight,
- Data Management and Statistical Analysis, and
- Data and Safety Monitoring.
Form DCC details how the PI will execute their responsibilities for study oversight. The IRB, by approving the oversight plan, allows the DCC to operate without the need to notify the CHOP IRB of every interim event. For example, by approving the method of site qualification, the CHOP IRB does not require approval of an amendment for each site that is selected or when each site obtains IRB approval. The DCC must submit a Study Progress Report at the time of Continuing Review that updates the IRB on the overall study progress.
Study documents could include the protocol, the consent form, advertisements, flyers, study tools (e.g., checklists) and letters. It is vital that all of the site investigators use the exact same protocol. If the study is based on a grant submission, the protocol should be prepared during the review period whenever possible, to minimize start-up delays.
Test Article and Materials Distribution
Studies that involve a test article (a drug, biologic or device) require compliance with FDA regulations. When the test article is investigational, then the DCC or the PI will usually hold the IND or IDE. This individual is termed a sponsor by the FDA and must comply with the requirements of 21 CFR 312.
Site Management and Oversight
When the CHOP PI is responsible for Site Management and Oversight, they will need to list each participating site, the PI at the site, the Local IRB FWA# and indicate whether the local IRB or the CHOP IRB is serving as the IRB of record. The investigator also outlines their procedures for ensuring that each site has IRB approval prior to participation. As part of approval of the research, the CHOP IRB is approving DCC's procedures for study oversight and therefore, the IRB does not require an amendment to add or subtract sites (unless CHOP is the Reviewing IRB for that site). At the time of Continuing Review the Progress Report needs to include an updated listing of the study sites and their IRB approval status.
The sites for a multicenter study may be participants in a network funded by the NIH or other organization or they may be chosen by the PI of the study from amongst colleagues at other institutions. When sites are selected for a study, there are responsibilities for ensuring that the individuals are qualified, that they have the requisite staff, time and patient population to support the study and that they will ensure IRB approval prior to beginning the study. During the study, the DCC is also responsible for ensuring that each site is performing as expected and that they are maintaining IRB approval for their activities.
A good source for a listing of Site Management oversight responsibilities are those outlined in Subpart D of 21 CFR 312. The section of the regulations includes selection of investigators and monitors, record keeping, test article accountability, reporting requirements, and other assurance of IRB review.
Data Management and Analysis
The DCC component responsible for Data Management is responsible for the preparation of the Case Report Forms (CRF) and any required tools and explanations needed to complete the forms. CRFs may be paper or electronic and increasingly, these are prepared using web-based entry tools. The protocol should be sufficiently detailed so that the data manager can prepare the CRFs without the need to consult the PI.
The study statistician is responsible for the generation of randomization codes, sample size estimation, analysis plan and for performing the required analysis.
Data and Safety Monitoring
The Data and Safety Monitoring plan will vary depending on the nature of the study. As part of that plan there might or might not be a site monitoring program or just in-house review of the emerging data. The intensity of study monitoring will depend on the risks of the study intervention and the seriousness of the underlying disease being studied. The options can range from having a medical monitor (usually the study PI) to an internal data monitoring committee to an independent data safety monitoring committee (DSMB or DSMC). Studies that involve life-threatening conditions, diseases causing serious morbidity, novel treatments for serious or life-threatening conditions and interventions with significant risk for serious adverse events usually require a DSMB. The DCC is usually responsible for coordination of the DSMB and other safety assessment activities.
Reporting to Regulatory Authorities The details of how unanticipated problems will be reported to the relevant regulatory authorities (FDA or OHRP) and the funding agency, such as the NIH, should be clearly specified if not delineated in the protocol.
Use of a Central IRB for Multicenter Trials
Both OHRP and the FDA permit an IRB the option to rely on the review of another IRB. When this is the intention, the two institutions enter into an agreement referred to variously as either a Cooperative Agreement or an IRB Reliance Agreement . These agreements are executed between a Reviewing IRB and one or more Relying Institutions. The agreements can be for a single research study or for multiple studies (e.g., a Master Reliance Agreement).
Investigators who would like the CHOP IRB to serve as the IRB of record for one or more participating sites or who would like another IRB to serve as the IRB of record for CHOP should initiate discussions early in the planning process by emailing Amy Schwarzhoff, Director, IRB Office at SchwarzhoffA [at] email.chop.edu.
Resources and References for Data Monitoring of Multicenter Trials:
- The role of the data coordinating center in the DIG trial
- The role of the data coordinating center in the IRB review and approval process: the DIG trial experience
- The other side of clinical trial monitoring; assuring data quality and procedural adherence
- Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials
- Ensuring trial validity by data quality assurance and diversification of monitoring methods
- Using Central IRBs for Multicenter Clinical Trials in the United States
- StaR Child Health Group. Standard 3: data monitoring committees
- NIH Policy for Data and Safety Monitoring
- NIH: Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials
- FDA Guidance: Establishment and Operations of Clinical Trials Data Monitoring Committees
- European Medicines Agency: Guideline on Data Monitoring Committees