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Comprehensive Audit Report


Protocol: Burn Wound Repair with Cultured
Skin Substitute
IDE Number: G980023
Subjects #1-81

Conducted by: The Morley Research Consortium
August 01, 2010- December 29, 2010

Jane A. Green, PhD




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Table of Contents:
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Demographics/ Subject Status Summary. . . . . . . . . . . 3
3. Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4. Skin and Wound Organisms. . . . . . . . . . . . . . . . . . . . . . 8
5. Site Regrafted . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6. Site Regrafted Wound Closure. . . . . . . . . . . . . . . . . . . .12
7. Nature of Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8. Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
9. Final Conclusion and Assessment . . . . . . . . . . . . . . . . .17














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1. Introduction:
The initial part of the audit for the subjects for the Cultured Skin Substitute (CSS) study began
August 1, 2010 with the Morley Research Consortium (formerly the Walter B. Morley Research
Foundation) modifying the electronic database created solely for the purpose of collecting the
data for the CSS audit. This second audit was conducted for the initial subject numbers 1
through 81 that the University of Cincinnati was unable to complete due to lack of available
personnel. Morley Research Consortium (MRC) was retained to review these subjects based on
the corrective action plan submitted by the University of Cincinnati (UC) to the Food and Drug
Administration (FDA).
The case report forms and subject records were reviewed by MRC personnel. The Edmonton
Alberta Canada site requested that MRC audit on site, rather than transport records to the MRC
office. This was due to the fact that the site did not want to ship the subject records
internationally. MRC auditors J ane Green, PhD, and Donald J ohnson audited the one subject on
site in Edmonton, Canada in late November, 2010.
This report includes the findings of each section that was to be specifically reviewed, and a copy
of each individual subject record as an attached appendix.


2. Demographics/ Subject Status Summary
The demographics of the subjects of the Cultured Skin Study were captured on the case report
forms for general use. There were no restrictions per the protocol for age, gender, or race. The
age for the study participants ranged from a few months old up to 42 years old.
The breakdown for race, shown in figure 1.1, indicates that the majority of subjects were
Caucasian, then followed by Hispanic and African American, and Asian.
As shown in figure 1.2, the overall gender of the study audit population was male. Males are
shown to be five times more likely to be a burn patient with respect to the make-up of this study.
Per figure 1.3, the majority of study subjects were enrolled by the Cincinnati Shriners site,
followed by Sacramento Shriners, then the Boston Shriners, with one subject enrolled at the
Edmonton, Canada University Hospital site. The questions that evolved from the enrollment of
these outlying sites will be addressed within the specific section where the question occurred.
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Figure 1.1- Subject Race Summary
There were fifty (50) subjects identified as White in the audit sample. One subject (Subject 60)
was allotted two separate subject numbers (60 and 72) thus explaining the use of 51 subject
numbers, yet only having 50 subjects in the sample identified as White. Fifteen (15) subjects
identified as Black in the audit sample. Fourteen (14) subjects identified as Hispanic and one
subject identified as Asian in the audit sample.
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Figure 1.2- Subject Gender Summary
There were eighty (80) consented subjects in the audit population. Fifty-two (52) subjects
consist of the male sample and twenty-eight (28) subjects consist of the female sample. One
subject (Subject 60) was allotted two separate subject numbers (60 and 72) thus explaining the
use of 53 male subjects, yet only having 52 subjects in the audit sample. The audit population
was eighty-one (81), which includes subject 60 being allotted two separate numbers (60 &72).




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Figure 1.3- Subject Hospital Summary
Sixty-six (66) subjects that participated in the study enrolled at Cincinnati Shriners. One subject
(Subject 60) was allotted to have two separate subject numbers (60 and 72) thus explaining the
use of 67 subjects, yet only have 66 enrolling at Cincinnati Shriners. Eleven (11) subjects
enrolled at Sacramento Shriners. Two (2) subjects enrolled at Boston Shriners and one (1)
subject enrolled at Edmonton, Canada University Hospital.







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3. Microbiology


Figure 2.1- Microbiology Summary
The N/A column refer to the subjects that expired, discontinued/ not treated with study device,
covered with AG before CSS grafts were ready, or received skin reconstruction.
The No column refer to 163 Site As had no as a field for microbiologys completed and 322 Site
Bs had no as a field for microbiologys completed.
The Yes column refer to 747 Site As had yes as a field for microbiologys completed and 551
Site Bs had yes as a field for microbiologys completed.
The sum of Site A (N/A, No, & Yes) completed is 1230 and the sum of Site B (N/A, No, & Yes)
total is 1196.
N/A under the Site column refer to the Sources that were not skin (i.e. blood, sinus tract, chest,
sputum, tracheal aspirate, and urine) so, they received N/A for the site location as it relates to the
cultured organism that grew.
Conclusion:
The microbiology report does not provide any useful information given that the sites did not
record sites A and B correctly and accurately identify the exact body area (so that CSS could be
correctly identified) as opposed to the AG sites. Also the case report forms do not indicate
which set the microbiology reports represent. As many sets were performed together or within a
week of another set, it is impossible to determine any accurate data points from this information
as should have been if the protocol had been accurately followed.


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4. Skin and Wound Organisms

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Figure 3.1- Skin and Wounds Organisms Summary












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5. Site Regrafted


Figure 4.1- Site Regrafted Summary

Conclusion:
It appears that there were less regrafts needed for the CSS device, however the fact that there
were 87 unable to verify plus 1 unknown, makes it difficult to determine the outcome. If one
looks at the percentages of what was documented, one could assume that of that 88 probably 85
would have been AG and 3 would have been CSS. However this is not documented, therefore
the numbers again, do not provide the scientifc validation required for good clinical research.



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6. Site Regrafted Wound Closure



Figure 5.1- Site Regrafted Wound Closure Summary
The above graph identifies that the vast majority of the regrafting did have wound closure. As
most of the graphs were AG, this is not a significant finding for the study.









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7. Nature of Infection




Figure 6.1- Nature of Infection Summary
The collection of the Infection data was inconclusive. There was no documentation as to
whether the infections were related to any of the CSS placement or the burn. The vast majority
of the source documentation (Physician records) indicates that most of the infections were
related to conditions of the burn. The Physicians did not mention the CSS other than in the
surgical reports to say that the CSS was being placed on the subjects. This obviously follows
that same pattern as the previous audit, in the manner that the physicians were not trained in
good clinical practices (GCP). Individual records of the infections can be found in the appendix
of this report in the subject individual records.



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8. Survival

Figure 7.1- Survival Summary
Subjects that received CSS before expiration:
Subject 2 (TBSA 87.5%) received 2 sets of CSS and had 24 days of treatment. The AE occurred
9 J uly 1998, which the patient temperature spike suddenly to 42.9 degrees centigrade, had a
seizure, became tachycardic then bradycardic. ACLS protocol was implemented for an hour, but
patient was unresponsive to all cardiac medications. The episode occurred 2 months after the
burn. His wounds were covered and he was not under treatment for any infection or
complication. The coroner found no immediate explanation for death at this point postburn, on
gross exam. Exact cause of death has not been identified pending coroners final report. No final
coroners report was in the subjects file.
Subject 16 (TBSA 85 %) received 3 sets of CSS (days of treatment unknown). The AE occurred
19 August 1999, which the patient death was the result of multi-system organ failure and sepsis.
Subject 36 (TBSA 69%) received 2 sets of CSS (days of treatment unknown). The AE occurred
22 December 2000 despite efforts to achieve burn wound excision and coverage, this patient
became septic on two separate occasions, experienced hepatomegaly, compartment syndrome
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(abdominal), respiratory distress and renal failure. More than 2 months after the initial injury,
the patients status was critical/unstable, and the site was unable to oxygenate or ventilate the
patient. Despite maximal support, the patient was unable to survive his injury.
Subject 38 (TBSA 69.5 %) received 3 sets of CSS (days of treatment unknown). The subject
was in ICU on 8 April 2001 as a result of second bout of sepsis, started on triple antibiotics.
Condition worsened and on 11 April 2001 patient went into Septic Shock/ Renal & Pulmonary
failure. Despite aggressive treatment, patient experienced MSOF resulting in death on 18 April
2001.
Subject 42 (TBSA 93%) received 3 sets of CSS (days of treatment unknown). The subject
developed a fever of 42 degrees centigrade; her sputum revealed she was infected with
Pseudomonas Aeruginosa. The secretions increased and her ability to adequately ventilate
required for her to be placed on a ventilator. Despite multiple antibiotics the patient continued to
have high fevers. Patient expired on 14 August 2001 due to acute cardiac decompensation,
sepsis and complications from her initial burn injury.
Subject 64 (TBSA 95%) received 4 sets of CSS (days of treatment unknown). On 6 December
2002 the patient endured a septic event requiring ventilation, inotropic and CPR support. A blood
culture was positive for Klebsielia. Patient was treated for Klebsielia sepsis.
According to the Coroner Investigators worksheet from Sacramento County, the deceased was
an 8 year old male that was diagnosed with an intracranial bleed caused by a ruptured middle
cerebral artery aneurysm. A doctor at Shriners Hospital attributed the aneurysm to an infection
in the deceases blood that was caused by his extended hospitalizations after the patient suffered
90% TBSA burns during a Molotov cocktail explosion.
According to St. Josephs Medical records, the patient went into the Emergency Room on 8
February 2008 for an apparent fall, due to possible seizure, which caused an altered level of
consciousness. A CT scan showed a large left sided subdural hematoma. A craniotomy was
done to relieve pressure. There was a permanent tracheostomy in place, as well as PICC lines.
Arrangements for transfer to UC Davis Medical Center for continued care after the craniotomy
was made.
The patient arrived at Shriners Hospital via helicopter and was in ICU unit at the time of coding.
They noted slow systems failure, along with decreased brain activity. Apnea tests were
conducted and showed signs of brain death.
The death summary by the treating physician stated at that time, he was not expected to survive
those burn injuries. Over the course of approximately 4 years, the patient was in and out of
Shriners Hospital for medical care and was well known by them. The most significant
complicated hospitalization was for cardiomyopathy, which lasted for 2 years, multiple
infections, and sepsis episodes. He was able to recover sufficiently to be discharged home for
care provided by the mother. It was an opinion of the treating physician for Shriners Hospital,
that had not the burn injuries occurred, the patient would have never acquired the infections
associated and the Endocarditis would not have been there to contribute cause to the aneurysm.
Patient expired 9 February 2008.
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Subjects that died before CSS was applied:
Subject 1, Subject 8, Subject 18, Subject 21, Subject 26, Subject 32, Subject 37, Subject 43,
Subject 44, Subject 45, Subject 46, Subject 54, Subject 59, Subject 66, Subject 71 and Subject
81.
Six subjects were either discontinued/not treated with study device, received
reconstruction, or covered with AG before CSS grafts were ready.
Subject 23 (Living w/ problems)-discontinued from study without treatment. Subject 24 (Living
no problems)-was not treated but was a reconstructive case. Subject 30 (Living w/ problems)-
did not receive device but was a reconstructive case. Subject 49 (Living w/ problems)-was
covered with AG before CSS grafts were ready. Subject 52 (Living no problems)-was not
treated with study device. Subject 61 (Living w/ problems)-was not treated with study device.
Final Outcome:
6 Subjects received CSS before expiration.
16 Subjects died before CSS was applied.
6 Subjects are in other category.
45 Subjects are living with problems
8 Subjects are living no problems


Conclusion: There does not appear to be any deaths related directly to the study device. The
deaths appear to be related to the burn event. There are no subject survivors that are living with
problems that are related to the CSS device.








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9. Final Conclusion and Assessment

Study documentation data from the subject audit for numbers 1-81 of the CSS study show
similar flaws that the study audit of numbers 82-138 produced. The reasons have all been
previously documented in the prior audit report.
At this time, the auditors would like to note that treating physicians for the burn subjects all feel
very strongly that the Cultured Skin Substitute helped save many lives. The fact that the
majority of subjects that did receive the CSS device are still alive and functioning with minimal
releases and regrafting required is significant enough to note. An opinion of the Edmonton,
Canada primary burn physician is that the CSS is superior to all other alternative treatments for
burn patients. This opinion was given during an interview with the physician that was in charge
of the CSS study.
While the study information cannot stand up to the scientific rigor that is required by a clinical
trial, survival statistics show that the CSS has significant merit. A proper well controlled
redesigned study utilizing the CSS, with meticulous attention to details of the protocol, and
thorough training and documentation processes being provided to the physicians, nursing and
research staff would be beneficial to the scientific community. The audit shows that the benefit
of the CSS has a major importance to offer to burn victims.