Getting Through Inspections: Seasoned Research Institution Details Successful Strategies
To make FDA trial inspections go as smoothly as possible, it’s important for responsibilities to be divvied up strategically at sites and for certain documentation to be prepared before, during and after the FDA’s visit.
Indiana University (IU)’s Quality Improvement Office (QIO) does this by appointing an institutional liaison, or “inspection shepherd,” to handle essential tasks during FDA inspections, according to Neala Lane, associate director of IU’s QIO.
Specifically, this liaison is responsible for notifying institutional leadership of an inspection, setting up standardized materials in the days before an inspection and prepping the study team and principal investigator (PI) on inspection basics right before the visit happens. The shepherd is also tasked with escorting the inspector to lunch, the bathroom, coffee breaks and the like so that the person placed in the “hot seat” (usually the primary study coordinator) gets moments to breathe and gather themselves.
The liaison also serves as a resource for IRB processes, IRB submissions and institutional policies and helps answer questions on site, as well as document questions and conversations that arise during the agency’s visit, Lane explained during the Association of Clinical Research Professionals 2021’s Sept. 23 session on regulatory trends and compliance.
The standardized materials put together by the institutional liaison are ready to go when the agency calls to announce an impending inspection. One critical element to have ready is an IRB history “cheat sheet” that helps the inspector with regulatory review and ensures that the inspector and study team are using the right protocol and consent form versions.
“In your model, if you have a fairly small portfolio, you can start and make these and keep these up to date as you go,” she said. “Make sure it’s meaningful, helpful information. What was the bulk of the reason for that amendment? When did you switch consent form versions? What were the IRB’s directions about whether or not you needed to re-consent? What were the major recordable events you had? You guys can make that and keep that up to date now and you won’t have to do it last minute.”
It’s also essential to have the investigator study list ready well before the agency announces an inspection. The document is required by the Bioresearch Monitoring Program manual and the inspector will ask to see it every time, she said. It’s arduous to put it together from scratch if you aren’t prepared, so doing it in advance is important.
In addition, make sure that anyone who could get that surprise call from the FDA is aware of just how important that call really is. Make something small but bright that can be taped above phones that outlines who in the research team the inspection announcement information should be forwarded to, Lane advised. Because it’s not always clear what number the agency will dial, and it may be someone with the clinical staff, do a Google search of your PI, call the phone numbers that show up and see who answers. At the very least, whoever picks up the phone needs to be informed about the importance of the agency’s preannouncement and how to properly handle it.
“Worst-case scenario, if FDA’s made the attempt to announce and no one’s called them back, they will show up anyway. That’s what we don’t want, is the PI to be blindsided,” she said. “We have had, way before my time, a PI walked into a meeting that was on his calendar … and it was the FDA. A clinical secretary had made an appointment when the FDA called and said sure, you can meet with him next week, no problem. Put it on his calendar. The PI had no idea that he was walking into an FDA inspection.”
Similarly, have some attention-getting signs that can be posted to remind people when an inspection is occurring. It’s also helpful to have a task list prepared that lays out who will do what during the inspection.
IU also creates a “Notice of FDA Inspection” template for each agency visit that helps with preparation. This template is used to record details of the inspection and directs whoever is communicating with the agency to gather specific information prior to the visit. This includes who/what is being inspected; why the inspection is happening; any specific inspection requirements related to personnel or facilities; whether the agency wants monitor access to EMR; and if the agency wants specific documents to be made available, among other items.
Having a standard set of PowerPoint slides that outlines inspection basics is also helpful for sites. These should be reviewed with the PI and study team right after an inspection is announced and should explain crucial prep tasks, how responsibilities are delegated and important dos and don’ts. The slides should also be updated based on inspection experience, she advised.
Lastly, IU uses a Form 483 response template so that PIs don’t have to worry about formatting when they’re writing their response, she said.
For sites with multiple locations, a number of considerations come into play for study binders. For instance, you should know where your study binders are at any given time and how they must be transported if you’re consolidating to a single site for an agency visit. It’s important to consider whether protected health information (PHI) needs to be moved across longer distances or if it’s stored off-site because a study was closed. If a study was closed by a different person who has since moved elsewhere, you still need to know where the information is being kept, she said.
“We have a standing policy about transporting PHI between our work locations, and that is not just ‘throw it in the trunk of your car and go along,’” she said. “That requires a secure transport mechanism — do you have a policy like that that you might not be aware of because you’ve never had to use it before? We require secure either totes or envelopes … to actually move those materials between sites.”
It’s also important to consider the logistics of a site and how it actually operates. For example, determine if a site has the proper space to host an inspection; having a conference room is ideal as they allow plenty of room and are separated from other study records, staff, conversations and distractions. At the same time, don’t have the inspector in a location so isolated that it’s difficult to escort them around, such as to the copying room or restroom. Additionally, know if that hosting area needs to be reserved in advance and, if so, how to do that. Also be aware of any site visitor access policies, especially in light of COVID-19, and what policies are in place for electronic medical record (EMR) access for external monitors/auditors. Know the request process for EMRs, how long it takes and what information you’ll need to obtain from an inspector to get them access, Lane recommended.
Also consider things from a site training angle. For instance, it’s essential that staff are adequately cross-trained so they’re capable of stepping in when issues arise.
“The FDA never calls when it’s convenient. They’re not calling to ask you when is a good time, they’re calling to tell you when they’re coming,” she said. “What if you’re on vacation that week? What if you have to cover for a coordinator who’s on vacation? What if you have a whole week of research subject visits already scheduled? Is your site staff sufficiently versed in the totality of your portfolio to be able to … cover as needed?”
IU tasks the study team with actually corresponding and coordinating with the FDA inspector. They’re responsible for notifying other parties of the study team, departmental leadership, the sponsor and others and are charged with assembling all the records necessary for the site visit. They also review and finalize the study list, which is drafted by the liaison, and provide daily/as needed updates on the inspection.
The person most knowledgeable about the trial is chosen by the study team to sit in the “hot seat,” where they navigate the study records during the inspection to find the data the inspector wants to verify. IU also tasks that person with answering questions about study team processes and serving as an intermediary for the sponsor, PI, pharmacy, study team and the site/facility, she said.
After communicating the results of the visit, the study team drafts a response and gathers attachments if there were FDA findings. They’re also the ones that handle the important task of implementing any necessary corrective and preventive action (CAPA) plans and collecting appropriate documentation as needed.
After the inspection, the liaison meets with the study team and PI to debrief on the inspection as a whole, particularly on elements of the inspection that were unexpected. They also review the institution’s expectations for the 483 response, if one is needed, and review the response once it’s ready, assisting with finalizing attachments and submission. If any follow-up submissions are needed, the liaison will prompt the study team, Lane said. In addition, they pitch in on the redaction of inspectional documents for future sponsor or IRB requests.
Even if the FDA doesn’t find anything during an inspection, you shouldn’t put your guard down; sometimes a lack of findings can move inspectors to conduct an expanded audit, Lane cautioned. To prepare for this possibility, Lane advised assessing any open studies and ensuring they’re ready for a potential inspection.
When there are findings, make sure the citations are crystal clear before the inspector heads out, as revisions can’t be made to Form 483s after they leave and they won’t answer questions once they’re gone, she said. Additionally, in responding to a Form 483, it’s incredibly helpful to go over warning letters the agency has issued to gain a greater understanding of citations and poor CAPAs and responses. It’s also important to clearly state that you agree with the agency’s citations in your response and include how the PI will be personally involved in taking action.
IU, a major research institution, is no stranger to FDA inspections, having hundreds of investigators, coordinators and trials and around four to six agency visits every year. According to the university, it has more than 200 research centers and institutes and an even greater number of labs and research facilities.