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An FDA Warning Letter Update

With all this banter of a friendlier FDA, the FDA has still been issuing Warning Letters to the medical device industry at a good rate. If you ever get a chance to read or peruse these letters on a regulatory basis (and I don't mean getting your Warning Letter synopsis from costly newsletters) you really start to see what the FDA is keying in on.

So mdi Insight will try from time to time pull out some of the more interesting or what we notice as a trend and supply our website visitors some tidbits on the FDA WARNING LETTER, an update.

Please note we will try to keep these Warning Letter reviews current but sometimes the FDA releases the information long after the FDA inspection occurred.

The FDA has been conducting a lot of Clinical Investigation Site audits to determine compliance to the IDE regulations. In a June 7th letter to a San Diego, California company that was to monitor a clinical trial, concerning a core study that they were monitoring. The FDA inspection revealed that the firm lacked written procedures describing the process by which the clinical investigation were to be monitored and how compliance with the investigational plan and regulations would be assured.

The FDA Warning Letter goes on to state that the monitoring reports reflect a failure to identify all deviations from the approved protocol and when corrections to case report forms were made and the reasons for the corrections documented. Records reflect that your firm failed to review over four hundred protocol deviations and failed to assure that all study subjects met the minimum requirements for inclusion/exclusion. Furthermore, the approved protocol was not amended to accurately described the new primary endpoints or the FDA approved statistical analysis methods.

Another observation indicated that despite periodic clinical monitoring visits made, serious protocol violations were repeatedly made by several of the participating clinical investigators. It goes on to state that, A sponsor who discovers that a clinical investigator is not complying with the signed agreement or investigational plan is required to secure compliance or discontinue shipments of the device to the investigator.

You should be aware that the FDA is conducting these Clinical Investigation audits to assure that the clinical protocols are being followed and that the monitoring is being performed adequately. A failure in these areas could cost a company in time and money and having the clinical investigation rejected and having to be redone.

In a May 28th letter to a manufacturer of microbiological specimen collection and transport devices in Wiltshire, England, the FDA alludes to the response the company made to the FDA 483 issued at the end of their inspection which took place in March/April this year.

The FDA felt that the firm's responses to the fact that their failure investigation of the cause of non-conformities relating to product, processes and quality system was not adequate. The FDA found that there was a non-sterile sample and after retest of the batch was released on the basis that all other results met specifications, alluding to the non-sterile test as a false positive. No investigation was conducted to determine how the problem occurred. The company's was non-specific as to the possible cause of the contamination, just that the product was not the cause. It did not address previously shipped lots.

In reviewing the numerous points on this Warning Letter, the problem is not in what the company intended to do, but knowing what had to be done to satisfy the FDA and how to adequately respond to the FDA483 to prevent the issuance of the Warning Letter. (See Next Month's Insight "Responding to the FDA 483") This inspection resulted in the FDA issuing a warning that the company's products would be detained upon entry into the US until the violations had been corrected. Another response will be required as well as a follow up FDA audit to determine corrective actions before the automatic detention would be lifted.

Another recent Warning Letter, June7th, to a company in Minn. contained a negative recommendation for the clearance of their class III device until corrections to the deviations had been verified during a follow up inspection. In this case the manufacturing facilities were in England. The deviations found included at least one observation from each area of the QSR. It is unfortunate that a company that is actually expecting the FDA to visit as part of the PMA approval process would have so many deviations. Being well prepared for such an inspection is as critical as the preparation of the PMA application.

The FDA conducts inspections of Institutional Review Boards (IRB) of hospitals. In a Warning Letter issued to an IRB in Napa, California on June 7th, as a result of an inspection conducted Nov-Dec of 1998, the FDA states that the IRB failed to follow written procedures for conducting initial and continuing review of research. In this case the IRB did not have complete copies of the study protocols necessary for review. The IRB stated that in their written procedures that they require a majority of the members present at the meeting. There were meetings where there were less than the 50% members present and they continued to review the studies. The IRB procedures required that they retain documents for at least three years after the completion of the study. They were deficient in this area also. In a response to the FDA the IRB did not supply supporting documentation nor did the response specify when corrective actions would be taken. This is imperative in any response to the FDA483 and to a Warning Letter. The FDA goes on to state that any corrective action should include training of the IRB members and clinical investigators in applicable institutional procedures and policies. The FDA stated that they would review their response and determine whether the actions are adequate to permit the IRB to continue unrestricted activities.

These are a few of the FDA Warning Letters and the problems to be faced by the industry when not prepared for an FDA inspection. This is especially true of foreign manufacturers who may think that being ISO 9001 certified would assure them clear sailing through an FDA inspection.

If there are any questions or requests for copies of these Warning Letters please contact mdi offices or email us.

Next Insight - "How to Respond to an FDA 483 Warning Letter"

If you have any comments on these INSIGHTS we hope that you let us hear them. If you have any of your own INSIGHTS that you feel would be of value to other companies, we would be pleased to hear from you and to discuss them with you and if you allow, we would even put them up on this site for others to learn from.
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