One way that the Food and Drug Administration (FDA) protects public health and ensures compliance with the Food, Drug and Cosmetic Act is by conducting inspections of clinical trial investigators, clinical trial sponsors, Institutional Review Boards (IRB) and facilities that manufacture, process or pack FDA-regulated products. At the conclusion of an investigation, a site may be issued a Form 483 or a Warning Letter. Read on to learn the differences and similarities of these forms of communication provided by the FDA to the inspection site.
What is a Form 483?
- A list of observations made during the inspection that is communicated at the conclusion of the inspection.
- The observations are listed in descending order of importance
- The list is a snap-shot of observations noted, not an all inclusive list
What to do at the conclusion of an inspection and after when issued a Form 483:
- Take time with the inspector at the conclusion of the inspection to review the Form 483
- Gain an understanding of observations noted and assure their accuracy
- Understand the broader message the agency is sending
- Identify and discuss any errors in observations
- Ask questions!
- Demonstrate awareness of applicable regulations
- Consult with legal counsel as necessary
- Respond formally in writing
- Not required, but demonstrates good practice
- Address to the District Director with a courtesy copy to the lead investigator
- Respond within 15 days or the agency does not have to consider the response in their decisions for subsequent actions
Taking the opportunity to ask questions and understand the observations noted in the 483 prior to the inspector leaving the site will help formulate a future response and implement corrective action plans. Challenges or questions to the observations noted are not uncommon, as long as the focus is on the issues and not the inspector personally. If convincing information is provided regarding an observation, it may be deleted from the 483.
What is a Warning Letter?
After a Form 483 is issued and the inspector completes the Establishment Inspection Report, the agency may issue a Warning Letter. A Warning Letter indicates that higher FDA officials have reviewed the observations and that a serious violation may exist. This formal notification allows for voluntary and prompt correction action. A Warning Letter:
- Includes evidence collected to support observations and provides further explanation
- Establishes a background of warnings should further action be required by the FDA
- Might be hand-delivered or the agency may invite top corporate management to a meeting at the District Office or Center
- The site must reply, in writing, within a time line as prescribed (usually 15 days) or request an extension and provide justification for request
Form 483s and warning letters are public information. Form 483s are difficult to obtain quickly and one has to know that it exists to request it. Adversely, Warning Letters are published upon issuance and promptly posted on http://www.fda.gov.
During IMARC’s FDA Warning Letter week you can learn tips on how to respond and what to avoid when responding to FDA Warning Letters and Form 483s as well as how the FDA assess responses.
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