FDA 438 warnings are dreaded by many companies as they affect reputation of those who are concerned. It begins with the issue of  FDA 483 form . This may be issued to inform the Principal Investigator or the institution of important unpleasant conditions observed during an FDA inspection. This letter can be issued for many reasons relating to FDA violations. When the response to FDA 483  form is inadequate,  warning letters called FDA 483 warnings  is then issued.

A review of 2012, 2013, and 2014 FDA 483 warnings to clinical investigators shows three prominent areas that occurred frequently as violations. These are:

• Conduct and supervision of clinical trials
• Maintenance of accurate case histories
• Informed consent

Failure to personally supervise clinical investigations

This was the most common reason for the warning FDA 483  warnings to clinical investigators. It is related to a commitment made in FDA Form 1572. Many investigators do not appear to realize the implications of signing this form in terms of their commitment. Some investigators delegated duties and ignored their own which cannot be delegated. There was a 24% increase in these violations over a three year period.

Typically FDA inspectors remind the Clinical investigators of their responsibilities by the following statement.

“You failed to personally conduct or supervise the clinical investigations [21 CFR 312.60]”.

Clinical trial participant

“When you signed the Statement of Investigator (Form FDA 1572) for the above-referenced clinical trials, you agreed to take on the responsibilities of a clinical investigator at your site. Your general responsibilities as a clinical investigator include ensuring that the clinical trials are conducted according to the signed investigator statement, the investigational plan, and applicable regulations; protecting the rights, safety, and welfare of subjects under your care; and ensuring control of drugs under investigation [21 CFR 312.60]. By signing Form FDA 1572, you specifically agreed to personally conduct the clinical trial or to supervise those aspects of the trial that you did not personally conduct. While you may delegate certain study tasks to individuals qualified to perform them, as a clinical investigator you may not delegate your general responsibilities. Our investigation indicates that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that the clinical trial was conducted according to the signed investigator statement, the investigational plan, and applicable regulations, and in a manner that protects the rights, safety, and welfare of human subjects”.

 Most investigators tried to defend their case but the defense was not accepted because they did not provide the required information. The FDA adds the following statement in their FDA 483 warnings letter:

“Your response is inadequate because it does not contain sufficient detail. Specifically, you did not provide details regarding how you will implement your corrective action plan. Without those details, we are unable to determine whether your corrective action is adequate to prevent similar violations in the future.

FDA 483 Warnings and Failure to maintain accurate case histories

The second most frequent reason for FDA 483 was failure to maintain adequate and accurate case histories. The clinical investigator failed to provide accurate records of observations and other data. This failure can cause harm to the subjects as well as waste resources.

In 2012 there were 83 cases on record while in 2013 there were 85 cases recorded. 2014 saw an increase to 99 cases. There was a 19% increase in these violations over the three year period.

The clinical investigators received the following in the violation letters:

‘You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)].

As a clinical investigator, you are required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation.”

 Failure to obtain informed consent: a common cause of FDA 483 warnings

The third most common reason for the warning involved informed consent. The clinical investigators received the following violation in their letters:

You failed to obtain informed consent in accordance with the provisions of 21 CFR Part 50 [21 CFR 312.60].

Except as provided in 21 CFR 50.23 and 21 CFR 50.24, no investigator may involve a human being as a subject in research unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative [21 CFR 50.20]. Informed consent must be documented by the use of a written consent form approved by the IRB and signed and dated by the subject or the subject’s legally authorized representative at the time of consent [21 CFR 50.27(a)].

As a clinical investigator, it is your responsibility to obtain informed consent in accordance with 21 CFR part 50. FDA’s regulations at 21 CFR 50.20 state that, except as provided in 21 CFR 50.23 and 21 CFR 50.24,  no investigator may involve a human being as a subject in research covered by the regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative. You failed to obtain legally effective informed consent.

For this violation there was a significant change in the numbers. The recorded cases for 2012, 2013, and 2014 were 20, 18, 13 respectively. There was a 35% decrease in these violations over the three year period.

 Summary of the Most common FDA 483 warnings relating to clinical investigators

 Do not ignore FDA 483 warnings

If you do not make an acceptable response to FDA 483 letter after an inspection, you will get a warning letter which will now get listed amomg other FDA 483 warnings. The FDA 483  form indicates that you have violated some regulations. The warning Letter which may follow the form depends on the response to the issues raised in the  483. The warning letter is one of FDA’s key methods of achieving immediate compliance.

The FDA has the authority to “disqualify,” or remove, researchers from conducting any clinical testing of products for licensing, when the researcher has repeatedly or deliberately not respected the rules intended to protect study participants and ensure data integrity. Further, the FDA can debar a clinical investigator who has repeatedly or intentionally submitted false information to the agency or study sponsor in a necessary report.

The FDA can debar or ban individuals or companies from the drug industry that are convicted of certain offences related to drug products. Once you are subjected to “debarment,” you will not be to work for anyone with an approved or pending drug product application at FDA. Thus researchers should take FDA 483 warnings seriously.

If your company is debarred you can’t even submit abbreviated drug application for licensing.

It is therefore important that you know how to respond to warning letters. Contact us for advise or help.

References

U.S. Food and Drug Administration (FY 2014 Inspectional Observation Summaries)

http://www.fda.gov/ICECI/Inspections/ucm424098.htm

U.S. Food and Drug Administration (FY 2013 Inspectional Observation Summaries)

http://www.fda.gov/ICECI/Inspections/ucm381526.htm

U.S. Food and Drug Administration (FY 2012 Inspectional Observation Summaries)

http://www.fda.gov/ICECI/Inspections/ucm326984.htm