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Editor's Note: The burn treatment described below is the same as "PermaDerm" (tm), a cultured skin substitute developed at Shriners Hospital in Cincinnati. PermaDerm (tm) is currently being brought to market by a new company named Regenicin. It is not clear if the product's developer or those at Regenicin have disclosed the below information, especially about the adverse effects, including death, and that the study was shut down by the FDA due to thousands of clinical research violations, to their investors, the SEC, the Patent Office, the Office of Human Research Protection (OHRP) and/or the high profile, influential board members who have come aboard to help get FDA approval for this burn treatment as it heads towards a market worth $3 billion.
Sandy Frost, Starbucks, WA September 13, 2010
A twenty-year clinical study to develop a burn treatment conducted by doctors at the Shriners Burn Hospital (SHC) in Cincinnati and overseen by the University Of Cincinnati (U of C) School Of Medicine Institutional Review Board was such a mess that:
- The Office of Human Research Protection (OHRP) issued warnings in August, 2000
- FDA conducted a "for cause, high priority inspection" from March 7 – June 21, 2006
- FDA's June 23, 2006 Establishment Inspection Report listed hundreds of violations
- FDA sent warning letters to both SHC and U of C in January, 2007
- FDA issued Integrity Hold letter on February 2, 2007 that suspended the study
- Two independent audits found hundreds more violations, even after suspension
- FDA recently denied a compassionate use exemption for a badly burned boy
Two weeks ago, on June 15, the FDA denied a compassionate use request from the U of C to use an experimental cultured skin substitute (CSS) on eight year old Alfred Real, who’d been admitted to the Shriners Burn Hospital after playing with gasoline and suffering burns over 80% of his body.
News outlets mistakenly blamed the FDA for initially denying the burn treatment without correctly reporting that it was doctors and officials at both SHC and U of C who gave the agency cause to suspend the study. The FDA suspended the SHC study in February, 2007 for “lack of data integrity, system wide failures in the methods for conducting and managing clinical trials and patient safety violations.”
The FDA’s letter stated “We regret to inform you that your request (for compassionate use) is not approved and you may not treat this patient with the above cited investigational device.” It explained that the U of C’s compassionate use request failed to prove how using the burn treatment was less dangerous than the burn patient’s condition and failed to convince agency officials why the experimental cultured skin substitute should be used when FDA approved alternative treatments were already being used by doctors in burn units.
The letter continued:
“Given the availability of the above-mentioned alternatives and the lack of sufficient credible information about the investigational device FDA cannot assume that the probable risk of using the investigational device is not greater than the probable risk from the disease condition. FDA would welcome the opportunity to learn more about the safety of this product if you can identify clinicians who are knowledgeable about the Autologous Cultured Skin Substitute because considerable concern exists about the validity of the data generated under this IDE, we believe that these knowledgeable clinicians should be independent from the two investigators performing this study and their understanding of the product should be derived from experience other than this IDE study or publications by Drs. Kagan and Boyce.”
In other words, the FDA would and did consider a second compassionate use request as long as it excluded research from or publications produced by the doctors in charge of the suspended study. The FDA did grant a compassionate use application to the U of C on June 28 after the school accepted total responsibility for the procedures and the patient’s safety.
The FDA’s denial letter spelled out three areas of concern, even after U of C and SHC doctors, officials and staff have had over three years to resolve these failures, including:
Problems with data integrity
- Failures to maintain accurate, complete, and current records regarding each subject’s case history and exposure to the device, including all relevant observations.
- Failures to report unanticipated adverse device effects to the sponsor and reviewing IRB.
- Failures to maintain accurate, complete, and current records regarding the receipt, use, and disposition of a study device and failure to maintain each subject’s case history and exposure to the device, including all relevant observations.
- Failures of the investigator to maintain records of protocol deviations.
- Failures to obtain approval of significant changes to the protocol from the sponsor and reviewing IRB.
System wide failures in the methods of conducting and managing clinical trials
- Failure to ensure investigator compliance with the signed investigator agreement; investigational plan, and applicable federal regulations, (e.g., diagnostic procedures/assessments were not performed and unanticipated adverse device effects were not documented and reported).
- A lack monitoring procedures and the absence of monitoring clinical studies.
- Deficient records of device accountability.
- Failure to submit IDE progress reports at regular intervals and at least yearly to FDA and reviewing IRBs.
These Patient safety issues were called out in a third party audit submitted to the FDA on March 25, 2010
- Auditors determined that only 5 of 24 subjects which should have received additional informed consent information, were properly re-consented, (page 10).
- Auditors found that the sites did not understand the reporting of adverse events (page 44).
- Based on the definition of unanticipated adverse device effects and serious adverse effects developed by your Data Safety Monitoring Board (DSMB), 1782 out of a total of 7331 adverse events were reported. An additional 5547 AEs were extracted by the auditors based on the DSMB-generated list of adverse event reports (page 77).
- In the 2007 annual report (i.e., after issuance of the Warning and Integrity Hold letters), only 8 adverse events (AEs) were reported. During the independent audit a total of 695 reportable AEs were identified. In the 2008 annual report 36 unanticipated adverse device events were reported. In contrast, the auditors identified 760 such events (page 144).
- The case report forms (CRFs) for 33 of 44 subjects audited from 2003 – 2009 were not properly completed. Individual pages were incomplete and follow- up visits were not documented, even when subjects were being seen in the outpatient clinic (page 16).
- Less than half of the subjects had results from the pre-treatment serum antibody tests (page 40) and 119 of 159 antibody tests required by the protocol at POD 28 were not performed (page 60). This led auditors to conclude that “the results of the serum antibody studies were virtually impossible to identify. The records were maintained in an extremely poor manner and not sufficient for auditor review” (page 40).
- While documentation states that the principal investigators (PIs) did not check the “Post Operative Date Completion for all Sets” CRFs until the subject completed the initial year, some of these “checks” were signed up to two or three years after the closure of the subject’s initial year on study (page 44).
- Regarding microbial cultures, the auditors noted a decline in data collection the longer the time period after treatment. For example, the number of completed samples was 120/159 (pre-operation), 119/159 (POD 0), 111/159 (POD7) and 77/159 (POD 14) (page 52).
- The audit report states (page 177) that a uniform protocol was not used at all of the study sites. Dr. Boyce stated that the same protocol was not used at each of the Burn centers and protocols had variations that were site specific. This suggests that the study was performed with protocols that were not reviewed or approved by FDA.
- There was no evidence that appropriate data safety monitoring was put into place as part of the research plan, thereby ensuring that appropriate risk assessments were being made as part of the screening process (page 22).
- Regarding device quality assurance testing, the auditors determined that:
1. Only 67/155 (43%) histological exams were completed and could be verified by source documents.
2. There was not sufficient documentation with respect to the storage, shipment, handling or disposition of the device used in the study.
3. While sterility tests were to be performed both five days before and on the day of surgery, only 10/159 (6%) tests were completed five days before surgery. The majority of the sterility tests were performed 7-10 days before surgery. 43 of 159 tests (27%) were not done on the day of surgery. Five additional samples had incomplete data or could not be verified. (page 121 - 122).
The letter concluded “FDA believes it is appropriate to stop further enrollment of compassionate use subjects” until the U of C submitted a Corrective Action Plan that addressed unresolved concerns, three years after the fact.
The following illustrates events that gave the FDA cause to suspend the study as well as exclude the doctors in charge from compassionate use consideration.
In 1998, Dr. Steven Boyce began developing a burn treatment otherwise known as a cultured skin substitute while working at both U of C and SHC. The study was conducted at the Shriners Burn Hospital under the oversight of the University of Cincinnati’s School of Medicine’s Institutional Review Board or IRB. According to a Shriner fact sheet:
"The Cincinnati Shriners Cultured Skin Substitute was developed through nearly two decades of research by Dr. Steven Boyce. The process begins when a business card size piece of skin is taken from the burned child and is cultured to grow in about three weeks to the size of 100 business cards. The cultured skin substitute is then taken to surgery for application to the burn site.”
Problems with the study were first noticed by the Office of Human Research Protection or OHRP between 4/15/98 – 7/17/00 when the agency found that the informed consent documents used by the first 28 subjects enrolled between these dates 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.
On August 7, 2000, the OHRP presented SHC doctors 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 detailed 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 November 21, 2002, the OHRP sent a letter of noncompliance to U of C regarding Shriners’ CSS study.
An April, 21, 2003 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."
In other words, the OHRP asked that the doctors in charge of the study audit patient records for proper informed consent and to make sure protocol changes got IRB approval.
Three years later, the FDA conducted a “high priority, for cause” inspection and found that doctors had not complied with the OHRP’s requirements in addition to discovering hundreds of other violations detailed in the inspector’s Establishment Inspection Report (EIR) issued on June 23, 2006.
The EIR explained that “Dr. Kagan is the principal investigator for this trial and as such, is responsible for overseeing initial patient assessments, planning surgeries, estimating the amount of cultured skin substitute needed, performing surgeries and assessing healing and progress.”
It further stated that:
“Dr. Kagan did not complete, review or sign any case report forms. He is the principal investigator of the trial, but he did not seem to have the most knowledge of the trial…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 (the FDA inspector) 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."
Six months later, on January 12, 2007, the FDA sent a warning letter to Dr. Richard Kagan, chief of staff at SHC Cincinnati.
Two weeks later, on February 2, 2007, an FDA Integrity Hold Letter formally suspended the study.
March 25, 2010 audit submitted to FDA.
June 15, 2010 FDA denies compassionate use request from U of C.
The audit showed that though the study had been suspended, violations continued. The audit found that:
- Only 19% of adverse events as defined by the Data Safety Monitoring Board were reported.
- The 2007 annual report reported only 1% of adverse events even after the warning and integrity hold letters.
- The 2008 annual report reported only 2% of adverse events.
- Case forms for 33 out of 44 subjects audited from 2003 to 2009 were not properly completed.
All copies of material reprinted or duplicated from "by Sandy Frost" must include the following credit line: From http://sandyfrost.newsvine.com. Copyright (c) 2010 by Sandy Frost. Used by permission.
