INVESTIGATOR – Initiated Research Woes Lead to FDA Warning Letter

The Food and Drug Administration (FDA) inspects (audits) clinical sites under the Bioresearch Monitoring Program (BIMO):

• routinely to verify data that has been submitted to the Agency
  
• as a result of a complaint to the Agency about the conduct of the study at the site
    
• in response to sponsor concerns or termination of the clinical site
    
• at the request of an FDA review division
   
• when related to certain classes of investigational products that the FDA has identified as products of special interest in its current work plan
  

If the inspector (auditor) finds that the site has not complied with Federal guidelines, they will issue a Form “483” to the Principle Investigator (PI). The PI will have an opportunity to respond to the FDA findings that are documented in the “483”, and to correct the deficiencies. In case of serious deficiencies, the FDA may issue a “Warning Letter” based on the initial inspection. This is an uncommon, but very serious matter and it is FDA’s warning that the PI may face disqualification if he or she does not diligently work to correct the problems. A “Warning Letter” also may be issued following a “483” issuance, if the FDA does not believe the PI has adequately addressed the site’s shortcomings.

At clinical research industry conferences and meetings in which the FDA participates, a common topic is the pitfalls involved when the PI acts as both the investigator and the sponsor. PIs who do not understand or fulfill the responsibilities of sponsors may encounter trouble and incur liability to their institutions

An example of such a situation resulted in a Warning Letter from the FDA to an investigator at a major teaching hospital

The investigator, a physician, who received this Warning Letter was conducting a vaccine study in which she was both the sponsor and the clinical investigator. Among the observations listed in the Warning Letter was the finding that the investigator failed to submit Investigational New Drug Applications (INDs) for the vaccines to be administered, as required in 21 CFR 312.20(a). Comments by the FDA inspectors indicate that when the study began, the investigator did not know that an IND was required. However, even after the FDA informed her that an IND was required, she did not submit one.

Recommendations for Remediation:

The situation concerning lack of a required IND or other required documentation is, in our experience, not that uncommon with investigator-initiated studies. In these studies in which the investigator is the sponsor, the investigator must assume all of the roles and responsibilities of the sponsor.

In order to avoid a situation in which a PI does not submit all required documentation:

• The affiliated institution should have required training for any investigator who will act as a
  sponsor.
• A Standard Operating Procedure or process document describing all steps to be taken to initiate such a study should be developed and followed.
• The institution should require monitoring and auditing of studies to ensure that required documents are available. This monitoring and auditing can be performed by a neutral party at the institution, or by a third party such as PSC Clinical.

SAMPLE HANDLING OUT OF CONTROL

Successful clinical research relies on producing data that are reliable, accurate, attributable, and secure. Some of the data produced in studies comes from testing performed on blood samples drawn from subjects. It is, therefore, critical that blood samples are identified, handled, stored, and shipped in a manner that allows accurate and reliable test results to be obtained from that blood. The wrong results will be associated with a subject if the samples are mishandled in any of the following ways:

• The blood is misidentified
• The blood is separated in a way that allows the wrong subject identifier to be associated with a sample
• The blood is stored or shipped at temperatures that affect the constituents being tested

That is why it is essential that a complete audit of a clinical study include a look at sample handling.

In this case, PSC Clinical auditors reviewed the area responsible for processing blood samples from study subjects from multiple clinical trials, as well as storage prior to shipping to a central laboratory. Some of the findings included.

• Inconsistent sample labeling: When samples arrived in the processing area from the blood drawing area, they were labeled only with the subject’s initials. This is, of course, risky because many studies were being conducted at this clinic and more than one subject had the same initials. Samples should be labeled with a unique subject identifier (initials and number, for example), the study identifier (name or number), the date and time the sample was drawn, and the initials of the person drawing the sample.

• No SOPs: There were no written Standard Operating Procedures (SOPs) and no quality control process for centrifuging samples, labeling sample tubes, and transferring serum to tubes. As a result, this procedure was performed differently by each individual. Some individuals used procedures that minimized the risk of sample mix-up, but others did not.

• No freezer labeling: There was no record of the exact freezer in which samples were stored prior to shipping. Sponsors of trials and regulatory agencies need to know the exact location of storage for samples so that the path of all samples can be traced from subject to testing.

• No freezer temperature controls: Freezers used for storing samples were not temperature mapped, which ensures that the temperature is maintained consistently in all areas of the freezer. Freezers should be equipped with alarms that will alert personnel if the temperature goes out of specification. In addition, an accurate record of the freezer temperature should be maintained at all times.

Recommendations for Remediation:

PSC recommends that the site should remedy these findings by taking the following steps:

• Develop an SOP for tube labeling. Train staff on how to label tubes.
• Develop an SOP for sample centrifugation and separation. Include a Quality Control step, such has having a second person verify the labels of the original tubes and the transfer tube. Train staff on how to perform this procedure according to the SOP.
•  Develop a form on which to record the freezer location of samples when they are stored.
•  Perform equipment qualification and temperature mapping on the freezers used to store samples.
  

If you do not have a validation department or the resources to perform freezer qualification, a company such as PSC can provide these services.