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No. 11: July 19-23, 2010

Why it's best to respond in writing to FDA's Form 483

Question: I am a sponsor-investigator of my investigational new drug application (IND). The Food and Drug Administration (FDA) just completed an inspection, during which the inspector looked at and copied Institutional Review Board (IRB) correspondence, case report forms, informed-consent forms, adverse-event reports, and source documents. At the conclusion, the inspector presented me with a Form 483, Notice of Observations, discussed and reviewed the observations with me, and said I could respond to the observations if I want to. What should I do?

Expert Comments: Form 483 describes any inspectional observations that, in the opinion of the FDA investigator, represent deviations from applicable statutes and regulations. You may have responded to those observations orally to the FDA investigator at the conclusion of the inspection. You may also respond in writing to those observations.

There is no regulatory requirement to respond to the 483; however, it is in your best interest to respond in writing. The FDA’s Investigations Operations Manual (IOM) states: “This document [Form 483] lists observations made by the FDA representative during the inspection of your facility. They are inspectional observations, and do not represent a final agency determination regarding your compliance.”

After the inspection, the FDA investigator prepares the Establishment Inspection Report (EIR) and recommends classification of the inspection. The report and recommendation receive FDA supervisory review and a final inspectional classification is assigned. If Official Action Indicated (OAI) is assigned, it is referred to the FDA’s compliance branch for further review and action.

There are four reasons to submit a well-reasoned, complete, and timely response to the 483: It could possibly mitigate an FDA compliance decision for further action; demonstrates to the FDA an understanding and acknowledgement of the observations; demonstrates to the FDA the intent to voluntarily make corrections and comply; and establishes credibility with the FDA.

The written response to the FDA should include a commitment to compliance; address each observation separately; note whether you agree or disagree with the observation; provide the corrective action that has been accomplished or planned; provide time frames for the corrections; provide your method of verification and monitoring of the corrections. Consider submitting documentation of corrections; submit the response in a timely manner, usually within15 days.

The actions the FDA may take include: 1) a letter that generally states that FDA observed basic compliance with pertinent regulations; 2) an Informational or Untitled Letter that identifies deviations from statutes and that do not meet the threshold of regulatory significance for a Warning Letter. Generally, such letters request a written response from the clinical investigator; 3) a Warning Letter that identifies serious deviations from applicable statutes and regulations. Significant violations are those that may lead to enforcement action if not promptly and adequately corrected. Warning letters are issued to achieve voluntary compliance and include a request for correction and a written response to the agency; 4) a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE).

FDA may initiate a process to disqualify the clinical investigator from receiving investigational new drugs and/or biologicals or investigational devices if the investigator has repeatedly or deliberately filed to comply with applicable regulatory requirements or has deliberately or repeatedly submitted false information to the FDA.

FDA also posts final clinical investigator inspection classifications as well as warning letters, NIDPOEs, and other information about clinical investigators who have been disqualified or restricted in their ability to receive investigational products on its Web site.

FDA Inspections of Clinical Investigators

Clinical Investigator Administrative Action - Disqualification

Clinical Investigator Inspection List

Writing an Effective 483 Response

Warning Letters

Comments by Harvey M. Arbit, PharmD, MBA, the president of Arbit Consulting, LLC. He specializes in FDA regulatory affairs related to investigator-initiated IND and IDE research.

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