Dr. Chitra Lele, Chief Scientific Officer, Sciformix

FDA Warning Letters Related to Pharmacovigilance Operations

Dr. Chitra Lele Ph.D.

Regulatory inspections are an everyday reality now, given the heightened level of scrutiny that the industry is facing from all the regulators. We at Sciformix recently conducted a DIA webinar on the topic of FDA warning letters in the context of Pharmacovigilance (PV) operations. We focused specifically on the post-marketing safety monitoring related findings in the warning letters issued by the FDA. I am summarizing a few key points here from the discussion in the webinar.

The FDA at the end of an inspection provides a company with a list of findings most commonly 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 plan for correction. The warning letters are issued for major regulatory violations and may lead to an enforcement action if the findings aren’t adequately corrected. However, the FDA could take action even without issuing a warning letter. 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, Seizure, Injunction, Administrative Detention and Civil money penalties and/or prosecution.

FDA Warning letters for Post-Marketing Pharmacovigilance:
Warning letters are available in the public domain, while the 483 reports are generally not. The warning letters library on the FDA website has close to 6500 warning letters listed from 2005. These letters cover a wide range of violations from food issues to tobacco promotions. A search of this large library identified 17 letters pertaining to the pharmaceutical industry regarding post-marketing pharmacovigilance. All the warning letters followed an FDA inspection and the company’s response to the FDA form 483. 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 to small pharma including generic manufacturers. Thirteen letters 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.

Most Common Findings in Warning Letter Violations:
Though it’s not easy to compare the letters written by different people, when the letters and the findings were pooled together, the most common findings fell into two categories:

  1. Review of Adverse Drug Experience and written procedures around it
  2. Reporting of 15 day ‘alert’ reports or PADERs (lateness or quality)

Other findings worth mentioning included violations related to:

  1. Records and reports of Adverse Drug Experience on marketed drugs without approved ‘New Drug Applications’
  2. Written procedures for handling of product complaints
  3. Annual reports

Some findings are more common for large pharma and some for small pharma and generic companies.

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
  • If feasible, correct violations and notify in 483 response
  • If possible, provide evidence of these actions, e.g. SOP, protocol, missing reports etc.

The panel discussion in the webinar and the subsequent Q&A focused on the following questions, and the panelists’ and participants’ experiences and views on these aspects:

  • Why are violations most often identified for 15 Day Reports, PADERs, and SOPs?
  • Best practices for responding to FDA Form 483
  • Can an FDA warning letter trigger additional activities from regulators?
  • What methods should be employed within the company to ensure PV compliance?
  • What are the best procedures to obtain internal support for ensuring PV compliance?
  • Do small and large pharma companies have different challenges?
  • How can the PV group improve collaboration within the company for optimal results?

Most often when the FDA writes a warning letter, they have to document the compliance against a particular regulation. 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.

To listen to the complete recording of the webinar, please click here.