What is an adequate response to a Form FDA 483, Inspectional Observations? That question was discussed by two representatives of FDA at a training workshop hosted by the Pacific Regional Chapter of the Society for Quality Assurance and the Organization of Regulatory and Clinical Associates – Northwest. The workshop, held on 4-5 November 2010 in Seattle, featured discussions by Chrissy J. Cochran, PhD, from the Division of Bioresearch Monitoring (BIMO) at the Center for Devices and Radiological Health (CDRH) and Mihaly S. Ligmond, Consumer Safety Officer, Division of Domestic Field Investigations, Office of Regulatory Affairs (ORA). ORA is the field organization that conducts most FDA inspections. Both Cochran, who spoke by teleconference on the 4th, and Ligmond, who attended on the 5th, stressed the do’s and don’ts of responding to an FDA 483.
The Form FDA 483
Both FDA speakers stressed that the 483 is the preliminary observations of the field investigator, not the final compliance determination of the Agency. Both emphasized that there was no requirement to respond in writing to a 483. However, both told the training session that if there are issues identified on a 483, then a clear written response can help prevent enforcement action, including a Warning Letter, by FDA. Cochran discussed a few ineffective FDA 483 response letters received by CDRH. They included a clinical investigator who was using an informed consent form without all of the required elements required by 21 CFR 50.25. These elements include a clear statement of research; alternative procedures; a discussion of confidentiality and other important information. The clinical investigator complained that: “You cited us on a technicality.” This was a clear and significant violation of FDA clinical trial regulations and this was not an acceptable response.
Cochran gave an example of an adequate response to an FDA 483 for protocol violations. The response included a copy of a written procedure developed to prevent recurrence of the violation. The procedure was presented to a seminar for study staff with a sign-in sheet with the date of the seminar. It included implementation dates with a review scheduled after three months to determine the effectiveness of the corrective action.
The response to an FDA 483 should go to both the District Office and to CDRH, Cochran said. She stated that it is the assessment at BIMO that makes the final compliance determination for Bioresearch Monitoring inspections. She reviewed the issues that BIMO considers when reviewing an establishment inspection report (EIR) and a Form FDA 483, Inspectional Observations. These include:
• Are the FDA 483 observations actual violations of the regulations?
• Are there additional violations in the exhibits submitted with the EIR?
• Are the observations documented with exhibits or discussion in the EIR?
• Are the observations significant?
• Did the inspected party address the issue in their response?
• Is the response adequate? “We will carefully look at it.”
Ligmond, who is a National Expert for drug good manufacturing practice (GMP) inspections, gave the following recommendations for a response letter to an FDA 483:
• Set a reasonable timeline for taking action;
• Initiate a “Global Response” if the deficiency can impact other areas;
• Include details and attachments;
• Be comprehensive;
• Address disagreements with the observations;
• As a courtesy, copy the investigator
Corrective and Preventative Action, or CAPA, was discussed by both speakers. Ligmond said that a CAPA plan should address problems completely and in a timely manner. Cochran said that a good CAPA plan should assess the root cause of deficiencies; identify the problems; evaluate the extent of problems; give a clear timeline, describe the CAPA being taken; and reassess the root cause.
Inspection preparedness was also discussed. Ligmond said to spend each day as if you were going to be inspected by FDA. They stressed the importance of Mock FDA Audits in preparing staff for inspections.My own experience is that it is always a good idea to respond to an FDA 483. If there is a problem, then give clear details on how the problem is going to be fixed, with specifics such as a timeframe. If you disagree with the observation, then follow Ligmond’s advice to address it “with the facts” and with documentation of the facts. FDA rarely will accept excuses such as “I thought my study coordinator was going to do that.” However, if there is a legitimate response, you should make it in a clear, respectful manner. The 483 responses I have worked on always included specific actions, specific dates, and a specific person or department accepting responsibility for ensuring that the corrective action takes place. And they always include documentation of corrective actions. If it isn’t documented, then it’s just a rumor.
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