FDA issued a Warning Letter to a California oncologist that raised some questions about basic adherence to GCPs, not only by the oncologist, but also the sponsor and/or CRO. The Warning Letter, dated 17 March 2010, cites the Oncologist for the failure to calculate the study drug dose correctly. FDA stated “this miscalculated dose unnecessarily exposed the subject to an overdose, with the potential for increaased adverse events.” Patient endangerment is always a primary concern of FDA. Although only one subject received an overdose and the FDA accepted the PI’s corrective actions, it still resulted in being listed first on the Warning Letter. The most significant finding should be the first item listed on a Warning Letter.
The Warning Letter was issued by the Division of Scientific Investigations (DSI) in the Center for Drug Evaluation & Research. DSI had formerly been the FDA office that issued the fewest Warning Letters for GCP inspections. In 2005 and 2006, according to one report, DSI did not issue a single Warning Letter to clinical sites. In Fiscal Year 2008 there were at least 12. This sharp increase indicates an increased emphasis on enforcement brought on when Dr. Leslie Ball became DSI Director. I am attaching a link below to publicly available slides from a GCP presentation Dr. Ball gave to an industry meeting for her viewpoints on GCP compliance.
Half of the Warning Letter to the oncologist is a detailed listing of pharmacokinetic (PK) samples that were analyzed incorrectly. The listings show that, “Specifically the samples were collected after completion of the infusion rather than after initiation of the infusion.” It is not often that PK samples make their way into a Warning Letter. Perhaps this is a sign of things to come. The Warning Letter notes that study nurses and pharmacists were retrained, a corrective action not accepted by FDA. The question remains on how they were trained at the beginning of the study. It also could lead to questions about staffing levels during the PK portion of the study and if the investigator had allocated adequate resources.
The last citation was the failure to “maintain adequate and accurate case histories” and lists eight adverse events in source documents that had not been entered into the case report forms (CRFs). It turned out that the site had developed a policy to enter data into the CRFs during the sponsor’s monitoring visits to cut down on the number of queries they were receiving. The site was using an eCRF system. FDA noted that it would be 8-15 months from the adverse event being entered onto a progress note to being entered into the eCRFs. FDA stated that this was an unacceptable delay and the delay “may have jeopardized subject safety.” Again, the safety of study subjects triggered FDA concerns.
This Warning Letter raises a number of GCP questions about compliance with FDA regulations. Here are several to start with:
1. Where was the sponsor and/or CRO? It is the responsibility of the sponsor to select sites that have adequate resources. Did the sponsor review the PK samples with staff and ensure that they had been trained and had the resources to complete the study?
2. Where were the monitors? Why were there adverse events going unreported for 15 months? The primary responsibility of a monitor is to perform a comparison of CRFs against the source documents. Were the monitors properly trained? Were they given adequate time to review study charts or was it a case of “rip and run?”
3. Was there a major problem with the eCRF system? I have noticed in the past year or two that a number of eCRF systems are not yet ready for prime time. FDA recently issued a Warning Letter to a clinical site because they did not have access to the eCRFs from the vendor and could not print them out for an FDA field investigator. What were the reasons for the high number of queries? How did the sponsor respond?
Usually when FDA issues a Warning Letter it is perfectly clear where the responsibility lies. However, this time I wonder how much of the problem resides with the sponsor, the CRO and other clinical trial vendors. It will be interesting to see if there are future Warning Letters for sponsor responsibilities. It is quite possible that the clinical site will soon have company.
Here is the Warning Letter:
Here are Dr. Ball’s slides: