FDA vs. EU Inspections: Similarities and Differences

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

Objectives of EMA-FDA GCP Inspection Initiative

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

• Conduct periodic exchanges on GCP-related information in order to streamline sharing of GCP inspection planning information.
• Establish timely and effective communication on inspection outcomes.
• Collaborate on GCP inspections by sharing experience, inspection procedures, and best practices.
• Harmonize interpretation of GCP by keeping each regulatory agency informed of GCP-related legislation, regulatory guidance, and related documents.
• Speed up regulatory processes by minimizing duplicate inspections.

FDA vs EU Inspections

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.

FDA Inspection Practices

The FDA employs the following processes when completing inspections:

• Inspections are product specific.
• Site investigators follow FDA regulations specifically, including those found in 21 CFR 312 (Investigational New Drug Application).
• When assessing sponsors, CROs, and monitors, FDA inspectors will compare the practices and procedures conducted by the sponsor or CRO against the commitments made in the FDA application.

FDA Inspections During COVID-19 Pandemic

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:

• Records requests – Under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA), the FDA has authority to request records or information in advance of or in lieu of an on-site inspection. (Note: reviewing records is not an inspection.)
• Inspections preannounced – Prior to COVID-19, domestic inspections were unannounced. All inspections are now preannounced in order to ensure safety measures are in place and necessary personnel will be available. Inspectors will ask about your COVID-19 safety and employee testing processes.
• Border testing – Given that international inspections are limited due to travel restrictions, the FDA is inspecting more products that arrive at the U.S. border. This type of testing will most likely continue after the pandemic.

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

• Technology – Requires companies to have the necessary infrastructure.
• Shifting focus – Virtual inspections will likely have an increased emphasis on documents and records. This means higher scrutiny of data and documentation practices — including the ability to submit all requested documentation electronically.
• More rigorous inspections – Rather than having one or two inspectors visit the facility, remote inspections will enable the FDA to involve more subject matter experts (SMEs) as needed.

EU Inspection Practices

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.

EU Inspections During COVID-19 Pandemic

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:

• It places an additional burden (e.g., providing access to appropriate paper-based documentation or limited access to relevant electronic systems) on investigator site staff.
• Source documents may not be available due to data protection and accessibility.

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.

Regulatory Inspection Preparation

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:

• Be concise and answer only the questions that are asked.
• Do not volunteer information outside of what is asked.
• Do not guess or speculate.
• Do not refuse information requests or argue with inspectors.

Conducting Regulatory Inspections

Beginning the Inspection

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.

Document Requests

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.

Site Tour

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).

FDA Inspection Closeout Procedures

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.

EU

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.

Regulatory Inspections Recommendations

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.

References

1. “Good Clinical Practice,” Human Regulatory, European Medicines Agency, https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-clinical-practice#collaboration-with-the-food-and-drug-administration-section
2. “EMEA and FDA Launch Good Clinical Practice Initiative,” PharmaNews.eu, Aug. 4, 2009, https://www.pharmanews.eu/ema/285-emea-and-fda-launch-good-clinical-practice-initiative
3. “FDA Inspection and Enforcement Developments During the COVID-19 Pandemic,” Raj Pai, Jaime Jones, David J. Ludlow, Kathy Lee, PharmExec.com, Dec. 2, 2020, https://www.pharmexec.com/view/fda-inspection-and-enforcement-developments-during-the-covid-19-pandemic
4. “Guidance on remote GCP inspections during the COVID19 pandemic - EMA/INS/GCP/162006/2020,” European Medicines Agency, May 18, 2020, https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guidance-remote-gcp-inspections-during-covid-19-pandemic_en.pdf