In 2009, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) launched an initiative to harmonize regulatory supervision of clinical trials. The effort was designed to streamline collaboration and information sharing between the two regulatory bodies on good clinical practice (GCP) inspections, wherein both would have the same information about a facility and its study. During the pilot phase, which ran from 2009 to 2011, the FDA and EMA exchanged more than 250 documents relating to 54 different medicines.1
This inspection program applies to clinical investigators, companies submitting new drug applications and biologics license applications, and contract research organizations (CROs) in both the U.S. and the European Union (EU). The two regulatory bodies set out to foster globalization of clinical research while continuing to ensure the protection of clinical trial subjects. The high-level objectives of the initiative include:2
The globalization of regulatory processes is making significant progress toward innovation and enhancing public health. Understanding the inspection techniques, processes, and objectives of each regulatory body will help you prepare and conduct successful inspections.
The FDA employs the following processes when completing inspections:
The COVID-19 pandemic has compelled the FDA to change some of its policies and practices regarding domestic and international inspections. Early in 2020, the agency suspended all on-site inspections. The safety of the inspectors and site’s employees was the agency’s top concern. In July 2020, the FDA was able to start conducting inspections domestically for facilities manufacturing products it deems mission critical.
The FDA has looked into alternatives to on-site inspections; however, there is no guidance documenting the agency’s policies or processes. In addition to the information sharing agreements, the following are some of the practices the FDA is working on for both domestic and international inspections that manufacturers of mission-critical pharma and biologics products should be aware of:
The FDA is assessing the possibility of virtual inspections. However, there are several factors both the agency and manufacturers need to plan for with this approach:3
In the EU, regulatory oversight relies on the GCP Inspection Working Group (IWG) of the EMA. EMA inspections are requested by a specific division — usually based on special interest in a particular product or simply to verify compliance to GCP requirements. The IWG inspectors use the FDA/EMA harmonization initiative to ensure conformity among member states and to make sure trials stay in accordance with recognized agreements among European countries.
Requirements for the conduct of clinical trials in the EU, including GCP and good manufacturing practices (GMP), have been implemented in the Clinical Trial Directive (Directive 2001/20/EC), the GCP Directive (Directive 2005/28/EC), and related guidance documents.
During the COVID-19 pandemic, on-site inspections have not been possible due to restrictions on travelling between and within the borders of countries. In May 2020, the Committee for Medicinal Products for Human Use (CHMP) provided a guidance on conducting GCP inspections remotely during the COVID-19 pandemic.4
The inspection team, in agreement with the CHMP requesting the inspection, will make a case-by-case decision on whether a remote inspection is considered appropriate and feasible. Remote inspections will follow the applicable procedures that already exist for coordinating, preparing, and conducting GCP inspections. It will also take into consideration the limitations of a remote process and recognize that not all remote inspections can completely replace on-site GCP inspections.
Remote inspections at investigator sites are not considered to be feasible because:
Sponsors, CROs, and service providers will be evaluated for feasibility since they have electronic systems and virtual working environments. These technologies should be assessed to verify if they can allow the necessary access for inspectors to the relevant systems (e.g., electronic trial master file (eTMF)) remotely and enable appropriate communication settings during inspections.
During the initial remote inspection communications, the sponsor, CRO, or service provider should provide detailed information as requested by the inspection team to allow a feasibility assessment. Remote inspections could be longer in duration than those conducted on-site. Therefore, the host should coordinate the daily time schedule with the Inspection team.
Consider setting up a video streaming system with interactive tools for managing questions and sharing documents. An instant-messaging platform can be an alternative in case of interferences with sound or video systems. Any recording (audio/video/screenshots) that occurs during the inspection process must be agreed to by all involved parties prior to the inspection.
I highly recommend conducting a mock inspection to prepare the staff. The ICH/GCP consolidated guidance will help in developing a comprehensive checklist. Also, consider creating an essential documents checklist that aligns with the requirements of 21 CFR Part 11.
During this mock inspection, conduct practice interviews with your staff. Determine who will provide information for each area. Have personnel practice answering questions and discuss how each person will answer questions. Advise participants to:
An FDA inspector begins an inspection by presenting credentials and the original signed FDA Form 482. EU inspectors have no formal documentation at the beginning of an inspection. Instead, everything is discussed verbally during an opening discussion about the purpose of the inspection, expectations, and documents or people they will need to interview.
The FDA inspectors make verbal requests for documents. EU inspectors maintain a tracking log of all documents requested and received. This document is given to the company representative facilitating the inspection. Designate a staff member to remain with the inspectors and take note of all requests, questions, and comments. Also ensure all documents provided to the inspector are stamped “Confidential.” Whenever possible, remove subject identifiers from the copies provided to the inspector.
Both the FDA and the EU inspectors will request a tour of the facility. They will ask questions to evaluate and confirm that resources, personnel, and the overall facility are appropriate for the trial being conducted. During the tour, inspectors may request procedures and other documents (e.g., temperature controls/records for storage area where the product is maintained).
Prior to departing the facility, FDA inspectors are required to provide the inspection site with an FDA Form 483 – Observations of Inspection. This is a written list of objectional conditions (if any) relating to products, processes, or other violations of the FDCA observed during the inspection. The FDA Form 483 will list only observations which are significant and relative to regulated products or processes being inspected. It will also include any observations made during a prior inspection that have not been corrected or are recurring.
The EU inspectors do not provide a written list of objectionable findings. Instead, they discuss the observations verbally in the closeout meeting. The EMA provides an inspection report for each site inspected, as well as an Integrated Inspection Report (IIR). For site inspections, the investigator and the sponsor receive the report. With CRO/sponsor inspections, the report is provided to only the auditees.
Overall, be clear, be honest, and be prepared. Ensure that all requested records and documents are complete, accurate, and available as needed. During the closing meeting, take notes on all comments by the inspectors and record all commitments your company makes regarding the inspection. Discuss any questions or objections you have with their observations. Finally, be sure to clarify any issues before the inspectors leave.
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