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Officials at the FDA and the University of Cincinnati have confirmed investigations into the clinical study for a burn treatment developed at the Shriners Hospital for Children (SHC) in Cincinnati as it appears to be heading to market (1).
A 2006 FDA inspection, categorized as “high priority” and “for cause,” led to this 41 page report. It itemizes hundreds of violations found in the Shriners Hospital study of “Burn Wound Repair with Cultured Skin Substitutes” as SHC doctors experimented on badly burned children while trying to get a cultured skin substitute to market for commercial and military applications.
This list of observations resulted in the FDA sending a warning letter to Dr. Richard Kagan, Chief of Staff at SHC Cincinnati on January 12, 2007. This means that the study’s results could be invalid or even fraudulent if it can be proven that the patient’s charts were intentionally left incomplete, that adverse effects were intentionally and repeatedly not reported or if invalid informed consent forms were knowingly used on patients enrolled in the study.
Details about the unresolved warning letter can be read here.
The violations are organized according to six main categories of observation, including:
1. Not preparing and submitting complete and accurate reports of unanticipated device effects to sponsors. “Specifically, the subjects listed below, in which cultured skin substitute (CSS) was regrafted, was not reported as graft failures to the sponsor or the IRB and the case report forms do not reflect these losses.
”Informed consent not properly documented in that the written informed consent used in the study was not approved by the University of Cincinnati’s Institutional Review Board or IRB. The informed consent documents used by the first 28 subjects enrolled between 4/15/98 and 7/17/00 that received cultured skin substitute (CSS) in this study did not have the IRB approval. The first IRB approved consent forms were dated 9/6/00.”
2. The investigation was not conducted according to the investigational plan.
“Specifically, the investigational plans (the protocol and amendments) dated November 1, 1999 and June 1, 2004 were not followed.”
This includes not taking photographs and tracings within protocol timelines, not performing qualitative outcome and scaring assessments by an investigator not responsible for the acute care of the patient, not collecting wound cultures and antibodies during the specified timeframes, not irrigating wounds or changing bandages according to protocol and not applying graft to a comparative site when cultured skin substitutes were grafted.
3. Records for each subject concerning anticipated adverse device effects were not all accurate and complete.
“Specifically, none of the subjects anticipated adverse events were listed in the subjects case report forms or reported to the IRB or sponsor."
Unreported adverse events include pneumonnia, elevated temperature, conjunctivitis, necrotic muscle, six bouts of sepsis with elevated temperatures, fever, itching, jaundice, high blood pressure and vomiting.
4. Records of each subject’s case history were not all accurate and complete, specifically three cases of not documenting the receipt of a CSS, not documenting the application of a CSS to a patient’s abdomen, incomplete biopsy, blood culture, microbiology and photography logs and in one case, a blank photography log.
5. Records of each subject's case history are not all accurate and complete.
6. Records showing dates and reasons for each deviation from protocol are not all complete.
"Specifically, the investigator did not maintain records showing the dates and reasons for all protocol violations that occured during this study. Out of the30 subjects audited, I noted 423+ deviations that were not reported as protocol deviations."
The report further states that of the subjects enrolled, 61 were treated with cultured skin substitute and that “Of the remaining subjects, 14 expired prior to receiving the cultured skin substitute” with subject 036 expiring during this study.
The report further states that this trial obtained approval to operate on November 17, 1999 from the University of Cincinnati Medical Center Institutional Review Board or IRB. University representatives have declined to comment on the current situation because “It would be improper for us to comment on any aspect of the device while there is an ongoing audit.”
According to the FDA, “Every year since this trial began in 1990, Dr. Boyce has submitted an annual report to the IRB.” The annual reports contain the number of deaths and significant adverse events but reports for each year from 7/99 to 7/05 “do not contain all significant adverse events that were listed in the patient’s medical files. Additionally, graft losses were not reported to the IRB or sponsor.”
Successful clinical studies rely on traceable medical records and chain of custody source documentation to reproduce duplicatable results. The FDA violations mean that the doctors in charge of this SHC burn treatment study may not be able to reproduce and report successful results to financial sponsors including the National Institute of Health and those in charge of administering research grants for the Shriners, though all aspects of this research are supposed to be overseen by the University of Cincinnati Institutional Review Board (IRB).
The FDA is charged with making sure that these medical facilities meet certain guidelines and follow strict protocols concerning conflicts of interest and the protection of human subjects.
FDA Commissioner Margaret Hamburg M.D. told the Food and Drug Law Institute “Every company with products or activities under FDA’s jurisdiction has a duty to comply with the law…and to meet the standards that the FDA has set to protect the public.” (2)
This is the second time SHC Cincinnati received warning letters from a government agency about the same study. Violations were previously noted in this warning letter issued by the Office of Human Research Protection (OHRP) concerning studies being conducted by Dr. Glenn Warden, then chief of staff of SHC Cincinnati and Dr. Steven Boyce, principal investigator of the SHC study of “Autologous Cultured Skin Substitutes for Treatment of Full-Thickness Burns.” The OHRP required that the doctors audit the study’s patient records for proper informed consent but if they audited the records as the OHRP requested, would the FDA inspector have found the invalid informed consent forms three years later?
Dr. Warden, along with the current SHC Cincinnati chief of staff Dr. Richard Kagan, helped form another nonprofit group, Ohio Valley Skin and Tissue that was later renamed U.S. Tissue and Cell. According to their 2005 tax return, the group’s exempt purpose is to:
“Provide skin, bone and other tissues to the medical community for transplantation and research.”
This return has a few red flags.
Page 17 of the return shows that Dr. Warden, listed as President and CEO, was paid $573,960, much more than the $58,000 to $188,500 paid to the others.
Page 20 tells us that Dr. Richard Kagan earned $102,125 as full-time medical director for U.S. Skin and Tissue while also working as:
Chief of staff for the Shriners’ hospital
Director, University Hospital Burn Special Care Unit
Consulting surgeon for Cincinnati Children’s Hospital, Cincinnati VA Hospital and Drake Center
Faculty for the Compass Medical Education Network, Director of Surgery
This is in addition to his work for the American Burn Association, the advisory board for Allosource and six different editorial boards.
This editorial board part is important because those who oversee or write for professional journals, as well as those who give presentations or otherwise represent the validity of their clinical research, are supposed to disclose any financial interests in their research as was the case with Dr. Boyce, if they’re defendants in cases like the one against Allosource and U.S. Tissue and Cell for personal injury and professional liability or if they’re the subject of warning letters like those from the Office of Human Research Protection or the FDA.
Additionally, experts agree that these potential conflicts of interest “should be reported to sponsors contacting them about new clinical trials and to IRBs, including during the continuing review process.” Such disclosures let the public know that the doctors conducting such research to help others instead of helping themselves.
Disclosure also lets the public know who’s in bed with who.
The U.S. Tissue and Cell 2005 tax return fails to list the Shriners or the Jesters as related groups because of the common board memberships shared and positions held Drs. Kagan and Warden as well as William Siders, listed on the U.S. Tissue and Cell tax return as a trustee. He is a past chairman of the SHC Cincinatti Board of Governors and is listed on this Royal Order of Jesters 2005 tax return as “Royal Stage Manager, on this return as “Royal Tragedian” and on this return as “Royal Impresario.”
Back to the FDA report.
It continues 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. The report further states 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.”
So how did Drs. Kagan and Boyce react to this report?
"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."
Two years later, it appears that they’re still working on it, though their seemingly unduplicatable product is being guided through FDA approval and is expected to hit the marketplace in the next few months.
(1) “In 2007, nearly 100 companies were involved in developing engineered tissues, cell-based therapeutics, or related technologies (Applied Data Research, February 2007). Overall the industry had an annual growth rate of 16% from 1995-2001. The "structural" industry segment (e.g., skin, bone, cartilage) showed 85% growth from 1998-2001. In 2004, the U.S. market for tissue-engineered skin replacements/substitutes and active wound repair modulators were valued at approximately $195 million. Sales are expected to increase at a compound annual rate of 9.5%, reaching approximately $481 million in the year 2014 (MedTech Insight, Windhover Information, September 2005). The total U.S. market for advanced wound care technologies was worth more than $2.3 billion in 2005. By the end of 2006 the market will reach almost $2.6 billion, and over a five-year period will grow at an average annual growth rate of 12.3% to reach $4.6 billion in 2011 (BCC Research, PHM011E, January 2007).” From Patentdocs.
(2) Thanks to Newsvine columnist AdipicAcid for suggesting this link.
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.
