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By EAS Director of Regulatory Affairs and Submissions, Chris Celeste

Since December 1978, medical device manufacturers have been subject to FDA regulations and inspections based on the Good Manufacturing Practices (GMP) requirements. On June 1, 1997 FDA amended the 1978 regulations to include quality system regulations (QSR).

An FDA “Warning Letter” is considered by the agency to be the first step in the enforcement process. In the letter, the agency threatens to take regulatory action if a firm does not correct the violative conditions. The agency requests a response, normally within 15 working days. In situations of a danger to health, the agency may request a response in 24 hours.

In fiscal year 2013, FDA’s Center for Devices and Radiological Health (CDRH) issued 217 Warning Letters, seven more than the center issued in FY12. EAS reviewed a total of 105 of the warning letters issued to manufacturers or other establishments that market medical devices in the U.S. The following were the Top 10 observations noted in those letters:

  1. 21 CFR 803.17 – Failure to develop, maintain, and implement written Medical Device Reporting procedures
  2. 21 CFR 820.22 – Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system
  3. 21 CFR 820.30(i) – Failure to establish and maintain procedures for the identification, documentation, validation or, where appropriate, verification, review, and approval of design changes
  4. 21 CFR 820.50 – Failure to establish and maintain procedures to ensure all purchased or otherwise received product and services conform to specified requirements
  5. 21 CFR 820.75(a) – Failure to ensure that when the results of a process cannot be fully verified by subsequent inspection and testing, the process shall be validated with a high degree of assurance and approved according to established procedure
  6. 21 CFR 820.90(a) – Failure to establish and maintain procedures to control product that does not conform to specified requirements
  7. 21 CFR 820.100(a) – Failure to establish and maintain procedures for implementing corrective and preventive action
  8. 21 CFR 820.181 – Failure to maintain adequate device master records (DMRs)
  9. 21 CFR 820.184 – Failure of the device history record to demonstrate the device was manufactured in accordance with the Quality System Regulations
  10. 21 CFR 820.198(a) – Failure to maintain complaint files and establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit

How to Respond

A firm’s response to a warning letter may be its last chance, prior to a legal or administrative action, to adequately address a situation that FDA has concluded constitutes a violation of the Food, Drug and Cosmetic Act (FD&C Act). Therefore, it is particularly important that the communication be responsive to the issues identified by the agency. Frequently, the letter is the result of an investigator’s inspection and the agency has already received the response to the FDA observations noted on the FDA-483. In some cases, the response may be considered inadequate and FDA will state that and will explain why the response is inadequate. In other cases, FDA may be silent as to their evaluation of the submission addressing the FDA-483 observations. If the initial response has been determined by FDA to be inadequate in whole or in part, FDA has not acknowledged its receipt, or if the firm has not yet responded to FDA’s concerns; this may represent the firm’s last opportunity to prevent a more aggressive action. Immediate affirmative action to correct the objectionable conditions and inform the proper office of the action is necessary to satisfy FDA and to prevent further regulatory action.

FDA may conclude that a firm has already satisfactorily corrected the objectionable conditions, or accept a firm’s response that they have been corrected. However, FDA may still send a warning letter, because they have yet to confirm that the conditions have been corrected and they wish to establish a background of “prior warning” so that if the violations are repeated at some future date, the firm is “on notice” that a more serious regulatory action may result. It therefore, remains important that a firm’s response to a warning letter be adequate to address the issues set forth. It is also important to state what systems and controls have been put into place to prevent these deviations from occurring in the future.

When drafting a response to an FDA warning letter, it is important to remember that the agency has already tentatively concluded that a violation of the law has occurred. The response must contain solid facts to refute the allegations or represent the firm’s action and commitment to afford immediate and permanent correction. If the recipient of the warning letter disagrees with the contentions in the letter, there is an appeal process within FDA. However, our experience indicates that when the situation reaches the point where FDA concludes that the issuance of a warning letter is appropriate, such appeals are futile. The next step would be to have the issues resolved in court.

It is important to meet the FDA timeframe for submitting the response. If you can’t, notify the issuing office and request an extension. The firm should commit to immediate and permanent correction of the violative conditions. They should support their view with facts and expert views. A meeting can be requested with the issuing office to discuss the firm’s views and hear FDA’s position. The firm’s views can be provided in writing as well as verbally in a non-argumentative, straightforward manner. If a specific product(s) are involved, provide the agency with the action the firm intends to take on these products and why. If the firm does not agree with FDA’s conclusion, request a meeting with the issuing office to discuss differing views and hear FDA’s position. The firm should present its arguments in a factual, scientific and if appropriate legal manner.

If the response is satisfactory FDA will, conduct a follow up investigation to assure the corrective action taken is effective. If the response is inadequate or if it has not been accomplished as promised, further regulatory action by FDA is likely.

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