INSIGHT REPORT
Vol 5  No. 2
February
2002

INSIGHT REPORT

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Insight Report No.2  Vol.  5

Warning Letters Review

Be aware! The FDA is continuing its policy of issuing Warning Letters to companies as a result of violations conditions that they uncover. A Warning Letter is usually the second step in the FDA’s arsenal to get a company to understand that the agency is serious in their determination to bring the company into compliance. The FDA hopes that the company will do this voluntarily thus preventing further regulatory actions on the FDA’s part. The first notice of the FDA’s concern is usually the FDA483 issued during an inspection. A lack of an adequate response to the 483 could result in the issuance of a Warning Letter. Fortunately, not all 483s result in the issuance of a Warning Letter; but, an inadequate reply to the 483 or no response at all could result in receiving such a letter from the agency.

How can you tell if you are in receipt of an FDA Warning Letter? You will find, on the center of the cover page, the words, “Warning Letter” printed. As an aside, Warning Letters are available to the public via the Freedom of Information Act. Note that the FDA also makes all Warning Letters public on their website.

To help you understand this regulatory process, lets review a few recently issued Warning Letters to see what the FDA is keying in on and how a company could have possibly avoided the issuance of such a regulatory notice.

The FDA is still keeping close scrutiny into false or misleading promotional materials that they find by reviewing web sites on the Internet, when they receive complaints from a business’s competitors or when problems are discovered during FDA inspections. One such letter was issued to Yamila Abraham on Jan 2, 2002, WL NEW-11-02W. This stated that during a visit to their business facilities the FDA observed that the company was distributing a number of products that were being promoted as alternatives to illicit street drugs. That FDA visit was made in April 2001 almost a year prior to the issuance of the letter. So be aware that there is no real time frame on when you think that you have passed the time for receiving such a notification. Many times the FDA local office has to get a review from Washington before issuing a Warning Letter and this can take a substantial length of time.

In this case, the FDA picked up various labels and also visited the website which promoted the company’s products. They discovered an entire line of “pleasure herbs” that the company was promoting with claims that they were useful as alternatives to illicit street drugs.

The FDA felt that though these “herbs” were labeled as dietary supplements, they did not fall within the scope of claims permitted for such products and placed them in the category of a new drug requiring a New Drug Application. The area of dietary supplements is an area that the FDA has tried to stay away from. Will this still be the case if there is a new Congressional makeup in November? If the Democrats get the majority in the House, there is a good chance that FDA’s authority over dietary supplements may be greatly enhanced.

If you are monitoring the FDA Warning Letters, you know that there is no shortage of such letters issued for clinical studies of investigation products. The FDA has been closely monitoring this area and the FDA’s Bioresearch Monitoring Program is one of the more active programs in reviewing clinical studies.

One such clinical trial was audit and a Warning Letter was issued on Jan. 2, 2002 as a result of an inspectional that was conducted in August 2001. This letter was issued to the Angelo Creticos Cancer Center.

In this case the FDA used Parts 50 and 312 of the 21 CFR in determine the proper conduct of clinical studies involving investigational new drugs.

Some of the points of concern were: The firm failed to fulfill the general responsibilities of investigators in that they the failed to follow the investigational plan and adequately protect the safety and welfare of subjects. There were concern that the clinic was not conducting the study according to the protocol.

In my studies of recently issued Warning Letters, I have noticed that the FDA has become more active in reviewing clinical trial study centers to determine the compliance of the study. Unfortunately, there are a number of clinical trials are not being conducted in accordance with either the IND or the IDE.

Another example of a clinical trial Warning Letter is one issued to Mark H. Feldman, DPM, on Dec. 21, 2001, concerning deviations noted during an inspection of his clinical site. The inspection took place the week of Aug and Sept 2001.

The inspection revealed failures to comply with the regulatory requirements in the following areas: A failure to obtain signed and dated study inform consent documents from all study subjects; a failure to maintain device accountability records; a failure to conduct the study in accordance with the investigational plan; a failure to maintain accurate, complete and current subject records; a failure to submit progress reports to the sponsor and reviewing IBR; and, a failure to submit protocol changes to the reviewing IRBs for review and approval as well as not providing an IRB review of the subject recruitment materials or materials included on the website, among other deviations. The FDA goes on to state, ”that they consider all materials available to subjects and potential subjects of a clinical trial as educational materials and, therefore, part of the informed consent process. As such these materials must be reviewed and approved by the reviewing IRB(s) prior to use.”

In this letter, the FDA goes over point by point a written reply made by the clinical site and explains why they feel the reply was inadequate. The FDA did address the fact that “In response to a number of the Form FDA 483 statements you state that an observation is correct but give no corrective action to remedy it or prevent its reoccurrence. For example the FDA states, “the fact that protocol changes were not submitted for IRB review and approval and that periodic progress reports were not submitted to the sponsor. These are regulatory requirements. Your response in general indicates a continue lack of understanding of the regulatory requirements clinical investigators must meet, and your response includes few corrective actions taken or planned with regard to the deviations noted during the inspection.”

This is not an unusual case. For the most part, most clinical sites do not have a thorough knowledge of how to deal with the FDA, or the understanding of how to maintain their documentation. Perhaps this lack of a working knowledge is because there no quality system which provides guidance on how to have management meetings, make corrective actions and document these areas to assure compliance. Once a clinical site receives such a Warning Letter it could very damaging to the site’s reputation as it would relate to future clinical trials. Why would a sponsor use a site that came under such FDA scrutiny and which might jeopardize an approval submission.

The final Warning Letter to be reviewed at this time was issued to the parent company of Sonora Medical Systems, Misonix, after their FDA inspection resulted in serious GMP problems during an inspection conducted in Oct 2001.

This inspection revealed that devices were adulterated within meaning of Section 510(h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing, packing, storage or installation were not in conformance with the Quality System/GMP for Medical Device Regulation. The following deviations were listed: Failure to conduct management review meetings, for example, not all sources of quality data are reviewed, tracked or trended by management, such as Discrepant Material Reports or Corrective/Preventative Action Reports; Re-audits of deficient matters were not taken; Training records lack detailed information, including what training was conducted, when the training was conducted and by whom; failure to conduct a formal Design Control; CAPA was not being adequately maintained or conducted; No evidence that complaints were evaluated or have enough information to allow for evaluation of MDR reporting.

From these observations it is obvious to see that the company’s quality system was not being implemented or maintained. Yet, under the present FDA system of voluntary compliance to correct FDA 483 observations, this Warning Letter could have been avoided if the company had taken the appropriate steps to notify the Agency on what they were doing and what they planned on doing to bring the quality system into compliance. But remember, the response has to be appropriate, to the point with time frames for compliance and has to be into the FDA office within 5 working days after the issuance of the 483.

From this Warning Letter, there was no indication that the company even replied to the FDA483 observations. With such lack of concern, the FDA has only one option and in this case they used it.

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