Shriners Hospital Violated FDA Regs, Part 18

News Type: Event — Wed Nov 7, 2007 3:30 PM EST

The FDA News reported today that Timothy A. Ulatowski, Director of the Office of Compliance for the Center for Devices and Radiological Health, sent a warning letter to Dr. Richard J. Kagan, chief of staff at the Cincinnati Shriners Hospital, for violating FDA regulations.

Ulatowski's warning, found here, explains that the Cincinnati Shriners Hospital conducted a "Burn Wound Repair with Cultured Skin Substitutes" study to develop a cultured skin substitute (CSS) for burn wound repair. The hospital submitted a FDA application for premarket approval and the agency held an on-site inspection from March 16 to June 21, 2006 to verify that the Shriners Hospital's study data was scientifically valid and accurate, complied with federal regulations and was obtained while protecting human subjects from undue hazard or risk.

The Cincinnati district office conducted a three month investigation and found "objectionable conditions" as well as serious violations of FDA regulations regarding Investigational Device Exemptions (IDE) and Protection of Human Subjects.

Kagan and the Shriners Hospital were warned for failing to obtain informed consent, failing to report and accurately document unanticipated and anticipated adverse device events and failing to maintain accurate and complete case histories for each subject.

On September 6, 2000, the Institutional Review Board (IRB) approved the informed consent form (ICF) to be signed by the parents enrolling their burned children in the hospital's study. The study included data obtained from burned children enrolled from April 15, 1998 to July 17, 2000, though their parents had signed outdated and unapproved consent forms.

An audit of the study's investigational plans revealed that post operative data as well as engraftment assessments were found to be incomplete, performed on incorrect days or not completed at all.

Additionally, an audit of subjects' records found that no wound cultures were obtained at the required times, nor were the grafts taken or completed within the specified time frames.

Kagan and the Shriners Hospital were next warned for failing to report and accurately document unanticipated and anticipated adverse device events.

An audit of ten burned children's records found that none of their unanticipated adverse events or skin graft failures were listed in their case report forms (CRF) or reported to the IRB. Some of these adverse events included development of necrotic or dead tissue, pneumonia and elevated temperatures.

The FDA also questioned why the cultured skin substitute experiments were performed only in select situations in which grafting were needed.

Kagan and the Shriners Hospitals finally warned for failing to maintain accurate and complete case histories for each subject. Audited records found incomplete and inaccurate case report forms including missing Site Biopsy Logs and blank photography logs.

Kaplan and the Shriners Hospital were given a 15 day deadline to provide:

•proof that they have corrected these violations

•a plan to prevent future violations

•a complete list of all clinical trials for the past five years

The FDA News, provider of domestic and international regulatory, legislative and business news and information for executives in industries regulated by the U.S. Food and Drug Administration, reported that Kagan did not respond to requests for comment by press time.

The Shriners Hospitals is a 501c3 charity made up of 22 hospitals that provide free medical care to qualified burned or crippled children.

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8.6

3.6

{"commentId":1165899,"authorDomain":"acidreflux"}

AdipicAcidDeleted

{"commentId":1166564,"authorDomain":"marilynl"}

Marilyn L

Hi Sandy, Do you know if the clinical trial was for a specific product, or done on behalf of a for-profit company? Did the hospital receive funding for doing the study? I'm trying to figure out why they would cut corners, unless there's a commercial interest there somewhere.

{"commentId":1166564,"threadId":"172842","contentId":"1080364","authorDomain":"marilynl"}

4 votes

#2 - Wed Nov 7, 2007 8:18 PM EST

{"commentId":3183771,"authorDomain":"ceburke"}

psalm118:8-

I am curious as to why Sandy's comment was deleted? That looks pretty bad considering the nature of the question. I understand why the "Shriners" would look for funding, and I havn't seen anything that says they are immoral or unethicle. As a matter of fact everything I have seen says just the opposite. I have delt with them for almost 10 years now. Face it, they help thousands of children. I have (2) children that have received care from them. A daughter born with severly "Clubbed Feet" who can walk and run now, and a son that was severly burned and is scheduled for surgury soon. If I felt he were in danger I most certainly would "back out", But all my experience with the Shriners tells me otherwise, both of them recieved awesome treatment, care and attention. The staff was curtious and attentive each time we delt with them. The Doctors were knowledgable and caring.

I would like to point out that this was a "Study" done on specific children who probably didn't have another option. Before anyone "assumes" the Shriners are "using" people, I would suggest they look into these situations carefully. Our son was invoved in an "optional study" we were informed and briefed and given the option to not participate.
There are two sides to every "investigative report".

{"commentId":3183771,"threadId":"172842","contentId":"1080364","authorDomain":"ceburke"}

#2.1 - Sun Sep 28, 2008 10:37 AM EDT

{"commentId":1166810,"authorDomain":"SandyFrost"}

Sandy FrostDeleted

{"commentId":1171634,"authorDomain":"PamelaDrew"}

Pamela Drew

Sandy so great to know you are still keeping tabs on these crooks. What a horror for consumers and what a terrible reflection of the corrupt government that is supposed to provide oversight. I am clipping this to my column and a few places where folks who may not otherwise come across the story will see it. This is fabulous investigative reporting by you, as always. These are such critically important things for people to be aware of, thank you for doing the work!

{"commentId":1171634,"threadId":"172842","contentId":"1080364","authorDomain":"PamelaDrew"}

3 votes

#4 - Fri Nov 9, 2007 11:43 AM EST

{"commentId":1171635,"authorDomain":"SandyFrost"}

Sandy Frost

It appears that the Shriners Burn Hospitals provided research for Integra LifeSciences Corp. who, in 2002, received approval by the FDA to market a product that would help artificial skin grow on burn victims. Is there a relationship between the product release in 2002 and mortgages of $100,000 and $20,000 taken out by two Shriner executives in 2002 and paid back a year later? It also appears that the Shriners Cincinnati Burn Hospital sent out a press release announcing "Genetically Altered Cells May Help Artificial Skin Fight Infection" about cultured skin substitutes around January 8, 2007. The warning letter is dated January 12, 2007.
In other words, was the artificial skin press release sent out when the hospital board of directors and, presumably, all the way up the chain of command to Shriners corporate, knew that the FDA had sent the warning letter about how they endangered the burned children, kept incorrect records and failed to report adverse events like dead tissue and pneumonia?
Like Woodward and Bernstein taught us:
Who knew about the letter and when did they know about it?
And follow the money.
Thanks,
Sandy

{"commentId":1171635,"threadId":"172842","contentId":"1080364","authorDomain":"SandyFrost"}

4 votes

#5 - Fri Nov 9, 2007 11:44 AM EST

{"commentId":1171931,"authorDomain":"PamelaDrew"}

Pamela Drew

Do you have a link for the article about the genetically altered skin? I track the biotechs fairly closely though the web of influence and conflict is much more complicated than one group, certain hospitals and research centers seem to jump out above and beyond the pack and I like to add them as they appear on my radar.

{"commentId":1171931,"threadId":"172842","contentId":"1080364","authorDomain":"PamelaDrew"}

3 votes

#5.1 - Fri Nov 9, 2007 1:06 PM EST

{"commentId":1174132,"authorDomain":"acidreflux"}

AdipicAcid

If there was a three month inspection/investigation and the warning letter was issued in January, you can bet they knew it was coming. Warning letters are very rarely surprises, as most of the issues detailed within them will have been discussed during the inspectors' post inspection briefing with the inspected.

At least that is how it would go with a plant inspection. I am less familiar with clinical study inspections, but since the FDA literally bends over backwards to allow the inspected to correct violations, as that accomplishes the primary goal of protecting the public health in the quickest way possible, I have a feeling it's not much different on the clinical side.

There is no investigator response posted on the FDA web site yet, but I don't think FDA is obligated to post those in a timely manner. Only the warning letters themselves must be posted in a timely fashion. On the other hand, FDA News is reporting that the investigator will not comment on the letter, so I wonder what his response was. He's legally obligated to respond within 15 days if I recall. Warning letters are very serious despite their somewhat low-key naming.

{"commentId":1174132,"threadId":"172842","contentId":"1080364","authorDomain":"acidreflux"}

2 votes

#5.2 - Sat Nov 10, 2007 11:05 AM EST

{"commentId":1175036,"authorDomain":"PamelaDrew"}

Pamela Drew

They do have a turnaround on the Federal responses. In my experience its traditionally 30 days but that can say we're still working on it and have obstacles of an internal nature to resolve, opinion of council to seek, some laundry list of ways to delay but technically be in compliance. That's most of the dealings I've had but knowing government there's no telling for sure anything is a completely uniform standard.

{"commentId":1175036,"threadId":"172842","contentId":"1080364","authorDomain":"PamelaDrew"}

2 votes

#5.3 - Sat Nov 10, 2007 7:42 PM EST

{"commentId":1178197,"authorDomain":"melonhead"}

urbane gorilla

From newsrx.com, citing Blood Weekly (2006-04-27):

The hyperproliferative or activated phenotype in skin substitutes is similar to wounded native skin.

According to recently published research from the United States, "Cultured skin substitutes, consisting of fibroblasts and keratinocytes in a biopolymer matrix, are an adjunctive treatment for full thickness bum wounds.

"Previous studies revealed that cultured skin substitutes in vitro exhibit a gene expression profile similar to hyperproliferative skin or wounded normal skin. In the present study, we sought to determine whether this hyperproliferative phenotype is maintained after healing of grafted cultured skin in vivo."

It would appear that his is not genetically altered skin by most definitions. Rather, the skin substitute, which originates with the patients skin cells, goes through a change of gene expression as a result of its environment, the polymer matrix, not as the result of foreign genetic material being injected. This is significant since the success of skin substitutes would eliminate rejection problems associated with donor skin. Another issue (a "tissue issue" - sorry, can't help myself) is the obtaining of sufficient donor (cadaver) skin for burn victims. One of the biggest (sorry in advance) uses of cadaver skin is for a wholly elective procedure, penile enlargement, creating a shortage for burn victims.

My question would be if this research or something similar is being done elsewhere. It appears to hold promise, but Sandy makes very clear that this was not the testing that would prove so. This is too bad, since I can think of no injury as traumatizing both physically and mentally as severe burns, especially for children.

Thanks for you ongoing excellent research and reporting, Sandy.

{"commentId":1178197,"threadId":"172842","contentId":"1080364","authorDomain":"melonhead"}

2 votes

#6 - Mon Nov 12, 2007 9:11 AM EST

{"commentId":1178247,"authorDomain":"melonhead"}

urbane gorilla

Two self-corrections/expansions: Yes research is being done elsewhere as this citation from the University of Wisconsin demonstrates, and yes, genetic engineering is involved, though the details aren't provided (note: I do not assume that "genetically engineered" is automatically bad or dangerous):

We are collaborating with our colleagues in the Department of Pathology who have developed a Cultured human Skin Substitute (CSS) with enhanced vascularization properties for use in the treatment of large burn injuries and chronic wounds. Delays in vascularization of CSS's contribute to clinical failure. Our CSS is generated from a human cell line that has been genetically engineered to express proangiogenic factors such as VEGF and HIF-1 a . Structurally it has an epidermal and dermal layer, which makes it robust compared to existing CSS's made only of fragile epidermal sheets (Fig 1A). Using software we developed with our colleagues in the computer science department, we are able to quantify vascular growth in grafted specimens and provide a visual representation of the results (Fig 1B, C). Ongoing work will involve further characterization of NIKS cell lines and development of wound healing models with emphasis on vascular morphology, factors influencing angiogenesis, and wound healing.

{"commentId":1178247,"threadId":"172842","contentId":"1080364","authorDomain":"melonhead"}

2 votes

#6.1 - Mon Nov 12, 2007 9:40 AM EST

{"commentId":1193315,"authorDomain":"SandyFrost"}

Sandy Frost

Thank you all for your technical input!
My next question is "What types of conflict-of-interest documents or provisions must a doctor sign while coordinating or participating in a NIH/FDA clinical study?" Thanks,
Sandy

{"commentId":1193315,"threadId":"172842","contentId":"1080364","authorDomain":"SandyFrost"}

2 votes

#7 - Sat Nov 17, 2007 5:05 AM EST

{"commentId":1193487,"authorDomain":"acidreflux"}

AdipicAcid

I think the documents you want are on the FDA's web site. I'm no expert on clinical trials, although I do know someone who might be able to get me pointed in the right direction, but they're out of the country right now. I'd start there, as the FOIA office is slow as hell now that they've posted almost all of the routinely requested documents online.

{"commentId":1193487,"threadId":"172842","contentId":"1080364","authorDomain":"acidreflux"}

2 votes

#7.1 - Sat Nov 17, 2007 8:28 AM EST

{"commentId":1362319,"authorDomain":"fontmit"}

M. T.

The above posts sparked my interests re my concern for my cousin's seven (7) year old daughter, currently a burn patient of Shriners in Cincinnati. A concern by the mother about the inconsistency of pain medication was met, not only by a dismissive approach, but also by dire admonishment. In, essence, they were informed if a complaint was filed, they are to sign a letter consenting to have , Allysia, released from Shriners. In other words evicted and readmitted to another hospital at the parents' discretion. Totally unbelievable and offensive.

The have turned an issue that might have been a minor situation into something more serious and intractable. All that was needed was an explanation, apology or assurance that the matter would be corrected. It is imperative they adopt a constructive attitude towards complaints.

If anyone can advise as to how to proceed, I will gladly share your input with my cousin. Thank you vey much.

{"commentId":1362319,"threadId":"172842","contentId":"1080364","authorDomain":"fontmit"}

1 vote

#8 - Mon Jan 14, 2008 3:05 PM EST

{"commentId":1432538,"authorDomain":"SandyFrost"}

Sandy Frost

It is unbelieveable but not after what I've found in a couple of letters from the Office of Human Research Protection.
Stay tuned.
Sandy

{"commentId":1432538,"threadId":"172842","contentId":"1080364","authorDomain":"SandyFrost"}

#9 - Sun Feb 3, 2008 9:01 PM EST

{"canLink":false,"threadId":"172842","isPrivate":false}

SANDY FROST

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