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An FDA official confirmed last week that a "Close out letter" has not been issued to resolve a January, 2007 Warning Letter sent to Dr. Richard Kagan, Chief of Staff at the Shriners Hospital for Children (SHC) Cincinnati.
According to the FDA:
"If the FDA can determine, usually based on a re-inspection, that a firm has fully corrected the violations raised in a warning letter, we will provide to the firm a 'close-out' letter, indicating that the issues in the warning letter have been successfully addressed. To keep the public informed, we will indicate on our website when a firm has received a 'close-out' letter. The absence of a close-out letter on FDA's web site could mean a number of things. Among other things, it could mean that a re-inspection has not yet occurred or that all the issues in the warning letter have not been successfully addressed."
The unresolved warning letter states:
"The purpose of this inspection was to determine whether activities and procedures related to your participation in the clinical study 'Burn Wound Repair with Cultured Skin Substitutes,' Investigational Device Exemption (IDE) G980023, complied with applicable federal regulations."
The inspection "was a directed for cause inspection of a clinical investigator from CDRH, Division of Bioresearch Monitoring, HFZ-312, as high priority, dated March 14, 2006."
In other words, this was a high priority, "for cause " FDA inspection.
The letter explains:
"The purpose of this inspection was to determine whether activities and procedures related to your participation in the clinical study 'Burn Wound Repair with Cultured Skin Substitutes,' Investigational Device Exemption (IDE) G980023, complied with applicable federal regulations. Cultured Skin Substitute (CSS) is a device as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h). This letter also requests prompt corrective action to address the violations cited and discusses Dr. Boyce's written response, dated October 6, 2006, to the noted violations."
Hundreds of violations were organized according to the inspector's observations, spelled out in a two part Establishment Inspection Report (EIR) issued on June 21. 2006, available here and here.
The objectionable conditions include:
1) Failure to report unanticipated adverse device effects.
2) Unapproved informed consent documents were being used.
3) Failure to follow the investigational plan.
4) Failure to report and maintain records for all adverse events.
5) Subjects' case histories were not accurate and complete.
6) Failure to maintain or report protocol deviations.
The University of Cincinnati has been charged with oversight of this clinical study, provided by their own Institutional Review Board or IRB.
According to the " FDA :
"Under FDA regulations, an IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves an important role in the protection of the rights and welfare of human research subjects.
The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research."
Now, this FDA warning letter didn't just appear out of nowhere.
Allegations about the same study had been previously reported to the Office of Human Research Protection (OHRP). The OHRP oversees clinical research studies to make sure that human research subjects are protected, especially children.
This FAQ provides guidance and special requirements for clinical research studies using children as human research subjects.
This timeline chronicles specifics of human experimentation up to the formation of the OHRP in 2000.
According to this timeline:
"1997. Researchers at the University of Cincinnati publish findings of experiment attempting to create a 'psychosis model' on human beings at the Cincinnati VA. Sixteen patients, experiencing a first episode schizophrenia, were subjected to repeated provocation with amphetamine. The stated purpose was to produce "behavioral sensitization. This process serves as a model for the development of psychosis, but has been little studied in humans. Symptoms, such as severity of psychosis and eye-blink rates, were measured hourly for 5 hours."
Dr. Glenn D. Warden, then Chief of Staff at SHC Cincinnati, was also named in an August 7, 2000 OHRP letter regarding these same violations.
The same day, on August 7, 2000, the OHRP presented the same investigators an allegation from the Mother of a badly burned child who claimed that she was urged by a nurse to sign the informed consent document because "The Doctors need these papers signed immediately. If she has any chance at all, this is the only chance she has." It further explains "No one at any time explained the documents to her and/or that they were consent for Experimental Programs."
This same OHRP letter further details how an otherwise excluded pregnant woman was enrolled as a research subject, to include the "collection of skin tissue for preparation of grafts as part of the research." It continues that the OHRP was presented another allegation "that the investigators continued to conduct research on a subject after the subject's family withdrew permission for her participation in research."
The letter explains that though only the pregnancy allegation could be substantiated, guidance suggested changes in protocol and informed consent language so as to not inflate potential benefits to the research subjects.
On April, 21, 2003, the next OHRP letter noted that "the University of Cincinnati has required the investigators in the above-referenced research to conduct an audit of research subjects enrolled to ensure that no additional protocol violations had occurred. In addition, OHRP notes that the investigators have been made aware of the requirement to request changes to a protocol approved by an IRB prior to the initiation of such changes, except when necessary to eliminate apparent immediate hazards to the subject. OHRP recommends that UC also consider reminding all investigators of the regulatory requirements to obtain IRB approval for changes in approved research during the period for which the IRB approval has already been given."
The rest of this letter "finds that the corrective actions noted above adequately address the findings of noncompliance noted in OHRP's November 21, 2002 letter and are appropriate under the UC MPA and FWA."
MPA = Multiple Project Assurances. FWA = Federal wide Assurances, both submitted by an IRB to the OHRP to assure compliance with human subject protections, among other things.
So, from August 7, 2000 to April 21, 2003, the OHRP found informed consent problems related to the cultured skin substitute study at SHC Cincinnati. In an attempt to mitigate these violations, the OHRP required that the University of Cincinnati have SHC investigators audit all subject records for proper informed consent.
Then, three years later, the FDA held a high priority "for cause" inspection from March 7 to June 21, 2006 that found hundreds of other violations, itemized in the establishment inspection report and the current unresolved FDA warning letter sent to SHC Cincinnati in January, 2007.
Does the current FDA warning letter suggest a lack of communication between the University of Cincinnati IRB and investigators at SHC Cincinnati or did someone just ignore the OHRP's requirements to audit the patient's records for proper informed consent?
According to Observation 2 of the FDA Establishment Inspection Report:
"Informed consent was not properly documented in that the written informed consent used in this study was not approved by the IRB. Specifically, the informed consent documents used by the first 28 subjects enrolled between 04/15/98 and 7/17/00 that received cultured skin substitute (CSS) in this study did not have IRB approval. The first IRB approved consent form was dated 09/06/00."
If the doctors had audited the records, how could the FDA have found these violations?
The FDA inspector ended the EIR with this "General Discussion with Management":
"Dr. Steven Boyce and Dr. Richard Kagan stated that they did not realize the importance of following the investigational plan exactly. They misunderstood the requirements for operating the IDE. They felt that though this inspection revealed numerous deficiencies that patient safety was never put at risk. I explained the provisions that the FDA has available to them as a follow-up to the inspectional observations, which included a warning letter, disqualification or criminal prosecution. Dr. Kagan and Dr. Boyce are extremely concerned with addressing all observations and continuing to operate this IDE. They feel this trial is extremely important to the Shriner's patients and community and they will do all they can to meet all FDA concerns and regulations."
To date, it appears that they have yet to do so.
Next: What's in the FDA Establishment Inspection Report?
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