The document summarizes insights and trends from the FDA's 2021 GCP inspections. It provides an overview of total inspections, top 483 observations for drugs and devices, and warning letters. Key findings include COVID-19 reducing inspections and alternative tools being used, top drug and device 483 observations relating to documentation and procedures, and most warning letters issued in March and October relating to drugs. It also discusses anticipated changes from the draft ICH E6(R3) guideline and trends for 2022, such as a potential increase in enforcement and focus on data security, quality controls, and corrective actions.

1. Insights and Trends from 2021 FDA GCP Inspections

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Our Presenter:
Melissa Sullivan
Melissa Sullivan is a Senior Quality and
Compliance Specialist with 17 years of
experience in the pharmaceutical and
quality industry, specializing in Good
Clinical Practice (GCP) with experience in
Good Laboratory Practice. She is an expert
in planning, preparing, and conducting
audits in various GxP areas and maintains
a strong understanding of compliance
regulations and guidance.

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Agenda
• General Overview
• Inspections
• FDA Enforcement Trends: 483 Observations
– 483 Observations
– Top 3 Drug Observations/Top 3 Device Observations
– What does the data tell us?
• FDA Enforcement Trends: Warning Letters
– Total Warning Letters
– What does the data tell us?
• ICH E6(R3) and Trends for 2022
– What to expect?

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FDA GCP Regulatory Overview
The FDA oversees clinical trials to ensure they are designed, conducted,
analyzed and reported according to federal law and good clinical practice
(GCP) regulations.
FDA’s Office of Regulatory Affairs (ORA) is the lead office for inspections and
enforcement. ORA provides inspection and enforcement results to maintain
transparency and accountability at the beginning of each federal fiscal year.

5. Why Does the FDA Enforce?
• Products are safe and effective
• Honest and accurate informative representation
of products
• Correction of noncompliance or removal of
unsafe or unlawful products
• Human subject protection is a goal shared with
the Office of Human Research Protection (OHRP)
in FDA’s parent department, the Department of
Health & Human Services

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Why Review FDA Inspection and Enforcement Results?
• Identifies common issues to help highlight potential quality management
gaps and improvement opportunities within your own clinical research
portfolio
• Helps to pinpoint FDA observations and trends that will help direct your
quality system towards improvement and increased compliance

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What to Review
FDA Total Inspections
FDA Enforcement Trends: 483 Observations
FDA Enforcement Trends: Warning Letters
Trends & the R3 Draft
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3
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8. FDA Inspections

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Domestic Inspections FY 2021
FDA Data Dashboard

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Domestic Inspections by State - FY 2021
FDA Data Dashboard

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Totals by Product Type - FY 2021
FDA Data Dashboard
Classifications
• No Action Indicated (NAI)
• Official Action Indicated (OAI)
• Voluntary Action Indicated (VAI)

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Inspections Classification – FY 2021
No Action Indicated (NAI)
Official Action Indicated (OAI)
Voluntary Action Indicated (VAI)
FDA Data Dashboard

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COVID-19: FDA’s Use of Alternative Tools for Oversight of
FDA-Regulated Products
Resiliency Roadmap for FDA Inspectional Oversight

14. What Does the Data Tell Us?
• COVID-19 dictated the priority of inspections
• Majority of inspections were completed end of
fiscal year
• Alternative inspections and regulations were
followed
• Domestic inspections were dictated by
outbreaks
• Majority of inspections were No Action
Indicated
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15. FDA Enforcement Trends: 483 Observations

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FDA Enforcement Trends: 483 Observations Drug
Top 3 Drug findings:
1. Procedures not in writing, fully followed (80)
2. Investigations of discrepancies, failures (49)
3. Scientifically sound laboratory controls(44)

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FDA Enforcement Trends: 483 Observations Device
Top 3 Device findings:
1. Lack of inadequate procedures (77)
2. Lack of inadequate complaint procedures (49)
3. Purchasing controls, lack of inadequate procedures (31)

18. 59, 18%
45, 13%
44, 13%
31, 9%
31, 9%
30, 9%
27, 8%
24, 7%
23, 7%
22, 7%
Devices-21 CFR 820.100(a)-Lack of or inadequate procedures
Drugs-21 CFR 211.22(d)-Procedures not in writing, fully followed
Bioresearch Monitoring-21 CFR 312.60-FD-1572, protocol compliance
Bioresearch Monitoring-21 CFR 312.62(b)-Case history records-
inadequate or inadequate
Devices-21 CFR 820.198(a)-Lack of or inadequate complaint procedures
Drugs-21 CFR 211.192-Investigations of discrepancies, failures
Drugs-21 CFR 211.160(b)-Scientifically sound laboratory controls
Devices-21 CFR 803.17-Lack of Written MDR Procedures
Drugs-21 CFR 211.100(a)-Absence of Written Procedures
Devices-21 CFR 820.50-Purchasing controls, Lack of or inadequate
procedures
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Program Area-Citation

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100
556
602
6
76
8
0 100 200 300 400 500 600 700
Biologics
Bioresearch Monitoring
Devices
Drugs
Foods
Human Tissue for Transplantation
Radiologic Health
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Citations 2021 Domestic by Program Area

20. What Does the Data Tell Us?
• COVID-19 dictated the priority and type of
inspection
• Top 3 drug results: documentation and
discrepancies
• Top 3 device results: documentation and lack of
procedures
• Remote inspection due to the pandemic =
higher focus on procedural infrastructure and
documentation findings
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21. Warning Letters

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24. What Does the Data Tell Us?
• Majority of warning letters were filed March and
October
• Drug was the top category for warning letters
• Warning letters issued in fiscal year 2021 were
based on reviewing written responses to record
requests, not from traditional onsite inspections
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25. ICH E6(R3)

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ICH E6(R3)
The ICH E6(R3) and ICH E8(R1) revisions are part of the (GCP) Renovation initiative.
The two guidelines interplay to support clinical trial design, conduct, and data
quality. ICH is ensuring ICH E6(R3) is updated to map to these aspects of ICH E8(R1),
the “master” E guideline:
– Quality by Design (QbD) of clinical studies
– Critical to Quality Factor focus
– Risk proportionate approach
– Involvement of a wide range of stakeholders in clinical trial design
– Study participant engagement
– Decreased burden to sites

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Examples of Modernization of the Draft Guideline Includes:
• Focus on the need to identify critical to quality elements and to build
Quality by Design (QbD) into every aspect of the clinical trial
• Ensuring diverse and representative study participants focus on simplifying
the comprehension of the increasingly long and complex informed consent
form
• Emphasis on participant data protection and privacy
• Focus on quality and reliability of trial results

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Final Updates and Timelines
• 12 principles rather than 13, and they have been expanded, reorganized, and
reworded
• Major focus to align with the new ICH E8(R1) expected to be final this
summer
• ICH E6(R3) Expert Working Group delayed due to pandemic
• Draft Annex 1 delayed from original December 2021
• When it reaches Step 3 of the guideline development process, public
comment will be requested

29. Trends and Moving Forward

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Considerations
• FDA issued guidance documents and enforcement policies to address the
evolving crisis relating to manufacturing, supply chain and clinical
development
• Absence of a confirmed FDA commissioner and vacant status of principal
deputy commissioner, chief scientist and chief counsel
• Growing number of enforcement actions stem from inspection alternatives
• The pandemic reduced FDA’s ability to conduct onsite inspections except for
those deemed “mission critical”
• Inspections were reduced and used alternative tools, such as relying on
information submitted in response to requests for records

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Guidance Issued & Updates 2021
• March 2021 - Establishment Registration & Device Listing system to avoid fraudulent
claims of approvals
• April 2021 - Remote Interactive Evaluations of Drug Manufacturing and Bioresearch
Monitoring Facilities During the COVID-19 Public Health Emergency: Guidance for
Industry
• June 2021 - Sponsor Responsibilities - Safety Reporting Requirements and Safety
Assessment for IND and Bioavailability/Bioequivalence Studies
• July 2021 - Established the FDA Inspectional Affairs Council (FIAC)
• Sept 2021 - Investigator Responsibilities – Safety Reporting for Investigational Drugs
and Devices
• FDA discontinued its previous Inspection Classification Database. The FDA Data
Dashboard is now the database holding firms’ inspection history.

32. What Does the Data Tell Us?
• Decreased FDA enforcement in traditional areas
of focus
• Shift of priority for patient regulatory decision
making and patient care
• Lack of permanent Commissioner showed a
deficit in cohesive policy agenda
• Mission critical on-site inspections only
• Uptick in regulatory guidance for to ensure
safety in remote inspections
• COVID-19 research was the continued focus
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Inspection Trends for 2022
• Withdrawal of many COVID-19 enforcement policies and reorganization of
key FDA divisions signal an increase in enforcement
• Compliance and enforcement trends focusing on data and security risk
• Quality control unit procedures (written and followed)
• Written procedures for Production and Process Controls
• Corrective and preventive action (Each manufacturer shall establish and
maintain procedures for implementing corrective and preventive action)
• Corrective and preventive action (All activities required under section (a),
and their results, shall be documented)

34. Thank you!
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