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IRB Audits and Inspections
IRB audits can be conducted by federal agencies overseeing research such as the FDA or the Office for Human Research Protections, research bases, study sponsors, and IRBs. Pharmaceutical sponsors do routine monitoring of their studies at regular intervals. The Toledo Community Oncology Program’s research bases only audited the program every three years. This can make it difficult to know about mistakes made years earlier and to put quality assurance processes in place when needed.
For this reason, the IRB is the most important auditor of their own IRB. When the author first started to work with IRBs, internal audits were not conducted. At that time, clinical research sites had fewer studies, and studies were less complex. In today’s clinical research environment, it would be very difficult to pass an audit or inspection without an internal audit process. Oversight of studies is a tremendous responsibility, and internal audits enable IRBs to identify mistakes, correct them, and take actions to prevent the same mistake from re-occurring.
Someone on the IRB, either the chair or another IRB member, should be part of the internal auditing process. At a minimum, the results of internal IRB audits should be reported to the IRB every month.
A full circle audit starts with the initial IRB approval and continues through informing investigators of any new addendum or investigator-driven adverse events (Table 3) occurring after IRB approval. This author utilized the same process that an FDA investigator utilized while auditing the Toledo Community Oncology Program and then developed the full circle audit process in her IRB office. A full circle audit consists of reviewing documents from point A to point Z on one study. If a study was approved, ensure that physicians were notified; if physicians were notified, document how the notification took place; if there was notification of approval of a study, did it follow the IRB policy? This is a full-circle audit. Review of A should take you to review of B, and end up back at review of A. The author also incorporated suggestions such as putting protocol version dates on agendas so that these could be compared to the investigator’s brochure. The IRB will learn lessons during an audit that will help it improve its processes and results.
Research bases and other organizations that are auditing the IRB are the best sources of information about IRB audit guidelines. The North Central Cancer Treatment Group, one of the Toledo Community Oncology Program’s research bases, utilized a checklist during audits with a cover sheet to note IRB deficiencies and whether they were considered as major or lesser deviations. The IRB at the Toledo Community Oncology Program reviewed these audit guidelines for each of its research bases, utilizing them for its own internal audits. This allowed the IRB to be audit-ready at all times, following the same process for auditing as their research base.
FDA Inspections
FDA inspections of IRBs ensure the protection of the rights, welfare, and safety of human subjects and the quality and integrity of the data submitted to the agency. Inspections are not designed to make life difficult for clinical research professionals or IRB offices. They can serve as an education tool, which clinical research professionals and IRB’s can utilize and find useful.
The FDA can conduct the inspection at clinical research sites or at central administrative offices such as the Toledo Community Oncology Program. The FDA can also visit clinical investigators at hospitals, and study sponsors. The agency provides advance notice of where it will visit.
The use of the word “should” in the federal regulations means that something is suggested or recommended, but not required. The author believes, however, that when the FDA says, “should,” clinical research professionals or IRB offices should definitely follow that suggestion or recommendation. The FDA is strongly suggesting or recommending the action for a reason, and it is likely to become mandatory in a few years. For example, the FDA states that the IRB members should not all be the same gender. While the agency will not issue a deviation for having an IRB with members of only one gender, it is in the IRB’s best interest not to have a only one gender participating on the committee.
There are two types of FDA inspections: surveillance and directed (Table 4). Surveillance inspections are usually regular inspections done every five years. Directed inspections are conducted when there is a reason for the FDA to inspect an IRB. The FDA will contact the IRB and issue a notice of inspection. When the investigator arrives, the IRB coordinator should ask for his/her credentials. Not doing this is a red flag for the investigator, as it indicates that the IRB may show its files to anyone without asking for appropriate credentials. The inspection will include interviews with key individuals and should definitely include the IRB coordinator and the IRB chair if he/she is available.
One of the author’s first experiences with the FDA turned out to be a great experience. The FDA investigator was new to cancer research, and it was a productive learning experience, not only for the IRB Coordinator, but for the investigator as well.
During an IRB inspection, the FDA investigator evaluates the IRB’s performance by reviewing its records, which must be in place. The IRB’s processes are important. The records must show that the IRB implemented the federal regulations in policies and procedures and reviewed these regularly. The Toledo Community Oncology Program’s IRB had a sub-committee that reviewed its policies and procedures every year to ensure that they were up-to-date. The FDA investigator will also want to see the IRB’s roster. Rosters should be kept up-to-date at all times, and past rosters should be filed for review by an investigator.
An FDA inspection of an IRB can create anxiety. If, however, the IRB has been actively performing internal audits and is prepared for the FDA, there will be far less anxiety. The IRB coordinator must develop a process to ensure that the office is prepared for all audits and be able to show an investigator the necessary IRB documents. The author had two days’ notice for her first FDA inspection. The investigator provided a list of what he wanted to see, and the author and her team were able to prepare and were audit ready.
Most Common IRB Deficiencies and Notes of Caution
Table 5 highlights the most common IRB deficiencies noted during FDA inspections. Inadequate initial and continuing review is the most common deficiency. The IRB completes an initial review; however, a subject is enrolled before the IRB has approved the study. Subjects cannot be enrolled until the IRB provides its final approval for the study. Inadequate standard operating procedures and membership rosters are also common problems. The federal regulations clearly outline the necessary requirements of an IRB.
Inadequate meeting minutes are a common deficiency found in FDA inspections of IRBs. The meeting minutes from the Toledo Community Oncology Program’s IRB were routinely about 10 pages long. Minutes must include everything that the IRB discussed at a meeting, showing actions, voting process, and final actions/requests by IRB.
If the organization establishes an IRB whose members take their responsibilities seriously, having a quorum at meetings should never be an issue. Quorum issues, however, are a common deficiency found in FDA inspections of IRBs. If an IRB member routinely cannot make meetings, the IRB chair must talk to the member about stepping down.
The Toledo Community Oncology Program’s IRB met monthly and never had a quorum issue. The IRB members took their responsibilities very seriously. Having a dedicated IRB committee, who are able to meet quorum, reflects on the efficiency of the IRB as a whole.
Inadequate communication with the investigator or the institution is another common deficiency found in FDA inspections of IRBs. The FDA wants proof of IRB discussions, requests from/to the investigator and institution, and notification and discussions regarding approvals/disapprovals.
Notes of caution include use of central IRBs. In 2014, the Toledo Community Oncology Program was mandated to start using a central IRB. The program used a central IRB for all new studies and utilized a local IRB for historical studies and industry trials.
The author gave out a major deviation to a clinical research site that did not have a study re-approved within 365 days of the initial approval. This particular study had a central IRB as IRB of record, but a re-approval was not received in the appropriate time frame. The site felt responsibility for the deviation should fall to the central IRB; however, the responsibility always falls back to the institution and investigator. The author strongly recommends a 10-month re-approval period to ensure that a study is re-approved on time.
Assistants can be a great resource for an IRB office. However, the IRB coordinator must be the coordinator in charge of the office, overseeing all processes. An IRB coordinator should never solely rely on the assistant to complete a task. When the FDA investigator arrives, the IRB coordinator, not the assistant, will be involved in the inspection and responsible for all actions.
An IRB Coordinator should ensure that documents are reviewed by IRB members, safeguarding that items are not being “rubber-stamped” for approval without first being reviewed. Having a primary review system can ensure that IRB agenda items are being carefully reviewed by an IRB member and that all items have been completed as needed.
Tunnel vision and lack of new processes can be detrimental to your IRB procedures. The IRB must continually move forward and improve its processes. It cannot rely on old policies or the way things have always been done. The IRB must also make changes necessary to comply with new or revised federal regulations.
Lessons Learned
As IRB coordinator at the Toledo Community Oncology Program, the author learned several lessons, including the need to ensure that appropriate processes are in place. Without solid processes, it will be very difficult to manage an IRB office. The IRB coordinator can use the processes developed by a previous IRB coordinator, but he/she should always identify and implement improved processes.
Following the federal regulations and the organization’s processes is crucial. If the IRB does not follow the regulations and its own processes, it will not pass an inspection. Internal audits must be “clean.”
Continued education on IRB matters is crucial. This is necessary in order to keep IRB members updated on changes to regulations. Be sure to document completion of education by your IRB members, obtaining appropriate certificates when possible. Utilize IRB meetings as an avenue for your IRB chair to provide education. Education stimulates more interest in serving on the IRB and illustrates how to be a responsible IRB member.
The IRB should never cram for an FDA inspection. If the correct processes are in place as outlined in the FDA regulations, and if the IRB has an internal auditing program, the IRB will always be ready for an FDA inspection.
TABLE 1
IRB Authority and Functions
- Authority:
- Require progress reports from investigators and oversee conduct of the study
- Suspend or terminate approval of a study
- Place restrictions on a study
- Functions:
- Conducting initial and continuing review
- Reporting, in writing, findings and actions to the investigator/site
- Determine which studies require review more often than annually
- Ensure that changes in research are not initiated prior to IRB review and approval except where necessary to eliminate apparent immediate hazards
- Ensure prompt reporting to the IRB, appropriate institutional
officials, and FDA:
- Unanticipated problems involving risks to subjects/others
- Serious or continued non-compliance of 21 CFR Parts 50/56
TABLE 2
Written IRB Procedures Required by the FDA
- Operations of the IRB
- IRB recordkeeping requirements
- Information the investigator provides to the IRB
- IRB procedures and guidelines
- Documents related to the studies given by the clinical investigator to the IRB
- Documents related to the studies sent by the IRB to the clinical investigator
- IRB documentation:
- IRB meeting minutes and materials
- IRB agenda
- Attendance
- Voting sheets
- Adverse event reports
- Education administered at meetings
TABLE 3
Full Circle Audit
- Is the initial approval from the minutes reflected on the agenda?
- Do the minutes accurately reflect approval action from the initial approval?
- Are voting members who approved the study accurately reflected on the roster?
- Was the study reapproved within 365 days of the initial approval?
- Were there addenda to this study and were they reported within 90 days?
- Was a new investigator’s brochure issued, and did the IRB approve it?
- Were the investigators informed of any new addenda or investigator’s brochure-driven adverse events?
TABLE 4
FDA inspections of IRBs
- Types of FDA inspections:
- Surveillance
- Directed
- Before the IRB inspection:
- The FDA will contact the responsible individual at the institution
- The FDA will issue a notice of inspection (Form FDA Form 482)
- Conduct of the IRB inspection:
- Appropriate interview at the site with key individuals
- Thorough review of IRB policies and procedures
- Thorough review of IRB records
- Evaluation of the IRB’s performance
- Review of membership rosters
TABLE 5
Common IRB Deficiencies in FDA Inspections
- Inadequate initial and/or continuing review
- Inadequate standard operating procedures
- Inadequate membership rosters
- Inadequate meeting minutes
- Quorum issues
- Inadequate communication with the investigator or institution
- Lack of or incorrect determination of significant risk/non-significant risk trials
excellent review of processes and audit inspection readiness for IRBs