Clinical Researcher—June 2019 (Volume 33, Issue 6)

PEER REVIEWED

Mary Kay Kessinger Sobcinski, RN, BSN, MHA; Susan Wiskow, CCRP

The U.S. Food and Drug Administration’s (FDA’s) Bioresearch Monitoring (BIMO) program is designed to protect the rights, safety, and welfare of subjects, verify the accuracy and reliability of clinical study data, and assess study compliance with FDA regulations. BIMO inspections can be conducted by FDA at any time during a clinical study, “for cause,” near the time of study closure, or during agency review of a marketing application.

At the conclusion of an inspection, FDA may issue a Form 483, which outlines specific findings that need correction. If the findings are not addressed to the agency’s satisfaction, or if the findings are egregious enough, FDA may issue a Warning Letter. These actions by the agency can delay or even obviate product approval. It is therefore imperative that study sponsors and sites are always prepared for a BIMO inspection. This article presents several recommendations to help ensure successful inspections.

Background

During FDA’s fiscal year 2017 (FY17), the agency’s Center for Devices and Radiological Health (CDRH) division conducted 287 domestic inspections. Of these, 198 were inspections of clinical investigators or study sites, and 48 were inspections of sponsors, clinical research organizations (CROs), or monitors.{1} The most common investigator/site deficiencies were:

Failure to follow the investigational plan/agreement or regulations, or both.
Protocol deviations.
Inadequate recordkeeping.
Inadequate subject protection (informed consent issues and failure to report adverse events [AEs]).
Inadequate accountability of the investigational product.
Inadequate communication with the institutional review board (IRB).
Investigational product represented as safe/effective.

The most common sponsor/CRO/monitor deficiencies were:

Inadequate monitoring.
Failure to bring investigators into compliance.
Inadequate accountability for the investigational product.
Failure to obtain FDA and/or IRB approval prior to study initiation.

It is important to note that FDA also inspects entities outside the United States (OUS). In FY17, CDRH inspected 13 investigators/sites and four sponsors/CROs/monitors and found deficiencies similar to those identified domestically.

Many sponsors erroneously assume that FDA will not inspect OUS sites, but this is a dangerous assumption. FDA expects all study sites, regardless of location, to adhere to federal study regulations, and the agency will inspect OUS sites using the same rigor as it inspects domestic sites. Sponsors need to ensure their OUS sites are as carefully monitored and prepared as their U.S. sites, and it is especially important to ensure OUS sites that contribute a substantial portion of study data to the marketing application are well prepared.

Ultimately, study integrity and compliance are the responsibility of the sponsor, who is charged by federal regulation to ensure the compliance of the investigators and their study site staff, CROs, monitors, and all other contractors to regulations and the study protocol. Delegating responsibility to another entity does not absolve the sponsor of its oversight responsibility.

Ensuring compliance is an ongoing activity, spearheaded by robust monitoring efforts to ensure sites and sponsors are always “inspection ready.” To support inspection readiness, FDA has posted the Compliance Program Guidance Manuals online to direct its field inspectors on inspection conduct. These publicly available manuals are valuable resources for sites and sponsors/CROs/monitors as they indicate the information that will be reviewed by inspectors and serve as a great tool for inspection preparation.

Readiness requires top-level sponsor commitment and departmental prioritization to ensure all internal and external team members are confident and well-trained, processes are adequate and adhered to, and documentation is in place in order to demonstrate compliance. Sponsors need to ensure that their own files and those of their site contractors are ready at all times for a BIMO inspection.

Sponsor Readiness

The most effective and efficient way a sponsor can help sites and contractors to be ready is by setting standards for inspection readiness. Key measures include:

Ongoing and robust clinical trial document generation, collection, review, and filing.

Everyone who has worked on a clinical study, whether at the sponsor, CRO, or site level, knows that there is an extensive and never-ending stream of study documentation required by law and good clinical practices. Managing this mountain of paperwork is daunting and, frankly, not very interesting; however, it is critically important.
Failure to properly manage study documentation throughout a study will result in extensive, time-consuming, and very expensive remediation measures at the time of BIMO inspection. It is cheaper, easier, and far less stressful to develop a file management system before the trial starts and to maintain it for the entire course of the study, whether on paper or electronically in a 21 CFR Part 11–compliant system (as detailed in the Code of Federal Regulations).
It can be difficult to convince management of the criticality of robust study file management; it’s often seen as an unnecessary administrative task. However, at the end of the study, FDA cares about two things: the integrity of the study data and how well the study was conducted, including subject protection. Every aspect of the study must be carefully, thoroughly, and accurately documented to assure the agency that the trial data are accurate, that subject safety was protected, and that the study was conducted in compliance with regulations and the protocol. If it’s not documented, it wasn’t done.
Recommendations to help ensure robust study file management include designating and training file management personnel on using a 21 CFR Part 11–compliant electronic trial master file system (eTMF). If an eTMF is not used, develop automated trackers to manage trial documents.

Development and ongoing review of standard operating procedures (SOPs) that encompass all clinical trial activities, are compliant to applicable regulations for all relevant geographies, reflect best clinical practices, and outline the actual processes used by the sponsor.

It is challenging to develop SOPs that provide enough procedural structure to ensure regulatory and clinical practice compliance and consistency across studies, while remaining flexible to avoid boxing yourself into a corner with too much detail. Sponsors must be able to produce adequate documentation during an inspection that confirms SOPs are being followed, or that the sponsor recognized an SOP needed to be modified.
If modifications were needed, the sponsor must demonstrate that appropriate revisions were made, training was conducted, SOP modifications have been evaluated for effectiveness, and that all of these elements are documented. FDA does not necessarily judge the quality of an SOP per se; the agency judges if an SOP is in regulatory compliance and if documentation adequately demonstrates it is being followed. The agency also looks for evidence that shows the sponsor recognizes when an SOP is not robust enough or is ineffective, and that it makes improvements to ensure compliance.

Systematic review of study operations and compliance at the site level through onsite and remote monitoring; this may be done by the CRO or monitor.

To ensure study integrity; to oversee protection of human subject health, safety, and welfare; to assess for fraud; and to ensure site compliance to regulations and the protocol, FDA mandates that a sponsor monitor its studies. Monitoring assures these key study elements are compliant and facilitates achievement of enrollment goals. Monitoring also builds important relationships with site personnel, including the investigators who are your customers, and allows you to correct mistakes that may affect the study’s ultimate success and product approval. Monitoring is an excellent opportunity to ensure or correct site compliance and train sites for inspection readiness, including document organization, file review for completeness, proper inspection conduct, and how to interact collaboratively and effectively with FDA.

Conduct BIMO inspection training and mock inspections to ensure sponsor and site personnel are knowledgeable about the study and its current status and conduct a protocol review.

Site training should include a review of the site’s specific contributions to the study as reported to FDA, including the site-specific start/stop dates; number of subjects screened, enrolled, and treated with investigational product and/or withdrawn, including reason for withdrawal; as well as the number and type of protocol deviations and the number and type of AEs. Provide each site with a copy of its protocol deviation and AE listings from the regulatory submission for product approval to ensure the site records match what was reported to FDA, and to be able to address discrepancies during the inspection.
Train the sponsor and site teams on what to expect during the inspection, including examples of the types of questions that may be asked, how to interact with the inspector(s), and how answer questions accurately and confidently without overexplaining or providing information that is not requested, speculating, or talking just to fill periods of silence.
If the sponsor does not have prior experience with FDA inspections, it is recommended to seek assistance from a clinical research consulting firm or CRO with proven inspection success helping sponsor and sites prepare for a BIMO inspection.

Clinical Investigator Inspections

Sponsor and CRO assistance to sites during a BIMO inspection helps ensure that site personnel feel well-supported and that they are able to act with confidence, ultimately contributing to a successful inspection. While some sites do not allow sponsors to be present during an inspection, in-person sponsor or CRO support before and/or during an inspection can be very helpful, especially for studies that had a long duration, were complicated, or closed more than a few months before FDA’s visit.

Several days before the inspection, if the site allows, the sponsor should go to the site and assist the study coordinators with reviewing the study files to ensure they are in good order and to re-familiarize them with the study history and file structure. During the inspection, it can be helpful to have sponsor representatives ready to assist the investigators and study coordinators with locating documents requested by the inspector, logging the requested documents on the audit log, taking notes, supporting their responses to FDA questions, and providing guidance as appropriate to the site team. Onsite support of OUS sites is especially important and helpful, as site staff in these locations may be less familiar with FDA regulations, inspection practices, and how to work with the agency during an inspection.

Key Points for Sponsors and Sites to Remember During an Inspection

Be polite and collegial. Alert your receptionist that an FDA inspector may be coming and what to do when the inspector arrives, such as who to notify and in what order.
Do not leave an inspector alone or allow her/him to wander around unaccompanied. Inform all staff that an inspector is on site and to keep all documents off desks, counters, printers, etc., and to be mindful of hallway, elevator, and bathroom conversations.
During the inspection, record the inspector’s questions, requests, and comments, and log the documents provided to the inspector. Only provide the requested documents and be sure they are complete and in good order before you deliver them. Make two copies of each document: one for FDA and one for you.
Be sure you understand a question before answering it and ask for clarification if you are uncertain. Never guess, speculate, or lie. If you do not know an answer, it’s acceptable to tell the inspector you’ll provide the answer later.
At the end of each day, ask for a summary of the day’s activities, clarify any issues that were raised, and try to resolve them immediately. Ascertain if there are any findings that may lead to a Form 483 issuance and ask for the next day’s agenda.

What if You Receive a Form 483?

Don’t panic! Form 483 is an official list of “Inspectional Observations” issued after an inspection, usually at a closing meeting. Sponsors should use the Form 483 as a guide for corrective action, as the FDA inspector does not usually make specific recommendations. Your firm can and should respond to the Form 483 during the discussion with the investigator before the investigation concludes. In fact, corrective actions or procedural changes that were accomplished immediately in the presence of the investigator are regarded as positive indications of your concern and desire to voluntarily correct discrepancies.

Consider seeking outside expertise for assistance in determining appropriate corrective actions and/or for help with your response. It is critical that you respond in writing with a thorough plan of corrective actions within 15 calendar days to satisfy the requirements of the FDA. The agency will issue an acknowledgment letter to confirm receipt of your response and may ask for additional information or notify you the corrective actions are not adequate. Failure to respond or failure to respond adequately may result in escalation to a Warning Letter. If you receive a Warning Letter, you must respond in writing within 30 days.

Be aware that FDA may conduct a future (and unannounced) inspection to verify corrective actions were implemented and adequately addressed the findings; this may occur as a result of a Form 483 or Warning Letter. Within six months of an inspection, FDA issues an Establishment Inspection Report (EIR), which is a factual narration of the inspection. Form 483s and EIRs are available through the Freedom of Information Act. However, Warning Letters are published on the FDA’s website on a monthly basis and are therefore easily accessible to competitors and other interested parties.

Positive Results of Sponsor/CRO BIMO Inspection Support

Presented here are several case studies of successful BIMO inspection readiness activities. The readiness activities addressed potential or identified areas of risk, and ultimately resulted in a successful FDA inspection with no findings.

Case Study 1: BIMO Inspection of a Recently Closed Study

An application for an implantable Class III device was submitted to FDA for Premarket Approval (PMA), which triggered an expected FDA BIMO inspection. The sponsor proactively identified areas of risk for the study and sites, implemented appropriate readiness activities, and had successful inspections.

Areas of Risk

Investigator noncompliance (repeated protocol deviations, inadequate device accountability).
Inadequate efforts to secure investigator compliance or discontinue shipment.
Inconsistent safety event review (lack of documentation to support that all AEs were reviewed by the Clinical Events Committee [CEC] as required).

Sponsor Readiness Activities

The CRO conducted mock BIMO preparation audits at targeted sites and at the sponsor.
A corrective and preventive action (CAPA) program was initiated by the sponsor to address noncompliance.
The CRO provided BIMO inspection readiness training to sponsor and site personnel.
The CEC adjudicated all AEs as required per the protocol prior to FDA inspections.

Results

No Form 483 or Warning Letter was issued.
The PMA application was approved.

Case Study 2: BIMO Inspection of an Archived Study

In a more unusual case, a clinical study for an implantable Class III device was successfully conducted and closed with statistically satisfactory results. However, the sponsor decided to not proceed with a PMA application for business reasons, so all study documents were archived. Several years later, the device was acquired by another firm, which proceeded with a PMA application submission.

Areas of Risk

The study had been closed and archived for several years. There was extensive sponsor and site staff turnover.
Some sites had missing files.
Some sites had closed.
FDA expressed concern that it would not be able to view source documents and verify that case report form data were true and accurate.

Sponsor Readiness Activities

All sites were contacted by the CRO well in advance of the PMA submission to determine which study staff were still available, the status of the study documents, and the logistics involved with retrieving them from archive.
The CRO retrieved the files from storage and carefully categorized and reviewed each document to ensure its completeness. Spreadsheets were developed to catalogue the documents at both the sponsor and individual site levels and missing/incomplete documents were noted.
All available site files were retrieved from storage and carefully cataloged and filed by the sites.
FDA was notified which sites had missing or inadequate files.
Sites were given customized webinar training to refresh them on the study and their site’s study details and results.
The CRO supported the site inspections onsite and remotely by providing requested but missing documents in real time during the inspections.

Results

FDA acknowledged the challenges for the sites to undergo inspections years after study closure and commended the sponsor for its inspection support.
The CRO also underwent a successful inspection.
No Form 483s or Warning Letters were issued for the sponsor, CRO, or sites.
The PMA application is pending.

Conclusion

FDA inspections are an important component to ensuring product and subject safety and study integrity. Undergoing an inspection is often stressful, but being well organized throughout the study, keeping sponsor and site files in pristine order, training staff on inspection conduct, conducting inspection readiness activities prior to the inspection, and maintaining your composure during an inspection will help ensure a successful outcome.

Reference

Bioresearch Monitor (BIMO) Fiscal Year 2017 Metrics: https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RunningClinicalTrials/UCM604510.pdf.

Mary Kay Kessinger Sobcinski, RN, BSN, MHA, is Senior Principal Advisor, Clinical Sciences with RCRI (Regulatory & Clinical Research Institute, Inc.) in Minneapolis, Minn.