FDA 483 vs Warning Letters



Following an FDA inspection, a clinical research site may be issued an FDA Form 483 or a warning letter.

The Form 483 and FDA Warning Letter both serve a similar purpose-to inform sponsors and principal investigators of issues requiring corrective action-but there are some important differences. A Form 483 is less formal but can escalate to a warning letter in the same way a tornado watch becomes a more serious warning.

Read on to learn the differences between Form 483s and FDA Warning Letters, as well as potential changes on the horizon.

What is An FDA Form 483?

A Form 483, also called "Inspectional Observations," is a list of conditions or practices that indicate a potential violation of the FDA's requirements. The observations are listed in descending order of importance. This is not an all-inclusive list, but more of a snapshot of possible issues noted at the site.

Although Form 483s are public documents, they are available only by request and may be difficult to obtain in a timely manner.

How Do I Respond To A Form 483?

As a clinical research professional, you should take time to review the Form 483 with the inspector once the inspection is finished. This is your opportunity to:

  • 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

Taking the opportunity to ask questions and understand the observations noted in the Form 483 prior to the inspector leaving the site will help formulate a future response and implement corrective action plans.

While you are not required to submit a written response to a Form 483, it's considered good practice to do so. You should address your response to the district director with a courtesy copy to the lead investigator. You should respond within 15 days, or the agency does not have to consider your response in their decisions for subsequent actions.

What Happens Next?

The FDA Form 483 is not considered a final agency determination of whether any condition is in violation of FDA regulations. The FDA will consider the Form 483, along with a written report called an Establishment Inspection Report and your response as it considers what further action, if any, is appropriate.

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.

Changes to the Form 483 process may be coming soon.

The FDA recently drafted a proposal to allow clinical research sponsors to request nonbinding feedback after inspections in certain circumstances.

"Timely nonbinding feedback can help device firms determine whether proposed actions to address inspectional observations are adequate, possibly avoiding unnecessary investment in potential solutions not likely to satisfactorily address an inspectional observation," the FDA states in its proposal, which is currently under review.

What is a Warning Letter?

After a Form 483 is issued and the inspector completes the Establishment Inspection Report, the agency may issue an FDA 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 is typically hand-delivered or discussed during a meeting at the District office. It includes evidence collected to support observations and provides further explanation. It also includes a background of warnings, should the FDA require further action.

Sites are required to respond to warning letters in writing, typically within 15 days.

What Are Common Violations Noted In Warning Letters?

The FDA maintains a database of warning letters and publishes them regularly on its website.

IMARC's most recent review of warning letters issued shows the most common FDA violations for Investigative Sites fell into three main categories:

  • Failure to ensure that the investigation was conducted according to the investigational plan (for instance, failing to ensure study subjects met the established criteria)
  • Failure to maintain adequate and accurate case histories that record observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation (for instance, failing to accurately document study procedures)
  • Failure to maintain adequate records of the disposition of the drug, including dates, quantity and use by subjects

Proper training, monitoring and auditing can help your company avoid FDA violations.

A contract research organization (CRO) can also provide third-party oversight and guidance, helping you catch issues before the FDA does.

IMARC's team has a stellar record with the FDA. In our 20-year history, we have never had a single FDA Warning Letter issued to one of our sites or sponsor companies.