Warning letters are issued by the US FDA to persons or organizations for violations of regulatory significance. While they are characteristically informal and advisory, their ultimate aim is to establish voluntary compliance with the law. This article will present best practices and recommendations that can be employed to improve a PV organization’s structure, develop appropriate SOPs and processes, measure the performance of important PV functions, and ensure inspection readiness.

At the end of an inspection, if there are observations, the FDA provides a company with a list of findings in a document referred to as an FDA Form 483. The company has 15 days to respond. The warning letter is issued after an inspection and after the company has responded to the findings in Form 483. A warning letter may be issued even if the response to Form 483 shows ongoing action and a plan for correction. Consequences of FDA warning letters and potential enforcement action by the FDA are serious (e.g., loss of trust by patients and HCPs regarding company products, damaging effect on stock prices, and negative impact on approval of future submissions). The FDA’s enforcement actions can include product recall, injunction, administrative detention and civil money penalties and/or prosecution.

Analysis of FDA Warning Letters for Post-Marketing Pharmacovigilance

FDA warning letters are available in the public domain, while the 483 forms are generally not. The warning letters library on the FDA website has close to 6,500 warning letters listed from 2005. These letters cover a wide range of violations from food issues to tobacco promotions. An analysis of this large library identified 17 letters pertaining to the pharmaceutical industry regarding post-marketing pharmacovigilance.  Most of the letters stated that the company’s responses to the 483 were inadequate and also that these were repeat findings from previous inspections. Details of findings that led to warning letters aren’t public knowledge, which is a limitation in such analysis of warning letters.

Three of the 17 warning letters were to large pharma companies while the other 14 were to small pharma including generic manufacturers. Thirteen were written as primary pharmacovigilance violations. Three warning letters were focused on good manufacturing practices but also had comments about PV. One letter was focused on a new drug definition.

The Most Common Findings in Warning Letter Violations

Though it’s not easy to identify the root causes of each warning letter, the most common findings fell into issues with two categories:

  • Review of Adverse Drug Experience and written procedures around it
  • The quality and/or late reporting of 15 day ‘alert’ reports or PADERs
  • Other findings related to PV worth mentioning included violations related to:
    • Records and reports of Adverse Drug Experience on marketed drugs without approved New Drug Applications
    • Written procedures for handling of product complaints
    • Annual reports

Advice on Responding to the FDA form 483

Appropriate and complete response to form 483 is crucial. Following an inspection, the FDA will issue a form 483 listing its findings. The company usually has 15 days to respond. It’s advisable to use the following best practices while responding to form 483:

  • Address each observation separately
  • Acknowledge the problem
  • Demonstrate an understanding of the problem
  • Evaluate the impact and determine the cause
  • Describe correction and preventative actions clearly and in a way that conveys understanding of the issue and a thorough root cause analysis
  • If feasible, correct violations immediately and notify in 483 response
  • If possible, provide evidence of these actions, e.g. a new or a revised SOP, documentation of its training and implementation etc.

It is important that each response address the central issue(s) identified in the observations made by the FDA. It should also provide factual and objective evidence that can be evaluated and help in understanding the response.

If for some reason, you disagree with the 483 observation, you need to support this with clear evidence, facts and data, and explain why the observation is inaccurate rather than simply overrule the claims of the FDA.  For example, if there’s an observation about the contents of the Safety Data Exchange Agreement (SDEA) with a partner, it’s best to provide the relevant excerpt from the agreement and explain why it addresses the issue contained in the observation, rather than simply stating the observation is not valid since the wording in the SDEA is adequate.  You should absolutely avoid whimsical assertions and unsupported narratives because it will discount the integrity of your response with the FDA. Failure to take these steps will provide leverage for the FDA to escalate your issues to a warning letter.


Most often when the FDA writes a warning letter, they have to document a company’s lack of compliance against a particular regulation that has been violated.  It’s rare to see a general comment implicating a wide range of things. They will always identify the regulation that has been violated. Thus the most common findings from warning letters mostly related to PV fundamentals such as 15 day reports, PADER issues and SOPs.

Repeat findings and poor responses to the form 483 increase the risk of a warning letter drastically and there are serious consequences for failure to correct the issues identified in the warning letter. An organization should be proactive and put in place processes and procedures that prevent these issues from arising and thereby avoid an FDA warning letter.

PV operations form a considerable part of our business and we have provided guidance and advice on these aspects to our clients. If you’d like any sort of assistance please feel free to reach out to Sciformix at ask@sciformix.com.

Author: Dr. Chitra Lele, Chief Scientific Officer, Sciformix Corporation