Comprehensive CSS MOrley Audit Report - 25MAR2010

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Comprehensive Audit Report

Protocol: Burn Wound Repair with Cultured
Skin Substitute
IDE Number: G980023

Conducted by: The Walter B. Morley Research Foundation
January 2009- December 2009

Table of Contents: Page:

1. Demographics/ Subject Status Summary 3
2. Informed Consent 7
3. Compassionate Use 12
4. Case Report Form Summary 15
5. Subject Eligibility 19
6. Randomization/ Wound Site Selection 23
7. Pre Treatment of Study Sites 29
8. Burn Area Estimates 33
9. Summary-Pre-Study Visit 36
10. Pre-Study Medical History 37
11. Pre-Study Physical Exam 38
12. Pre-Study Serum Antibodies 39
13. Pre- Study Skin Biopsy for Tracing 40
14. CSS Tracings in Vitro 41
15. Post Operative Date Completion For All Sets 42
16. Biopsy of Recipient Sites 46
17. Photography of Wound Bed/ Pre-Surgery 47
18. Photography Post Graph 48
19. Study Site Tracings for POD 14/ POD 28 49
20. Microbial Cultures 51
21. Healed Wound Biopsy 52
22. Healed Area/ Donor Area Ratio 53
23. % Engraftment Completed for POD 14 55
24. % Engraftment Completed for POD 28 56
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25. Physical Exam Conducted at POD 0 57
26. Physical Exam Conducted at POD 28 58
27. Serum For Antibodies Completed for POD 28 59
28. Investigator Global Assessment 60
29. Qualitative Outcome 62
30. Adverse Event Summary for POD 14/28 68
31. Cultured Skin Substitute Wound Care 70
32. Unanticipated Adverse Devices Effects/Serious 76
Adverse Events/ Event Reporting

33. Concomitant Medications 96
34. Abnormal Laboratory Values 111
35. Primary Study Endpoints 112
36. Secondary Study Endpoints 116
37. Device Quality Assurance Testing/ Sterility Testing 120
38. Device Returned 122
39. Device Labeling/Device Storage 124
40. Device Disposal 126
41. Device Shipping Information Available 128
42. Protocol Deviation Summary 130
43. Protocol Deviation Reported to IRB 131
44. Protocol Deviations Reported To Sponsor 133
45. Sample Audit of the First 81 Subjects in the CSS Study 134
46. Annual Reports 135
47. Standard Operating Procedures (SOPs) Review 145
48. System Audit Conundrums 146

49. The Morley Research Foundation Interview Report 146
For Physicians and Nurses Involved in the CSS Clinical Trial
50. Data Safety Monitoring Board (DSMB) Report 150

Audit of Regulatory and Institutional Review Board 163

Appendix A: Various Versions of Qualitative Outcome 197
Case Report Forms
Appendix B: Listing of Adverse Events 200
Appendix C: Investigator Global Assessment Case Report Forms 201
Appendix D: Copy Device Label Provided to Auditors 202
Appendix E: Safety Monitoring Procedure 203
Appendix F: Conflict of Interest Statement 205
Appendix G: Article Medical Advances Incubate in Corryville 207

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1. Demographics/ Subject Status Summary
The demographics for 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. Figure 1.1 (below)
illustrates that the ages for the study participants ranged from a few months old up to 27 years old.
As shown in figure 1.2, the overall gender of the study audit population was male. Males were shown to
be five times more likely to be a burn patient with respect to the make-up of this study.
The breakdown for race, shown in Figure 1.4, indicates that the majority of subjects were Caucasian,
closely followed by Hispanic, then few numbers for African American and others.
Per figure 1.3, the majority of study subjects were enrolled by the Cincinnati Shriners site, followed by
Galveston Shriners, then the Sacramento Shriners, with one subject enrolled at the Boston Shriners 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 Age Summary
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Figure 1.2 Subject Gender Summary

Figure 1.3-Subject Location Summary
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Figure 1.4-Subject Race Summary

As noted in Figure 1.5 (below), there were fifty seven (57) subjects in the audit population. One subject
(Subject 86) was allotted two separate subject numbers (86 and 118) thus explaining the use of 58 subject
numbers, yet only having 57 subjects in the audit population. This subject was originally randomized as
number 86 and then randomized a second time as 118. Of the fifty-seven (57) subjects, forty-four (44)
subjects were enrolled and treated with Cultured Skin Substitute. Thirteen (13) subjects were consented
for the study, but did not receive treatment (see below). Seventeen (17) subjects were enrolled and treated
under compassionate use. Four (4) subjects were enrolled and treated on study, but did not meet all
inclusion/exclusion criteria. Eligibility was unable to be verified on six (6) subjects.

Figure 1.5-Treated Subjects Summary
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The following subjects were consented, but not treated with device:
Subject Number Location Reason for Non-Treatment
83 Cincinnati unknown
85 Sacramento Subject had infection at biopsy
site
89 Cincinnati unknown
90 Galveston unknown
101 Sacramento unknown
125 Cincinnati Subject expired prior to receiving
device
135 Cincinnati Subjects parent withdrew
consent (did not want any further
heroic measures) and subject
expired soon after

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2. Informed Consent Form
All subjects had an informed consent signed by a parent or guardian. Per the Code of Federal Regulation
Part 50.25 (1); Part 50.25 (2) and Part 50.25 (b) (5), the informed consent process should have been
consistent throughout the study and at all sites. While there were some irregularities regarding the
Informed Consent Form (ICF) issues (as noted on the individual subject forms), the most serious issues
identified, are listed below:

Subject #90: The ICF (Spanish version) signed by the person obtaining consent and the parent of
the subject on 8/10/04. This was 3 days after consent signature of PI and interpreter. The ICF
copy in the CRF does not show an IRB approval date. The IRB approved the emergency use of
the CSS on 8/10/04. There is no documentation that shows approval of this emergency use by
UC (sponsor)
Subject #93: My child is listed on first page of ICF instead of actual childs name. Childs
name should have been entered instead of my child.
Subject #95: Signatures are not noted as to the relationship to the subject.
Subject #100: IRB review date of April 2005 on ICF. Only month and year are noted; no ICF
approval date or expiration date on ICF.
Subject #104: No HIPAA form was located. Since subject and family was from Mexico and
signed an English ICF, there should have been a note to file stating that the person signing the
consent was bilingual and could understand the English ICF.
Subject #105: The ICF received approval from University of Texas IRB, but a HIPAA form was
not present. Auditors were able to identify a request to FDA for the compassionate use of CSS.
However, no FDA approval or UC approval for compassionate use could be located.
Subject #107: A request (dated September 8, 2005) to FDA requesting enrollment this patient
into the study under compassionate use was present, however auditors were unable to locate FDA
approval.
Subject #109: Spanish version of ICF signed was received from Cincinnati May 2004 and was
revised in Galveston 12/14/2004 and again on 8/12/05. The revisions are unknown as the ICF is
in Spanish and no documentation is available to identify the changes. There is a second copy,
same version signed on 10/31/05. The reason is unknown why two copies of the ICF were signed
one day apart.
Subject #114: The version date of ICF is unknown. A sticker, with hospital information, was
placed over the top of the version date on each page of the consent form.
Subject # 119: The subjects name is not written, and only the phrase my child appears in the
space provided for the subjects name. The subjects mother provided only initials instead of
completing her signature on both the ICF and HIPAA. There was no documentation available to
support why this occurred as part of the ICF process.
Subject #123: ICF IRB approval date was 6/7/06 with an expiration of 7/20/06 which is more
than one year. There are two consents of the same version signed on two different days with no
explanation of why this occurred.
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Subject #124: ICF (version dated 9/1/ 2005) was only approved for 10 days by the UC IRB. The
IRB approval date was 7/10/2006 and the date of IRB expiration was 7/20/2006.
Subject #127: ICF (version dated 9/1/2005) states my child instead of childs name. This
subject appears to have been a compassionate use subject however documentation not found to
substantiate these findings.
Subject #129: ICF (version dated 9/1/2005) is on plain paper, no heading for Shriners Hospital or
University of Cincinnati.
Subject: #138: Parents signed ICF (version dated 6/1/2008) on 11/11/2008, and FDA did not
approve compassionate use until 11/12/2008.

Figure 2.1- Informed Consent Summary
Per Figure 2.1 above:
The second bar on the graft shows that 40 patients signed the HIPAA form and this was verified by a
copy in the medical charts, 17 subjects did not have a signed HIPAA form in their medical records.
The third bar on the grafts indicates that most ICFs had an IRB approval date on the consent form. Three
subjects did not have the stamped approval. One subjects ICF approval stamp was covered by the
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hospital record stamp, another subjects approval stamp was too faint to read, and the third subjects ICF
had no stamp of IRB approval on it.
The fourth bar on the graft shows that only 5 subjects were ever re-consented out of the 57 study subjects.
Twenty four subjects should have been re-consented. The consent forms that had procedure changes for
the subject or changes in the risk section should have been presented to the subject and/or their family for
re-consent. Subjects who are presently enrolled and actively participating in a study should be informed
of a change if it might relate to the subjects willingness to continue participation in the study as per
CFR50.25 (b) (5) - A statement that significant new findings developed during the course of the
research which may relate to the subject's willingness to continue participation will be provided
to the subject.
These are as follows:
Subject #86: Should have been re-consented 4 times.
Subject # 87: Should have been re-consented 4 times.
Subject #97: Should have been re-consented 1 time.
The 2006 Standard Operating Procedures copies from the University of Cincinnati IRB, which were
provided to the Morley Research Foundation, were missing several pages. Of those missing pages was
the informed consent information; therefore, it is not known what the policy on re-consenting was at that
time. There was no SOP regarding re-consent process made available to the auditors.
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Below is a table of the ICF changes that required ICF amendments and thus should have necessitated
re-consenting of subjects:

Date of ICF Changes Made IRB Approval Date
August 2002 Original ICF for audit purposes 07/23/2003
April 2003 First bullet point in Risk section: Added in Each preparation of
cultured skin substitutes is tested before clinical use, and must be
negative for infection. Second bullet point adds in Also, similar
kinds of materials used for similar kinds of tissue repair have been
associated with the development of auto-immune disease at a later
time in life, but this has not been seen with cultured skin substitutes
in more than 15 years experience. Added in as the third bullet point:
the polymer fabric, and other materials used in preparation of the
cultured skin substitute are from bovine sources (cows or beef).
Also, several drugs are used for preparation and application of
cultured skin. These drugs include penicillin, streptomycin,
neomycin, polymyxin B, mupirocin, ciprofloxacin, amphotericin B,
hydrocortisone and insulin, If the patient is known to be allergic to
these materials or drugs; she/he should not be treated with cultured
skin substitutes. Added a fourth bullet point: It is also possible that
an allergic reaction and loss of cultured skin grafts could occur
from the treatment of burn scars, if the original burns were treated
with cultured skin. Specific tests will be performed to determine
whether a risk of allergic reaction may occur for treatment of burn
scars. Deleted bullet point #6 referring to mouse cell preparation of
CSS.
06/22/2003

October
2003
Change in Risk Bullet point #2 was changed back to match the
August 2002 ICF version. Bullet point #3 regarding the polymer
fabric from bovine sources was deleted. Bullet point #4: allergic
reaction of loss of CSS was deleted.
01/27/2004
May 2004 Procedures section: added in and/or clinical examination that
follow the course of the healing process. And Joint range of
motion will be recorded when applicable. Risks section: added the
allergic reaction by CSS made from the bovine cells paragraph that
was removed in the October 2003 version.
06/23/2004
September
2005
Risk section: Number of patients changed from 75 to 125 of
experience with CSS and no incidence of autoimmune disease.
Section 16: Changed number of participants from 30 at 3 sites to
180 at 5 sites.
09/28/2005
January
2006
Procedures section: changed the term debridement to removal;
added on a reason of traced and photographed treated areas to
evaluate whether the cultured skin is growing normally with the
rest of your body. Changed the range of motion recording to
Passive range of motion. Change in Experimental Procedures:
Added in a bullet point that states: Skin test for allergic reaction if
burn scars were previously treated with cultured skin. Change in
03/08/2006
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Risk section: added in first bullet point Also, antibiotics are
applied to the cultured skin for several days to reduce chances of
infection. Deleted CSS from cadaver skin will only be used if it
has tested negative for HIV (AIDS) and hepatitis, and also has
satisfied all other safety standards that are required for tissue
banking. General Information: changed from 5 participating
institutions, back to 3 institutions.
July 2006 Procedures section: surgical removal is now back to debridement;
Added in for the treated areas traced and photographed at one year
changed to add and periodically between three and five years post-
grafting. Added in the wound biopsy section of procedures
routine clinic visits after your discharge. Deleted the passive in
the range of motion recorded section. Added in skin test performed
to evaluate whether CSS skin may be used for treatment of burn
scars after treatment of original burns with CSS. In the
Experimental Procedures section: Deleted the skin test for
allergic reaction if previously treated with CSS. In Risks section:
first bullet point: deleted the sentence regarding antibodies are
applied to the CSS for several days to reduce chances of infection.
Added in a bullet point: a chance of rejection of the skin
substitute, if allogeneic cells from cadaver skin are used. The
chance of rejection of cultured allografts (cadaver skin cells) is no
greater than the chance of rejection of cadaver skin that is routinely
used as a temporary wound cover. Next bullet point added in
cultured skin made from cadaver skin will only be used if it has
tested negative for HIV (AIDS) and hepatitis, and also has satisfied
all other safety standards that are required for tissue banking.
General Information: Changed back to 5 institutions participating.
07/10/2006
June 2008 In the Commercial Products section there is a section added in per
IRB instructions regarding Conflict of Interest: adds in Dr. Steve
Boyce, a sub-investigator on this study, has received payments
from the company that owns the rights to the process used in this
study. This disclosure is made so that you can decide if this
relationship will affect your willingness to participate in this study.
06/18/2008

No documentation is identified explaining why sentences were added in, then taken out, then added back
in again.

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3. Compassionate Use

The total number of compassionate use subjects was seventeen (17) for the CSS study. Figure 3.1, below,
demonstrates the compliance of the compassionate use information gathered during the audit.

Figure 3.1-Compassionate Use Summary

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The regulation below states the proper conditions in which compassionate use informed consent should be
utilized:
Compassionate Use (or Single Patient/Small Group Access) as per Medical Devices FDA Guidance
IDE Early/ Expanded Access
The compassionate use provision allows access for patients who do not meet the requirements for
inclusion in the clinical investigation but for whom the treating physician believes the device may provide
a benefit in treating and/or diagnosing their disease or condition. This provision is typically approved for
individual patients but may be approved to treat a small group.
Criteria: Serious disease or condition or no alternative
Time-frame: During clinical trial
FDA recognizes that there are circumstances in which an investigational device is the only option
available for a patient faced with a serious, albeit not life-threatening, disease or condition. In these
circumstances, FDA uses its regulatory discretion in determining whether such use of an investigational
device should occur.
Prior FDA approval is needed before compassionate use occurs. In order to obtain Agency approval, the
sponsor should submit an IDE supplement requesting approval for a protocol deviation under section
812.35(a) in order to treat the patient. The IDE supplement should include:
A description of the patient's condition and the circumstances necessitating treatment
A discussion of why alternatives therapies are unsatisfactory and why the probable risk
of using the investigational device is no greater than the probable risk from the disease
or condition
An identification of any deviations in the approved clinical protocol that may be needed
in order to treat the patient
The patient protection measures that will be followed. (Informed consent, concurrence of
IRB chairperson, clearance from the institution, independent assessment from uninvolved
physician, authorization from IDE sponsor)

As figure 3.1 demonstrates, the compassionate use regulations were not always followed by the
Sponsor/investigator. The source documentation needed to substantiate that all the above reference points
were completed. Auditors could not locate all authorizations required by the regulations to enroll a
subject as a compassionate use subject. The graph indicates what items could not be identified. There are
references to emails for approval however it does not appear that all emails were printed out. There is
certainly not a clear documented progression showing when the request came in from the site,
documentation of all approvals needed, then documentation back to the site stating that documents were
approved. All signed ICFs were able to be located.

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Figure 3.2 identifies the location breakdown for all compassionate use subjects in the treated population:

Figure 3.2 Compassionate Use Patients By Location

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4. Case Report Form Summary
As figure 4.1(below) indicates, the case report forms were not completed in a consistent manner
throughout the study. The Boston Shriners site was the only outlying site that had a record of who
attended the training session regarding the cultured skin substitute. There was no documentation on what
was included in the training session, just that a training session took place. Therefore, there was no
documentation that any of the sites received proper training on CRF completion.

Figure 4.1-Case Report Form Summary
The Code of Federal Regulations 312.62 Investigator recordkeeping and record retention (section b):
Case histories. An investigator is required to prepare and maintain adequate and accurate case histories
that record all observations and other data pertinent to the investigation on each individual administered
the investigational drug or employed as a control in the investigation. Case histories include the case
report forms and supporting data including, for example, signed and dated consent forms, any medical
records
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The Code of Federal Regulations 812.140(a)(3)(i) A participating investigator shall maintain the following
accurate, complete, and current records relating to the investigator's participation in an investigation:(3) Records
of each subject's case history and exposure to the device. Case histories include the case report forms and
supporting data including, for example, signed and dated consent forms and medical records including, for example,
progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. Such records shall include:
(i) Documents evidencing informed consent and, for any use of a device by the investigator without informed
consent, any written concurrence of a licensed physician and a brief description of the circumstances justifying the
failure to obtain informed consent. The case history for each individual shall document that informed consent was
obtained prior to participation in the study.;812.140(a)(3)(ii) A participating investigator shall maintain the
following accurate, complete, and current records relating to the investigator's participation in an investigation:(3)
Records of each subject's case history and exposure to the device. Case histories include the case report forms and
supporting data including, for example, signed and dated consent forms and medical records including, for example,
progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. Such records shall include
:ii) All relevant observations, including records concerning adverse device effects (whether anticipated or
unanticipated), information and data on the condition of each subject upon entering, and during the course of, the
investigation, including information about relevant previous medical history and the results of all diagnostic tests.
812.140(a)(3)(iii) A participating investigator shall maintain the following accurate, complete, and current
records relating to the investigator's participation in an investigation:(3) Records of each subject's case history and
exposure to the device. Case histories include the case report forms and supporting data including, for example,
signed and dated consent forms and medical records including, for example, progress notes of the physician, the
individual's hospital chart(s), and the nurses' notes. Such records shall include: (iii) A record of the exposure of
each subject to the investigational device, including the date and time of each use, and any other therapy.
812.140(a)(4); A participating investigator shall maintain the following accurate, complete, and current records
relating to the investigator's participation in an investigation:(4) The protocol, with documents showing the dates of
and reasons for each deviation from the protocol.
812.140(a)(5) Any other records that FDA requires to be maintained by regulation or by specific requirement for
a category of investigations or a particular investigation.
The case report forms were not consistent for all sites of the study. Major variations are listed below:
Qualitative Outcome Form: Different forms used throughout the study; two different forms
were used within the same subject. The forms do not reflect a revision date: one form has no
date on it and one form has a revision date of October 2003. One form has a label (e.g. none = 1,
hypo = 2, normal = 3, hyper =4 for pigmentation) under each number specified. The other form
shows the numbers as 1 through 4, however the label is none under 0; the label normal is between
the numbers 1 and 2 and hyper is the label under number 3. The same type of variance occurred
on the skin pliability. One on form 0 = normal; 1 = supple; 2 = yielding, 3 = firm; 4 = rope; 5 =
contracture. The other form has normal under 0; 1 by itself, 2 has the label firm 3 is by itself and
the label contracture goes across the number 4 and 5. By not using a consistent format for the
collection of the Qualitative Outcome data the results do not accurate reflect these outcomes.
Subject #82: The CRFs were not completed. Consistency in CRF collection is not the same
between the sponsor and the sites. Sacramento Shriners made their own forms for data collection
and only used a few of the CRFs from the sponsor. The data was combined for Post Operative
Date (POD) 91,182 and 365. Sets 3 and 4 were combined.
Subject #84: Information written in on CRFs at different times in different handwriting, with no
initials/signatures or date given. Follow up was not done per protocol, even though the subject
did return to clinic for follow up visits per the medical records.
Subject # 86: The CRF/Source was copied and sent to UC Shriners. The CRFs were typed and
there is no signature or date identifying when these were completed or who completed them.
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Subject #87: CRF pages were not completed. The Boston site stated that they would only record
information regarding safety and efficacy as subject is emergency use and not an actual research
subject. On 8/12/04 M. Reed from UC Shriners requested forms from Boston site.
Subject #91: CRFs not complete, including physical exam form and Qualitative Outcome form
for set one.
Subject #92: POD 81, 182, and 365 data collection was not done. Other CRFs were done a week
or more out of window with no reason why it wasnt completed on time as subject was in the
hospital and there was access to the subject. Logs were not completed.
Subject #93: CRFs not signed some not dated and incomplete forms. Incomplete forms include:
physical exam form for set one, Qualitative Outcome for set one /POD14, IGA for set one/ POD
14, and Qualitative Outcome for set one/POD 28
Subject #95: CRFs not signed, incomplete, many CRF pages are marked thru with a line and the
note says to see the treatment summary in medical chart; however medical treatment summary
was not present.
Subject #96: CRFs are incomplete to include: Microbiology for set one, Qualitative Outcome for
sets one, two and three.
Subject #97: CRF pages appear to be written by two different people (handwriting different and
different pens used). No dates or initials to indicate when additional information was written in.
Other than set 2, no set was completed past POD 28, no Physical Exams (PE) were done.
Subject #99: CRF corrections were made during the audit. Blanks in CRF were left blank for
several years then completed in 2009. Errors marked thru with no initials, date, or reason why
change was made.
Subject #100: CRFs not completed, notes state to see patient treatment summary. Subject died
three days after receiving CSS. No initials, signatures, dates on CRFs. Forms were filled out with
header information from POD 0 thru POD 365, forms were then marked through with a line
across the page, after the subject died.
Subject #102: Corrections made after annual reports to FDA, major burn magazine publications,
and national talks given. Most CRF pages have edits made on them with the accompanying date
of correction noted as August 26, 2009.

Subject #104: CRFs are incomplete-Specifically: physical exam form for Set 1/ POD 0 and
several Qualitative Outcome and Investigator Global Assessment Forms. There are changes made
by Peggy Simpson, RN at UC Shriners on the Galveston Shriners forms. Peggy initialed but did
not date the changes. Other changes are scratched thru (e.g. PE pre study) with no initial or date
as to who or when they were done. Set 1 Qualitative Outcome form is signed and dated (by M.
Reed RN, who was a research nurse at UC Shriners) on a Galveston subject.
Subject #106: Forms not completed until two years after the subject was treated. Many CRFs
not signed or dated. No PI review of CRF. Changes made to CRF forms several years later than
original entry made. On 11/10/2005 a protocol deviation was generated for a Set 2 physical exam
not being completed. However, Peggy Simpson completed a physical exam page for Set 2, four
years later. The IGA for Set 1, POD 14 and 28 were edited by Peggy Simpson on 8/19/2009. Not
all changes are signed and dated.
Subject #107: CRFs not completed until Peggy Simpson RN at UC Shriners completed forms in
July 2009.
Subject #108: CRFs were not completed for set 1 from POD 14 to POD 365. Set 2 and 3 had no
collection performed.
Subject #109: CRFs are typed, no signature. PE for pre study visit has a date of 10/29/2 005
which is prior to ICF consent.
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Subject #112: This is a hairy cell nevus, not a burn subject. All CRF forms were for burn study
subjects, no CRFs exists for data collection for a hairy cell nevus subject.
Subject #114: A few CRFs were completed approximately 3 years after the initial CRF
documentation was performed.
Subject #115: This was a scar contracture release and re-grafting. The CRFs were designed to
collect data for burn subjects, not a later contracture release and re-grafting.
Subject #120: CRF has changes that were performed by Peggy Simpson, RN at UC Shriners.
These changes were made on August 2009, which is three years after the initial information was
reported. OR report dated 4/21/2006 contradicts what is reported in the CRF with regards to no
comparative site available.
Subject #121: The CRFs appear to have been typed up after the initial information was
gathered. The site was handwriting the information on CRFs, and the medical records were
mostly hand written. It is unknown how these typed forms appeared in the CRFs.
Subject #123: Corrections to CRFs were made by Peggy Simpson, research nurse at UC Shriners
in July 2009; 3 years after the initial CRFs were completed.
Subject #124: PI review was signed off by Dr. Kagan and Dr. Boyce in July 2009. Subject
records were completed in 2006.
Subject #130: PI review and sign off by Dr. Kagan was done on 01/29/2009 when subject was
completed in September 2007.
Subject #131: PI reviewed and signed off on 01/29/2009 when subject was completed in August
of 2007.
Subject #133: CRFs incomplete. This subject received CSS for scar contracture due to previous
burn. The CRF was not designed to capture information for scar contracture subjects. Therefore, a
majority of this information was left blank.

The case report forms were overall, very poorly designed. There were areas of data capturing that did not
sync with the protocol. Additionally, there was no documentation for site personnel training, with respect
to CRF completion. There is question about who was responsible for CRF completion, why some of the
CRFs were completed in a typed format (specifically from the Galveston site), and in what timeframe the
CRFs were completed.
The majority of the CRFs were completed with ink in standard pen/paper format. However, there were
several CRFs that were typed, and multiple cases where typed CRFs appeared even after deviations were
noted by Dr. Steve Boyce that the information had not been collected. The auditors identified Peggy
Simpson, RN, research nurse at the UC Shriners site as making corrections/changes to CRF documents
during the course of the audit. This information was provided, via email, to the FDA representative Ms.
Sonali Gunawardhana, and Mrs. Simpson was directed to immediately stop making corrections or
changes to the CRF pages. The compliance office at UC was also notified.
As figure 4.1 clearly outlines, the majority of the subject population (33 subjects) did not have proper
CRF completion. Individual pages were incomplete, and follow- up visits were not being documented,
even as subjects were being seen in the outpatient clinic.
CFR 812.140(a) (4) Investigator records: A participating investigator shall maintain the following
accurate, complete, and current records relating to the investigators participation in an investigation:
The protocol, with documents showing the dates of and the reasons for each deviation from the protocol.
This regulation was violated in approximately half of the subjects enrolled. The investigators at the sites
did not oversee the research protocol as follows:
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1. CRFs were not completed properly
2. CRFs were improperly corrected
3. CRFs were not signed off by the PI and/or sponsor
4. Diagnostic Test were not signed off by the PI
5. Source Documentation was not maintained. CRFs were used as source documentation.
6. CRF completion could not be verified, as some CRFs were not signed by the person completing
the document; however the original CRFs did not have a place designated for a signature and date
on many of the pages.
7. CRFs that were typed in, appear to have been done at a later date, however they were signed off
by someone (name not legible) and dated back at the date the form should have been done.
Without running a full investigation into this matter, there is no way to tell if this was actual study
misconduct with back dating. It does appear suspicious as several subjects had deviations written
by Dr. Boyce regarding the fact that no data was collected, and yet there was typed data, with a
signature and date from years ago on the form.

5. Subject Eligibility
Per CFR 812.40 the Sponsor did not provide the study sites with the information they need to conduct the
investigation properly:
Per CFR 812.25 (c) The investigational plan shall include : Risk analysis: A description and analysis of
all increased risks to which subjects will be exposed by the investigation; the manner in which these risks
will be minimized; a justification for the investigation; and a description of the patient population,
including the number, age, sex, and condition.

The November 2003 protocol does not identify a description of the patient population. Per Case Report
Form Page (Form CSS 7.2, revised October 2003) the following inclusion/exclusion criterion is noted:
Inclusion:
Age is birth -75 years, TBSA > 50% (or 10% full thickness)
Burn includes full thickness
Patient is not showing signs of sepsis
Expected to need grafting after 3 weeks post primary biopsy
Informed Consent signed
Exclusion:
Patient is pregnant or lactating
Patient is prisoner
Patient is mentally incompetent.

21

The following subjects were enrolled on study, and did not meet all inclusion/exclusion criteria, specified
per Case Report Form CSS 7.2:

Subject 120: did not have 50% TBSA or 10% full thickness burns
Subject 107: did not have 50% TBSA or 10% full thickness burns

Per the Sponsor provided Informed Consents dated April 2003, May 2004, Sept 2005, Jan 2006, and July
2006, the following allergies were noted as study risks:

If a patient is known to be allergic to beef, s/he should not be treated with cultured skin substitutes.

allergic reactions to several drugs used for preparation and application of the cultured skin could
occur. These drugs include penicillin, streptomycin, neomycin, polymixin B, mupirocin,
ciprofloxacin, amphotericin B, hydrocortisone and insulin. If a patient is known to be allergic to
these drugs, s/he should not be treated with cultured skin substitutes.

These risks should have been included in study inclusion/exclusion criteria, as it clearly states that
subjects with these known allergies should not be treated with cultured skin substitute. Study data does
not indicate that subjects were specifically being evaluated for these specific allergies at the time of study
entry.

The following subjects should not have been enrolled and treated with CSS, per the risk
assessment information presented in the Informed Consent:

Subject 82: Subject had history of allergy to Penicillin
Subject 121: Subject had history of allergy to Penicillin

22

Per 45 CFR 46.111 (a) (6) When appropriate, the research plan makes adequate provision for monitoring
the data collected to ensure the safety of subjects.

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.

Figure 5.1-Subject Status Summary

23

Per Figure 5.1: Of the forty-four (44) treated patients, eligibility was unable to be verified on six subjects:
and the reasons noted are as follows:

Subject 87: Unable to verify that subject was
not showing signs of sepsis

Subject 96 Unable to verify that subject was
not showing signs of sepsis

Subject 106 Unable to verify if patient was
mentally competent

Subject 107 Unable to verify if subject had
sensitivity of CSS of any of its
components

Subject 114 Unable to verify if subject was not
showing signs of sepsis

Subject 130 Unable to verify if subject was not
showing signs of sepsis

24

6. Randomization/ Wound Site Selection

Protocol d.2.1 Wound Site Selection:
Two comparative sites of similar area and depth will be selected for each test. After selection, Site A
will be defined as the right most location, the upper most location, or the front most location. Site B
will be defined as the left most, the lower most or the rear most location. After the selection and
definition, cultured skin or split-thickness skin will be applied according to the computer-generated
randomized schedule. Wherever possible, contra-lateral sites will be used. Comparative sites will
not include joints hands or face. Sites will be randomized according to the schedule (provided in
protocol). If enrollment exceeds 36, an additional randomized schedule will be generated.
Protocol d.2 Study Format:
The paired-site comparison format will be used to evaluate cultured cell-collagen- GAG skin and
conventional split-thickness skin graft for closure of full-thickness, excised burns. This study will be
performed in a prospective, randomized design with each pair in the same patient on wounds of
similar area and depth. For each administration of cultured cell-biopolymer skin substitute to a
wound site, a comparative site will be treated with meshed or unmeshed split-thickness skin.
Whether site A or B is treated with the experimental skin substitute will be randomized by
computer generation prior to initiation of the study. The other site of the pair will be treated with
split-thickness skin. Each application of cultured skin or split-thickness skin to sites A or B will
follow the randomization schedule. Up to 20 randomized pairs will be generated for each year of
the study.

The following subjects were randomized correctly, and protocol adherence was maintained for the wound
site selection:
Subject 92
Subject 124
Subject 132

Per CFR 812.110, investigators did not follow the investigational plan (protocol) dated November2003,
with respect to wound site selection of study sites and randomization:
Per d.2.1: Two comparative sites of similar area and depth will be selected for each test:

Per review of all study subjects, there was no documentation to support that the comparative
study sites were measured for similar areas or depths.

25

A comparative site (split thickness autograft ) was not grafted on the following study subjects:
Subject 84 Subject 114

For each administration of cultured cell-biopolymer skin substitute to a wound site, a comparative
site will be treated with meshed or unmeshed split-thickness skin.

The following subjects had multiple applications of CSS whereby a comparative sites of split-
thickness skin was not grafted with each CSS administration:

Subject 82 Subject 86/118 Subject 88 Subject 93
Subject 97 Subject 98 Subject 99 Subject 103
Subject 139

Per Figure 6.1: It is noted that the majority of the comparative sites were placed with the first application
of CSS. However, the protocol does not specify that the first application is to be used as the comparative
set; rather it states that for each administration of CSS, a comparative site will be treated with split-
thickness skin.
26

Figure 6.1- Comparative Site Summary

After selection, Site A will be defined as the right most location, the upper most location, or the
front most location. Site B will be defined as the left most, the lower most or the rear most location:

The following subjects were not grafted in accordance with protocol section d.2.1, as noted
above:

Subject 95: Autograft (Site B) was placed in a strip across lower abdomen. CSS (Site A) was
placed on abdomen, face and neck

Subject 96: CSS (Site A) face, neck bilateral shoulders and (Site B) Autograft was applied to the
chest

Subject 102: CSS (Site A) was placed on the back. Autograft (Site B) was placed on left
shoulder and left/right buttocks.

Subject 104: CSS (Site B) was placed on the face. Autograft (Site A) was placed on right leg,
just below the knee (joint).

27

Subject 106: CSS (Site A) was placed on anterior chest. Autograft (Site B) was placed on right
anterior chest.

Subject 107: Autograft (Site A) was placed on the left thigh. CSS (Site B) was placed on the
right foot.

Subject 109: Per the graft location diagram in CRF, Autograft (Site A) was placed in pieces on
the head, right shoulder, left hand, top of the left foot, buttocks, posterior head, lower back,
posterior left arm, and the left calf. This graft placement does not follow what is specified per
protocol

Subject 112: CSS (Site A) was placed on the buttocks and back. Autograft (Site B) was placed
on left posterior thigh and buttocks

Subject 133: CSS (Site A) was placed on front and back of right leg. Autograft (Site B) was
placed on front of right foot.

Comparative sites will not include joints, hands or face:

For the following subjects, comparative sites were not placed in accordance with protocol section
d.2.1:

Subject 104: Set 1: CSS (Site B) was placed on the face and the Autograft (Site A) was placed
on right leg, just below the knee (joint).

Subject 96: Set 1: CSS (Site A) face, neck bilateral shoulders and (Site B) Autograft was applied
to the chest

Subject 92: In Set 1, CSS (Site A) was placed on the right knee (anterior/posterior)

Whether site A or B is treated with the experimental skin substitute will be randomized by
computer generation prior to initiation of the study. The other site of the pair will be treated with
split-thickness skin. Each application of cultured skin or split-thickness skin to sites A or B will
follow the randomization schedule.

Figure 6.2 (below), illustrates the overall number of subjects with respect to
randomization. The following subjects were not randomized, or randomized incorrectly:

Subject 84: Not randomized no comparative site administered
Subject 87: Not randomizedno comparative site administered
28


Subject 95: Per the protocol randomization schedule, the subject was randomized correctly, however there
was no source documentation available in this subjects study file in order to verify how the site
determined or completed the randomization.

Subject 82: Per the protocol randomization schedule, the subject was randomized correctly, however there
was no source documentation available in this subjects study file in order to verify how the site
determined or completed the randomization.
29

Figure 6.2-Correctly Randomized Subjects

30

7. Pre Treatment of Study Sites
Protocol d.2.2 Wound treatment:

Before excision, wounds will be treated identically according to prevailing standards of burn care.
In cases of burns involving very large area of body surface, eschar may be excised and wounds
covered temporarily with human cadaver allograft, or the dermal replacement, Integra Artificial
Skin (Integra). One day prior to skin auto grafting, patients treated with allograft will have it
excised to viable tissue which most frequently is subcutaneous fat. Excised wounds are soaked
overnight in 2.5% (wt/vol) solution of sulfamylon (mafenide acetate), and grafted the following day.
In the operating room, wounds will be irrigated thoroughly with saline to reduce the residual
concentration of sulfamylon which is known to be highly toxic to cultured keratinocytes.
Alternatively, if Integra was used as a temporary cover, the outer silicone layer will be removed to
expose the vascularized wound bed. After preparation of the wound bed, meshed or unmeshed AG
will be applied to one site and CSS with backing of N-Terface (a non-adherent dressing) to the
other site, and secured to wounds with surgical staples.

with respect to pretreatment of study sites:

Before excision, wounds will be treated identically according to prevailing standards of
burn care: Prevailing standards of burn care were noted as varied, amongst the institutions.

Per Figure 7.1: It was identified that burn wounds were typically being treated according to
appropriate standards of burn care:

31

Figure 7.1-Wounds Treated According to Prevailing Standards of Burn Care

The protocol specifies that the burn wound sites will be treated identically. The following
subjects were noted as having different types of temporary wound coverage for Site A and Site B
(prior to the first application of CSS) for which a comparative site was used:
Subject 93: Site A: Integra Site B: Allograft
Subject 102: Site A: Integra Site B: Autograft

In cases of burns involving very large area of body surface, eschar may be excised and
wounds covered temporarily with human cadaver allograft, or the dermal replacement,
Integra Artificial Skin (Integra):

The following subjects were noted as having temporary wound coverage obtained with Autograft,
which is not specified as a temporary wound cover per protocol:
Subject 92: Site A: Autograft Site B: Autograft
Subject 102: Site A: Integra Site B: Autograft
Subject 109: Site A: Autograph w/homograft overlay
Site B: Autograph w/ homograft overlay
32

Figures 7.2 and 7.3, illustrate the overall temporary wound coverage for Sites A and B prior to the first
CSS application.

Figure 7.2-Temporary Wound Coverage for Site A Prior to CSS Application
33

Figure 7.3-Temporary Wound Coverage for Site B Prior to Application

Excised wounds are soaked overnight in 2.5% (wt/vol) solution of sulfamylon (mafenide
acetate), and grafted the following day. In the operating room, wounds will be irrigated
thoroughly with saline to reduce the residual concentration of sulfamylon which is known to
be highly toxic to cultured keratinocytes:

Per overall review of subject data, these specific procedures were not noted as being consistently
followed as the protocol standard with respect to the pretreatment of burns. Specifically, there
was no documentation of the process of wound irrigation to eliminate sulfamylon concentration
as specified in protocol section d.2.2

34

One day prior to skin auto grafting, patients treated with allograft will have it excised to
viable tissue which most frequently is subcutaneous fat.--- Alternatively, if Integra was
used as a temporary cover, the outer silicone layer will be removed to expose the
vascularized wound bed.

The sites were consistently reporting, on study source documents, the Pre-Study date of Eschar
Excision as the date that temporary wound cover was excised prior to the first application of CSS.
There was no consistent documentation regarding the removal of the silicone layer from Integra
prior to CSS or Autograft placement.

There were no protocol specifications provided for pretreatment of non- burn wounds, being
treated with CSS. The following subjects were treated for indications other than burns:

8. Burn Area Estimate
The Burn Area Estimates are relevant in that the initial burn estimate reported on the registration page of
the CRF sometimes differed from the actual anatomical burn estimate page. The chart listing below
indicates 11 of the 43 2
nd
degree burn estimates did not match. Of the 43 subjects that had 3
rd
degree
burns 18 of the subjects had a variance and of the total burn estimate 21 of the 43 subjects had
inconsistencies. Some of the subjects had variations in both 2
nd
and 3
rd
degree burn areas.
Several of the inconsistencies can be attributed to the fact that the area on in the CRF was left blank thus
created a 0 in the database. There was only one or two people recording information for the CSS study
subjects. It seems intuitively obvious that someone (PI) should have been looking at these inconsistencies
and requesting a clarification for the data records. These discrepancies show a consistent lack of attention
to the details of the study which demonstrates a lack of commitment to follow the CFR section 812.40
regarding Record
Keeping.
Subject 85: Treatment Indication: Giant Hairy Nevus
Subject 112: Treatment Indication: Giant Hairy Nevus
35

Burn Area Estimates
Highlights difference in burn estimate data recorded in initial overall estimate and summed estimates by body
Includes treated patients only
2nd Degree Burns 3rd Degree Burns Total Burn Area
Anatomical Anatomical Anatomical
Enroll #: Initial Est. Burn Est Difference Initial Est. Burn Est Difference Initial Est. Burn Est Difference
82 0 0 0.00 85.5 86.5 1.00 85.5 86.5 1.00
84 8 8 0.00 48.5 45.5 -3.00 59.5 53.5 -6.00
86 0 95 95 0.00 95 95 0.00
87 16 11 -5.00 68 79 11.00 84 90 6.00
88 1 60.5 62 61.5 -0.50
91 3 3 0.00 61 51.5 -9.50 64 54.5 -9.50
92 30.5 27.5 -3.00 31.75 34.75 3.00 62.25 62.25 0.00
93 6.5 6.5 0.00 52.5 52.5 0.00 59 59 0.00
95 3 3 0.00 67 67 0.00 70 70 0.00
96 1 1 0.00 95 95 0.00 96 96 0.00
97 0 0 0.00 88 88 0.00 88 88 0.00
98 4.5 4.5 0.00 54 54 0.00 58.5 58.5 0.00
99 0 0 0.00 88.5 88.5 0.00 88.5 88.5 0.00
100 0 0 0.00 67.5 67.5 0.00 67.5 67.5 0.00
102 0 0 0.00 65.5 65.5 0.00 65.5 65.5 0.00
103 0 88.5 88.5 0.00 88.5 88.5 0.00
104 0 87 87 0.00 87 87 0.00
105 0 85 81 -4.00 85 81 -4.00
106 0 0 0.00 86.5 86.5 0.00 86.5 86.5 0.00
107 0 30 18 -12.00 30 18 -12.00
108 35 0 -35.00 50 0 -50.00 85 0 -85.00
109 5 0 -5.00 75 55.2 -19.80 80 72.2 -7.80
112 0 0 0 0 0.00
113 0 0 0.00 71 71 0.00 71 71 0.00
114 0 50 20 -30.00 50 20 -30.00
119 72.5 70.5 -2.00 18.5 18.5 0.00 91 89 -2.00
120 10 4 -6.00 60 29.25 -30.75 70 33.25 -36.75
121 1.75 1.75 0.00 89 89 0.00 91 90.75 -0.25
123 4 4 0.00 85 85 0.00 89 89 0.00
124 0 0 0.00 86 83.75 -2.25 86 74.75 -11.25
126 10 10.5 0.50 72 72.25 0.25 82.75 82.75 0.00
127 11 10.75 -0.25 72 72.5 0.50 83 83.25 0.25
128 7 7 0.00 66 66.5 0.50 73 73.5 0.50
rptBurnAreaEstimateSummary

36

Burn Area Estimates (cont)
Highlights difference in burn estimate data recorded in initial overall estimate and summed
estimates by body includes treated patients only
2nd Degree Burns 3rd Degree Burns Total Burn
Area
Anatomical Anatomical Anatomical
Enroll #: Initial Est. Burn Est Difference Initial Est. Burn Est Difference Initial Est. Burn Est
Difference
129 1 1 0.00 80 80.25 0.25 81.25 81.25 0.00
130 10 10.4 0.40 84 85.15 1.15 94 0 -94.00
131 0 0 0.00 90 90 0.00 90 0 -90.00
132 0 0 0.00 68 68 0.00 68 68 0.00
133 0.75 0.5 -0.25 58.75 58.75 0.00 59.5 48.25 -11.25
134 7 7 0.00 65 65 0.00 72 66 -6.00
136 24.25 24.25 0.00 43.5 43.5 0.00 67.75 67.75 0.00
137 12.5 12.7 0.20 58.5 58.6 0.10 70.5 71.2 0.70
138 0.5 0.5 0.00 75.5 75.5 0.00 76.0 76 0.00
139 0 0 0.00 69.85 69.85 0.00 69.85 69.85 0.00

37

9. Summary of Pre-Study Visit: Informed Consent; Medical History Completed;
Microbial Culture of Recipient Sites; Physical Exam Completed; Serum Antibodies
Collected; Site Biopsy Conducted.

Figure 9.1- Pre-Study Visit
Figure 9.1 illustrates a summary of the overall completion of the pre study visit information. There are
additional grafts below that separate this information.
There were forty four (44) treated subjects in this study population. It was observed that all 44 treated
subjects had signed the Informed Consent Form (ICF), and thirteen (13) untreated subjects also signed
ICF. While all of the subjects reviewed in this part of the audit, did sign the ICF. There were some
discrepancies, as noted below:
Subject 129 - ICF is on plain paper, no heading for Shriners Hospital or UC. ICF states that the
study has periodic visits for the 1st year; however subject not brought back in for visits 91,182 or
365. There is no documentation that the subject withdrew from the study.
38

Subject 121 - There is an ICF for Galveston Hospital which states received from Cincinnati May
2004; revised in Galveston 12/12/04 and then revised again 02/24/06. Subjects mother signed
the Spanish ICF. It is unknown what changes were made in the two revisions.
Subject 104 - No HIPAA form located in copies given to auditors. Since subject and family was
from Mexico and signed an English consent, there should have been a note to file stating that the
person signing the consent was bilingual and could understand completely the nature of the ICF.

10. Pre Study Medical History

Figure 9.1- Pre-Study Medical History Completed
Both the total pre study visit chart and the individual detailed chart show that one hundred percent of the
subjects did have a pre- study medical history completed as per the protocol requirements. This pre study
medical history was taken from the initial History and Physical (H&P) reports when the subject was
initially brought into the ER facility and/or the Shriners Hospital H&P notes. The medical history often
was provided by the parents or guardian who accompanied the subject to the hospital.

39

11. Pre-Study Physical Exam
The physical exam graph (Figure 11.1) shows that eighty six (86) percent of the subjects had a complete
Physical Exam (PE) performed. The other fourteen (14) percent was incomplete. The sites were
completing the PEs based on information located in the medical records, and usually the research nurse
was the person responsible for completing the PE form. Fourteen percent of the PE forms were left
incomplete, sometimes only one or two areas were not completed, however for baseline information all
categories should have been completed per CFR 812.140(a)(3) - Records of each subject's case history
and exposure to the device. Case histories include the case report forms and supporting data including,
for example, signed and dated consent forms and medical records including, for example, progress notes
of the physician, the individual's hospital chart(s), and the nurses' notes. Such records shall include:

Figure 11.1- Pre-Study Physical Exam Completed

40

12. Pre- Study Serum Antibodies

Figure 12.1- Pre-Study Serum Antibodies
The overall pre study visit chart shows that forty (40) subjects had the serum antibodies collected and four
(4) did not. Of the four that did not have antibodies drawn, three had them drawn per Dr. Boyces
database, however could not be confirmed by auditors in the medical records. One subject did not have
the serum antibody drawn at pre study and subsequently died at POD 12.
The detailed pie chart for the serum antibodies collected shows that only 9% of the 91% of the number of
antibodies were not done. This was from the four identified patients referenced in the above paragraph.
The results of the serum antibody studies were virtually impossible to identify. The records were
maintained in an extremely poor manner and not sufficiently for auditor review. Less than half of the
subjects, twenty four (24) had actually results, and thirty three (33) did not have any results identified. It
is uncertain what the purpose of the antibody collection was per the protocol. The ICF states that the
antibodies were to be drawn to test for allergic reaction of the cultured skin. Since less than half of the
subjects actually had results from the testing done, and there were no notes to file to explain why these
tests results were not obtained. The subjects had their blood taken twice during the study (Pre study and
POD 28) and these antibody tests were not performed.
This is a violation of CFR 812.100 Subpart E-Responsibilities of Investigators: An investigator is
responsible for ensuring that an investigation is conducted according to the signed agreement, the
investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of
41

subjects under the investigator's care, and for the control of devices under investigation. An investigator
also is responsible for ensuring that informed consent is obtained in accordance with part 50 of this
chapter. Additional responsibilities of investigators are described in subpart G.

13. Pre-Study Skin Biopsy for Tracing
Figure 13.1, below, illustrates that (forty) 40 subjects had the biopsy done and that the appropriate
protocol mandated tracing was completed of the biopsy. The biopsy tracings could not be located for
four subjects. As the pie chart shows, the majority of subjects did have the skin biopsies for tracings
performed by the site. Biopsy tracings could not be verified for the following subjects: Subjects 88,
Subject 91, Subject 114, and Subject 120

Figure 13.1-Pre-Study Skin Biopsy For Tracing Conducted

42

14. CSS Tracings in Vitro

Figure 14.1-CSS Tracings in Vitro Completed for POD 0
The protocol specified procedures required that CSS tracings in vitro be completed at POD0. These were
tracings that were completed for all pieces of CSS in the set. The following was observed with regards to
CSS tracings in vitro:
Subject #105: was listed as incomplete as it was observed that a set that was not applied due to
contamination.
Subject #134: originally had a set 3; however the information regarding the CSS tracings could
not be located or verified.
Subject #124: expired prior to set 1 being applied.
Subject#113: expired prior to set 2 being applied.
Subject #112: the first set was not applied due to contamination of grafts.

43

15. Post Operative Date Completion for all Sets

Figure 15.1-POD Completion by Set Number

Figure 15.2-Total POD Completion Across All Sets
Figures 15.1 and 15.2 identify a lack of follow up on the study subjects as mandated per:
44

CFR 812.140(a)(3)(i) Documents evidencing informed consent and, for any use of a device by the
investigator without informed consent, any written concurrence of a licensed physician and a brief
description of the circumstances justifying the failure to obtain informed consent. The case history for
each individual shall document that informed consent was obtained prior to participation in the study.;
812.140(a)(3)(ii) All relevant observations, including records concerning adverse device effects (whether
anticipated or unanticipated), information and data on the condition of each subject upon entering, and
during the course of, the investigation, including information about relevant previous medical history and
the results of all diagnostic tests.; 812.140(a)(3)(iii) A record of the exposure of each subject to the
investigational device, including the date and time of each use, and any other therapy.; 812.140(a)(4) The
protocol, with documents showing the dates of and reasons for each deviation from the protocol;
812.140(a)(5) Any other records that FDA requires to be maintained by regulation or by specific
requirement for a category of investigations or a particular investigation.
Auditors observed that the sites lacked compliance in completion of the data sets for POD 0, POD 7, POD
14, and POD 28, as not one of these sets was completed in 100 % accordance with the study protocol.
Overall PI or Sponsor oversight is in question. Documentation that states the PI (Drs Boyce and Kagan)
did not check the CRFs until the initial year was completed by the subject was present. However, the
issue is that these checks or PI signed template sheets were signed up to 2 or 3 years after the closure of
the subjects initial year on study. Auditors observed the lack of attention to gathering the data requested
per the protocol and in the CRF, in the study visits following POD 28. Subjects were still in the hospital
or returning as outpatients, however there is nothing to support why the follow- up visits were not
completed. It was observed, however, that many of the photographs were taken at or near the correct
follow up dates, yet the other study procedures, which should have been completed, were not.
Subsequently, there was no documentation to support these study discrepancies.
In reviewing the medical records the subjects were still in the hospital or being seen regularly in the
outpatient clinic. There was no viable reason why the follow up data could not have been obtained on the
majority of the subjects. Per the CRFs the only data that needed to have been collected was the
Photography, the Healed Wound Biopsy (as possible), and Qualitative Outcome (QO) and at visit POD
365 the addition of the Investigator Global Assessment (IGA). The site only needed to complete photos
and (QO) three (3) times over a period of 11 months. At the end of the one year, an additional (IGA)
would have needed to be completed.
The CRFs were often used as the source documentation. It was observed that there were no dictated notes
or any records found that could substantiate the information recorded on QO or IGA forms. The CRF
forms also did not have proper completion instructions present, thus variations in completion were noted.
For example the QO stated it was based on the Vancouver Scar Scale. Presumably, everyone that
completed the QO form would know exactly how to complete this form. The instructions on how to
assess the pliability (for example) should have been included on the form or given to the site in a written
manner so that consistency could have been maintained throughout the study and throughout personnel
changes.
The clinical scar assessments are subjective and validation is operator dependent. To use clinically, the
raters should have been trained. Interpretation of the results is subjective.
The IGA form is another example of the same type of problem. The majority of the IGA forms have a
question that asked were there any adverse events?, and was typically answered with a no and the
adverse event page was marked no. The sites did not understand the reporting of adverse events, and the
majority of event that did get reported were acknowledge as part of the burn and not related to the CSS.
Auditors also observed that Steve Boyce Ph.D., wrote the protocol, was in the operating room when
45

subjects were treated with the CSS, often completed the CRFs himself, compiled the data, reported the
data, and published the data.
The Physical Exam (PE) reports were completed by the research nurses, as was confirmed through the
interview portion of the audit. According to the interviews with the Cincinnati Shriners research nurses,
the nurses would go back into the computer medical records and complete the PE form from the nursing
assessments of the patient. While these nurses were listed as sub investigators for the study, the PE forms
were not completed in a consistent manner. Some forms, for example, listed Sinus Tachycardia as normal
and others listed it as abnormal on PE page under cardiac. The training should have been made clear to
the sites, how to complete the PE form. PE forms were often completed based on expected burn status of
burn patients. However there were subjects where the PE appeared to have completed correctly. Some
forms (especially the typed ones) were identical from previously forms with no changes except for dates.
The primary factor is that the PE forms were not consistent.
Some examples of what was noted during the audit are listed below:
Subject 124: Form states patient records from July 11, 2006 - September 12, 2006 were reviewed by Dr.
Boyce July 10, 2009 and Dr. Kagan on July 23, 2009.
Subject 84: No comparative site utilized. Information written in on CRFs at different times in different
handwriting, with no initials/signature or date given. Follow up not done per protocol, even though
subject did return to clinic for follow up visits.
Subject 132: Error corrections were not signed or initialed; Template form stating PI Dr. Kagan has
reviewed all data from beginning to end on this patient, and signed and dated 1/29/09. Pre- study PE was
done as same day of PE for set 1. The pre study PE was noted with all no's recorded and the PE for set 1
used the H&P notes dated 12/22/07.
Subject 131: The CRF has a boilerplate page in the very front that states "I have reviewed all case report
forms and the results of all diagnostic tests for research subject (131 written in the blank) from enrollment
(24 Aug 2007 written in the blank ) through (29 Aug 2007 written in)" ---It was signed and dated by Dr.
Kagan on 1/29/09
Subject 99: CRF corrections made during audit. Blanks in CRF were left blank for several years then
completed in 2009. Errors marked thru with no initials, or date, or reason why change.
Subject 109: Forms are typed; auditor unable to ascertain name of person signing. Unknown if person is
eligible to sign off forms. PE for pre-study has a date of 10/29/2005 which is prior to ICF consent.
Subject 120: CRFs have many changes noted by Mrs. Peggy Simpson in July 2009, which is three years
after information was recorded. Not all changes were noted as to why they were marked through or dated
and initialed. The appearance to auditors is that Mrs. Simpson, was trying to clean up data without
knowing when or why changes were made, ultimately makes it more difficult to discern what occurred.
Subject 133: Template page for PI to sign off for review. Signed and dated by Dr. Kagan on 01/29/2009
and Dr. Boyce 02/06/2009. CRFs have mark outs with no initials or dates. All visits have not been
completed.
Subject 82: Consistency in documentation is not found between the sponsor and sites. Sacramento
Shriners made their own forms for data collection, and only used a few of the CRFs from the sponsor.
46

The data for the Qualitative Outcome report switched the numbering system from the original CRF, so
looking at the numbers the data would be off. The sets were combined for POD 91,182 and 365 which is
in error. Sets 3 and 4 were combined. Either the sponsor did not conduct training, or there was no
communication about how to complete forms.
Subject 104: CRFs are incomplete, there are changes made by Peggy Simpson, RN at Cincinnati Shriners
on the Galveston forms. Mrs. Simpson initialed but did not date changes. Other changes are scratched
through, without accompanying initials and date, in order to track the data change (for example: Physical
Exam Pre-Study). Set 1 Qualitative Outcomes report is signed and dated by Melissa Reed, research nurse
in Cincinnati, regarding a Galveston patient.
Subject 86: The CRF/Source was copied and sent to University of Cincinnati. The pages were typed and
there is no signature or date identifying when these were completed or who completed them. It appears
that Steve Boyce, who at this time was the PI listed, gave approval as the sponsor, and then completed
many of the CRFs himself. Auditors question bias and accuracy as Dr. Boyce had total control of this
subject's information.
Subject 123: Many corrections were made by Peggy Simpson in July 09; three years after the initial data
was recorded. Errors previously crossed out with no initials Drawings of graft placements were done on
female and baby forms when this was a 13 yr old male.
Subject 101: Subject signed consent and underwent a biopsy for making CSS. There is no
documentation found in subject's medical records, as well in Dr. Boyce's database to explain why subject
did not continue in study. Additionally, there was no record of what became of the biopsy. The Sponsor
had received information, based on an email found from Cincinnati to Sacramento which states shipment
of CSS was expected for August 3, 2005. There are no CRFs completed, except for 3 lines regarding the
biopsy. No reason is noted as to why this subject did not continue on study, or if any follow- up was
completed.
Subject 102: Corrections made after annual reports reported to FDA and major burn magazine
publications, and national talks given. Most pages have changes made on them on August 26, 2009.
Subject 106: Case report forms (specifically the IGA and Qualitative Outcome) were not completed until
a couple of years after the fact. Several CRFs were not signed or dated. No review by PI of case report
forms as no PI review form was present in the CRF. Changes are made to CRF forms several years later
than original entry made. Not all changes are signed and dated at each change.
Subject 97: There are pages with two different hand writing styles and types of ink used. No dates or
initials to indicate when additional information was written in. Other than set 1, no set was completed past
POD 28, no PE's were done, protocol was not followed, see deviations and comments for further
information.

47

16. Biopsy of Recipient Sites
Figure 16.1 is showing the biopsy of recipient sites completed. This graph demonstrates that that the
biopsies were overall not completed in a protocol compliant fashion The X axis represents the number of
Sets applied (Sets 1- 12) and the Y axis represents the number of biopsies completed for the total number
of set numbers applied. For example, of the total number of Set Ones applied (42) only 25 biopsies could
be verified as completed. Set two has an equal number biopsies performed as well as the same number
as not performed, and the same can be observed for Set Four. It can be observed for sets 3, 5, 6, 7, 8, 9,
10, 11, and 12, that the overall biopsy collections not completed was greater than the biopsies completed.
These biopsies were to be collected at POD 0 (date of surgery) from the subjects. Some of the dictated
OR reports stated the biopsies were collected, however many did not. The investigators for the study did
not always document information regarding the research part of the subjects care. Auditors observed that
the investigators relied upon the research nurses to document the biopsy; however it is ultimately the
responsibility of the principal investigator to see that the information is collected and documented. There
were no notes to file to explain why the biopsies were not being performed and recorded in the CRFs as
the protocol required.

Figure 16.1-Biopsy of Recipient Sites Completed (Site A and B)

48

17. Photography of Wound Bed, Pre-Surgery
Figure 17.1, below, is graphic representation of how the sites performed the required photography of the
wound bed, per protocol. While the documentation reflects that the photography was done for the most
part, when the sets 11 and 12 were documented, they were incomplete. Only sets 9 and 10 were done
totally correct. Auditors observed that the photography was consistently the most well documented and
most completed procedure for the study.

Figure 17.1-Photography of Wound Bed, Pre-Surgery (Site A and B)
A specific photography discrepancy noted:
Nursing Note dated 02/08/08 states Dr. Boyce is here to take pictures. However, in the CRF
photography log (dated 02/08/08) the Photographers ID is signed by Peggy Simpson, RN.

49

18. Photography Post Graft
Figure 18.1, demonstrates the consistent decline in the post graph photography from POD 0 to POD 365.
There were to have been 159 photographic events for the study population. This is based on the 159 total
CSS sets applied. The graft illustrates that at POD 0, 129 photos were completed and 30 were either
incomplete not done, or unable to verify. The decline shows that at POD 7 only 108 photos were done
completely, at POD 14 only 104 were done completely and at POD 28 only 90 were done completely.
It is noticeable that after POD 28, completed photographs were minimal. Only 29 were done completely
at POD 91, 28 were done completely at POD 182, and only 26 were done completely at POD 365. This
was in part to the lack of POD 91-365 completion throughout the entire subject population. The sites,
especially Cincinnati, took full body photos, which made it impossible to compare previous photos as
those photos were done on specific areas. The photos were not done in a consistent manner across all
sites. There were no written instructions identified in file records informing sites of how to capture the
photos in a dependable method. Some photos were close ups of the areas grafted with CSS or AG and
others were from a distant of an entire body area or the whole body. The graph also shows that many of
the later POD information were not captured, at all, by the sites.

Figure 18.1-Photography Post Graft

50

19. Study Site Tracings for POD 14/ POD 28
Figure 19.1 shows that out of the one hundred fifty nine (159) site tracings that should have been
completed at POD 14, only 101were completed per protocol. Thirty eight (38) were incomplete, four (4)
were not applicable due to the grafts were not applied, or the subject was a giant nevus, nine (9) were that
the entire POD 14 was not done, and seven (7) had information that was unable to be verified by the audit
team.

Figure 19.1-Study Site Tracings for POD 14

51

Figure 19.2 shows similar information to the POD 14 information collected for the site tracings. The
numbers completed, incomplete, not applicable, and unable to verify are almost identical. A point that is
noteworthy here is that the number of totally not done at POD 28 from POD 14 almost doubled. This was
only 14 days after the POD 14 information was collected, and prior to the subject being discharged from
the hospital. There was no information the auditors could discover as to why the data collection was not
continued in a manner to comply with the regulations regarding the record keeping required for research
studies.

Figure 19.2 Study Site Tracings for POD 28

52

20. Microbial Cultures
Figure 20.1 illustrates overall that the microbial tests were performed on the subjects. Per protocol, these
microbial culture tests were to be completed Pre0, POD 0, POD 0, POD 7, and POD 14. For the most
part the tests were executed and an organism was identified or not as determined through the
microbiology testing. A decline of data is noted the further out the subject went from Pre-study to POD
14, as is similar to the data collected on most all of the other protocol procedures. Data at the beginning
(Pre-study 0) was one hundred twenty (120) completed cultures and thirty nine (39) incomplete, not
applicable, or unable to verify. For POD 0 one hundred nineteen (119) was completed and forty (40)
were not completed as the study required. For POD 7, One hundred and eleven (111) were completed and
a total of forty eight (48) were not completed properly. By the time POD 14 came due only seventy seven
(77) of the subjects had the microbial cultures performed and eighty two (82) subjects did not have the
microbial cultures done.
The data collection for the microbial cultures follows the same trend as the other information collected for
this study. The initial information, pre study and POD 0 was completed and documented fairly well
However, at each subsequent visit, following POD0, the data collection dropped off to approximately half
by POD 14, as observed in the graph below.

Figure 20.1-Microbial Culture of Recipient Sites

53

21. Healed Wound Biopsy

Figure 21.1- Healed Wound Biopsy Completed for PODs 7-365

Figure 21.1, illustrates an overall lack of compliance with respect to the collection of a healed wound
biopsy at all protocol specified time points. The protocol states that healed wound biopsies will be
obtained on post operative dates 7,14,28,91, 182 and 365, not to exceed more than six biopsies total.
There were so few actual healed would biopsies performed on the subjects, the information gathered
would be negligible. The healed would biopsies were to be sent to a dermatologist for dermato-
pathologic interpretation. No records were identified with any results, so the few biopsies performed
were not evaluated by a dermatologist.
There were records that indicated subject was not in the operating room on the day that the biopsy was to
have been performed, and that is why the biopsy was not taken. The fact that so few biopsies were
performed when up to 6 should have been done questions the collection process.
While the protocol states the healed would biopsies would be performed as possible, this process was a
secondary endpoint of the study under protocol section d.4.5. Out of the 159 sets of grafts applied to
subjects, only 16 sets had the healed wound biopsies completed, but then not read by a dermatologist.
There is a lack of valid data to make any assessment of this endpoint.

54

22. Healed Area/Donor Area Ratio
The completion of this data does not follow the protocol. The protocol states in section d.2 Study Format:
For each administration of cultured cell-biopolymer skin substitute to a wound site, a comparative site
will be treated with meshed or unmeshed split-thickness skin.
As the CFR 812.140 (a) (4) states: A participating investigator shall maintain the following accurate,
complete, and current records relating to the investigators participating in an investigation: (4) the
protocol, with documents showing the dates of and reasons for each deviation from the protocol.
The case report form Investigators Global Assessment (IGA) for POD 14 asked the question: Healed
area: donor area ratio for cultured skin substitute. The same question was asked on the same form for
POD 28. However, per the protocol schedule of events, this assessment was to be completed only at the
POD 28 time point.
Figure 22.1 shows that this information was periodically collected at POD 14, and that the majority of the
healed area donor area ratio evaluations were completed at POD 28, as outlined in the protocol schedule
of events. However, there were deficiencies in the overall collection of the appropriate data point of post
operative day 28. The fact that this data was to be used as an end point for the study and the data was
not captured as per protocol, and deviations were not reported as per protocol, raises serious questions as
to how determinations were made for annual reports, presentations, and publications that were prepared
by Steve Boyce, PhD during the years this CSS study has been ongoing.

Figure 22.1-Healed Area Donor Ratio Completion for POD 14
55

Figure 22.2- Healed Area Donor Ratio Completion for POD 28

56

23. % Engraftment Completed for POD 14

Figure 23.1- % Engraftment Completed for POD 14
Figure 23.1 illustrates that most subjects did have this event completed in the case report forms. The
column reporting not applicable is reporting subjects where sets were not applied, therefore engraftment
was not evaluated. The sites occasionally consolidated sets and applied as one set during one operation,
thus engraftment was evaluated collectively, for multiple sets. The not done category was where the case
report form pages were not completed. The POD column indicates that the entire post operative date
information was not done. The unable to verify column denotes that there was not enough information
provided to validate the information in the case report form. Out of the potential one hundred fifty nine
(159) events one hundred thirty three (133) engraftments were completed on the case report forms.

57

24. % Engraftment Completed for POD 28
Figure 24.1: % Engraftment Completed for POD 28

Figure 24.1, for POD 28, again shows that the majority of the case report forms were completed with
information for this date. This chart is the same as the previous engraftment chart for POD 14. There is a
higher incidence of the entire POD 28 not being completed at all at day 28 than what was identified at
POD 14.
This engraftment information is one of the primary endpoints for the CSS clinical trial.

58

25. Physical Exam Conducted for POD 0
Figure 25.1 displays that 41 Physical Exams were not done, two where the entire POD was not done, and
one was incomplete. The 4 that were listed as n/a were graft sets that were not applied.
Record keeping is required by the CFR 812.140 as well as Good Clinical Practice. POD 0, POD 7, and
POD 28 were key study data capture points for this CSS study. For POD 0 there are only 5 required
events that needed to be recorded for the case report forms.
There was a specific research nurse at each site that was responsible for the data collection. In addition to
a specified research nurse, the PIs responsibility is to see that the events were performed and recorded.
On top of those two people, it was the sponsors duty to hold the sites accountable for the data collection.
All of these processes that should have been in place failed.

Figure 25.1-Physical Exam Conducted for POD 0

59

26. Physical Exam Conducted for POD 28
Figure 26.1 shows that at POD 28, which is a primary data analysis point per the protocol, 159 physical
exams should have been performed for all of the sets that were grafted throughout the research subject
population. Of the 159 physical exams to be completed, 36 were not done at all, 17 were part of an entire
POD visit which not done, one was unable to be verified against source data, and 4 were not done due to
the grafting not being done on a particular set. This diagram explains that 36% of the information, for
this key primary data analysis time point, was not collected as specified in the protocol.
Code of Federal Regulation 812.40 is clear regarding the mandated record keeping and proper
documentation of required data for a clinical trial. The process of a research nurse to record the data, the
PI to review and sign off on the data, the sponsor to review and query the site if the data poses questions
all failed to be adhered to on this study. It is apparent that the PI at the site did not accurately review the
records as well as the sponsor (either Dr. Boyce earlier on, or UC later in the study-as both were
considered sponsors). The lack of documentation could have been exposed earlier and the site may have
been able to gather the data in a timely manner with proper oversight.

Figure 26.1-Physical Exam Conducted for POD 28

60

27. Serum Antibody Collection at POD 28

Figure 27.1-Serum Antibody Collection for POD 28
Figure 27.1 illustrates that one hundred nineteen (119) serum antibody tests that were scheduled for POD
28, were not done. In addition to the 119 not done, 4 were noted as n/a, meaning that those sets were
not grafted. Of the total of 159 serum antibody tests that were required for POD 28, only twenty eight
(28) were done and documented in a manner that auditors could identify. For the seven that the auditors
noted as unable to verify, specific notes were located as to the serum antibody being drawn from the
subject however no results were found to match this documentation. The medical records did not indicate
that the serum antibodies were drawn, and very few research nurse notes identified documentation
regarding the serum antibody tests. Results of the test were not documented in the case report forms or
medical records. The only location that results were acknowledged was the spreadsheet that Steve Boyce,
Ph.D. was keeping. There was no way to identify if the test was done, who performed the actual testing,
and what the result of the test was other than the spreadsheet Dr. Boyce maintained. Without actual test
results to identify the serum antibody outcomes, the spreadsheet remains unverifiable.

61

28. Investigator Global Assessment:
Per protocol section d.4.2, data will be collected on the Investigators Global Assessment (IGA) form
on days 14 and 28.
At POD 14, the IGA assessed the following (per Case Report Form CSS 7.10):
1. Percentage Healed graft (from tracing) for Site A and Site B
A. Cause(s) of failure of autograft/ CSS
B. Was re-grafting needed?
C. Date that the manufacturer was notified of device failure
D. The date of the Monday of the week in which regrafting was expected to be performed
E. The type of graft that was expected to be used and reason
2. Healed area: donor area ratio for cultured skin substitute
3. Were there any adverse events during the course of the this study
4. Status of the subject (continues in study/ discontinued in study)
5. If subject was discontinued from study, indicate reason
6. Was the subject discharged with cultured skin intact?

The percentage healed for sites A and B was to be obtained from the study site tracing obtained at POD
14 and POD 28. Per protocol section d.3.2: the total area, open area, and closed area of wounds at
POD 14 and 28 will be obtained by direct tracings onto a plastic sheet. Tracings on plastic sheet will
be measured by computer-assisted planimetry and values entered into the data table.
Auditors observed that the sites were reporting numbers for this evaluation as whole number percentages
as well as specific values to the hundredth place. It is unclear how these assessments were made by the
investigators if computer assisted planimetry was necessary. There is no documentation on the process
by which these values were obtained. The Investigator Global Assessment was intended to be an
assessment to be completed by the appropriate participating Investigator; therefore the appropriate
investigator should have been making all assessments as required. There was no standard of completion
noted throughout the study documentation.
There were differences on the IGA noted between the two protocol specified time points. Specifically at
POD 28, the Investigator Global Assessment Form (per Case Report Form CSS 7.11) omitted section A-E
as noted above. However, graft failure was noted as occurring in between POD 14 and POD 28.

62

Per the protocol schedule of events and Protocol section d.3.3, Healed Area /Donor Area ratio for CSS is
to be evaluated at POD 28 only. It is unclear why the POD 14 IGA also requested a Healed Area: Donor
Area Ratio for CSS. Sites were often reporting a ratio of healed area versus donor area at the POD14
time point. Per Figure 28.1 it is noted that a Healed Area/Donor area ratio was calculated at POD 14 at
least once, for each of the 12 groups of sets applied across the subject population. This conflicts with the
protocol, and it is unknown how and why this assessment was calculated if POD 28 was the appropriate
time point for this evaluation.

Figure 28.1- Healed Area Donor Ratio Completion for POD 28

63

29. Qualitative Outcome

Per CFR 812.110, investigators did not follow the investigational plan (protocol) dated November2003
with respect to collection of the Qualitative Outcome data:

Per Protocol: d.4.3.4 Qualitative outcome and scarring for each site will be scored at each time
point using the Vancouver Scar Scale that uses ordinal scale of 0-3, with 3 being the worst. Scoring
will be performed by an investigator not responsible for the acute care of the patient. Factors to be
scored include: erythema, pigmentation, pliability, and raised scar. The requirement for site
reconstruction will also be scored as an absolute event. One scoring sheet will be completed for each
patient at each time point including both the A and B sites. Evaluation of qualitative outcome will
begin at day 14 after grafting, be performed no less than weekly during the acute hospitalization,
and at subsequent visits to the outpatient clinic.

The data collection for the Qualitative Outcome assessment was captured on Case Report Form CSS 7.9.
(See Appendix A). It was noted that the factors of erythema, pigmentation, and scar height were scored on
the ordinal scale of 0-3. However, per this form, the factor of skin pliability was scored on a scale from
1-5, which is not consistent with how the protocol defines this assessment should be scored. Different
versions of this form were identified throughout the subject study record. Additionally, there were noted
variations in the ordinal scales used for scoring the qualitative factors between the different forms. An
example of this was identified in Subject 134, Set One, at POD 365. In this particular case, the
Qualitative Outcome form reported Pigmentation as Hypo (0-1), Normal (in between 1 and 2) and Hyper
(3). The more commonly noted versions of this form had ordinal scales as follows: None (0), Hypo (1),
Normal (2) and Hyper (3).
The Qualitative Outcome form (form CSS 7.9) acted as both source documentation and the Case Report
Form. The data captured on this assessment was unable to be verified against any additional medical
records. Additionally, this page was consistently not signed and dated by the person completing the
evaluation; therefore the identity of the person making the assessment was not able to be determined.
Whether an investigator was independent of the subjects acute care was also not able to be determined.
This form, however, was often identified as being completed by Dr. Boyce, but it is unclear if he or
someone else made the actual assessments.
There were noted inconsistencies in how this data was captured by the investigators. This indicates a lack
of protocol training and overall monitoring for study compliance as per CFR 812.40. For some subjects,
the factors, to be scored, were reported as a numerical value over the selected score (i.e.: 100 would be
entered over the value for Red with regards to erythema) and in some cases an X was placed over the
selected value. In the instances where by a number was placed over the selected score, the values were
often broken down over the scale. (i.e.: 80 would be reported over Red and 20 would be reported
Pink, for the factor of erythema). It is unclear how data could be appropriately extrapolated from this
assessment if multiple values were present for the factors being scored.
64

Per the protocol schedule of events, the Qualitative Outcome evaluation was required at POD 14, 28, 91,
182, 365 and greater than 365 (if possible). This is not consistent with protocol section d.4.3.4, whereby it
states that this assessment should begin at day 14 and be performed no less than weekly during the acute
hospitalization. Overall, the Qualitative Outcome data was not being captured at weekly intervals during
the acute hospitalizations for the subject population as specified by protocol.

Per Figure 29.1: Qualitative Outcomes were observed as not being completed beginning at POD 91
through POD 365 over the entire subject audit population.

Figure 29.1 Qualitative Outcomes
65

Figure 29.2-Qualitative Outcome POD 14

66


67



68


69

30. Adverse Event Summary by Set for POD 14
Figure 30.1: This information comes directly from the Investigator Global Assessment form. There is a
question on that form that states Were there any adverse events during the course of this study? The box
was to be checked yes or no. As figure 30.1 shows, the CRF was checked no the majority of the
time. The FDA came to the Cincinnati site between March 16 and June 21, 2006 and sited the site for
failure to report and accurately document unanticipated and anticipated adverse device events to the
sponsor and reviewing IRB. After the Warning Letter and the subsequent Integrity Hold Letter, Peggy
Simpson RN, research nurse for the study, began to review the subjects CRFs and initiated
documentation of the adverse events. Sometimes the no reported on the CRF Investigator Global
Assessment form was changed to a yes.
Additional details regarding this information are can be located in the UADE/AE/SAE section of this
report. It is noteworthy that the Integrity Hold letter was dated February 2, 2007 and the site did not start
to record the adverse events until the fall of 2008 and continued into early 2009. There was much
discussion between the University of Cincinnati and FDA regarding the reporting of adverse events and
as this discussion was still ongoing when the MRF came on board this project.

Figure 30.1-Adverse Event Summary By Set for POD 14

70

Adverse Event Summary for POD 28
Figure 30.2, illustrates the adverse event summary for POD 28, and is similar to that of POD 14
information. The Nos are more in number than the Yess recorded, however the figure shows that
for the later graft sets, the numbers start to level out and be more equal. This graph, and the previous one,
includes the changes made from the original nos to yes by Peggy Simpsons changes made to the
case report form documents.

Figure 30.2-Adverse Event Summary for POD 28

71

31. Cultured Skin Substitute/ Wound Care

Protocol - d.2.2 Wound Treatment
Wound dressings will be administered similarly to descriptions in previous studies by the principal
investigator, using a non-adhesive porous dressing (i.e. , N-Terface) in direct contact with the
cultured skin. Wet dressings soaked with solutions of non-cytoxic antimicrobial agents and
nutrients will be maintained for 5 days over both sites if they are under a common dressing.
Alternatively, if AG is under a separate dressing, it may be irrigated according to prevailing
standards which at present are alternating 2 hour administrations of GU irrigant (400 Units/mL
Polymixin B and 40 g/mL Neomycin) and 5% sulfamylon. Topical irrigation with non-cytotoxic
antimicrobials and nutrients does not inhibit engraphment of AG. However, sulfamylon solutions
will not be used on CSS sites due to high toxicity. At post-operative day (POD) 5, wet dressings will
be discontinued and dry dressings will be administered daily until POD 7 at which time dressing
changes will be performed twice daily. Subsequently, CSS sites will be cleansed with non-detergent
cleanser (i.e. , Shur-clens, Allclenz), rinsed x3 with saline and allowed to dry. Open areas will be
treated with a non-adherent dressing (i.e. Adaptic) coated with an ointment consisting of equal
parts of Neosporin, Bactroban and Nystatin. Dry keratinized areas will be treated with a
moisturizing lotion (i.e., Curel) and covered with bulky cotton gauze.
The specific nursing care instructions for CSS are described per IDE application, Attachment 4
(section f.1.4.3)

or the nursing care instructions (per IDE application Attachment 4, section f.1.4.3) with respect to the
care of Cultured Skin Substitute

Per overall review of subject records, there was no consistent documentation of completion with
regards to the specified requirements for treatment of CSS.
Per protocol d.2.2: .sulfamylon solutions will not be used on CSS sites due to high toxicity:

Subject 129: Sulfamylon was reported as being used on CSS sites on 7/20/2007,
7/22/2007, 7/23/2007, 7/24/2007, and 7/26/2007

Per Protocol d.2.2: At post-operative day (POD) 5, wet dressings will be discontinued and
dry dressings will be administered daily until POD 7 at which time dressing changes will be
performed twice daily. The following subjects were not treated according to protocol
(November 2003):
72

Subject 82: Set 1 POD 10: 1 of 2 dressing changes were completed
Set 1 POD 11: 0 of 2 dressing changes were completed

Subject 86: Set 1 POD 9: 0 of 2 dressing changes were completed
Set 4 POD 8-14: 1 of 2 dressings changes were completed
Set 6 POD 11-14: 0 of 2 dressing changes were completed
Set 7 POD 8-14: 0 of 2 dressing changes were completed

Subject 103 Set 1 POD 8-14 1 of 2 dressing changes were completed
Set 4 POD9 1 of 2 dressing changes were completed
Set 5 POD4 Subject taken out of wet dressing 1 day early

Subject 107: Set 1 POD 8-14 1 of 2 dressing changes were completed

Set 6 POD 8-14 1 of 2 dressing changes were completed


Subject 130: Set 6 POD 4 1 of 2 dressing changes were completed
Set 6 POD 5 1 of 2 dressing changes were completed
Set 11 POD2 0 of 1 dressing change was completed

Subject 137: Set1 POD14 1 of 2 dressing changes were completed

Subject 139: Set 1/ 2 Subject was taken out of protocol dressings
Set 3 An unscheduled dressing changed was completed at POD1

Subject 138: Set 5 Taken out of dressing from POD 10-14
73

Per IDE application, Attachment 4 (section f.1.4.3): CSS sites are to be irrigated every 8
hours with CSS solution of a specified volume (usually 30 ml/graft) beginning at POD 0
through POD 5. The following subjects were not treated according to the investigational plan,
specifically regarding the completion and frequency of CSS site irrigations between POD 0 and
POD 5:
Subject 82: Set 2 POD2: 2 of 3 CSS irrigations were completed

Subject 86: Per nursing notes dated 9/14/2004 at (0400 and 0636) both time points specify
that grafts were soaked with CSS solution. This was not at a frequency of q8 hours.
Set 8 POD 2: 2 of 3 CSS irrigations were completed
Set 5 POD4: 2 of 3 CSS irrigations were completed

Subject 87: Set 1 POD 1: 0 of 3 CSS irrigations were completed

Subject 108: Set 2/3: CSS irrigations were completed q4 hours

Subject 130: Set 6: grafts were placed in dry dressing instead of CSS irrigation

Subject 131: Set 6: grafts were placed in dry dressing instead of CSS irrigation

Subject 136: CSS grafts were taken out of dressing protocol and placed in DAB/Sulf solution post
operatively

Subject 139: Set 1 and Set 2 grafts were put in dry dressing instead of being irrigated with CSS
solution

Cultured Skin Substitute Solution

Per IDE application, Attachment 4 (section f.1.4.3): CSS sites are to be irrigated every 8 hours with
CSS solution of a specified volume (usually 30 ml/graft) beginning at POD 0 through POD 5

There are no consistent records available identifying that CSS solution was used as specified, or
recording the amount of CSS solution used per application
74

There was reported misuse of CSS solution:
Subject 86: Per operative note dated 5/28/2004: It was noted that entire subject was prepped
with CSS irrigation solution. It was noted that CSS was not grafted during this operation.
The CSS solution was used as a standard surgical prep with no supporting documentation for
the reason why this occurred.
The CSS solution was prepared, by the Sponsor, specifically for the care of Cultured Skin
Substitute. It was used because of its non-cytotoxic, antimicrobial agents for management of
microbial contamination on wounds. There are no accountability records regarding the
preparation, storage, transport, or dispensing of this solution.
There were no specifications regarding the contents of the CSS irrigant. The contents of this
solution should have remained consistent throughout the study. There were noted substitutions
and changes made to this solution during the study:

Subject 95: It was noted that site ran out of CSS solution. Site was instructed by Melissa
Reed, at the University of Cincinnati, to use 1mL of Neosporin GU Irrigant in 1000mL of
saline for irrigation.

Subject 105: It was noted that the solution was changed by the site. There is an email,
filed with the CRF, dated Nov 18 2005. The email is from Melissa Reed to Carol Fabby
and Alandra Mangold (at Galveston). The email states awareness of modification to the
CSS irrigation solution by the Galveston Site. This modification was noted for Subject
105, for Set 1 and Set 2 POD 2-7. The solution was noted to have been modified, per the
request of a Galveston attending, and contained Neomycin GU in normal saline base,
which is noted as not containing all the proper antibiotics for microbial coverage. It notes
that the Galveston staff has been educated and informed that modifications to the CSS
and the protocol cannot be made without permission thru the IRB and FDA.

Subject 131: Double antibiotic solution was used for one (1) irrigation of CSS for Set 5
at POD 5, instead of CSS irrigation solution

Microbe sensitivity tests to the CSS solution were often performed at the University of Cincinnati
site, but not noted as being completed at any of the other study sites. The protocol does not
specify that these sensitivity tests are to be completed, however, it was frequently noted that CSS
sites were infected with microbes noted to be resistant to the antimicrobial agents in the CSS
solution. There were no specified procedures given on how to treat the CSS sites that were found
to have CSS solution resistant microbes. In many cases, the sites were grafted with CSS even
75

when CSS solution resistant microbes were detected prior to grafting. Therefore, there was no
non-cytotoxic, antimicrobial management available for these sites:
Subject 130: There were four (4) reported deviations (8/24/2007, 8/31/2007, 9/7/2007,
9/14/2007) of CSS being place on contaminated wound beds whereby the organisms
identified were noted as resistant to CSS nutrient solution and CSS saline solution.
The sensitivity tests, which were performed, against the CSS irrigant were reported as resistant or
sensitive to CSS Nutrient and CSS Saline. The protocol does not detail two separate
irrigations used on the CSS sites rather this irrigant was described as one solution with nutrient
and antimicrobial components
Per Table 31.1: Of the irrigation sensitivity tests run, there were a total of thirteen (13)
subjects who had reported microbe resistance to either the CSS solution or CSS nutrient
components of the irrigation.

76

Table 31.1
Sensitivity to Irrigation
R = Resistant S = Sensative R = Resistant S = Sensative
Enrollment # Set Result Enrollment # Set Result
Result for CSS Nutrient 88 1 S Result for CSS Nutrient 112 2 R
Result for CSS Nutrient 88 2 S Result for CSS Nutrient 112 2 S
Result for CSS Saline 88 2 S Result for CSS Saline 112 2 S
Result for CSS Saline 91 2 S Result for CSS Nutrient 120 1 S
Result for CSS Nutrient 92 1 R Result for CSS Nutrient 124 2 S
Result for CSS Nutrient 92 1 S Result for CSS Saline 124 2 S
Result for CSS Nutrient 92 2 R Result for CSS Saline 126 1 S
Result for CSS Saline 93 1 S Result for CSS Nutrient 126 4 R
Result for CSS Nutrient 97 1 S Result for CSS Saline 126 4 R
Result for CSS Saline 99 6 S Result for CSS Nutrient 130 1 R
Result for CSS Nutrient 103 7 R Result for CSS Saline 130 3 R
Result for CSS Saline 106 1 S Result for CSS Saline 130 4 R
77

32. Unanticipated Adverse Event (UADE)/ Serious Adverse Event / Adverse Event
Reporting

Prior to the onset of this third party audit, the FDA and University of Cincinnati agreed upon a list of
adverse events (See Appendix B) that the sites were to use in order to extract specific adverse events
from the subject data and report prospectively. This, however, was only completed for a few subjects at
the University of Cincinnati, therefore the majority of adverse event data was extracted by the auditors, as
part of the audit process, per the previously agreed upon list of events.

Per Figure 32.1, the total number of adverse events reported for this subject population was 733l. Of the
total number of events, 1782 events were identified by the sites either during study, or as part of the event
reporting agreement with the FDA, for the purpose of this third party audit. From the 1782 events
identified by the sites, seventy (70) events were reported as unanticipated device events, four (4) events
were reported as serious adverse events and two (2) events were reports as both serious and unanticipated.

Figure 32.1-Adverse Events Reported By Site

78

Figure 32.2: -Other Events: Shows the overall events of ARDS, Death, and infection.

79

Below shows a listing of the 7331 events, and the number of each event identified for this study:
Number and type of Adverse Events Identified
Adverse Event Number Identified
Microbial colonization of burn wounds 1305
Other infection 508
Hyperthermia (>/=39.5C) 408
Burn wound excision 372
Hypothermia (<37.2C for 2 hrs) 334
Pruritus (requiring medication) 289
Grafting with autrograft 284
Diarrhea (>/= 2/shift or >/= 6/day) 271
Leukocytosis (WBC > highest normal range) 256
Grafting with allograft, Integra or other temporary wound 253
Sinus tachycardia 199
Atelectasis 195
Hypertension 192
Tachypnea 188
Respiratory failure PaO2 < 60 mm Hg and/or PaCO2 > 45 181
Thrombocytosis (plt >/= 350) 170
Mild coagulopathy (PT>12.3, PTT>36.5) 148
Grafting with CSS 128
Graft Loss >10% 126
Hyperglycemia (glycosuria, insulin drip) 106
C-reactive protein (>/= 30) 93
Hypotension 91
Leukopenia (WBC < lowest normal range) 91
Graft loss (</= to 10% of the extent grafted) 85
Vomiting (>/= 2/shift or >/= 6/day) 82
Thrombocytopenia (plt </= 145,000) 81
Pulmonary edema 60
CSS regraft 59
other surgery 58
Wound infection 53
pain 43
Sedation 40
Anemia 39
Graft site contracture requiring release or revision 30
Constipation 29
Amputation of extremeties/digits from deep burn 28
Pain from primary injury 27
Sepsis/septicemia 27
Urinary tract infections (>100,000 CFU) 25
Nausea 20

80

Asymptomatic electrolyte imbalance 19
Renal tonic dopamine 18
Urinary tract infection, early 17
Inhalation injury and/or airway (req. intubation) 16
Pneumothorax 15
Pressor or ionotrope requirement 15
Pleural Effusions 13
Coagulopathy (twice the upper limit of the normal range 12
Confusion/delirium 12
removal of silatica from Integra 11
Unplanned surgical intervention 11
hypoglycemia 9
Pulmonary Infiltrates 9
Line infection (>100,000 CFU of organisms) 7
rash 7
Compartment syndrome (extremity) 6
Autograft/regraft 5
Death 5
Mental status changes 5
Pneumonia 5
suprastomal granuloma 5
Urinary tract infections 5
Acute renal failure 4
Congulopathy (twice the upper limit of the normal range 4
Dysrhythmia 4
Intubation due to declining respiratory status not related 4
Repeat grafting to same body site (>10% org grafted) 4
Abdominal Compartment Syndrome 3
Autografting to donor site for failure to heal 3
Celluitis 3
Electrolyte Imbalance (non specified) 3
Exploratory Surgery 3
Multiple organ failure/multi-system organ failure 3
Renal failure 3
ventilated 3
ventilation required 3
Acute Respiratory Distress Syndrome (ARDS) 2
airway obstruction 2
bloody secretions from trach req. bronchoscopy 2
fluctuant mass 2
81

Hematomas 2
hypothermia 2
kidney stones 2
Reinsertion of Trach Tube 2
tachycardia 2
wound excision 2
other surgery 1
abscess of thumb 1
anoxic injury 1
autograft regraft of CSS 1
back pain 1
bilateral corneal abrasions 1
bilateral subdural effusions 1
bleeding from tracheostomy 1
blisters 1
brain atropy 1
Brain/Skull Injury 1
cardiac arrest 1
cardiomyopathy 1
cerebral atrophy 1
Change in Vision 1
Chronic pain and burn like sensation to the right ankle 1
constant staph infection on bilateral lower extremities 1
css regraft of CSS 1
CSS regraft with Autograft 1
CSS regraft with CSS 1
decubitus 1
deep vein thrombosis 1
Diarrhea (>/= 2/shift or >/= 6/day) 1
dysphagia 1
excision and grafting of burn injury 1
Excision of hypertrophic scar 1
Excision of ulceration 1
Extraction of Dressing Material 1
fracture to femur 1
fractured femur 1
fungal infection of the left jaw 1
grafting with Amnion 1
Hypertension 1
hypospadias 1
82

Hypothemia 1
Inadequate Soft Tissue Coverage 1
intubation with ventilation 1
Jaundice 1
metabolic acidosis 1
Occluded trachestomy 1
other 1
pancreatitis 1
Particulate Granules associated with CSS 1
Phimosis 1
pressure area 1
Reaction to Fresh Frozen Plasma 1
Removal of Left Thumb Digital Stacking 1
removal of silastica from Integra 1
Repeat autografting to same body site (>10% org grafted) 1
repeat failed attempts at trach capping 1
repeat grafting of same body site (>10%) 1
repeat grafting to same body site >10% 1
respiratory depression 1
sebaceous cyst 1
sedation 1
seizure activity 1
small bowel obstructioin 1
systemic inflammatory response syndrome 1
thrombocytosis 1
tibia and fibula fracture 1
unexplained eosinophilia and itch 1
ventilation 1
worms 1
Total Adverse Events: 7331

83

The 10 most frequently reported events were as follows:

Event Number of Events Reported
Microbial Colonization of Burn wound 1305
Other Infection 508
Hyperthermia (>/= 39.5 C) 408
Burn Wound Excision 372
Hypothermia (<37.2 C) 334
Pruritus (requiring medication) 289
Grafting with Autograft 284
Diarrhea (>/=2 per shift or >/= 6 per day) 271
Leukocytosis (WBC >highest normal range) 256
Grafting with Allograft, Integra, other 253

Per CFR 812.3 (s) a unanticipated adverse device effect is any serious adverse effect on health or safety
or any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or
death was not previously identified in nature, severity, or degree of incidence in the investigational plan
or application (including a supplementary plan or application), or any other unanticipated serious
problem associated with a device that refers to the rights, safety or welfare of the subjects.

The Sponsor did not identify expected adverse device effects as part of the Investigational Device
Exemption Application (January 1998) or in the investigational plan (e.g. protocol) dated
November 2003.

The sites and Sponsor were responsible for reporting any serious adverse effects on health and
safety or any life-threatening problems or death as an unanticipated adverse event, as no events
had been previously identified as expected.

Subject 100: Event of Death was reported as an SAE by the site, but not reported as an
Unexpected Adverse Device Event.

84

Per CFR 812.40: Sponsors are responsible for selecting qualified investigators and providing them with
the information they need to conduct the investigation properly

Unexpected events, noted during the clinical progression of this trial should have been updated and
information reported to all sites participating in this study. This was not completed by the Sponsor.

Per CFR 812.50 (1) An investigator shall submit to the Sponsor and to the reviewing IRB a report of any
unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event
later than 10 working days after the investigator first learns of the effect.

Per the overall review of subject records, there was not adequate record of adverse event reporting to the
Sponsor and to the appropriate reviewing Institutional Review Boards. The sites were not reporting
adverse events per Form CSS 7.8 in the Case Report Form. Per the protocol schedule of events (version
November 2003), an adverse event summary was to be collected at Post Operative Days 14 and 28. This
summary was incorporated into the Investigator Global Assessment as the question Any AEs? and
was answered Yes or No. The sites should have been evaluating subjects for adverse events and possible
UADEs during the entire study duration and not only at these specific time points.

Figures 32.4 and 33.5, (below), show the summary of AE reporting for POD 14 and POD 28 (as noted on
the Investigator Global Assessment) across the 159 CSS sets applied. The majority of the reporting
indicated that no adverse events were present. However, because no expected events were ever
identified as part of the investigational plan, investigators and Sponsor should have been reporting events
in accordance with CFR 812.3. Additionally, seventy events were noted as Unexpected Events per the
reports completed and filed with the subject records. It is unclear why similar events were not consistently
reported as unexpected across the subject population. For instance, there were 126 events of graft loss
greater than 10% identified, yet only 26 of these events were identified as unexpected. There were no
parameters on why certain events were considered unexpected.
85

Figure 32.4- Adverse Event Summary By Set for POD 14
86

Figure 32.5-Adverse Event Summary for POD 28

87

Per Figure 32.6: Of the 70 UADEs reported in the subject records; only 54 could be verified as reported
to the appropriate Institutional Review Board.

Figure 32.6- Unanticipated Device Event Reporting

88

The following reported UADEs were not reported to, or could not be verified that they were reported the
appropriate Institutional Review Board:

Subject 131: Hypotension/ Onset date: 8/27/2007
Subject 131: Repeat Regrafting of same body site (>10%)/ Onset date: 1/25/2008
Subject 131: Repeat Regrafting of same body site (>10%)/ Onset date: 12/21/2007
Subject 128: Particulate Granules associated with CSS/ Onset date: 2/2/2007
Subject 130: Leukopenia/ Onset date: 10/2/2007
Subject 126: Pain/ Onset date: 1/3/2007
Subject 96: Constant Staph infection on bilateral lower extremities/ Onset date: 4/27/2005
Subject 98: Graft Loss >10% / Onset Date: 4/29/2005
Subject 134: Suprastomal Granuloma/ Onset Date: 6/5/2008
Subject 134: Fluctuant Mass/ Onset Date: 5/28/2008
Subject 134: Occluded Trachestomy/ Onset Date: 5/16/2008
Subject 134: Suprastomal Granuloma/ Onset Date: 5/2/2008
Subject 134: Graft Loss >10%/ Onset Date: 6/4/2008
Subject 134: Graft Loss>10%/ Onset Date: 5/30/2008
Subject 134: Graft Loss >10%/ Onset Date: 5/9/2008
Subject 113: Sepsis/Septicemia/ Onset Date: 4/17/2006

Per CFR 812.46 (b) A Sponsor shall immediately conduct an evaluation of any unanticipated adverse
device effect

Per review there was no documentation of the Sponsor following up on a report of a UADE from the
study sites.

89

Reported Deaths:
There were a total of five (5) deaths reported from the treated study subject population subjects 82-139

Subject 100:

Reported that subject died on 7/2/2005. Cause of death was reported as still under investigation.
Medical records reported that subject had a large bowel movement and subsequently became agitated
with a low O2 saturation. Subject became cyanotic and death was pronounced after 35 minutes of CPR.
The report states that subject developed sudden mottling followed by arrest, suggesting a possible
embolism to his aorta. An autopsy was not performed.

Causality to device was reported: Not Related
Number of Day from Device Application: 3
Reported to the IRB: Yes
Reported to the Sponsor: Yes
Reported to the FDA: Yes

Subject 103:
Reported that subject died on 10/30/2005 as a result of cardiopulmonary arrest.

Causality to device was reported: Not Related
Number of Days from Device Application: 23
Reported to the IRB: Unable to Verify

Subject 113:
Reported that subject died on 4/17/2006 as a result of deep necrosis and compartment syndromes.

Causality to device was reported as: Not Related
Number of Days from Device Application: 3
Reported to the Sponsor: Unable to Verify
Reported to the FDA: Unable to Verify

90

Subject 123:
Reported that subject died on 9/6/2006 as result of sepsis and multi-organ failure.

Number of Days from CSS Application: 11
Reported to the Sponsor: Unable to Verify
Reported to the FDA: Unable to Verify

Subject 124:
Reported that subject died on 9/12/2006 as a result of sepsis.

Number of Day from CSS Application: 59

Graft Loss/ Re grafting

It was observed that there was no consistency with regards to the determination or reporting of graft loss
at either the CSS or autograft sites. The investigational plan did not identify parameters for an expected
versus an unexpected event of graft loss. Additionally, graft loss was not captured by the sites in a manner
in which the graft loss or re-grafting could accurately be quantified.

Per protocol d.4.3.1: Graft failure will be characterized as sites that remain wet at the surface,
progressively become more red, and form granulation tissue. Partial or complete graft success will
be scored as an outer wound surface that is epithelialized, keratinized and dry.

Sites were not reporting graft failure or success on the protocol defined criteria as noted in section d.4.3.1.
From the events of graft loss, which were reported by the sites, graft loss was based on the Investigator
Global Assessment evaluation regarding percentage healed graft from tracing for both POD 14 and 28
(See Appendix C). Events of re-grafting were also reported as part of the Qualitative Outcome
assessment, collected at PODs 14, 28, 91, 182, 365 and greater than 365,( as possible).

91

Per Figure 32.7(a) (b) (c): 126 events of graft loss greater than 10% were identified and 85 events of graft
loss less than or equal to 10% were identified. This includes both the CSS and Autograft sites.

Figure 32.7 (a)
92

Figure 32.7 (b)
93

Figure 32.7 (c)
94

From the 126 events of graft loss identified, only the following events were identified as Unexpected
Adverse Device Events (as reported per the investigator on the Adverse Event Report Form). It is unclear
why only these specific events of graft loss were noted as unexpected.

Graft Loss >10% reported as Unexpected, per subject records:

Subject 130: event date of 11/23/2007
Subject 136: event date of 9/10/2008 (x2 events)
Subject 136: event date of 9/26/2008 (x2 events)

Graft Loss less than or equal to 10% reported as Unexpected, per subject record:


95

Per Figures 32.8 and 32.9: The number of CSS and autograft re-grafts are shown for the subjects who had
reported re-grafts. Re-grafting was captured as part of the POD 14 Investigator Global Assessment.
Additionally, the Qualitative Outcome also reported re-grafts. It is unclear how subsequent assessments
were calculated from the time of re-graft. For example, if a subject was re-grafted at POD 14, then the
next assessment reported was for POD28. However, this is not an accurate time frame for assessment.
There was no clear documentation, for how the re-grafts were being assessed independently as per
protocol section d.3.2: Repeat graftings will be considered independent events.
Figure 32.8-Reported Auto Re-grafts

96

Figure 32.9- Reported CSS Re-grafts

97

33. Concomitant Medications
The concomitant medications were collected as a part of this audit report as a special request by FDA.
The study case report forms were not designed to gather any medication information. The MRF audit
team recorded the medications that were created between UC and FDA in conference calls regarding the
affect medications may or may not have had on the device. Table 33.1 shows an overall listing of
concomitant medications noted and the frequency of event in the audit population. The individual subject
reports, identify the specific medications noted for each subject.
The medications used to treated burn study patients were listed in order of how they related to the device.
The medications were given a number as to whether the medication affected the device or the medication
is affected by the device. Only the medications that affects the device are listed in this report, as all the
medications that could be affected by the device were labeled a 1 meaning not related at all, thus this
category was eliminated from the final report.
Per table 33.2 and as Figure 33.3 identifies, there were 225 times medications were used on subjects that
definitely affected the device. These drugs were listed as a 5 on the scale meaning definitely affected the
device. There were two drugs used Mafanemide Actate Cream was used 125 times and Mafanemide
Acetate solution 0.5% was used 100 times. The medical records only noted the use of the medications
and not why they were used, thus making any interpretation from this data is out of the scope of the
auditors.
There were 66 times that medications were used on the study subjects that were rated a 4 as probably
affected the device. These drugs were Levophed; Growth hormone; Epinephrine Solution and
Epinephrine. The medical records only noted the use of the medications and not why they were used,
thus making any interpretation from this data out of the scope of the auditors.
There were 458 incidences of medications used that were rated a 3 as possibly affected the device. These
drugs were: Oxandralone, Bactroban, Neomycin, Amphotericin B, Vitamin C, Zinc, and Ibuprofen.
Neomycin was used 180 different times. Again the medical records only noted the use of the medications
and not why they were used, thus making any interpretation from this data out of the scope of the
auditors.
There were 1,016 drugs rated as a 1 as unlikely affecting the device. A listing of those drugs is shown
below the pie chart. The individual subject records have the complete record for which subjects received
which drugs and on which dates. For any specific information please refer to the individual patient record
con med section (concomitant medication section). There are a total of seven thousand eight hundred
seventy (7, 870) con meds listed in this audit report. That includes the topical medications applied to the
subjects as well as all other medications given to the subjects.
Table 33.4 is a listing of all topical concomitant medications noted as applied, and the number of times
each topical drug was applied.
98

Table 33.1

Con Meds Utilized and Number of Events
Drug Number of Events
Ketamine 605
Packed RBC 385
Vancomycin 312
Bacitracin 279
Amikacin 274
Zosyn 270
Whole Blood 238
Tylenol 219
Silver Sulfadiazine 213
IVIG 176
Neomycin 172
Fentanyl 170
Electrolyte solutions 149
Benadryl 146
Morphine 141
Versed 139
Mafanemide Acetate Cream 125
Eucerin 123
Fresh Frozen Plasma 119
Nystatin 112
Albumin 109
Mafanemide Acetate sol 0.5% 99
CSS Irrigation Solution 96
Lasix 86
Potassium 83
Propofol 80
Albuterol 79
Calcium 75

99

Con Meds Applied and Number of Events
Vecuronium 70
Methadone 68
Tylenol w/codeine 64
Vitamin C 62
Insulin 61
Nystatin 58
Magnesium 55
Polymixin B 54
Dopamine (renal dose) 53
Ambien 52
Ativan 50
Carafate 50
Folic Acid 43
Hydroxyzine 41
Valium 41
Seroquel 40
Folic Acid 40
Dulcolax 39
Platelets 39
Tylox 39
Zinc 38
Primaxin 37
Neurontin 37
Zinc 37
Precedex 35
Polymixin B 35
Nystatin 33
Oxandralone 32
Ibuprofen 32
100

Benadryl 28
Phenergan 27
Pipercillin 27
Nystatin topical 27
Benadryl 26
Aquaphor 26
Ativan 26
Risperdal 25
Epinephrine 25
Mineral Oil 25
Methadone 25
Seboflurane 25
Dobutamine 23
Hydromorphone 23
Tylenol 22
Packed RBC 21
Curel 21
Oxandralone 20
Versed 19
Aquacel Ag 19
Ascorbic Acid 19
Hydrocortisone 18
Polymixin B 18
Colistin 17
Claritin 17
Vitamin C 16
Prilosec 16
Whole Blood 16
101

Fentanyl 16
Ambien 15
Neurontin 15
Potassium 15
Zantac 15
Vitamin D2 14
Bactroban 13
Trazodone 13
Potassium 13
Miralax 12
Heparin 12
Vitamin D2 12
Lasix 12
Seroquel 12
Azactam 11
Phosphorus 11
Erythromycin 10
Ciprofloxacin 10
Fentanyl 10
Ampho B 10
Vicodin 9
Pavulon 9
Growth hormone 9
Vitamin D3 9
Ketamine 9
Levophed 9
Phenergan 9
Prozac 8
102

Pavulon 8
Flovent 8
Milk of Magnesia 8
Neosporin 8
Cymbalta 8
Diflucan 8
Protonix 7
Ibuprofen 7
Lunesta 7
Ativan 7
Carafate 7
Growth hormone 7
Pepcid 7
Ciprofloxacin 7
Epinephrine 7
Hydroxyzine 6
Ketamine 6
Cryoprecipitate 6
Cefapime 6
Tygacil 6
Epinephrine Solution 5
Zyvox 5
Benadryl 5
Prevacid 5
Pepcid 5
Vancomycin 5
Neomycin 5
103

IVIG 5
Vancomycin 4
Vasopressin 4
Heparin 4
Clindamycin 4
Hydrocortisone 4
Methadone 4
Lexapro 4
Lyrica 4
Diflucan 4
Fentanyl 4
Propofol 4
Precedex 4
Albumin 4
Albuterol 4
Tylenol w/codeine 4
Benadryl 4
Risperdal 3
Zyvox 3
Tylenol 3
Zosyn 3
Ampicillin 3
Oxandralone 3
Zoloft 3
Packed RBC 3
Diamox 3
Bacitracin 3
Seroquel 3
Prevacid 3
104

Phenergan 3
Phosphorus 3
Polymixin B 3
Dopamine (renal dose) 3
Vecuronium 3
Carafate 3
Folic Acid 3
Magnesium 3
Mineral Oil 3
Miralax 3
Valium 3
Mupirocin 3
Magnesium 3
Tylenol 3
Morphine 3
Tylox 2
Protonix 2
Ascorbic Acid 2
Percocet 2
Zinc 2
Zinc 2
Fentanyl 2
Polymixin B 2
Dulcolax 2
Magnesium 2
Hydroxyzine 2
Moisturel 2
Prilosec 2
105

Tube feeding 2
Platelets 2
Elavil 2
Lunesta 2
Polymixin B 2
Posaconazole 2
Neomycin 2
Nystatin topical 2
Insulin 2
Albuterol 2
Hydromorphone 2
Diflucan 2
IVIG 2
Carafate 2
Erythromycin 2
Growth hormone 2
Amikacin 2
Mupirocin 2
Versed 2
Whole Blood 1
Unknown 1
Precedex 1
Ciprofloxacin 1
Calcium 1

Vitamin D3 1
Celexa 1
106

Carafate 1
Potassium 1
Ciprofloxacin 1
Amphotericin B 1
Mupirocin 1
Albuterol 1
Zosyn 1
Albuterol 1
Ambien 1
Risperdal 1
Zoloft 1
Morphine 1
Rifampin 1
Neomycin 1
Amphotericin B 1
Prozac 1
Aquaphor 1
Propofol 1
Azactam 1
Azactam 1
Rocuronium 1
Zantac 1
Amikacin 1
Lasix 1
Tube feeding 1
Levophed 1
Pepcid 1
Folic Acid 2

107

Vicodin 1
Nystatin 1
Lasix 1
Fortaz 1
Seroquel 1
Gentamycin 1
Phosphorus 1
Tylenol w/codeine 1
Heparin 1
Tylenol w/codeine 1
Ketamine 1
Hydrocortisone 1
Oxandralone 1
Vasopressin 1
Oxandralone 1
Versed 1
Ibuprofen 1
Pavulon 1
Vitamin D2 1
Clindamycin 1
Clotrimazole 1
Colistin 1
Posaconazole 1
Cryoprecipitate 1
Vitamin D3 1
Erythromycin 1
Valium 1
Insulin 1
108

Diflucan 1
Vitamin C 1
Timentin 1
Lidocaine Injection 1
Vancomycin 1
Dulcolax 1
Dulcolax 1
Dulcolax 1
Platelets 1
Phosphorus 1
Epinephrine 1
Vitamin D2 1
Nitric Oxide 1
Tylenol w/codeine 1
Potassium 1

109

Table 33.2 2/12/2010
12:34 PM
Medications used and the likelihood it Affected the Device
Definitely Likelihood this Medication Affected the Device
Medication: Mafanemide Acetate Cream How often was it used: 125
Medication: Mafanemide Acetate sol 0.5% How often was it used: 100
Probably Likelihood this Medication Affected the Device
Medication: Levophed How often was it used: 10
Medication: Growth hormone How often was it used: 18
Medication: Epinephrine Solution How often was it used: 5
Medication: Epinephrine How often was it used: 33
Possibly Likelihood this Medication Affected the Device
Medication: Oxandralone How often was it used: 57
Medication: Bactroban How often was it used: 13
Medication: Neomycin How often was it used: 180
Medication: Ampho B How often was it used: 10
Medication: Vitamin C How often was it used: 79
Medication: Zinc How often was it used: 79
Medication: Ibuprofen How often was it used: 40
Unlikely Likelihood this Medication Affected the Device
Medication: Eucerin How often was it used: 123
Medication: Aquaphor How often was it used: 27
Medication: Bacitracin How often was it used: 282
Medication: Clotrimazole How often was it used: 1
Medication: Curel How often was it used: 21
Medication: Dopamine (renal dose) How often was it used: 56
Medication: Heparin How often was it used: 17
Medication: Insulin How often was it used: 64

110

Figure 33.3

111

Table 33.4
12:29 PM
Topicals Applied and Number of Events
Bacitracin 279
Silver Sulfadiazine 213
Neomycin 172
Mafanemide Acetate Cream 125
Eucerin 123
Nystatin 112
Polymixin B 54
Nystatin topical 27
Aquaphor 26
Mineral Oil 25
Curel 21
Aquacel Ag 19
Bactroban 13
Erythromycin 10
Neosporin 8
Hydrocortisone 4
Mupirocin 3
Moisturel 2
Unknown 1
Propofol 1
Azactam 1

112

34. Abnormal Laboratory Values
The MRF recorded all abnormal laboratory values for each subject audited in the Cultured Skin Substitute
(CSS) study. The lab values are noted as abnormal if the laboratory range for the subjects age is above
or below the range for that particular patient.
Each subject has full listings of all the laboratory values that were identified as abnormal in the individual
subject section of this report. The auditors did not separate out these values for charts or graphs as
abnormal lab values are a given with the extent of the subjects injuries on this study. The MRF did chart
out a few subjects; however the graphs simply showed a high increase of abnormal values dropping down
consistently to back in the normal lab ranges as time progressed. The improved lab values could be
contributed to the subjects improved health overall as the study proceeded.
Auditors can isolate any laboratory value recorded in the subject record or a combination of laboratory
values for the FDA if so required, however the labs were collected with the criteria of the name of the
laboratory test (i.e. BUN, Ca, C-reactive Protein, etc.); the date the lab value was done; the time it was
drawn; the value of the lab; if the lab result was signed off by the PI or a Sub-I, and the date it was signed
off.
Per the DSMB report, provided to MRF on March 24, 2010, abnormal lab values are classified as Minor
complications.
If the FDA wanted to specify labs pertaining to anemia, the MRF could assemble the WBC, etc. and print
those off in graph form. Given that 99,983 labs were noted as abnormal for the audited subjects, the MRF
has listed all the labs recorded, and will provide FDA with any subsequent charts or graphs FDA deems
necessary.
This study had no specific laboratory values consistently recorded in the CRF. Abnormal lab values were
captured as part of this third party audit and not as part of the investigational plan.

113

35. Primary Study Endpoints
There were four (4) primary study endpoints identified in the current investigational plan (Nov 2003
protocol):
d.3.3: Primary endpoints after grafting will be determined for both cultured skin substitutes and
split thickness skin autograft. Data collected will test the hypothesis that the cultured skin
substitutes reduce requirements for harvesting of split thickness skin for wound closure
End point 1: Protocol Section d.3.3.1: Ratios of closed area/donor area (both in cm sq) will be
expressed as a dimensionless factor to quantify wound closure/cm sq of donor skin for each type of
graft. If cultured skin substitutes are efficacious, then a statistical increase in healed area/donor
area is expected. This will demonstrate whether CSS reduce requirements for donor skin
harvesting to complete wound closure
This calculation is defined as: Healed area at POD 28/Donor area
Per protocol section d.3.2: the total area, open area, and closed area of wounds at POD 14 and 28
will be obtained by direct tracings onto a plastic sheet. Tracings on plastic sheet will be measured
by computer-assisted planimetry and values entered into the data table.
Per the Investigator Global Assessment, this calculation is reported as the Healed Area / Donor Area ratio
for CSS. This evaluation was intended to be completed by the investigator at the study site; however there
was no documentation on the process by which investigators were calculating these values being reported
on the subject Case Report Forms.
Since study site tracings were to be obtained by investigators or appropriate study staff, it is unclear on
the process by which these tracings were measured by computer assisted planimetry. However, values
for Healed Area Donor Area Ratio for CSS were being reported on the Case Report Forms. Per protocol
section d.3.3.1, a calculated measurement of healed area at POD 28 was required by investigators in order
to complete the Investigator Global Assessment section for Healed Area/ Donor Area Ratio for CSS.
Additionally, it was observed that this assessment was also reported at POD 14, by some investigators
(See Figure 35.1), which is not consistent with the protocol as noted in section d.3.3.1. This endpoint does
not clearly define how instances of re-grafts are factored into the analysis. Furthermore, the sites were
typically only grafting one comparative autograft site per patient, but evaluating multiple CSS sets per
patient. The difference in CSS versus autograft sites would seem likely to impact this endpoint
significantly.
114

Figure 35.1-Healed Area Donor Ratio Completion for POD 14

115

Endpoint 2: d.3.3.2: % TBSA closed with each graft type will be determined to quantify the
magnitude of impact of cultured skin substitutes on wound closure. It is expected that CSS will
be less than autograft. This endpoint will also be expressed as % TBSA/ donor area by dividing
the product of this calculation by column E (Treated Area)

This calculation is defined as: (Healed area at POD 28/TBSA) x 100 = %TBSA healed

This endpoint assessment does not factor in the events of graft failure requiring re-grafting. It was not
clear how the sites were capturing the healed area of re-grafted sites at POD 28, as it was noted that
much of the re-grafting took place between POD 14 and 28.

The measurement of healed area at POD 28 was dependant on the study site tracings being completed and
measured. Per Figure 35.2: 61 study site tracings were either not completed, or could not be verified as
completed at the POD 28 time point, therefore, making it unclear how this endpoint could be analyzed in
these instances. Additionally, the sites were typically only grafting one comparative autograft site per
patient, but evaluating multiple CSS sets per patient. This difference in CSS versus Autograft sites would
seem to likely impact this endpoint significantly.

Figure 35.2
Study Site Tracings for POD 28

116

Endpoint 3: Protocol Section d.3.3.3: Ratios of healed area/treated area x100 = % engraftment at
day 14 will be compared statistically for the two types of skin grafts. If a statistical difference is
found, the graft type with the lower % engraftment will be considered less efficacious than the
other. This end point contributes to determination of d.3.3.1 and d.3.3.2 above and d.3.3.6 below

This calculation is defined as: (Healed area at POD 14/Treated area) x 100 = %engraftment

Figure 35.3-Study Site Tracings for POD 14

The measurement of healed area is taken from the study site tracings as noted per protocol. Per Figure
35.3: above, it is noted that 54 tracings were either not completed or could not be verified as completed at
the POD 14 time point. It is unclear how this endpoint could be measured in these instances.
Additionally, the sites were typically only grafting one comparative autograft site per patient, but
evaluating multiple CSS sets per patient. This difference in CSS versus autograft sites would seem to
likely impact this endpoint significantly.

117

Endpoint 4: d.3.3.4: # of regraftings for each graft type will be recorded during the acute phase of
hospitalization and will be compared statistically. The graft type with the greater # of regraftings
will be considered less efficacious than the other.

There was no consistent documentation of the number of re-graftings for each graft type during the acute
phase of hospitalization.

36. Secondary Study Endpoints

with respect to collection of data at POD 7 and 14 on the Site Assessment Form.
Per review of subject records, there was not a specific form utilized at POD 7 or 14 entitled Site
Assessment Form. Protocol section d.4.3 Endpoints states that multiple evaluations will be performed
on days 7 and 14, and data will be collected on the Site Assessment form, however this form was never
located in subject records.
Per the Protocol, there are four (4) secondary study endpoints identified in the investigational plan

Protocol- d.4.3.1 Incidence of engraftment --will be scored as a trinomial event with failed grafts
designated 0, partial engraftment designated 1, and >80% engraftment designated 2. Engraftment
will be scored at a single time point, 14 days after surgical application of each pair of grafts.
Engraftment will be characterized as treated sites that develop dry, keratinized surfaces which
blanch with gentle pressure. Graft failure will be characterized as sites that remain wet at the
surface, progressively become more red, and form granulation tissue. Partial or complete graft
success will be scored as an outer wound surface that is epithelizlized, keratinized and dry.
Per protocol d.4.3.1, engraftment will be scored at a single time point 14 days after surgical application of
each pair of grafts. The protocol schedule of events specifies that the percent engraftment is evaluated at
POD 14 and 28. This is not consistent with what is reported in protocol section d.4.3.1. Per review of the
study records, it is not clear if subjects were being evaluated based on the criteria identified in protocol
section d.4.3.1. There was no documentation to support that the sites were assessed for keratinized
surfaced based on the application of pressure. The percent engraftment appeared to be reported as part of
the Investigator Global Assessment. There were no parameters provided for partial engraftment or graft
failure. (i.e. Graft failure = 0% - 10% healed / Partial engraftment = 50% healed).

118

with respect to collection of the Incidence and degree of bioburden
d.4.3.2 Incidence and degree of bioburden in treated wounds will be monitored by swab or
quantitative microbial culture of the wound site. Microbial cultures will be taken from the center of
each treated wound site. Treated sites that have not developed a dry, keratinized external surface
by the 7
th
and 10
th
post surgical day will be subjected to a additional microbial cultures. Incidence
will be scored on the operative day, and at post operative day 7 in a binomial manner (i.e. no
growth=0, growth =1). Degrees of microbial growth are defined as low (<10 organismis/gm tissue),
moderate (10 <10x5 /gm tissue), or high (>10x5 gm/tissue). Records will also be kept of the species
of organisms in the wounds.
Per protocol schedule of events, a microbiology culture of the recipient sites was to be collected Pre-
Study, POD 0, POD 7 and POD 14. There was no evidence of sites being assessed at POD 10 for
additional microbial testing. Figure 36.1 shows the overall number of Microbial Cultures performed at
each of the specified time points. At POD 14 it was noted that 59 of 159 cultures were not completed.
While microbiology reports were available with the study documents, the Case Report Forms did not
capture any specific microbial testing results, including the species of organisms in the wounds.
Therefore, it is unclear how this specific data was submitted to the Sponsor for endpoint analysis.

Figure 36.1 Microbial Culture of Recipient Sites
119

with respect to collection of the Dermato-pathologic data:

Per protocol d.4.3.5: Dermato-pathologic interpretation will be made from histological slides and
transmission electron micrographs of biopsies taken from healed wounds. A dermato-pathologist
will interpret the epidermis, and underlying connective tissue in comparison to biopsies from areas
treated with split thickness skin. Biopsies from wounds treated with meshed split-thickness skin will
be collected both from locations with grafted dermis and from mesh interstices. Interpretations of
the epidermis, the dermal-epidermal junction and the dermis will be made according to standard
dermato-pathological standards for assessment of histologic parameters of scar.
Investigational sites were consistently noted as not collecting healed wound biopsies at the time points
indicated per the protocol schedule of events. The schedule of events does indicate that these are only
collected as possible, however there was no documentation supporting why a biopsy could not be
collected. Per Figure 36.2 : Only a small percent of these biopsies were actually completed for the 159
CSS sets applied across this subject population. For the small percent of biopsies collected from the
healed CSS sites, there were no histology reports available to substantiate that a dermato-pathologist
made the appropriate interpretations of these biopsies, as specified per protocol section d.4.3.5. There
was also no documentation, to support that biopsies were collected from the healed comparative autograft
sites. The Case Report Forms did not collect data with regards to dermato-pathologic interpretation, so it
is unknown how, if any, of this data was reported to the Sponsor for analysis.

120

Figure 36.2-Healed Wound Biopsy Completed for PODs 7-365

121

37. Device Quality Assurance Testing/ Sterility Testing
Overall, auditors observed there was not sufficient documentation with respect to the storage, shipment,
handling, or disposition of the device utilized in this study (CSS). This finding is also consistent with
available documentation for device quality assurance testing.
Per Protocol d.2.5: Two assessments of CSS quality are performed on each preparation of cultured
grafts. 1.) Surface electrical capacitance (SEC) with the Dermal Phase Meter and 2.) Histological
examination of 18 CSS in each set of grafts.
Surface electrical capacitance (SEC) with the Dermal Phase Meter measures surface hydration by
conductance or impedance of a weak electrical current across the instrument probe. The
corresponding signal is transmitted to a computer and is read for 10 seconds in each of four
locations on each CSS graft. The final reading is defined as the continuous capacitance and is
recorded to a notebook computer. The values from all reading are transferred to an MS Excel
spreadsheet and average values are determined. Low values represent low hydration (dry surface),
and high values represent high hydration (wet surface). The scale for the instrument ranges from
90 (very dry) to 900 (very wet). These readings correlate with the formation of epidermal barrier.
Therefore, SEC indicated the development of the epidermal phenotype of keratinized stratum
corneum.
Two sets of readings are recorded, typically on incubation days 6 and 9. To pass the quality test,
each CSS graft must decrease in DPM values, which corresponds to a decrease in surface
hydration. This negative change indicates that epidermal barrier is forming which is criterion for
release for surgery.
Auditors were unable to locate documentation of two specific SEC readings for the CSS grafts
which were cultured as required per protocol d.2.5. A pass/fail rating for SEC evaluation was not
clearly stated in the device documentation.
However overall, Surface Electrical Capacitance test was observed as having the best supporting
documentation for the device quality assurance testing.
Per Protocol d.2.5: Histological examination of CSS is performed by embedment of samples in
glycol methacrylate which provides superior anatomic preservation and image resolution. CSS
samples are evaluated on a qualitative scale of: Excellent, Good, Fair, or Poor (as determined on
condition of Epithelium, Fibroblasts, and thickness of Biopolymer Matrix)
Per figure 37.1, only 67 histological exams were completed for which the auditors could verify through
supporting source records. This same graph shows that 88 were unable to be verified. . The protocol
states that the scoring for the Histological Scores was to be listed as Excellent, Good, Fair, and Poor.
This scoring was rarely seen. Most of the scoring in the device records listed Good, Slightly thin, Thin,
Patchy, Slightly Patchy, Very Thin, Slightly Thin Center. The scoring scale from the protocol was not
used as the proper documentation for the Histological examination of the CSS.

Per Protocol d.2.5: Sterility tests of CSS are performed five days before surgery, and on the day of
surgery to verify the absence of microbial contamination.
122

Sterility tests, as per the protocol, were to be performed five days before surgery and on the day of
surgery to verify the absence of microbial contamination. As per protocol, these tests in addition to the
SEC and histological testing would ensure both the quality and safety of the device. Figure 37.1 shows
that only ten of the sterility tests were completed five days prior to surgery. The vast majority of the
sterility tests were observed to have been completed 7 10 days prior to the surgery date. There is
nothing specified in the protocol that indicated the sterility test could have been performed earlier than
five days prior to application.
In addition, sterility test were to be performed on the day of surgery. One hundred eleven sterility tests
were performed as the protocol designated, however 43 were not done day of surgery and 5 others were
either incomplete data, or unable to verify the data. Most of the not done category was left blank in the
case report forms, and there was no documentation in the medical records.
The protocol did not provide flexibility in when these sterility tests were to be performed, and testing time
frames were clearly stated in the investigational plan.

Figure 37.1-Device Quality Assurance Testing

123

38. Devices Returned
Figure 38.1 reveals that the majority of the CSS grafts sets were placed on the human subjects on this
clinical trial. When sets were not used or returned, there was not consistent documentation of why
devices were returned or not used. Documentation was elusive in the records regarding the devices. Some
instances show, if grafts were left over from one set they might be added with the next graft set. Some of
the documentation was written on the back of the page of the burn diagram which specified where the
grafts were placed. There was no consistency for documentation. Examples of this are as follows:
Subject 84: Set 2: Seven grafts were not used and no record was available with documentation as to how
or where they were stored until used at a later date for spot re-grafting. Additionally, there was no
documentation on as to reason grafts were not used initially.
Subject 86: Set Seven: 32 grafts were sent to Galveston for set seven, however only 14 grafts were used.
Auditors were unable to verify what was done with the remaining 18 grafts.
Subject 103: Set seven had eight grafts returned from the OR, and no reason was noted. The same
subject for set two had two grafts that could not be accounted for. No reason given why the two grafts
were not sent to the OR.
Subject 107: Set two had six grafts returned. It is unknown why the grafts were not used.
Subject 119: Set One. Notes state that 32 grafts were cultured. A handwritten note in the device
documentation states that grafts #1 15 were meshed and prepped for surgery, however only #1 8 were
applied and grafts 9 15 were returned from the OR and discarded. No indication of the balance of the
grafts being discarded due to QA issues, or any other reason.
Subject 130: Set Six: Unable to verify what happened with the eight grafts that were not placed on the
subject. Set two: two grafts were unused, without documentation or record of these being returned to
sponsor. No record of disposition was present.
Subject 136: Set two; four grafts were held and re-cultured, per written note in paper records Dr.
Boyces database reported all 32 grafts were applied. CRF states 4 were returned to sponsor, no reason
noted.
Subject 139: Set 3: 21 grafts not used; no documentation if the grafts were not sent to OR, or sent and not
used.
124

Figure 38.1-Number of Sets with Devices Returned

125

39. Device Labeling/ Device Storage
Auditors observed that the sponsor did not comply with CFR 812.25(f): The investigational plan shall
includecopies of all labeling for the device or CFR812.45: A sponsor shall supply all investigators
participating in the investigation with copies of the investigational plan and the report of prior
investigations of the device
The sponsor did not include a copy of device label as part of the investigational plan (protocol).
Additionally, the device label was not made available to all investigators participating in this study.
Auditors could not verify that any device utilized in this study was labeled in accordance with CRF
812.5(a )(b): Contents. An investigational device or its immediate package shall bear a label with the
following information: the name and place of business of the manufacturer, packer, or distributor (in
accordance with 801.1), the quantity of contents, if appropriate, and the following statement:
"CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use."
The label or other labeling shall describe all relevant contraindications, hazards, adverse effects,
interfering substances or devices, warnings, and precautions. Prohibitions: The labeling of an
investigational device shall not bear any statement that is false or misleading in any particular and shall
not represent that the device is safe or effective for the purposes for which it is being investigated.
During the course of the audit, a copy of a label was made available to the audit team. (Appendix D) The
auditors were informed that the noted label is what was currently being used to label the device. No
copies of patient specific labels were noted with subject study records; therefore auditors could not verify
the use of this label.
The laboratory, whereby the CSS is made, is located on the fourth floor of the Shriners Hospital Building
in Cincinnati, Ohio. Access to the floor is by computer key card access only. New employees or visitors
must obtain the computer key card access from the security office of Shriners Hospital. The laboratory
which is approximately half way down the hall way is reachable by a door from both sides of the hallway.
The laboratory is located in the middle of the building. During the year that the auditors were present,
people walked in and out of the lab at will. It did not appear that an additional key card or code of any
sort was needed, once the laboratory was initially unlocked each morning.
As figure 39.1 illustrates, the audit team was unable to verify any element of device storage. This includes
monitoring of security of storage area, specifically temperature monitoring. Thereby, auditors were
unable to determine if any storage temperature excursions were reported to the Sponsor. The development
of the CSS grafts was overseen by Steve Boyce, Ph.D. Dr. Boyce also determined graft QA approval and
he was often in the OR for the placement of the grafts. With either Dr. Boyce or the research nurse
involved in the process consistently, it appears that much of the communication may have been verbal
with respect to the device records. The MRF audit team was not provided with any monitoring logs
regarding the laboratory where the CSS was stored. The storage units that held the devices were
identified and the auditors were informed by Dr. Boyce, during the site tour, that the units were checked
daily but no logs for storage temperature control, or any other type of monitoring was accurately
maintained.
126

Figure 39.1-Device Storage

127

40. Device Disposal
Figure 40.1, illustrates that the investigative sites did not maintain proper device disposal records as
mandated per 21 CFR 812.140 (a)(2)(iii): A participating investigator shall maintain the following
accurate, complete, and current records relating to the investigators participation in an
investigationRecords of receipt, use or disposition of a device that relate to: Why and how many
units were returned to the sponsor, repaired, or otherwise disposed of
Per 21 CFR section 812.110(e): Upon completion or termination of a clinical investigation or the
investigators part of an investigation, or at the sponsors request, an investigator shall return to the
sponsor any remaining supply of the device or other dispose of the device as the sponsor directs.
The auditors were told verbally by Dr. Boyce that the device was disposed in a manner consistent with the
Standard Operating Procedures of Shriners Hospital.
The auditors could only ascertain one record that specifically related to the disposal of the cultured skin
substitute grafts. No other records were identified. There was no discussion in the operative notes as to
grafts remaining, being returned to the laboratory, or disposed of.
Auditors were unable to verify that the CSS disposal met with the regulations of Tile 29 Part 1910 and
Title 42, Part 72 and 73 of the CFR. The auditors requested numerous times for ALL information,
regarding the device, to be supplied to them. No device disposal logs were ever mentioned, or given to
the auditors at any time throughout the audit. There were no records supplied to the auditors regarding
CSS that was returned to laboratory from the OR. There were notes adding the grafts to the next grafting
procedure sometimes. Proper documentation of records was not found by the auditors regarding the
device disposal.
128

Figure 40.1 Device Disposal

129

41. Device Shipping Information Available
Per CFR 812.140 (a)(2)(i)(ii): A participating investigator shall maintain the following accurate,
complete, and current records relating to the investigators participation in an investigationRecords of
receipt, use or disposition of a device that relate to the type and quantity of the device, the dates of its
receipts, and the batch number or code markthe names of all persons who received, used, or disposed
of each device.
There were very few shipping records available for grafts shipped from the Sponsor to the remote
investigational sites, as noted in figure 41.1. Additionally, figure 40.1 (above) illustrates that no batch
code or number could be verified in device record as required per CFR 812.140 (2) (i), which is noted
above. The shipping records identified were for shipments of the device to Sacramento and one shipment
to Galveston. Auditors could only verify the following for device shipped to remote sites: date of
shipment for eight (8) of the shipments, that the device was consistently transported via Delta Dash (as air
bills were present), and the date of receipt on six of the eight shipments. The names of all personnel
handling the device were not consistently documented, with the exception of the signatures noted on the
Delta Dash air bills.
The temperature of each shipment was not recorded and no temperature tracking records were provided to
the audit team. It was observed that one shipment was lost due to the extreme weather conditions. E-mail
communication, was observed by auditors, which identified a need for temperature tracking instruments
with device shipments; however this was never actually identified as being accomplished.
Due to the Integrity Hold letter, no further shipments of CSS have occurred. The compassionate use
subjects who are continuing to be enrolled are being seen at the Cincinnati Shriners Hospital and while
there is not actual shipment of the CSS, the record keeping between the laboratory and the OR should be
better documented in regard to listing of devices made, transported to the OR, returned from the OR,
copies of the label of each CSS set, and signatures with dates for who signed out the devices, carried the
devices, and returned or disposed of the devices.
130

Figure 41.1-Device Shipping Information Available

131

42. Protocol Deviation Summary:
Through the course of the audit, it was noted that approximately 370 protocol deviations were identified
by the sites, or thru the audit process. Figures 43.1 and 44.1 show a break out of the 370 protocol
deviations and the reporting trends to the IRB and Sponsor. However, the most common protocol
deviation noted, was lack of adherence to completion of protocol procedures. Table 42.1 gives an overall
estimate of the procedures which were not completed for the subject audit population.

Table 42.1
Estimate of Protocol Procedures Not Completed
Procedure Number Incomplete
Informed Consent: 1
Past Med History: 0
Physical Exam Pre-Study: 0
Serum Antibodies Pre-Study 9
Serum Antibodies POD28 119
Physical Exam POD 0 41
Physical Exam POD 28 17
Skin Biopsy for Tracing 9
Microbial Culture of Recipient Sites: Pre-
Study
48
Microbial Culture of Recipient Sites: POD 0 29
Biopsy of Recipient Sites POD 0 83
Photo of Wound Bed (Recipient Site) 31
Photography Post Graph 58
CSS Tracings in Vitro 2
Study Site Tracings POD14 38
Study Site Tracings POD28: 38
% Engraftment POD14 8
%Engraftment POD28: 8
Healed Area /Donor Area Ratio (POD 28) 84
Qualitative Outcomes(For all time points) 5
Healed Wound Biopsy 901
Adverse Event Summary POD 14 1
Adverse Event Summary POD28 1
Investigator Global Assessment Unable to be determined
PODs NOT DONE 390

132

43. Protocol Deviations Reported to IRB

Figure 43.1-Protocol Deviations Reported to IRB
The protocol deviation detail, figure 43.1 unmistakably illustrates that the audit team could not verify that
protocol deviations had been submitted to the IRB. The UC IRB does not acknowledge receipt of
protocol deviations back to a site. There were also several forms used for protocol deviation reports.
Some had UC IRB at the top, some were Shriners Hospital forms, and some were simply blank pages
with the deviations typed up. No documentation was identified that showed where it was faxed, no
handwritten note stating the deviation report had been submitted, no way to verify that it went to the IRB.
The figure below shows 370 protocol deviations noted in the auditors database. The audit of the UC IRB
protocol files did not reflect the number of protocol deviations that should have been located within those
files. In fact, some of the deviations noted were not protocol deviations for the CSS study. They were
noted as being misfiled. There was not a standard operating procedure found for reporting of deviations to
the UC IRB.

133

The University of Cincinnati IRB website has a deviation form template available, however it is not the
same form that has been used in the CSS study records. The website does not list requirements as to
when or how the deviations should be reported. The website deviation form has a date of 7/31/2006 on
it.
Of the 370 protocol deviations recorded in the audit data base, only nineteen of those can be confirmed as
being received at the IRB. The vast majority (310) were unable to be verified as being submitted to the
IRB, and the forty one (41) nos were deviations identified by auditors, therefore the site did not report
these specific deviation.
After reviewing the IRB records, it is not possible to match the records of the deviations. The record
keeping was minimal from the standpoint of the IRB records as well as site records. This study has been
ongoing from 1998 to present, however the IRB records were made up of three small volumes of
paperwork, as this was all that was supplied to the auditors from the IRB as to their records for this study.

134

44. Protocol Deviations Reported To Sponsor
Figure 44.1-Protocol Deviations Reported to Sponsor

Figure 44.1, shows the number of protocol deviations that were identified as reported to Sponsor. There
is a higher number reported to the sponsor as at the beginning of the records for the audit Steve Boyce,
Ph.D. was listed as PI for the study and the sponsor. Many of the protocol deviation reports were
recorded and signed off by Dr. Boyce himself, thus the sponsor had knowledge of the deviation. After
Dr. Kagan became the PI, it is not clearly documented that the deviations went to the sponsor. Much of
the documentation for the deviations was noted as completed one to two years after the fact. A few
examples noted are:
#84 Deviation of 2/10/2004 Written by Dr. Boyce on 3/5/2007
#99 14 out of 20 deviations occurred in 2005 Written by P. Simpson on 9/1/2009
#109 2 typed deviation forms on plain paper No signatures or dates
#109 1/19/2006 deviations Written by Dr. Boyce on 4/2/07

135

#109 1/1/06 deviation lists events not done Signed by Dr. Boyce on 2/4/07 Events
Typed CRFs; no signatures

# 120 Deviation of 5/26/06 Reported 7/17/2009
The sponsor records indicate that Dr. Boyce initially was in charge of, listing adverse events in the
continuing review form only. Deviations were not reported to the IRB by the sponsor until the last three
years 2007 to current.

45. Sample Audit of the First 81 Subjects in the CSS Study

Prior to the initiation of this independent third party audit, University of Cincinnati, had agreed with
FDA, to conduct a separate audit of the first 81 subjects. Upon conclusion of the separate audit, MRF
agreed to a subsequent, random sample audit of the first 81 subjects.
The MRF auditors were never informed, by UC, that the initial 81 subjects had been audited. There was
communication between UC Compliance and MRF about using the MRF database, to conduct the audit of
the first 81 subjects. Additionally, UC Compliance also requested a bid from MRF about allowing MRF
to complete the audit of the first 81 subjects. However, to date, MRF has not been notified that subjects
1- 81 have been audited. Therefore, MRF did not complete the agreed upon sample audit of 8 to 12
subjects as was outlined in the audit plan.
The first 81 subjects were enrolled under different versions of the protocol, yet these subjects make up the
majority of the overall study population and generated the majority of the study data. Because the
findings of the third party audit are only inclusive of data collected from subjects 82-139, it is unknown if
the findings from the initial subject population could have had any impact of the outcome of this audit. In
particular, safety and efficacy data cannot be assessed in its entirety, without data from the review of the
initial 81 subjects.

136

46. Annual Reports
The Annual Report for period January 1 June 2004 was reviewed by auditors. Similarly as the audit
started with subject #82, the audit review comes in middle of the annual reports.
Based on the regulations cited below S. Boyce, Ph.D. did not fulfill the requirements for reporting. At the
initial reporting date of January 1, 2003 Steve Boyce, Ph.D. was assuming the role of the PI/Sponsor.
During the initial time period of the first report for this audit group of subjects for the CSS study
(beginning 2003) the annual report should have been submitted every six months, thus there should have
been a report for:
January 1, 2003 June 30, 2003
July 1, 2003 December 31, 2003
January 1, 2004 June 30, 2004
January 1, 2005 June 30, 2005
January 1, 2006 June 30, 2006
January 1, 2007 June 30, 2007
January 1, 2008 June 30, 2008
July 1, 2008 - December 31, 2008 Total of 12 Annual Reports Due to FDA

CFR 812.150(a)(3): Investigator reports. An investigator shall prepare and submit the following
complete, accurate and timely reports (3) Progress. An investigator shall submit progress reports on
the investigation to the sponsor, the monitor, and the reviewing IRB at regular intervals, but in
no event less often then yearly.
CFR 812.150(b)(5): Sponsor Reports. A sponsor shall prepare and submit the following complete,
accurate, and timely reports: (5) Progress reports. At regular intervals, and at least yearly, a sponsor
shall A sponsor of a treatment IDE shall submit semi-annual progress reports to all reviewing IRBs
and FDA in accordance with 812.36(f) and annual report in accordance with this section.
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CFR 812.36(0): Reporting Requirements: The sponsor of an IDE shall submit progress reports on a
semi-annual basis to all reviewing IRBs and FDA until the filing of a marketing application
Annual Reports were submitted by S. Boyce, Ph.D., for the periods:
January 1, 2003 June 30, 2004 Period of 18 months
July 1, 2004 December 2005 Period of 18 months
January 1, 2006 December 31, 2006 Period of 12 months
Total of 5 Annual reports submitted to FDA
Other information of note in the Annual report for January 1, 2003 June 30, 2004
Section 11.2 Number of investigators (16)/ investigational sites (3): Steve Boyce PhD writes that
he is adding three (3) physical therapists who will be collecting post-grafting data of skin
pliability and range of motion as investigators to the CSS protocol. It is unclear why this
occurred, when the pliability record was on the Qualitative Outcome (QO) Case Report Form
(CRF) and there was nothing in the CRFs for the range of motion record. The research nurses at
the sites were recording the information for the QO forms.

1. The subjects that were enrolled (Subjects 74, 86 and 87) were enrolled per Steve Boyce as
compassionate use subjects. However in Table 3: Specification of subject enrollment and
treatment by medical condition; it appears that Dr. Boyce included them in the total number of
acute burn subjects. As Dr. Boyce does not list the subject numbers that are included in the total
number of burn subjects it is not possible to assess this accurately. However the University of
Texas IRB specifically stated in their approval letters that compassionate use subjects data may
not be used in the research study.
2. It is also noted that while Dr. Boyce asked for and received permission to enroll subject with burn
scars and giant nevus; there were no changes to case report forms to reflect capture of data for
these subject. Many of the queries that were on the case report forms cannot be answered in
response to scar or giant nevus skin grafts. Instead of modifying the case report forms to
accurately collect data, the same forms as acute burns were used, and the research nurse simply
did not complete the forms.
3. Section 11.4.2.1 Qualitative outcome by assessment with a composite Vancouver Scar Scale. As
previously discussed this form is filled out by different personnel, sometimes the research nurse
on the study, and sometimes Dr. Boyce filled them out. This raises a question of bias by the
study personnel.
4. The engraftment graft data cannot be evaluated at this time, as this audit group did not audit the
first 81 subjects.
5. The preclinical information cannot be assessed by this audit team. The preclinical and laboratory
issues are not in the scope of this audit.
6. Adverse Events for these subjects cannot be verified as the majority of the subjects fall into the
previous subset of subject that the MRF did not audit.
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According to the audit records there were 108 adverse events noted in 2003 and 1,268 noted for 2004.
The annual report lists four subjects with an adverse event from January 2003 June 2004. The
auditors could not split the numbers to match the annual report, as the annual report included
seventeen months of data.

Information of note in the Annual report for July 1, 2004 December 31, 2005
1) Galveston subjects treated under compassionate use. Subjects #90 and 94 were Informed Consent
(ICF) only, no treatment occurred.
2) Subject #104: Subjects family signed an English ICF, and yet they were from Mexico. There is
no documentation that English was understood by the family. This same subject was on three
additional research studies and the family signed these ICFs that were in Spanish. There was no
UC approval on file; there was a letter to FDA requesting approval, however no letter of approval
from FDA granting approval for this subject was located. Information for set 1, POD 28 was
completed by Melissa Reed, research nurse in Cincinnati when the subject was in Galveston,
again no reason noted why this was done. There is a deviation report dated 02/28/2007 by Dr.
Boyce that states no microbiology log for set 1, and no logs for biopsy, micro, cultures, re-
grafting for set 2. These all have typed logs now in the files. When and where they were done,
cannot be determined as they are typed (all previous forms from Galveston had been hand
written) and there is no date or signature on any of them.
3) Subject #96: No records located regarding approval from UC, UC IRB, or FDA. The ICF that
was signed by the subject's mother did not have a signature rather a printed version of her name is
placed where the signature should be. There is no note to file to explain why the subjects mother
printed rather than signed her same. The ICF is from the University of Cincinnati's IRB and this
subject was deemed by the UTMB IRB as an emergency use subject. The sponsor and FDA refer
to this as a compassionate use case for this subject. The study at this current time period was not
approved at the Galveston site.
4) Subject # 105: Galveston Shriners requested compassionate use for this subject. Records show
Galveston request to Dr. Boyce at Shriners in Cincinnati. There is no official approval from Dr.
Boyce as the PI/or sponsor. There is a request from Dr. Boyce to the FDA for approval.
However, no further documentation is found with the CRF information. There is an email filed
with the CRF dated Nov 18 2005. It is from Melissa Reed to Carol Fabby and Alandra Mangold
(at UC). The email states awareness of modification to the CSS irrigation solution by the
Galveston Site. This modification was noted for Subject 105- For Set 1 and Set 2 POD 2-7. The
solution was noted to have been modified, per the request of a Galveston attending, and contained
Neomycin GU in normal saline base, which is noted as not containing all the proper antibiotics
for microbial coverage. The correspondence also notes that the Galveston staff has been educated
and informed that modifications to the CSS and the protocol cannot be made without permission
thru the IRB and FDA. There are numerous deviations to protocol which are shown in detail in
the individual subject record. Auditors noted that the information in the CRF is typed in, and
there is no reference to the person or date for which many of the documents were completed.
5) Section II4.2.1: Qualitative outcome by assessment with a composite Vancouver Scar Scale and
CSS growth. Dr. Boyce adds data in that he states he collected on eight subjects between 2-7
years after the grafting which demonstrates that the auto-CSS grows with pediatric patients and
suggest that there may be fewer needs for scar reconstruction. As Dr. Boyce states this is not an
endpoint in this study so the information should not be included in this data. There was no
information in the subset of subjects audited by MRF that showed any data in this 2 7 year after
initial CSS graft placement. Also unknown is how Dr. Boyce selected these particular subjects to
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follow. Auditors could find information to substantiate, however this type of information would
either call for an amendment to the study or a new study to determine the relevance of this
information.
6) Auditors were unable to assess the engraftment, donor skin information in section II4.2.2 due to
the inclusion of the first study subjects that MRF did not review.
7) Adverse Events are assessed separately in the audit report. As a note for July 1 2004
December 31, 2005, 1,268 adverse events were entered into the MRF auditing data base, and the
annual report which includes portions of this time frame lists subjects with three adverse events
only.
8) Section IV. Other Changes: There is a change requested for the expanded assessment of burn
scars. Three requests were made to the site for the complete annual reports. The three copies of
the annual report that MRF received did not have this form. However, during the audit, this form
was not seen.
None of the appendix list of information was attached to the annual report thus MRF was not able to
review this information.
Information of note in the Annual report for January 1, 2006 December 31, 2006
II.l Summary of Study: In February 2006, the technology rights for this device were acquired by a
commercial developer who will assume responsibility for filing of applications for marketing
permissions.
What does not appear in the annual report, or any subsequent financial disclosure forms, is that
Cutanogen Corp was founded in 1997 by Dr. Steven Boyce (per a published newspaper article Medical
Advances Incubate in Corryville by Tim Bonfiled with the Cincinnati Enquirer (local newpaper) dated
June 30, 1998. (Appendix G) The article below shows that in 2006 Cambrex BioScience Walkersville,
Inc. purchased Cutanogen in the amount of $1.5 million fully paid at the closing with additional purchase
price payments of up to $4.8 million subject to certain milestones.
On 05/26/2006 Dr. Boyce completed the Conflict of Interest (COI) form for the UC IRB. Dr. Boyce
states that there are two patent applications pending with UC/SHC. Dr. Boyce is the sole inventor on
those patents. Dr. Boyce stated that the technology and licenses for patents were acquired by Cutanogen
and sold to Cambrex on 2/28/06. Dr. Boyce currently serves as a paid consultant for Cambrex to assist
with product development. Also, that the sale of Cutanogen to Cambrex provides for additional payments
to Dr. Boyce upon accomplishment of specific milestones in product development. No actual dollar
amount was disclosed.
On 06/11/2006 Dr. Richard Kagan completed a COI disclosing that he now owns equity or other
ownership in the company or other legal entity who drug, procedure, technique, device or software I am
testing. (Does not state the name of the company)
May 11, 2007 COI for Steve Boyce PhD still indicates a yes for equity, yes for holds patent rights,
yes for consultant, yes for royalty income. Still no dollar amount noted.
On June 20, 2007 the UC IRB minutes from meeting state that Dr. Boyce is no longer involved in the
enrollment or consenting processes of this protocol because of his significant conflict of interest.
On May 9, 2008 Dr. Boyce again completed the COI form (Appendix F) with a yes indicated for equity
ownership, patent rights, consultant, and royalty income. The bottom of the UC COI states in bold capital
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letters IF ANY BOX ABOVE IS CHECK YES, INCLUDE ON A SEPARATE SHEET AN
EXPLANATION OF THE CONFLICT (INCLUDING THE AMOUNT OF MONEY) FOR THE
IRBS CONSIDERATION. INFORMATION PROVIDED IS CONSIDERED CONFIDENTIAL.
Attached to the COI form is Dr. Boyces explanation which states that he founded Cutanogen and in 2006
sold all of the stock (including stock owned by Dr. Boyce). The sale is scheduled to be paid in six
installments, one of which is completed and five are pending accomplishment of milestones. That
consultant agreement was from March 2006 February 2007, however the consulting agreement has
expired. There is additional information provided that on February 5, 2007 Cutanogen and CBSW
(Cambrex) was sold to Lonza Corporation, a Swiss BioPharma company. CBSW is now named Lonza
Walkersville, Inc. The performance milestones of Cutanogen remain pending completion.
There was never a disclosure of any amount which Dr. Boyce may have received even though the IRB
requested it. The IRB board stated that there is a perception of conflict. The IRB offered three options:
1) assign another person as PI for the study; 2) disclose in the consent form the detailed information of
how the investigator is involved with the company ; or 3) attend the next IRB meeting and discuss why
there is no conflict. Dr. Boyce changed the PI of the study to Dr. Richard Kagan and in June of 2008
revised the ICF to state: Dr. Steven Boyce, a sub-investigator on this study, has received payments from
the company that owns the rights to the process used in this study. This disclosure is made so that you
can decide if this relationship will affect your willingness to participate in this study. The below article
was identified that may clarify the relationship. It is not known if the payments were made solely to Dr.
Boyce. However since this was a published article found on the web with little effort, it is unclear why
Dr. Boyce was so resistant to disclosing a dollar amount to the IRB.

Cambrex Acquires Cutanogen Corpoation
07 Feb 2006 - Cambrex Bio Science Walkersville, Inc., a subsidiary of Cambrex Corporation, announced it has
entered into a purchase agreement for all of the stock of Cutanogen Corporation, a privately-held biotechnology
company that is focused on products used to treat patients with severe burns. The Company believes that the lead
Cutanogen product PermaDerm(TM) cultured skin is the first multi-layered product that combines autologous
epidermal and dermal layers of the skin in a product for severe burns that is pliable and grows with the patient. The
purchase is expected to close within thirty days, subject to the completion of customary closing conditions.
1) The purchase price consists of $1.5 million to be fully paid at closing with additional purchase price
payments of up to $4.8 million subject to the achievement of certain regulatory and commercial milestones.
The Company expects to expense all purchase price payments prior to regulatory approval of the product as
in-process R&D. The transaction is projected to be dilutive by approximately $0.15 per share in 2006
primarily due to the purchase price payments and accretive in 2007 and thereafter.
Per Code of Federal regulations section 812.43 (5): Sufficient accurate financial disclosure information to
allow the sponsor to submit a complete and accurate certification or disclosure statement as required
under part 54 of this chapter. The sponsor shall obtain a commitment from the clinical investigator to
promptly update this information if any relevant changes occur during the course of the investigation and
for 1 year following completion of the study. This information shall not be submitted in an investigational
device exemption application, but shall be submitted in any marketing application involving the device. .
Dr. Boyce failed to comply fully with the disclosure requirements.
II.2 Number of Investigators/Investigational sites: Annual report states that after the FDA inspection of
March 7, 2006 and the Form FDA 483, issued of June 2006, it became clear that the degree of monitoring
required for the sites outside of Cincinnati was beyond the resources available to the project.
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Consequently, the sites of Galveston, Boston, and Sacramento have been closed. The two sites in
Cincinnati remain open under compassionate use permission.
Per a discussion with Joann Lindwall, Sr. Regulatory Analyst, FDA Specialist of the Office of Research
Compliance at the University of Cincinnati, the monitoring of this study was not going to be done until
the completion of the independent audit.
Upon the receipt of the Form FDA 483 the University of Cincinnati clearly understood that the University
was now the sponsor and had the responsibility to monitor this study per CFR 812.46Monitoring
investigations-
(a)Securing compliance. A sponsor who discovers that an investigator is not complying with the signed
agreement, the investigational plan, the requirements of this part or other applicable FDA regulations, or
any conditions of approval imposed by the reviewing IRB or FDA shall promptly either secure
compliance, or discontinue shipments of the device to the investigator and terminate the investigator's
participation in the investigation. A sponsor shall also require such an investigator to dispose of or return
the device, unless this action would jeopardize the rights, safety, or welfare of a subject.
(b)Unanticipated adverse device effects. (1) A sponsor shall immediately conduct an evaluation of any
unanticipated adverse device effect.
(2) A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk
to subjects shall terminate all investigations or parts of investigations presenting that risk as soon as
possible. Termination shall occur not later than 5 working days after the sponsor makes this
determination and not later than 15 working days after the sponsor first received notice of the effect.
(c)Resumption of terminated studies. If the device is a significant risk device, a sponsor may not resume a
terminated investigation without IRB and FDA approval. If the device is not a significant risk device, a
sponsor may not resume a terminated investigation without IRB approval and, if the investigation was
terminated under paragraph (b)(2) of this section, FDA approval.
Monitoring of this study has not been done to date even though patients continue to be enrolled in this
study under compassionate use.
II.4.2. Adverse Events: Dr Boyce reported only ten UADEs. The FDA sent a warning letter on January
12, 2007 and noted that there had been previously identified failure to report and accurately document
unanticipated and anticipated adverse device events to the sponsor and the reviewing IRB which violates
21 CFR 812.140(a)(3)(ii)- All relevant observations, including records concerning adverse device effects
(whether anticipated or unanticipated), information and data on the condition of each subject upon
entering, and during the course of, the investigation, including information about relevant previous
medical history and the results of all diagnostic tests; CFR 812.150.(a)(1)- Unanticipated adverse device
effects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated
adverse device effect occurring during an investigation as soon as possible, but in no event later than 10
working days after the investigator first learns of the effect.
The annual report for 2006 was not sent to FDA until February 12, 2007 which was a month after the
warning letter had been issued to the site. Dr. Boyce continued to disregard the FDAs warning regarding
the report of unanticipated and anticipated adverse device events. The auditors data base recorded 1,455
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adverse events during the time frame of this annual report, of which as stated above, 10 were noted by Dr.
Boyce.
Section III: Risk Analysis: The annual report states that a safety monitoring process (appendix 2) has
been developed and approved by the UC IRB. At the present time, all adverse events are recorded in the
case report forms, UADEs are reported to the local IRB and deaths are also reported to FDA
independently of an annual report.
The Safety Monitoring Procedure that is attached in the appendix lists four (4) objectives (see a copy of
this in (Appendix E) The first point is Review of Medical Records. This procedure listing states it is the
responsibility of the PI, Sub-Investigators and the CRC to review the subjects medical record for adverse
events throughout the subjects participation in the study, at time intervals that have been predefined in
the protocol and will include any SAEs that occur within 30 days after the subject completes the
protocol. The protocol states Adverse Event Summary to be done at POD 14, and 28. Based on federal
regulations 812.50 (1) a report of any UADE occurring during an investigation should be reported as soon
as possible, but in no event later than 10 working days after the investigator first learns of the effect.
Thus, the procedure sheet attached in the annual report was set up to fail as it disregards the federal
regulations. The procedure sheet also does not have a name as to who authored it or a date of when it was
written on it.
The second point on this safety monitoring procedure page again lists the PI, Sub-I, and CRC as the
personnel responsible for the determination of severity. This form maintains that the adverse event will
be assessed to determine if it meets the definition of a serious adverse event.
The third point, again lists the PI, Sub-I, and CRC as personnel responsible for the determination if the
event is expected or unexpected.
The fourth point, lists the PI, Sub-I, and CRC as personnel responsible for the Internal Safety Monitoring.
The process for this safety monitoring as stated is as part of the bi-monthly research department meetings
all protocols will be reviewed. This process will incorporate a review of serious adverse events and will
allow for the analysis of both the individual events and possible trends that are not readily discernable
when events are considered individually. This process will be reflected in the meeting minutes.
Auditors never located any minutes of the research departments monthly meetings. If indeed this was
done, and the information was not given to the audit team, the case report forms and the audit adverse
event section does not correlate with the information that the procedure list specified. Throughout 2006,
2007, 2008, and 2009 UADEs continued to not be reported per the audit team review of the CRFs.
In addition, the procedure form states that the PI, Sub-I, and CRC were the personnel responsible for
seeing the above reference four objectives to be met. It is the Principal Investigators sole responsibility
for the conduct of the study and by listing a minimum of three people or more as potential responsible
parties it yet again emphasizes the fact that Dr. Boyce ignored the federal regulations as they pertain to
the sponsor and the investigator of an IDE study.

The 2
nd
page of this appendix refers to Serious Adverse Event Reporting. The flow chart provided
pertains to IND submissions and not IDE. While similar reporting requirements are adhered to, the
verbiage on this page is reflective of IND reporting and given that this study is a device the language
should be that of device reporting.

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The Federal guidance document states the investigational device exemption (IDE) regulations define an
unanticipated adverse device effect (UADE) as any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was
not previously identified in nature, severity, or degree of incidence in the investigational plan or
application (including a supplementary plan or application), or any other unanticipated serious problem
associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)).
UADEs must be reported by the clinical investigator to the sponsor and the reviewing IRB, as described
below:

For device studies, investigators are required to submit a report of a UADE to the sponsor and the
reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first
learns of the event ( 812.150(a)(1)).

Sponsors must immediately conduct an evaluation of a UADE and must report the results of the
evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the
sponsor first receives notice of the effect ( 812.46(b), 812.150(b)(1)).

The IDE regulations, therefore, require sponsors to submit reports to IRBs in a manner consistent with the
recommendations made above for the reporting of unanticipated problems under the IDE regulations.
The receipt of a large volume of individual AE reports without analysis of their significance to a clinical
trial rarely supports an IRBs efforts to ensure human subject protection. Sponsors can assess the
implications and significance of AE reports promptly and are required to report serious, unexpected
events associated with the use of a drug or device, including analyses of such events, to investigators and
to FDA. In addition, sponsors are required to report analyses of unexpected adverse device experiences to
IRBs. FDA encourages efforts by investigators and sponsors to ensure that IRBs receive meaningful AE
information. The ultimate goal is to provide more meaningful information to IRBs, particularly when
sponsor analysis (including an analysis of the significance of the adverse event, with a discussion of
previous similar events where appropriate) is made available to IRBs.
No analysis was seen in the review of the IRB documents, the regulatory documents of Dr. Boyce or in
any other place during this audit. The event is most often attributable to the underlying disease.
In this annual report there is an adverse event report of a non-healing donor site to the left flank that was
granulating without evidence of epithelialization requiring an operating procedure for closure. The event
occurred on June 5, 2006 and the UC site was made aware and it was reported was June 16, 2006. There
is no explanation of why this event was not reported within the 10 day requirement.
Information of note for Annual Report January 1, 2007 December 31, 2007
Based on the fact that the integrity hold was placed on this study on February 2, 2007, and Dr. Boyces
statement that the sties cannot be monitored it was stated that the Galveston, Boston, and Sacramento
sites will be closed formally as soon as possible. The list of investigators still shows the Boston and
Galveston investigators as active when it would seem that these sites should have become inactive
between February 2, 2007 (Integrity Hold letter) and the close of this annual report (December 31, 2007).
There is a change in the risk analysis section regarding a revision of the 10% graft loss. It is unclear how
the IDE PI can make a change in the safety reporting while the study is under integrity hold from FDA.
Revising the definition of expected adverse events as they related to endpoints of the study should have
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been approved by the FDA prior to being submitted to the IRB and this documentation is not identified in
the study files.
Adverse Event Reporting has improved with this annual report, however neither the site or the sponsor
seems to understand the FDAs constant notifications (Warning letter of January 12, 2007 or the Integrity
Hold letter of February 2, 2007) in addition to the warning letter issued to the Sacramento site in March of
2006, regarding the failure to report and accurately document unanticipated and anticipated adverse
device events. The third party audit has identified 695 adverse events and the site/sponsor reported eight
(8) for the year 2007.
Information of note for the annual report dated January 1, 2008 December 31, 2008.
The annual report for 2008 delineates the audit process, the changes in University staff, and FDA staff
changes. There is an explanation of the suspension of operations of the Shriners Burn Hospital in
Galveston due to the hurricane of September 13, 2008. The subjects enrolled in this time frame were all
compassionate use subjects.
The adverse events reported for 2008 were 36 UADE reports by Dr. Boyce, whereas the auditors recorded
760 events. While this number of events reported increased over last year, the reporting is still not as
complete as the auditors identified additional events which should have been reported.
This is the first annual report that lists deviations. The deviations listed either events that should have
occurred per protocol, or CRF completion that was not done. The sponsor and the PI (original Dr. Boyce
and later Dr. Kagan and site specific PIs) were not reviewing the CRFs to see that they were completed.
Dr. Boyce even stated in writing that the CRFs were not reviewed until the end of the subjects treatment
had occurred. This is not proper oversight of the clinical research study per the FDA regulations. This
again references the warning letter to Sacramento and Cincinnati Shriners sites and UC Integrity Hold
letter.
Continues failure to ensure an investigation is conducted in accordance with the signed agreement with
the sponsor, the investigation plan, applicable FDA regulation and any conditions of approval imposed by
the FDA or the IRB (21 CFR 812..100, 812.110(b).
The monitoring plan was labeled with the date January 2009 and was to begin with subject 129. In
reviewing Subject 129, and later enrolled subjects, it does not appear that monitoring actually had been
implemented. It was the understanding of the audit team that Angela Braggs Brown was hired in the
summer of 2009 by the compliance office (JoAnne Lindwall). The MRF auditors did not know if she was
hired to monitor subjects 129 and above or audit the first 81 subjects of the CSS trial. She was observed
sitting in the same office with Peggy Simpson, RN, research nurse for CSS study for several weeks.
During this time period, MRF was approached by the Compliance office of the University and asked
about the use of the database for the first eighty subjects enrolled on this study. It was the Foundations
understanding that Mrs. Braggs-Brown was to monitor initially, then auditors were under the impression
that maybe Mrs. Braggs-Brown was brought into audit. Given the fact that Mrs. Braggs-Brown was a
personal friend of Peggy Simpson, it did not appear, to the MRF auditors, that either way could be a truly
unbiased monitoring or auditing situation
Section II.4.4 Reprints of articles published by the investigator in relation to the study. The presentation
Dr. Boyce delivered as an oral presentation at the Army Science Conference on December 8, 2008
appears to be in conflict with CFR 812.7 (d)- Represent that an investigational device is safe or effective
for the purposes for which it is being investigated.
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Dr. Boyce made the statement based on the presentation of two burn subjects enrolled as compassionate
use subjects in 2007 that These results demonstrate that ESS (engineered skin substitute) reduce
requirements for donor skin harvesting for grafting of excised, full-thickness burns involving most of the
TBSA. In section ll.1 Summary of Study of this same annual report it states The objective of the
quantitative data is to determine whether treatment of full-thickness burns with cultured skin substitutes
reduces the requirements for harvesting of split-thickness skin autograft. It is uncertain why a definitive
statement was made when this cultured/engineered skin is still being studied and specifically why this
presentation was made while the study was on an Integrity Hold. The initial statement referred to at the
beginning of this paragraph is repeated in the Conclusions section of the presentation.
Dr. Boyce also presented this report as a poster presentation at the Advanced Technology Applications for
Combat Casualty Care conference on August 12, 2008 and as an oral and poster presentation at the
Armed Forces Institute for Regenerative Medicine All Hands meeting on January 14, 2009. Dr. Jane
Strasser of the UC Compliance Department sent a formal notification advising Dr. Boyce to suspend any
presentations, publications, and/or media relations regarding the IDE project until FDA removes the
Integrity Hold. During this time period, (December 29, 2008) a media publication of UC Health News
announced CINCINNATIUniversity of Cincinnati (UC) researchers have received $1.3 million to
further develop and commercialize engineered skin substitutes for burn injury repairs as part of the newly
formed Armed Forces Institute of Regenerative Medicine (AFIRM). There is no documentation
associated with these presentations to request a waiver from FDA for the presentation of this data.
Section III. Risk Analysis states that safety monitoring process dated February 2007and the Clinical Trial
Monitoring Plan (20090 was implemented and is in use. The MRF has seen nothing that assures these
two plans are actually functioning. As stated earlier there was 36 adverse events identified by Dr. Boyce
to the IRB and FDA, and the auditors noted 760 adverse events per the guidelines established by UC and
the FDA prior to this audit undertaking. No monitoring reports were ever seen in either Dr. Boyces
sponsor files, and/or any of the site regulatory files.
Section V: Future Plans: Dr. Boyce states that the future plans have changed due to the complexity and
indefinite timeline of the Integrity Hold. He states that at present, the procedures of cGMP manufacturing
of this device are being established with a commercial developer, Lonza Walkersville, Inc., and plans for
alternative pathways for clinical use of the technology are under review. This last statement may suggest
that new studies will be designed for the cultured skin substitute, perhaps under the engineered skin
substitute; however the fact remains that much of the data for the IDE under audit cannot be verified.

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47. Standard Operating Procedures (SOPs) Review
Prior to the employment of Jane Strasser, Ph.D., with the Compliance Department, Dr. Melissa Colbert
had called the Morley Research Foundation to request standard operating procedures. After discussions
between Melissa Colbert and Jane Green, the University of Cincinnati purchased the Morley Foundations
Standard Operating Procedures for Research Sites. UC customized these procedures and put them online
for use throughout the University. Upon arrival of the audit team, JoAnne Lindwall realized that UC
needed device sponsor SOPs and Institutional Review Board SOPs. The Foundation supplied UC with
the SOP templates for Device Sponsors and IRBs which were then customized for UC use. Prior to this
year the SOPs in place for the IRB were minimal and nothing was in place for device sponsors.
The Cincinnati Shriners Hospital provided MRF auditors with a copy of Shriners SOPs as they pertain to
research. The copies supplied to MRF had an adopted date of l/5/2006 however none were signed as
approved by anyone. There were some Shriners Review of documents noted but it was not consistently
reviewed by Shriners each year in regard to the informed consent process as outlined in Shriners SOPs.
According to the Shriners SOPs the informed consent form was to receive approval by the Corporate
Office of the Director of Research Programs and then was to be followed by the IRB approval of that
informed consent form. Per Shriners SOPs Revising an Informed Consent Form standard operating
procedures state that revisions are necessary when the protocol is modified, new risk to subjects are
identified The Cincinnati Shriners research staff did not follow their own SOPs as none of the CSS
subjects were ever re-consented.
The SOP that pertains to Responsibilities of the Research Team number 13 relate to the disclosure to the
IRB, SHC, sponsor, and/or subjects of all potential Conflicts of Interest of Research Team members
(financial, etc.). This is addressed in detail in the report on Annual Reports.
The SOP regarding Maintaining Regulatory Files specifically identifies information to be retained in the
regulatory files and as the results of the regulatory audit show this was not done as stipulated by the SOP.
There were clearly Shriners SOPs that were not being followed by the site.
Sacramento Standard Operating Procedures:
The MRF was supplied with the Table of Contents for the SOPs for Clinical Research and the only actual
SOP that was given to the auditors was the Informed Consent Process SOP. The auditors looked up on
the internet the website www.ucdmc.ucdavis.edu/clincialtrials/documents.html. The SOPs are listed on
the web for anyone to see.
Boston Standard Operating Procedures: The only SOP that was reviewed for the Boston Shriners
Hospital was the biohazard waste SOP. The Boston site enrolled one subject on the study in a
compassionate use setting, and only used the CSS for spot grafting on the subject.
When interviewing at each site, no one mentioned following their own or anyones Standard Operating
Procedures.

147

48. Systems Audit Conundrums

1) There is no clear process in place for deviation, anticipated adverse event, UADE from the site, to
the sponsor, to the IRB, to FDA. From an audit perspective an event that occurred cannot be
traced from the event through the process and acknowledgments back down to the site.
2) The site training was minimal and in the interviews with the investigators and nurses many
comments were derogatory regarding paperwork. The investigators appeared to feel that
placing the grafts on the patients, and the patient care was all that was really important. The
investigators gave the impression to the audit team that the paperwork was a hindrance and was
inconsequential. The big picture of results for the patients was what was important.
3) A couple of the research nurses, when interviewed, had been uncomfortable with the lack of
training and information passed on to them. They acknowledged that the protocol was poorly
written as were the case report forms, and stated that Dr. Boyce told them not to worry about it.
4) The IRB files were minimal. There were only three volumes of records found for a study that has
been ongoing for 12 years. In the early review of IRB files, lapses in continuing review were
noted.

49. The Morley Research Foundation Interview Report for Physicians and Nurses Involved in
the CSS - Clinical Trial.
Kendal Clinical Quality Assurance performed a systems audit January 14-16, 2008 which was already
presented to FDA and UC. The MRF performed its own systems audit related specifically to the study
completion during the time period of January 5, 2009 through November 5, 2009. During the
approximately 11 months that the MRF was on site at the Cincinnati Shriners Hospital and conducting
interviews with key personnel involved in the CSS IDE study it was easy to identify the difficulties that
plagued this particular CSS clinical trial.
Placement of cultured skin substitute on the study subject. Drs. Kagan, Warner, Bailey and Yakuboff
of Shriners in Cincinnati stated that the best possible recipient site is selected for the CSS graft placement.
The decision is made between the Surgeon, Dr. Boyce and sometimes the research nurse Peggy Simpson.
Not one of the physicians mentioned the randomization process that is required per protocol. This may
explain that while most subjects were randomized, the placement of the CSS did not always match the
randomization schedule and that different sets (not always the first or each set) was the randomized set
that was utilized on the subject.
Training of Surgeons regarding CSS placement: Dr. Kagan the Principal Investigator stated in the
interview that the training to applying the CSS would be similar to the training for Integra. He noted that
he had to attend a 1 day seminar to learn how to use Integra. He acknowledged that training would be
necessary regarding the wound bed preparation and the appropriate soaking of the wound bed prior to the
placement of CSS. He also stated that while the basics of burn care would already be established, all
physicians would have their own learning curve. There was no documented actual formal training for this
study. All participating physicians and nurses said they learned on the job and that Dr. Boyce came to
each site for the first application of CSS and was in the OR during the process.
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The majority of the nurses and a couple of the physicians actually stated that they had read the entire
protocol and felt they had a good understanding of what was involved. It remains vague why if the CSS
was placed, and Dr. Boyce felt he needed to be in the OR every time this occurred throughout the study.
While many of the nurses were experienced burn nurses, most of the research nurses learned their part in
the CSS study through on the job training. Some have since become certified clinical research
coordinators through either SoCRA (Society of Clinical Research Associates) or ACRP (Association of
Clinical Research Professionals).
It is significant, at this time to note that not one research nurse ever stated that they re-consented a
subject. It is apparent to auditors that neither the sponsor nor the investigators complied with the
following Code of Federal Regulations:

CFR 812.40- Sponsors are responsible for selecting qualified investigators and providing them with the
information they need to conduct the investigation properly, ensuring proper monitoring of the
investigation, ensuring that IRB review and approval are obtained, submitting an IDE application to
FDA, and ensuring that any reviewing IRB and FDA are promptly informed of significant new
information about an investigation. Additional responsibilities of sponsors are described in subparts B
and G.
CFR 812.43 (4) (i)- Conduct the investigation in accordance with the agreement, the investigational plan,
this part and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB
or FDA;
CFR 812.43(4) (iii) - Ensure that the requirements for obtaining informed consent are met a
CFR 812.100 -An investigator also is responsible for ensuring that informed consent is obtained in
accordance with part 50 of this chapter. Additional responsibilities of investigators are described in
subpart G.
CFR 50.25(b) Additional elements of informed consent. When appropriate, one or more of the following
elements of information shall also be provided to each subject:
(1) A statement that the particular treatment or procedure may involve risks to the subject (or to the
embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.
(2) Anticipated circumstances under which the subject's participation may be terminated by the
investigator without regard to the subject's consent.
(3) Any additional costs to the subject that may result from participation in the research.
(4) The consequences of a subject's decision to withdraw from the research and procedures for orderly
termination of participation by the subject.
149

(5) A statement that significant new findings developed during the course of the research which may
relate to the subject's willingness to continue participation will be provided to the subject.
(6) The approximate number of subjects involved in the study.
Randomization Process: It is worth mentioning that while each subject was randomized, based on
remarks made by nurses and physicians during the interviews, the decision was made on where to place
the CSS and AG comparative sites was based on the immediate need of the subject at time of placement.
While this is understandable due to the nature of the burn victim, the purpose of a research study is to stay
as close as possible to the study design for accurate study reporting of data. Based on the data, 34 of the
subjects audited by MRF were randomized correctly and 10 subjects were not randomized correctly in
that the subject did not have a comparative site skin graft.
Case Report Forms Utilized as Source Documentation: During the interview with Peggy Simpson, the
clinical research nurse, she stated that the Qualitative Outcome, Global Assessment, tracings,
photography log, biopsy log, surgery diagram and the screening form are all CRF pages that are used as
source documentation. She also stated she performs the global assessments and qualitative outcomes
herself, and the PI signs off. Mrs. Simpson further stated that she uses the nursing notes rather than the
physician notes to complete the Physical Exam CRFs as she feels the nursing notes are better than the
physician notes. Mrs. Simpson also stated that Dr. Boyce will fill in when she is not there. The
auditors did note that same CRFs were completed and signed off by Dr. Boyce.

SIGNIFICANT REMARKS FROM INTERVIEWS:
1. Peggy Simpson, Research Nurse The objectives (of the study) have been met and there is
nothing out there to save these patients and that this (CSS) is going to change peoples lives. This
(CSS) should be available to everybody and that she feels very strongly about this device. It
(CSS) is more pliable, requires less reconstructive surgery and the patients dont itch as much.
She knows there are big issues with the study, but this (CSS) is the best thing out there for burn
patients. She wants to get it out there regardless of what it takes.

2. Steve Boyce, Ph.D. Dr. Boyce noted that the analyzed data is reported to FDA. He (Boyce) has
the Biostats person to run the data but he (Boyce) provided the data to the statistician. He
(Boyce) did note that he completes all of the tracing data and the statistician reviewed and
compiled all data and determined data constraints. Additionally, when interviewing Dr. Boyce,
Dr. Green asked him a question regarding the reporting of UADEs. Dr. Boyce replied by asking
what is a UADE? An explanation was provided to him. Dr. Boyce did not demonstrate
knowledge of primary function of being the sponsor PI, on this study, as shown by a lack of
knowledge of important research terminology.

3. Richard Kagan, M.D. Dr. Kagan indicated that we know it works, it is taking too long to get
approved; if it was commercialized it (CSS) would revolutionize burn care; there is military
interest in this study, as that this could significantly save soldiers lives; it would shorten hospital
stay and decrease infection control.
150

4. Kevin Bailey, M.D. Dr. Bailey said that this study was draped in a morose of government red
tape and it is a travesty and heartbreaking on what has been opposed on this. He noted that this
goes beyond sanity and common sense. This device (CSS) was a major plus for burned children.

5. Kevin Yakuboff, M.D. Dr. Yakuboff stated I wish it could be made faster. He feels that
production will be better when it is massed produces. He does not see any negative and that this
is saving lives. He also stated that absolutely the objectives of the study were being met.

6. Johanna Sanders, Research Nurse in Sacramento, California: Ms. Sanders said that this is a
positive product and a terribly put together protocol. She noted that changes had to be made to
the protocol for functionality and safety. She noted that the data sheets (CRFs) were poor and had
to be changed to be functional at their site. Also that because the study was not monitored, that
she was never sure if she was doing things correctly.

7. David Greenhalgh, M.D. in Sacramento, CA Dr. Greenhalgh stated that he felt the objectives to
the protocol were met and that the skin worked marvelously. However, he felt that the IDE was
not well understood.

8. Robert Sheridan, M.D. PI in Boston Dr. Sheridan felt like the grafts did not take well, but that
he could not base any opinions off of only one patient.
Of Special Note:
During the interview process, it was observed by MRF consultants that after interviews, Angela Braggs-
Brown would return to Peggy Simpsons office and stay for a lengthy time period (30 minutes) each time.
During the interview with Peggy a specific question was asked: Did you and Angela discuss the
interview with Dr. Boyce yesterday afternoon? Peggy appeared shocked and stated Yes.
At the conclusion of the interview, Mrs. Braggs-Brown spoke up and stated that Dr. Boyce initiated the
conversation with Mrs. Simpson regarding audit interview questions, and that she (Angela Braggs-
Brown) was not discussing specific audit questions with Mrs. Simpson.
It is also of special note that during the interview with Dr. Petra Warner, Angela Braggs-Brown was
found to have a recorder which was being carried in under a notebook. Dr. Jane Green identified the
recorder upon standing at the conclusion of the interview with Dr. Warner and asked Mrs. Braggs-Brown
if she had taped the interview. Mrs. Braggs-Brown responded that the UC Legal Department had asked
her to tape the interview. Dr. Green immediately contacted Jane Strasser Ph.D., of the compliance
department, and stated that Mrs. Braggs-Brown had not informed anyone connected with the Morley
Foundation that she was taped and that it was completely inappropriate to tape someone without their
knowledge. Dr. Strasser contacted Charles Jake (UC Legal Department) and upon conversations between
Mr. Jake and Dr. Green it was agreed that the audit team should have been informed that the session was
being taped and that the tape would be destroyed.
One additional observation that the MRF believes the FDA needs to be aware of is that during the time
that Angela Braggs-Brown was either monitoring or auditing she sat next to Peggy in Peggys office. She
was also observed in Peggys office when not monitoring/auditing, just talking with Peggy and both
Peggy and Angela were observed more than twice going into Steve Boyces office shortly after the
conclusion of interviews with Cincinnati Shriners staff. The MRF is not drawing any conclusions from
151

this, however from an auditors position this behavior gives the appearance of potential bias and/or hints
at potential questionable behavior from someone who is employed as part of the compliance office of the
University of Cincinnati.

50. Data Safety Monitoring Board (DSMB) Report
A Data Safety Monitoring Board (DSMB) was never implemented during the course of this study. The
Sponsor did not make adequate provision for data or safety monitoring during the course of this study as
required per 45 CRF 46.111(a) (6): When appropriate, the research plan makes adequate provision for
monitoring the data collected to ensure the safety of subjects.
The purpose of the DSMB is to identify issues such as: unacceptably slow rates of accrual, high rates of
ineligibility determined after randomization, and protocol violations that suggest clarification or changes
to the protocol are needed. Additionally a DSMB ensures the credibility of a study, validity of study
results, and most importantly, protects the safety of trial participants. In the case of this study, a DSMB
review was only completed due to an integrity hold being placed on the study after the majority of all
study data had been collected.
Per the Integrity Hold Letter, issued to the University of Cincinnati on February 2, 2007, the FDA asked
University of Cincinnati to provide a patient listing of every patient complication, and categorize the
complications as major or minor. This was to be completed after all patient records had been audited.
Per the audit plan, MRF was only responsible for auditing subjects 82-139 and University of Cincinnati
would be responsible for auditing the first 81 subjects. To date, there is no evidence that the first 81
patients were ever audited. Additionally, the FDA asked that this patient complication listing be
facilitated by convening a Data Safety Monitoring Board (DSMB). The board was asked to generate
predetermined criteria for categorizing events as major or minor. The University of Cincinnati convened a
meeting of a DSMB on March 18, 2010. A report from the meeting was provided to MRF on March 24,
2010.
The DSMB report (below) was provided to MRF after the completion of the third party audit. Therefore,
MRF did not have all specific reporting criteria by which to report audit findings as noted in the DSMB
table. From the report provided to MRF, it was observed that the overall DSMB meeting solely identified
and classified medical events as major or minor. It is unclear which subjects were reviewed during
this meeting as no mention was made of the population reviewed. Furthermore, the first 81 subjects did
not undergo an audit, as requested in the integrity hold letter, so it is unknown if any subjects from the
unaudited population were reviewed at the DSMB meeting, as required per the integrity hold.
As customary for a DSMB, there is no evidence that a complete review of the protocol was conducted in
order to identify and define potential issues/current issues with the study design and investigational plan.
This would likely be important at this time point as subjects are still receiving this device, under
compassionate use. Additionally, no report was provided to summarize adverse events, safety profile, side
effects and tolerability. The DSMB should also review and report on the impact of any newly published
findings on the safety profile of the study. It is unclear if the DSMB will continue to meet and review the
data, for this study, as part of ongoing safety review.

152

DSMB Report Provided to MRF on March 24, 2010:
The board members noted present were:
David Arenholz, M.D. FACS: a burns specialist and associate professor of surgery at Minnesota
University Medical School
Edward Liechty, M.D.: a professor of pediatrics and research subject advocate at Indiana
University
Charles Lucas, M.D.: FACS: a general surgeon and professor of surgery at Wayne State
University
Gary Purdue, M.D.: a burns specialist and professor of surgery at UT Southwestern
Kurt Viele, Ph.D.: an associate professor of statistics at the University of Kentucky

The DSMB members will use medical and scientific expertise to categorize potential patient
complications for the given study population as major (i.e., serious to life threatening severity) and/or
minor (i.e., mild to moderate severity). In doing so, consideration should include patient impact and
interests. The DSMB must agree to the attributes of the grading scale by including defining parameters
(e.g., a laboratory range; context descriptions such as symptomatic therapy required, emergency
treatment required, death, etc.) and document conclusions accordingly. Uncategorized items (i.e., those
left blank) will require explanation. Additional items will be added to the form and applicable
information provided. The following tables are provided as a possible template to assist the DSMB with
this task. The DSMB should not assume that these tables are complete and is not obligated to use this
template.
Key issue - major complications are going to be present in a vast majority (all?) of the patients and in
and of themselves do not indicates a catastrophic value. Going forward, the main question is relative
incidence of these events between treatment groups.
All deviations from normal range in quantities on the first four pages (through blood gases) were
classified as minor. In some cases, major changes may occur in these measures but they will be caused
by major events in later categories?
HEMATOLOGY & COAGULATION
Minor Major Comments
White Blood Count X
Red Blood Count X
Hemoglobin X
Hematocrit X
153

Mean Corpuscular
Volume
X
Mean Corpuscular
Hemoglobin
X
Mean Corpuscular
Hemoglobin
Concentration
X
Platelet Count X
Lymphocyte Count X
Neutrophil Count X
Lymphocyte Count X
Monocyte Count X
Eosinophil Count X
Basophil Count X
Band Cells X

HEMATOLOGY & COAGULATION (Cont)
Prothrombin Time X
Partial Thromboplastin
Time
X
Activated Partial
Thromboplastin
X
Abnormal Fibrinogen X
International
Normalized Ratio
X
154

Drug Levels X

CHEMISTRY
Electrolyte Imbalance
X
Blood Urea Nitrogen
X
Creatinine X
Glucose X
Calcium X
Phosphorus X
Magnesium X
Total Protein X
Albumin X
Alkaline Phosphatase
X
AST (SGOT) X

CHEMISTRY (Cont)
ALT (SGPT) X
C-Reactive Protein X
Total Bilirubin X
155

Immunoglobulin G X
Prealbumin X
Retinol Binding
Protein
X
Transferrin X
Thyroid Stimulating
Hormone
X
Thyroxine (T4) X
Triiodothyronine (T3)
X
Alpha Acid
Glycoprotein
X
Alpha Antitrypsin X
Alpha Macroglobulin
X
Complement C3
X
Ceruloplasmin X
URINALYSIS
PH X
Specific Gravity X
Blood X
Protein X
Bilirubin X
Ketones X
Urobilinogen X
156

Nitrite X
Leucocyte Esterase X
Other
Other

BLOOD GASES
pH X
pCO2 X
pO2 X
Oxygen Saturation X
Ionized Calcium X
Other
Other

CARDIOVASCULAR
Cardiac Rhythm
specifically vtach/vfib
or bradycardia to 40
bpm
A variety of
arrhythmias are
common in these
patients
Blood Pressure
Blood Loss See transfusion
Transfusion
defined as transfusion
>40% in excess of age
and burn size
matched controls

157

PULMONARY
Respiratory Rate
Pulmonary Edema present
Pneumonia present (times)
Pneumothorax present
Pleural Effusions present
Atelectasis present
Pulmonary Infiltrates
present
Respiratory Failure
present treatable and
expected
Acute Respiratory
Distress Syndrome
present
Other(pulmonary
embolism)
present

GASTROINTESTINAL & RENAL
Nausea X
Vomiting X
Diarrhea X
Constipation X
Ileus X
Pancreatitis present
158

Renal Failure
defined as requiring
dialysis

Urinary Tract
Infection
uncomplicated UTI urosepsis
Urinary Retention
GI bleeding
upper GI bleed
requiring transfusion

NEUROLOGICAL
Mental Status
Changes
X
Sedation X
Infection
meningitis

Inflammation X
Nerve palsey any nerve palsey

MUSCULOSKELETAL & SKIN
Pruritis X
Graft Loss
graft loss requiring
regrafting of the
treated site

Amputation present
159

Graft Contracture X
Fracture if incurred in hospital
Rash X
Edema X
Dermatitis Fungal X
Other
Other

SYSTEMIC & OTHER COMPLICATIONS
Pain X
Microbial
Colonization
X
Wound Infection
X X only with sepsis
syndrome

Sepsis/Septicemia
present
Line Infection
X in absence of sepsis
syndrome
X if septicemic
Compartment
Syndrome
present
after application of
the investigation
product

Hypothermia X
Hyperthermia X
Cellulitis X
Surgical Intervention
X

160

SYSTEMIC & OTHER COMPLICATIONS (Cont)
Multiple Organ
Failure
X
Death X
Acquired
autoimmune disorder
X
Other

Number of infections is valuable information.
In addition to the above DSMB reporting table, UC provided relevant sections of their DSMB
meeting as clarification (below):
The absolute consensus of the Board is that all deaths and episodes of diagnosed sepsis or septicemia are
severe complications. It also clear that the vast majority of sepsis episodes are accompanied by a host of
other signs and symptoms. For example, septic patients may have any combination of fever, tachycardia,
leucocytosis, heart rhythm abnormalities, oliguria, hypotension, electrolyte disturbances and a host of
other abnormal findings. It is the consensus of the Board that an isolated change in one of these
parameters, in the absence of a diagnosis of sepsis, will be considered a minor complication. The items
evaluated are attached to this report.

All patients with life threatening burns will experience multiple infections, most commonly of the lungs
(pneumonia), bladder, venous cannulas (line infection) and the burned wound. It is impressive to the
Board members how frequently bladder infections and line infections respond to antibiotics, usually in
association with removal and/or replacement of the catheter, without developing the physiologic changes
associated with sepsis. The board considers uncomplicated bladder or line infections minor
complications. Pneumonia is difficult to diagnose and treat, but is classed as a serious infection. Burn
wound sepsis is a serious complication requiring urgent surgical excision of the burned tissue. For the
purposes of this study, colonization of a wound that responds to topical therapy is a minor complication,
unless there is graft loss sufficiently extensive to require re-grafting of that specific site. However, any
infection acquired from the cultured skin product is clearly a major complication.

161

Specific abnormalities by organ system.

Hematology and Coagulation
Each of the listed tests may have values elevated above normal or depressed below the normal range on a
given day. Although it is possible for an individual value to reach a critical or life-threatening number,
none of these would occur independent of a causative factor. Therefore, the presence of an extremely
abnormal white count will not be the only indicator of a major complication. The consensus of the Board
is that the wide range of values found in this patient population will not be considered de facto major
complications and will only confirm the diagnosis of a named major complication.

Chemistry
A similar range of deviations from normal chemistry values was discussed. Extreme variations from
normal will be clearly associated with the underlying etiology. Therefore, an isolated change in any of
the parameters listed under the chemistry section is classified for the purposes of this study as a minor
complication.

Urinalysis and blood gases.
A similar logic applies to the evaluation of the listed complications for urinalysis and blood gases.
Although abnormal values for these tests may confirm the diagnosis of a major complication, no one of
these would be de facto evidence of a major complication.

Cardiovascular
The group has discussed at length the cardiovascular complications encompassed by abnormal cardiac
rhythm. It is the consensus of the Board that persistent ventricular tachycardia, ventricular fibrillation or
bradycardia of less than 40 is a major complication in this patient population. Extreme variations in
blood pressure are frequent in severely burned patients, but are not solely diagnostic of a major
complication. Specifically, the Board feels that profound hypotension is always associated with a specific
diagnosis and this etiology will be listed as the major complication for the purposes of this study. The
group also notes that blood loss is universally found in these patients during operative procedures.
Therefore, the presence of a single transfusion, or even multiple transfusions, is not indicative of a major
complication. However, if patients receiving the investigational procedure require blood transfusions at a
rate significantly higher (>40% more) than age and burns size matched patients treated by conventional
means, this is a major complication.

Pulmonary
Changes in the respiratory rate, pleural effusions, atelectasis, pulmonary infiltrates, and respiratory
failure (defined as requiring ventilatory support using a mechanical ventilator) are identified as expected
and, therefore, minor complications in this patient population. The presence of pulmonary edema,
pneumothorax, acute respiratory distress syndrome, or pulmonary embolus are all identified as major
events. The incidence of pneumonia is very high because of the frequent primary injury to the lungs from
smoke inhalation. Nevertheless, the Board considers pneumonia, confirmed by bronchoalveolar lavage,
as a major complication.

Gastrointestinal and renal
Although major GI bleeding from Curlings ulcer was a common occurrence in burn patients 50 years
ago, it is now very rare. Therefore, evidence of upper GI bleeding requiring transfusion is a major
complication. Pancreatitis is rarely diagnosed in burn patients but is associated with a high mortality and
is also considered a major complication. Urinary tract infection is so frequent in our patients as to be
considered a minor complication because it is usually easily treatable and responds promptly to
parenteral antibiotics and catheter change. Virtually all patients with major burns require prolonged
162

placement of a Foley catheter, which is responsible for the high incidence of these infections. Urosepsis
with bacteremia would be captured under the sepsis and septicemia diagnosis as discussed above. Renal
failure requiring dialysis is a major complication, but not changes in the renal function tests.

Neurological
Evidence of any central nervous system infection, such as meningitis is a major complication. Any nerve
palsy, even if caused by intraoperative malpositioning, too tightly applied splints, or a missed
compartment syndrome, is also a severe problem.

Musculoskeletal and skin
The purpose of the investigational product is to replace skin that was lost as a result of thermal injury.
Excision of the wound is necessary to prepare the wound bed for definitive graft coverage. Although
virtually no graft will have 100% engraftment in this burn patient population, a major complication is
graft loss requiring re-grafting. The Board recognizes that re-grafting using the cultured skin product is
much less physiologically damaging than harvesting a new autograft. Although not life-threatening,
amputation is also a major complication. It is rarely caused by attempts at wound coverage and is usually
the end product of thermal injury destroying tendons, neurovascular structures, joint capsules, or even
bones. In contrast graft contractures will occur in 100% of these patients and are not associated with life-
threatening events, even though multiple revision surgeries may be necessary. Hospital acquired
fractures from any cause would be considered a major complication.

Systemic and other complications
Sepsis syndrome is a constellation of signs, symptoms and laboratory abnormalities and indicates an
inflammatory metabolic response to a systemic infection. No single finding is diagnostic.

Compartment syndrome is a major complication almost universally initiated in the resuscitation phase of
major thermal burns. For the purpose of this study it would be considered a major complication only if it
developed after application of the investigational product.

A portion of the experimental product is composed of cells not of autologous origin. Any evidence of an
acquired autoimmume reaction is considered a major complication.

163

Based on the DSMB report the following Major Events can be reported
for Subjects 82-139:

Pulmonary Edema 60 events
Pneumonia 5 events
Pneumothorax 15 events
Acute Respiratory Distress Syndrome 2 events
Pancreatitis 1 event
Renal Failure 3 events
Graft Loss (requiring re-grafting) 60 events
Amputation 28 events
Fracture 2 events
Wound Infection 53 events
Sepsis/ Septicemia 27 events
Line Infection 7 events
Compartment Syndrome 9 events
Multiple Organ Failure 3 events
Death 5 events

164

Regulatory (Sponsor and Investigator)/Institutional Review Board Audit For the Following
Sites: University of Cincinnati, Shriners Hospital of Galveston, Shriners Hospital of
Sacramento, Shriners Hospital of Boston

The Walter B. Morley Research Foundation (MRF) completed an audit of all regulatory/IRB documents.
The audit included all regulatory documents at each of the affiliate sites; Shriners Hospital for Children in
Cincinnati, Sacramento, Galveston, and Boston. IRB files that were audited were observed at the
Shriners Hospital for Children at Cincinnati for the University of Cincinnati IRB. All remainder of the
IRB files from all locations were also observed at the Shriners Hospital for Children at Cincinnati while
the audit took place.
Regulatory/IRB folders were given to auditors according to the date of files. The regulatory/IRB folders
were not placed according to corresponding criteria (site signature log, Curriculum Vitaes, informed
consents documents, correspondence, etc.), but placed by the date at the beginning of the file.

FDA Violations
Below is a list of the Violations that stemmed from the audit. These violations show: the regulatory
folder/IRB file that each violation was located during the audit, a description of each file, the date of the
file, MRF auditors comments about the file, actions to be taken by auditors in reporting, the FDA
violation number that each file corresponds. The violations comprise of both regulatory and IRB files
that were reviewed during the course of the audit.

Sec. 54.4 Certification and disclosure requirements.

(b) The clinical investigator shall provide to the sponsor of the covered study sufficient
accurate financial information to allow the sponsor to submit complete and accurate
certification or disclosure statements as required in paragraph (a) of this section. The
investigator shall promptly update this information if any relevant changes occur in the course
of the investigation or for 1 year following completion of the study.

Regulatory Folder Description of
File
Date of file Comments Action To Be Taken FDA Violation
IRB folder for 2006
(folder #1)
IRB COI
statement for Dr.
Richard Kagan
5/11/2006 Dr. Kagan states that he
owns equity in the
company or other legal
entity whose drug,
procedure, technique,
device, or software he is
testing
This COI has
changed from years
past were Dr. Kagan
did not disclose that
he had equity.
There is no
company that is
listed that he holds
54.4(B)
165

equity in.

Sec. 54.5 Agency evaluation of financial interests
(b)Effect of study design. In assessing the potential of an investigator's financial interests to
bias a study, FDA will take into account the design and purpose of the study. Study designs
that utilize such approaches as multiple investigators (most of whom do not have a disclosable
interest), blinding, objective endpoints, or measurement of endpoints by someone other than
the investigator may adequately protect against any bias created by a disclosable financial
interest.

Regulatory Folder Description of File Date of file Comments Action To Be
Taken
FDA
Violation
IRB folder for
2006 (folder #1)
IRB COI statement
for Dr. Steven Boyce
5/26/2006 Dr. Boyce states that he
owns equity in the company
or other legal entity whose
drug, procedure, technique,
device, or software he is
testing. He also holds the
patent rights to inventions
created, he is a scientific
advisor or consultant to the
company and receives
payments from the company,
he is entitled to royalty
income or income of the sale
of this product
The company that
he holds equity in
is the Cambrex
corporation
54.5(b)

166

Sec. 50.25 Elements of informed consent.
(a)Basic elements of informed consent. In seeking informed consent, the following
information shall be provided to each subject: (6) For research involving more than minimal
risk, an explanation as to whether any compensation and an explanation as to whether any
medical treatments are available if injury occurs and, if so, what they consist of, or where
further information may be obtained.

Regulatory Folder
Description of File Date of
file
Comments Action To Be
Taken
FDA
Violation
Regulatory files
for Sacramento
Shriners Sacramento
assent for the CSS study
version 03/28/00.
3/28/2000 The statement for question
#6 "Will you get better if you
are in the study?" The
answer that is given for the
assent states that "you will
probably get better even if
you are not in the study, but
we think you may get better
sooner by being in the
study." This answer leads
the subject to believe that if
they were on the study that
the study would help them
more than using another
option for the condition that
they have.
See comments
to the left
50.25(a)(6)

167

Sec. 50.27 Documentation of informed consent.
(a) Except as provided in 56.109(c), informed consent shall be documented by the use
of a written consent form approved by the IRB and signed and dated by the subject or
the subject's legally authorized representative at the time of consent. A copy shall be
given to the person signing the form.

File
Date of file Comments Action To Be Taken FDA
Violation
Regulatory files for
Boston
ICF for Boston
Shriners
(protocol
#2004p-000751
with Partners
IRB) version
09/99
version
09/99
The consent form was
approved by the IRB on
03/18/04 and expires on
03/18/05. This is
handwritten in at the
top of the first page of
the ICF that this is the
original copy and is
only approved for PG.
This version is not
the correct version
of the ICF that the
sponsor used. The
version of the ICF
that needed to be
used was the
05/2003 version not
the 09/99 version
which was replaced
by the 05/2003
version
50.27(a)
Boston
ICF version
08/2005
Aug-05 The ICF is version
08/2005. This version
is based on the 05/04
version of the protocol,
which was never
approved by the FDA
as a version valid for
the CSS study. The
ICF is not the correct
ICF that should have
been used to consent a
patient for the
compassionate use.
The term emergency
use has also been used
by the site, but then
changed over to
compassionate use.
The ICF is not stamped
by the IRB
See comments to the
left
50.27(a)

168

Sec. 812.140 Records.
(a) Investigator records. A participating investigator shall maintain the following accurate,
complete, and current records relating to the investigator's participation in an
investigation: (1) All correspondence with another investigator, an IRB, the sponsor, a
monitor, or FDA, including required reports.

Regulatory
Folder
Description of File Date of file Comments Action To Be Taken FDA Violation
Regulatory files
for Boston
email
correspondence
between the Boston
site (Martha Lydon)
and Melissa Reed
(UC) stating that
the data collection
packet was sent
from Boston to
Cincinnati
8/18/2004 The email states that
Melissa Reed confirmed
that the data collection
packet was sent back to
the sponsor and Melissa
Reed confirmed that the
packet was received
There is not a
completed data
collection packet in
any of the regulatory
files.
812.140(a)(1)
Regulatory files
for Boston
Notification of
expiration of IRB
approval for Boston
Shriners
9/6/2007 The IRB approval
expired on 09/06/07 at
the Boston site
according to the IRB.
The initial version date
was on 05/01/04. The
status is inactive-
expired. The IRB
requests that if the
continuing review is not
turned in by 09/16/07
the project will be
terminated.
. 812.140(a)(1)
Regulatory files
for Sacramento
SAE/injury report
for the UC Davis
IRB for subject
CSS 71
1/18/2003 The SAE was death.
The event is listed as
not unexpected. The
event is listed as
definitely not related to
the device.
There is no signature
or date for the SAE
report and there is no
indication for the IRB
acknowledgment of
the report
812.140(a)(1)
Regulatory files
for Sacramento
SAE/injury report
for the UC Davis
IRB for subject
CSS 66
8/4/2006 The SAE was death.
The event is listed as
not unexpected. The
event is listed as
definitely not related to
the device.
There is no signature
or date for the SAE
report and there is no
indication for the IRB
acknowledgment of
the report
812.140(a)(1)
169

Regulatory files
for Sacramento
letter from Mary
Beth Lawless to
IRB chairperson
responding to
changes requested
by the committee
4/23/2004 The inconsistent
reporting of the number
of subjects enrolled to
date between items 1
and 6. Item 1 states: a
total of 8 patients have
been grafted with
cultures skin at Shriners
Hospital for Children,
Northern California
(SHCNC). The first
patient was grafted
under emergency use
prior to initiation of the
protocol at this site. 7
patients have been
grafted since then. Item
6 states: There have
been 12 subjects
enrolled to date, with 7
subjects grafted with
CSS. Two subjects
were able to achieve
sufficient skin grafting
without using the CSS.
2 other subjects expired
prior to the grafting due
to the extent of the
injury. The second item
that the IRB requests is
for the page 5 on the
protocol to be changed
so that the description
of the subject selection
is adequate. The site's
response back was that
HIPAA language has
been added to this
section under the sub-
heading "subject
screening."
See comments to the
left
812.140(a)(1)
170

Regulatory files
for Sacramento
Memo from the
IRB reviewer
(Michaela Harris)
to the site
describing the
concerns of the IRB
about the
continuing review
from 04/12/04
4/14/2004 The concerns that
needed to be corrected
by the site were that
there is inconsistent
reporting of the number
of subjects enrolled
between the items 1 and
6, and the description of
the study was
inadequate for the IRB.
The IRB wanted to
know if the site was
going to use the HIPAA
worksheet how was the
site going to address
how they plan on
protecting patient
identifiers, the plan for
destroying the
identifiers, and the
language that "no
identifiers, used for the
recruitment purposes,
will be disclosed to a
third party except as
required by law for
oversight of the project.
See comments to the
left
812.140(a)(1)
Regulatory files
for Sacramento
Study renewal
Notice to the UC
Davis IRB from the
Sacramento
shriners site
3/26/2003 The due date of the
renewal form is on
03/20/03 and the
renewal was not signed
by Dr. Greenhalgh until
03/26/03. There are
missing pages to the
renewal (pages
1thorugh 3 are in the
regulatory files, and the
three other pages are
not).At the time of this
study, the following
personnel are listed on
the renewal form:
Greenhalgh, Palmieri,
Lawless, Sanders
See comments to the
left
812.140(a)(1)
171

Regulatory files
for Sacramento
Study renewal
Notice to the UC
Davis IRB from the
Sacramento
shriners site
1/20/2005 Pages 1-3 are in
regulatory file. Pages
4-6 are not. This form
was received on
01/31/05. PI signed on
01/20/05. At the time
of the renewal the
following personnel
was listed as being on
study: Greenhalgh,
Palmieri, O'Mara,
Lawless, Sanders, and
Mooney.
See comments to the
left
812.140(a)(1)
Regulatory
folder for
12/06/05 and
01/03/06
Investigator
Agreement for
Robert Sheridan
and CV (Boston)
12/21/2005 The CV for Dr.
Sheridan is not signed
and dated
Need signature for
date and signature of
CV
812.140(a)(1)
Regulatory
folder for
12/06/05 and
01/03/06
File for subject #96
with the description
of the treatments
and results of the
subject
No date on
file
The file shows what
date each study event
that happened and what
the result was. On
06/24/05 the file states
that subject #96 had 24
adverse events forms
reported regarding
mandible infection and
100% graft loss to set
#5.
The adverse event
forms that were
reported dont show
the number of 13
adverse events that
had occurred for this
study.
812.140(a)(1)
Regulatory
folder for
12/06/05 and
01/03/06
File for subject
#100 for death on
07/02/05 from
possible embolism
No date on
file
The file shows that
there was not an
autopsy performed on
the subject #100. The
FDA stated that they
would like further
clarification on the PI
judgment call would be
in this case.
Need to secure
documentation from
PI that explains the
reason for no autopsy
812.140(a)(1)
Regulatory
folder for
12/06/05 and
01/03/06
AE report for
Ucinn IRB for
subject # unknown
9/22/2005 Hispanic patient
suffered distal right
femur fracture, but
fracture were not
considered a
complication of a
severe burn injury
Need to secure
documentation form
PI that explains the
reason
812.140(a)(1)
172

Regulatory
folder for
08/23/07
Correspondence
from Dr. Boyce to
Dr. Durfor and Mr.
Carl DeMarco
(FDA) requesting
approval for two
subjects to be
placed with the
device for
compassionate use.
8/23/2007 The request states that
there were 3 copies
were sent to the IDE
document center as
supplement #57. There
are no copies that are
attached with this
correspondence, and the
documents cannot be
located. The
correspondence also
shows the approval that
Dr. Durfor (FDA) gave
to the site/sponsor
which stated "This
request is approved.
Good luck to the
physicians and prayers
for the patients."
Need to find what 3
copies were sent to the
IDE document center.
812.140(a)(1)
Regulatory
folder for
08/23/07
Letter from Dr.
Boyce to Charles
Durfor and Carl
DeMarco (FDA)
requesting the
compassionate use
of the CSS device
for two patients
8/23/2007 There is only an ICF
from one patient who
can be identified as HH,
but there is no ICF for
the other patient that is
in question. Dr. Durfor
(FDA) did give
approval for both of
them on the same date
as the fax page infers
via email back to Dr.
Boyce. There is a
HIPAA form and an
ICF form that are both
located in the folder.
The other ICF form still
has not been located in
the folders.
Need to find the ICF
that coincides with the
patient that the FDA
gave approval for.
The patient was an 8
month old female with
71% TBSA. There is
no ICF on file for this
patient in the
regulatory folder.
812.140(a)(1)
173

Regulatory
folder for
09/21/07
Adverse event for
subject #130 DH
9/20/2007 The subject had an
event of CSS graft loss
> 10%. The Nocardia
species is resistant to
the CSS irrigation
solution that is specified
in the protocol for
topical use of the CSS
wound post-operatively.
After consulting with
the medical staff, the
decision was made to
apply CSS regardless of
wound contamination
due to patient's lack of
available skin and
medical condition. The
patient has now
received 4 sets of CSS
that have been
evaluated for graft loss.
Each set is evaluated at
POD #14 and POD #20.
Graft loss for each set is
as follows: Set #1 POD
#28-14.6%, Set #2,
POD #14-46.5%, Set #3
POD #14-24.8%, Set #4
POD#14-46.2%. Also
of note, the patient has
been placed open
ventilatory support
(09/12/07) and
antibiotics (09/06/07).
The PI signed the
adverse event form on
09/20/07. The date
that the site was made
aware of the event
was 09/21/07. The PI
pre-dated the
signature for the
adverse event. The
outcome was never
resolved. The adverse
event was not
expected.
812.140(a)(1)
Regulatory
folder for
11/06/07
Adverse event for
subject #131 HH
for CSS graft loss >
10%
11/6/2007 Subject #131 had CSS
graft loss >10%.
Patient received a total
of 3 sets of CSS grafts
that have been
evaluated for graft loss.
Set #2 to the anterior
trunk was evaluated at
POD #14 to have 36.6%
graft loss. Re-
evaluation at POD #28
revealed graft loss of
20.8%. The cause of
the event that is listed is
from microbial
contamination of wound
bed and shearing.
The PI signed on
11/06/07. The
outcome is still
pending and there
doesnt appear to be
any resolution
812.140(a)(1)
174

Regulatory
folder for
02/22/08
Adverse event for
subject #132 who
had received a
IVIG which started
on 12/23/07
2/12/2008 The patient was on
IVIG which was started
on 12/23/07 per
protocol to receive
IVIG 500mg/kg (5gms)
every Wednesday and
Saturday. On 02/02/08,
the patient received a
dose that was stared at
2200 to infuse over two
hrs. On 02/03/08 at
0200, the patient was
noted to have a "very
red face." No change in
vital signs or level of
consciousness was
noted. The physician
was notified, PO
Benadryl 12.5mg was
given per feeding tube
at 0800. The "patients
color returned to pink
color by noon" but
"appeared red again this
afternoon" and received
a second dose of PO
Benadryl 12.5mg per
feeding tube at 1700.
The color (erythema)
decreased and has not
returned. IVIG was
discontinued. Patient
had received a total of
13 doses of IVIG.
The PI signed on
02/12/08 which is one
day before the site
knew that the event
had taken place. The
PI pre-signed the form
by a day.
812.140(a)(1)
Regulatory
folder for
07/14/08
Fax letter to the
FDA (Carl
DeMarco, and
Charles Durfor)
about allowing
UCinn the
compassionate use
of the device for a
10 year old patient
who had 68%
TBSA.
Supplement 74
7/14/2008 The fax cover sheet
states that Charles
Durfor, Ph.D. returned
Peggy Simpson's phone
call at 1745 on
07/14/08. According to
the handwritten note on
the fax cover letter,
Charles Durfor allowed
the enrollment under
compassionate use.
No letter back from
the FDA was located
that allowed the
compassionate use of
the device for the 10
year old patient.
Locate letter of
acknowledgement.
812.140(a)(1)
175

Folder for
Galveston
Shriners hospital
IRB approval
and consents
10/27/05
Informed Consent
form version
08/12/05
8/12/2005 The ICF is version
08/12/05, which is a
revised copy of the
12/14/04. The ICF
states on the form that
the original is from
Cincinnati on 05/2004.
This version was IRB
(UTMB) approved on
10/26/05 and is valid
through 01/31/06. The
PI is Arthur Sanford
and the co-investigators
are listed as Jong Lee,
MD and David
Herndon, MD. The
UTMB IRB protocol
number for this study is
05-050.
There is only the first
page for this
document which has
the 10/26/05 approval
stamp from the IRB.
There is no 2 through
11 pages that are
attached
812.140(a)(1)
UTMB
Galveston IRB
documentation
(2004-2008)
Multiple letters
from Dr. Arthur
Sanford and
Edward Sherwood,
MD, Ph.D. form
Galveston
requesting the CSS
from Dr. Boyce for
a patient with 95%
3rd degree burns
3/11/2004 There are multiple
copies of the letter
requesting the
emergency use for the
CSS. One letter is from
Dr. Sanford to Dr.
Patterson at the UTMB
IRB requesting the use
from the IRB, and other
letters are from Dr.
Sanford (alone) and
Drs. Sanford,
Sherwood, and Dr.
Woodson (chief of
Anesthesiology) to Dr
Boyce requesting the
use from the sponsor
Dr. Boyce's response
is not attached with
the letters
812.140(a)(1)

176

Sec. 812.35 Supplemental applications.
(a)Changes in investigational plan --(1)Changes requiring prior approval. Except as described
in paragraphs (a)(2) through (a)(4) of this section, a sponsor must obtain approval of a
supplemental application under 812.30(a), and IRB approval when appropriate (see 56.110
and 56.111 of this chapter), prior to implementing a change to an investigational plan. If a
sponsor intends to conduct an investigation that involves an exception to informed consent
under 50.24 of this chapter, the sponsor shall submit a separate investigational device
exemption (IDE) application in accordance with 812.20(a).
(3)Changes effected with notice to FDA within 5 days. A sponsor may make certain changes
without prior approval of a supplemental application under paragraph (a)(1) of this section if
the sponsor determines that these changes meet the criteria described in paragraphs (a)(3)(i)
and (a)(3)(ii) of this section, on the basis of credible information defined in paragraph
(a)(3)(iii) of this section, and the sponsor provides notice to FDA within 5-working days of
making these changes. (ii)Changes to clinical protocol. The requirements in paragraph (a)(1)
of this section regarding FDA approval of a supplement do not apply to changes to clinical
protocols that do not affect: (B) The scientific soundness of the investigational plan

Regulatory
Folder
Description of
File
Date of file Comments Action To Be
Taken
FDA Violation

Regulatory
files for Boston
Email
correspondence
from Lisa Petras
to Dr. Boyce
regarding the
Boston Shriners
IRB questions
and protocol and
consent
modifications
12/13/2006 Lisa Petras states to Dr.
Boyce that the Boston staff
has submitted a moderately
modified protocol and
modified ICF to the local
IRB. The protocol has been
modified from what the
sponsor had sent them which
was the 05/204 protocol that
was not approved.
See comments to
the left
812.35(a)(3)(ii)(B)
177

Regulatory
files for Boston
Email
correspondence
from Dr. Boyce
to Lisa Petras
(Boston
Shriners)
regarding
different
protocol use at
various sites
12/13/2005 The following is from an
email correspondence that
shows that a uniform
protocol has never been in
use for all of the study sites
involved in the CSS clinical
trial: Dr. Boyce states in the
email that, "At the present
time, we have not developed
a uniform protocol for use at
all four Shriners Burns
Hospitals. Melissa and I will
work on this during the next
couple of month, but it will
not be available for awhile.
Therefore, if Dr. Sheridan
would like to begin enrolling
patients in early 2006, I
suggest you submit the
revised protocol for
approval. The uniform
protocol can be submitted
later when it is ready.
Melissa and I will probably
circulate drafts of the
uniform protocol, consent,
and data collection forms to
the clinical research offices
of all of the Shriners Burns
hospitals to include as many
as possible of the local
considerations of each
hospital."
Dr. Boyce states
that the same
protocol was not
used at each of the
Shriners sites. The
protocol that was
using data each site
had variations that
were site specific.
The sponsor cannot
change the protocol
to make each
protocol fit the site.
812.35(a)(3)(ii)(B)
Regulatory
files for Boston
Email
correspondence
from Melissa
Reed (UC) to
Martha Lydon
regarding the
CSS renewal for
the IRB
8/31/2006 The email states that the
FDA has not provided the
sponsor approval for
amendments to the protocol,
and Melissa Reed tells Ms.
Lydon that she will send the
most recent approved
protocol which should be
just like the one used to
develop the Boston site's
protocol
The protocol that
Ms. Reed is
sending the Boston
site is not FDA
approved and the
protocol is for the
IRB to review for
their continuing
review.
812.35(a)(3)(ii)(B)
178

Regulatory
files for
Sacramento
Protocol version
08/22/01 (this
has a previous
date of
05/10/01) that
has been
approved by the
IRB on 10/03/01
8/22/2001 The protocol is the 08/22/01
version which was amended
from the 05/10/01 version
that has not been seen in the
files. The version of the
protocol has 16 pages where
the page 15 is stated as being
16 of 7 instead of 15 of 16.
The protocol has
seemed to change
drastically from 32
pages to 16 pages.
This is not the same
protocol that the
sponsor first gave
to the site. There is
no correspondence
from the site to
show this
812.35(a)(3)(ii)(B)
Regulatory
files for
Sacramento
Protocol version
04/2004
Apr-04 Verify that the protocol is
not a new protocol with
endpoints and procedural
points that are changed
The protocol that is
being used for the
Sacramento site
does not have the
same schema page
that the Cincinnati
site is using. The
protocols are
different and the
schema pages are
different as well.
812.35(a)(3)(ii)(B)
Regulatory
files for
Sacramento
Protocol version
04/2005 (with
approval from
the UC Davis
IRB on
07/11/07)
Apr-05 The protocol has an approval
from the IRB on 07/11/07
through 07/11/08. The
protocol and the study have
been suspended since 2005.
There are no subjects that are
receiving any treatments
during this time period. The
approval from the IRB is
unknown at this point. The
protocol that has been
approved is the protocol that
had been changed from the
sponsored protocol.
See comments to
the left
812.35(a)(3)(ii)(B)
Regulatory
files for
Sacramento
Protocol version
04/2005
Apr-05 The protocol is version
04/2005 (the protocol that
was never approved by the
sponsor) has an IRB
approval on it. The approval
date is 06/20/08 and the
expiration date is on
06/20/09. There is an IRB
stamp that the report is
approved on 06/20/08 and
expires on 06/20/09.
See comments to
the left
812.35(a)(3)(ii)(B)
179

Regulatory
files for
Sacramento
protocol version
05/2004
May-04 The version of this protocol
is version 05/2004. The
version was never approved
by the sponsor or the FDA.
The IRB has approved this
version of the protocol at
during the same time period
of the version of the protocol
04/2005. The UC Davis IRB
has had two separate
versions of the protocol
approved for the same time
period. Neither version is
the correct version for the
study. These protocols were
the last version that the IRB
was given by the site. The
approval time periods are
from 06/20/08 through
06/20/09.
See comments to
the left
812.35(a)(3)(ii)(B)

180

Sec. 812.150 Reports.
(a) Investigator reports. An investigator shall prepare and submit the following complete,
accurate, and timely reports: (7) Other. An investigator shall, upon request by a reviewing
IRB or FDA, provide accurate, complete, and current information about any aspect of the
investigation.

Regulatory Folder Description of File Date of file Comments Action To Be
Taken
FDA
Violation
Sacramento
Letter from Dr.
Greenhalgh to the IRB
chair (UC Davis)
updating the IRB on
the status of JSC who
was enrolled under
emergency use
4/1/2004 An email was sent to Dr.
Greenhalgh's research
coordinator stating that
the report required by
the IRB was not
received by the IRB
within the mandatory 5
working days, and the
IRB has not received the
report as of 04/01/04.
An email back to the
IRB committee analyst
from Johanna Sanders
states that a response
was sent to the IRB on
06/05/03, but she will
fax a copy of the letter.
See comments to
the left
812.150(a)
(7)

181

accurate, and timely reports: (1 )Unanticipated adverse device effects. An investigator shall
submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device
effect occurring during an investigation as soon as possible, but in no event later than 10
working days after the investigator first learns of the effect.

File
Violation

Regulatory folder for
07/12/05
Serious adverse
event report to
the UC Davis
IRB in relation to
the death of
patient #100
7/5/2005 The Serious adverse event
report states that in
section II of the report,
the question is if the event
being reported serious,
unanticipated and related
to the study. The answer
is no. The serious
adverse event was death.
This should have been
reported as a serious
event and not marked as
no.
The serious adverse
event that took place
was not reported as a
serious adverse event
even though it is on the
report. The event that
happened was
ultimately death. Dr.
Boyce wrote to Dr.
Charles Durfor (FDA)
that the Sacramento
site's patient death was
still undergoing
investigation as of
07/08/05. The
determination of death
was not yet known, and
there was not mention if
the device played a role
or not. The SAE report
states that the
investigator feels that
the device was not a
contributing factor
without knowing how
the patient expire
812.150(a)(1)
12/06/05 and 01/03/06
University of
Cinn. Internal
adverse event
report for subject
103
11/1/2005 The subject suffered from
cardiopulmonary arrest
and death on 10/30/05.
This should have been
reported as an SAE due to
death. The PI signed the
document on 11/01/05
which was one day prior
to the site being aware of
the death on 11/02/05 and
PI pre-dated signature,
and death should have
been reported as an
SAE instead of an
adverse event to the
IRB. The IRB form did
not have SAE on the
form and did not have
any information for
812.150(a)(1)
182

the date of the adverse
event was on 10/30/05.
device studies.
12/06/05 and 01/03/06
Report form for
adverse events in
human subjects
at UTMB. The
patient protocol
number is not
identified but the
UH# is 2787388.
no date on
file
AE is a staph infection in
the CSS on his legs with
all the CSS skin grafts
being lost after a 04/27/05
surgery. The physician
noted that the AE was
unlikely the result of
participation in the
research protocol. This
could possibly be patient
#96 MD, but not for sure.
The severity of the event
was never marked on the
section "this is a required
response to the severity."
The AE was not ever
signed or dated to the
IRB or the sponsor.
There was not any IRB
receipt that
acknowledges that the
SAE (AE) was ever
reported.
812.150(a)(1)
12/06/05 and 01/03/06
Report form for
adverse events in
human subjects
at UTMB. The
patient protocol
number is not
identified but the
UH# is 2787388.
no date on
file
AE is an invasive fungal
infection in his jaw that
required removal of
approximately 2/3's of his
lower jawbone on
03/24/05 and 03/28/05.
The AE is listed as
significant disability and
his whole lower jaw was
removed in two surgeries
about a week apart. The
first surgery took
approximately 2 hours to
remove the jawbone. The
patient had received a G-
tube into the stomach for
nutritional support. The
patient responded slowly
to all his lengthy
hospitalization. The AE
was marked as unlikely.
AE was never signed or
dated, and the AE was
not complete for the
section to designate the
severity of the AE. IRB
did not sign the bottom
of the page that the IRB
reviewed this AE.
812.150(a)(1)
183

03/18/08
Adverse event
for subject #130
for CSS graft
loss with
regrafting
follow-up #5
3/14/2008 The patient has had
contamination with
mycobacterium asscessus
and multiple other
microorganisms
throughout
hospitalization. The
patient has now received
12 sets of CSS that have
been evaluated for graft
loss and regrafting is
complete. Each set is
evaluated at POD# 14 and
POD #28.
Files do not have a date
that they were ever sent
to the IRB. There is no
acknowledgment form
IRB. AE was not sent
812.150(a)(1)
03/18/08
Adverse event
for subject #132
for graft loss >
10% with
regrafting
follow-up #1
3/14/2008 Patient received one set of
CSS (20 grafts) on
02/01/08. Wounds traced
at POD #12 revealed
30.8% graft loss. The
areas of graft loss were
regrafted with autograft
on POD #13 on 02/14/08
with wound closure
completed by discharge
acknowledgment form
812.150(a)(1)
03/18/08
Adverse event
for subject #132
for reinsertion of
traceostomy tube
follow-up #1
3/14/2008 The patient's
tracheostomy tube was
down-sized to a 3.0 on
02/09/08 and was plugged
on 02/11/08. The
removed on 02/12/08.
The patient was noted to
have moderate secretions
and frequent rhonchii on
auscultation of lung
fields. The patient
returned to the operating
room on 02/14/08 for a
serial excision and
grafting procedure to his
back. The patient was
intubated for the
procedure and placed in
the prone position. Upon
turning the patient form
the prone position to the
supine position, it is noted
that the ETT was partially
clogged. A 3.0
placed in the remaining
small orifice in the neck.
acknowledgment form
812.150(a)(1)
184

Breath sounds and
appropriate readings for
end-trial CO2 were noted
and the ETT was
removed. The result is
ENT performed a repeat
microlayngoscopy
bronchoscopy on
03/04/08. The findings
were mild tracheal
malacia and mild edema
of supraglottic structures.
The patient's
tracheostomy was
removed post-operatively
on 03/04/08.
05/29/08
Adverse event
form for subject
# 134
5/16/2008 Adverse event was that
the patient went to the
operating room on
05/16/08 for placement of
CSS grafts. At 1307, the
patient was noted to have
rapid and labored
respirations. Some
retractions were noted
and breath sounds were
diminished. The
tracheostomy was found
to be occluded. This was
replaced per anesthesia at
1308 with immediate
return of improved breath
sounds and regular
respirations. Patient has
received five grafts.
The site did not send the
AE until 12 days later
when the event
occurred. PI did not
sign the AE form until
12 days after the site
was made aware. No
reason given.
812.150(a)(1)
185

07/03/08
Adverse event
form from
subject #134
6/5/2008 The adverse event is for
the patient that received
autograft and CSS
grafting to the right thigh
and right shoulder on
05/23/08. The graft loss
of both CSS and autograft
was noted and operative
procedures were planned
for 06/05/08.
The follow up plan is
for the patient to receive
partial regrafting of
autograft with autograft
to the right inner thigh
on 06/05/08. The date
on the sponsor sent
form is almost a month
late (07/02/08) form
when the site first knew
about the event.
812.150(a)(1)
07/03/08
Adverse event
form from
subject #131
6/30/2008 This is a follow-up for the
event of a fractured left
femur. The patient was
rehab through regimented
schedule and the end
result seems to be that the
patient is full weight
bearing with no
abnormalities noted.
The PI signed the form
on 07/02/08 which the
date sent to the sponsor
was on 06/02/08. This
is not possible when the
date of the event
occurred on 06/30/08,
and the reported date
was on 06/02/08. A
note in the regulatory
folder under the email
correspondence was
asking the sponsor/site
to clarify the reason for
the mismatched dates
and to explain which
dates are correct.
812.150(a)(1)
186

02/12/09
Copies of the
adverse events
that the annual
report states were
reported to the
UCinn IRB and
the FDA.
2/12/2009 The following adverse
events do not have a
stamp from the IRB that
they were ever received
from the site. The records
to show no IRB response
will be listed as: subject
#, date of event, initial or
follow-up #, and
description. Subject #134
05/28/08 Initial Fluctuant
mass with foreign body

Subject #135 - 05/23/08
Initial Death
Subject #134 - 06/05/08
Follow-up #1
Suprastomal granuloma

Subject #134 - 06/13/08
Follow-up #1 Fluctuant
mass with foreign body

Subject #134 - 06/20/08
Follow-up #1 Graft loss
> 10% with regrafting

Subject #134 - 06/05/08
Initial Autograft loss >
10% with regrafting

Subject #131 - 06/30/08
Follow-up #1 Fracture of
left femur post discharge

Subject #136 - 08/11/08
Initial Suprastomal
granuloma

Subject #136 - 08/15/08
Initial Respiratory
depression and airway
obstruction secondary to
sedation
Subject #136 - 08/29/08
Initial CSS graft loss >
10%
Subject #136 - 09/12/08
The date of event
section on the IRB form
is always filled out form
the site as the date the
form is actually
completed on. The date
of the event should
remain unchanged from
the original date of the
event and the
subsequent follow-up
should change only
812.150(a)(1)
187

Follow-up #1 CSS graft
loss > 10%

Subject #137 - 09/15/08
Initial Autograft loss 10%

Subject #136 - 09/19/08
loss > 10%

Subject #136 - 09/22/08
Follow-up #1
Suprastomal granuloma

Subject #136 - 09/26/08
loss > 10%
Subject #136 - 10/02/08
loss > 10%

Subject #136 - 10/10/08
loss > 10%
Subject #137 - 10/09/08
Initial Autografting to
donor site for failure to
heal
Subject #130 - 01/11/08
Initial for sets #10-12 and
follow-up #4 for sets #1-9
CSS graft loss

Subject #131 - 01/18/08
Initial for sets #6, 6b and
follow-up #2 for sets #4-5
CSS graft loss

Subject #132 - 02/03/08
initial Erythematous Rash

Subject #132 - 02/13/08
Initial Graft loss > 10%
132 02/14/08 Initial
Reinsertion of
tracheostomy tube
188

Subject #131 - 02/22/08
Initial Fracture of tibia
and fibula

Subject #131 - 03/04/08
Initial Fluctuant mass
right flank without
drainage

Subject #130 - 03/10/08
Follow-up #5 for sets #1-
12 Graft loss > 10%
without regrafting

Subject #132 - 03/13/08
Follow-up #1 Graft loss >
10% with regrafting

Subject #132 - 03/13/08
Follow-up #1 Reinsertion
of tracheostomy tube

Subject #131 - 04/04/08
Follow-up #1 Fluctuant
mass right flank without
drainage

Subject #131 - 04/04/08
Initial Fracture of left
femur post discharge

Subject #134 - 05/02/08
Initial Suprastomal
granuloma

Subject #134 - 05/16/08
Initial Occluded
tracheostomy with
replacement
Subject #134 - 05/23/08
Initial Graft loss > 10%
with regrafting

189

03/17/09
The adverse
event for subject
140
3/19/2009 The adverse event is for
graft loss > 10%. The
graft loss is as follows:
Set #1-pod #14 19.5%.
The outcome is still
unresolved
There is no
acknowledgment from
the FDA that this
adverse event ever sent.
The current date of this
audit is 04/30/09. The
possibly of the FDA not
responding is still
ongoing.
812.150(a)(1)
UTMB IRB
documentation
SAE for
unidentifiable
subject (MR# is
2841680)
regarding balloon
broke off during
PEG tube
removal
1/23/2007 SAE is reported as:
during an attempt
removal on 01/22/07 of a
PEG tube the catheter
broke. The bell portion
on the gastric side
remained in the stomach.
Abdominal x-rays
suggested missing piece
was in the stomach.
Endoscopy for retrieval
revealed an empty
stomach. Subject passed
the balloon the next day
01/23/07 in his stool
without incident.
Response was good.
This is an initial report
to the IRB that the IRB
acknowledged on
02/23/07. There is no
verification when the
sponsor was notified
about this UADE.
Signed by the PI on
01/23/07. IRB was
notified on 01/25/07.
812.150(a)(1)
UTMB IRB
documentation
SAE for
unidentifiable
subject (MR# is
2822518) SAE is
death
12/23/2005 Listed as AE, but is a
UADE of death for a
subject that cannot be
identified. Worsening
condition due to burn.
Stopped heroic measures
at parent request. Autopsy
showed diffuse
pneumonia in all lobes of
her lungs, tubular necrosis
in her kidneys, gross
adrenal gland necrosis
and multi-system organ
failure
Signed by the PI on
12/23/05. Handwritten
note on AE report that
states that this was
faxed but not reported
to the IRB. Cannot
verify fax to sponsor or
timely response back to
the sponsor.
812.150(a)(1)
UTMB IRB
documentation
SAE for
unidentifiable
subject (MR# is
2822518) SAE is
death (follow-up
report)
3/7/2007 Listed as AE, but is a
UADE of death for a
subject that cannot be
identified. Worsening
condition due to burn, no
CSS applied. Stopped
heroic measures at parent
request. Autopsy showed
diffuse pneumonia in all
lobes of her lungs, tubular
necrosis in her kidneys,
Signed by the PI on
03/07/07. Cannot verify
fax to IRB or timely
response back to the
sponsor. This follow-up
is over two years after
the initial SAE of death.
812.150(a)(1)
190

gross adrenal gland
necrosis and multi-system
organ failure. (follow-up
report)
UTMB IRB
documentation
SAE for
unidentifiable
subject (MR# is
2827653) SAE is
death
4/27/2006 SAE was death that
occurred on 04/22/06.
Condition worsening and
responded poorly to all
medical treatments.
Subject had 99% 3rd
degree burns. No CSS
applied
Signed by the PI on
04/27/06. Cannot verify
fax to sponsor or timely
response back to the
sponsor.
812.150(a)(1)

Sec. 812.140 Records
(b)Sponsor records. A sponsor shall maintain the following accurate, complete, and current
records relating to an investigation: (1) All correspondence with another sponsor, a monitor,
an investigator, an IRB, or FDA, including required reports.

Regulatory
Folder
Description of
File
Violation
Regulatory
folder for
03/17/03
FDA letter back
to the site
granting approval
for the
"compassionate
use" to a subject
on 03/19/03.
3/19/2003 The letter back from the
FDA states that the
sponsor/site needs to have
completed the issues raised
from the FDA letter
02/14/03 that were identified
to get the study in
compliance and must only
use the device in the
compassionate use capacity.
Dr. Warden was a sub-
investigator on this study
and should not have signed
the letter as a non-involved
physician when he was
involved with the study. The
wording of the letter from
UCinn (Dr. Boyce) states
that Dr. Warden was not
involved with the subject at
the present time of the
compassionate use request.
Clarification as to why Dr.
Warden signed the letter for
compassionate use and was
involved with the study at
the present time.
812.140(b)(1)
191

Regulatory
folder for
10/24/03
Copy of the
research design
and methods
from the revision
of 05/01 (pages
38-46).
May-01 The version of this protocol
does not match up with the
promised revision that was
attached to the response
letter to the FDA letter for
07/30/03. The only version
of the protocol is the
05/2001 version
Clarification on the protocol
for the version that has been
attached to the FDA letter
for the response back to the
FDA. The version that
appears to have been sent
back was the version of the
05/2001 and not a revised
version of the protocol.
812.140(b)(1)
Regulatory
folders for
11/13/03
Adverse event
report form
(internal) for
subject DS
11/12/2003 The signature that is required
of the principal investigator
is actually signed by another
physician (writing
unreadable) for Dr. Glen
Warden MD. There have
been only 22 adverse events
reported for this study as of
11/12/03.
Need clarification on why
the IRB did not question the
signature for the adverse
events. The signature was in
place of the PI and not the
PI's own signature. There
were only 22 adverse events
that had taken place at this
point in the study.
812.140(b)(1)
Regulatory
folder for
08/12/05
Letter from the
FDA to Dr.
Boyce stating
that the FDA has
reviewed the
supplement
proposing 50
patients and 3
institutions to the
study. The
supplement is
approved
9/19/2005 There is not any
correspondence from the
sponsor/site that shows the
answers to the FDA letters
that granted them the
approval for the patient
enrollment increase nor the 5
institutions
Need to verify the location
of the letters or
correspondence back to the
FDA
812.140(b)(1)

192

Sec. 812.140 Records
(b)Sponsor records. A sponsor shall maintain the following accurate, complete, and current
records relating to an investigation: (3) Signed investigator agreements including the
financial disclosure information required to be collected under 812.43(c)(5) in accordance
with part 54 of this chapter.

Regulatory
Folder
Description of File Date of file Comments Action To Be Taken FDA
Violation
Regulatory
folder for
10/24/03
Investigator List as of
11/03/03 (excerpted from)
reporting period 06/01/00 -
10/31/01
11/3/2003 The list is from the
06/01/00 - 10/31/01
reporting period. The fax
went out in 11/03/03, and
there should be an
updated investigator list
or an explanation why the
list was not updated at
least yearly via annual
reports. There is a list of
investigator agreements
that were supposed to be
attached to this file. The
Investigator agreements
are not currently with the
file and cannot be located.
The original investigators
that were in the IDE
submission were Boyce,
Warden, Kagan, Meyer,
Yakuboff, and Rieman on
01/28/98. Two clinical
research nurses (Fowler
and Caudill) were added
as investigators in
Supplement 1 on
04/08/98. In a letter dated
06/30/99 Dr. Greenhalgh
and the Sacramento
Shriners hospital was
added as an investigator
and a participating
institution. On 06/2000
an IRB protocol was
approved by the
University of California
Davis for performance of
this study at the Shriners
in Sacramento California.
Dr. Meyer left the
The Sacramento site
according to the fax
submission of Dr. Boyce
has a letter that
Sacramento's
investigator and site
being added to the study
on 06/30/99. The first
subject went on study at
that site according to the
spreadsheet created by
Dr. Boyce on 06/25/99.
The subject according to
files went on study 5
days before the
investigator and the site
were approved. The
IRB protocol was not
approved until 06/2000
by the University of
California Davis' IRB
and there had already
been a subject on the
study since 06/25/99.
The study was in
complete non-
compliance from the first
subject.
812.140(b)(3)
193

university of Cincinnati
and shriners on 04/2000.
In 2001, Palmieri and two
clinical research nurses
(lawless and sanders)
were added as
investigators at the
Sacramento shriners
hospital (no date as to
when this was in 2001.
IN 2001. Dr. Warner was
added as an investigator
and Judy Nelson RN
replaced Lynn Caudill RN
at the Cincinnati hospital.

Sec. 812.150 Reports
(b)Sponsor reports. A sponsor shall prepare and submit the following complete, accurate, and
timely reports: (1) Unanticipated adverse device effects. A sponsor who conducts an
evaluation of an unanticipated adverse device effect under 812.46(b) shall report the results of
such evaluation to FDA and to all reviewing IRB's and participating investigators within 10
working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall
submit such additional reports concerning the effect as FDA requests.

Regulatory
Folder
Violation
Regulatory
folder for
08/19/08
Email from Joanne
Lindwall to Peggy
Simpson explaining
about adverse events
that were submitted
to the FDA
9/19/2008 The email explains that
there are five adverse
events that are being
reported to the FDA.
The adverse events are as
follows: subject #136-
occurred on 08/11/08 and
submitted on 08/19/08,
subject #136-occurred on
08/15/08 and submitted
on 08/26/08, subject
#136-occurred on
#136-occurred on
#137-occurred on
There is only one
adverse event that is
listed in the regulatory
folder with this email.
That is the 08/11/08
occurrence. There is
no other supporting
documentation to
show the other four
events in this portion
of the regulatory
folder.
812.150(b)(1
)
194

on 09/18/08.
Regulatory
folders for
11/02/05
University of
Cincinnati IRB
internal adverse
event report form for
patient# 103 (PI is
Kagan)
11/2/2005 Patient #103 had a
serious adverse event on
10/30/05 which was
death. The IRB form that
was used is only an
adverse event form
instead of a serious
adverse event form. The
date of the adverse event
(SAE) was on 10/02/05
and the date the UC site
was aware of the event
was on 11/02/05. Dr.
Kagan (PI) signed the
report on 11/01/05. He
signed the report one day
prior to the site having
knowledge (awareness)
of the report.
PI signature was pre-
dated, and the IRB
form does not list any
SAE questions nor do
the IRB forms have
device questions.
812.150(b)(1
)
Regulatory
folder for
12/06/05 and
01/03/06
Annual report dated
12/30/05 (PAGE 4)
12/30/2005 There is only one page to
the annual report from
12/30/05 that has the
number of subjects
enrolled, and the number
of devices used. Dr.
Boyce is stating the
history of the study and
the number of
enrollments that have
occurred over the period
of 1998 through 2005
Need to locate the
remainder of the
annual report in the
regulatory files
812.150(b)(1
)

195

(a)Investigator reports. An investigator shall prepare and submit the following complete,
accurate, and timely reports: (4)Deviations from the investigational plan. An investigator
shall notify the sponsor and the reviewing IRB (see 56.108(a) (3) and (4)) of any deviation
from the investigational plan to protect the life or physical well-being of a subject in an
emergency. Such notice shall be given as soon as possible, but in no event later than 5
working days after the emergency occurred. Except in such an emergency, prior approval by
the sponsor is required for changes in or deviations from a plan, and if these changes or
deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of
human subjects, FDA and IRB in accordance with 812.35(a) also is required.

File
Date of
file
Comments Action To Be
Taken
FDA
Violation
Regulatory for
folder 02/20/09
Adverse event
for subject #138
2/11/2009 The adverse event is for CSS
graft loss > 10%. Graft loss is as
follows: Set#2-POD #14 7.55%
and POD #28 1%, Set#3-POD
#14 27% and POD #28 16%, Set
#4-POD #15 16% and POD #28
3%, Set #4b-POD #14 17.6% and
POD #26 11%.
The Sets #4 and
4b have POD
days that are 15
and 26
respectively. The
POD dates
according to the
protocol are 14
and 28. The
dates that are
given are out of
window and
should be a
protocol
deviation
812.150(a)(4)
Regulatory folder
for 03/02/09
Adverse event
for subject 139
2/26/2009 CSS graft loss > 10% with
regrafting. The graft loss is as
follows: Set #1-POD #13 14.6%,
Set #2-POD #13 4.5%.
The sets 1 and 2
have POD days
of 13 on both
sets. The POD
day should be 14
and there is
nothing in the
protocol that
states that there is
room for plus or
minus any days
between the POD
dates. This
should be a
protocol
deviation
812.150(a)(4)
196

Regulatory folder
for 04/20/09
Protocol
Deviation for
subject # 134
6/5/2008 The deviation is that some areas
on or around grafts on the right
thigh and right shoulder have
been excised and autografted.
These have been placed in the
protocol dressings for post-
operative autograft
Peggy Simpson
RN writes on the
protocol
deviation that the
site will continue
to work with the
medical staff to
assess the most
appropriate
dressing for the
grafts as it
pertains to the
specific situation.
Not found in UC
IRB files
812.150(a)(4)

Sec. 812.140 Records.
(a)Investigator records. A participating investigator shall maintain the following accurate,
complete, and current records relating to the investigator's participation in an investigation:
(4) The protocol, with documents showing the dates of and reasons for each deviation from
the protocol.

Regulatory Folder Description of File Date of
file
Comments Action To Be Taken FDA
Violation
04/20/09
Protocol deviation
for subject #132
8/1/2008 POD # 182 not done Patient not present for
photos and data and
remains in Mexico. Study
coordinator will try and
communicate with family to
show importance of
returning for follow-up.
Deviation was not signed
for until 01/30/09 and was
five months after deviation
occurred
812.140(a)(4)

197

accurate, and timely reports: (3) Progress. An investigator shall submit progress reports on
the investigation to the sponsor, the monitor, and the reviewing IRB at regular intervals, but
in no event less often than yearly.

Regulatory
Folder
Violation
UTMB
Galveston IRB
documentation
(2004-2008)
UTMB IRB response to
Dr. Sanford about
continuing review for
03/21/08. The IRB
approves the study but
with stipulations.
3/21/2008 The IRB approves the
protocol but with
stipulations. Charles
Mitchell is still shown as
being on the study, and
the IRB asks for
clarification since
Charles Mitchell was
removed on 11/17/06.
Deb Benjamin was never
approved to be on the
study. A request to
provide reasoning for
low enrollment rate is
being asked by the IRB
as to why the study
should continue. The
IRB asks these responses
be sent to them no later
than 03/31/08 or the
study may not continue.
Administrative deferral
would happen on
05/15/08 if not
answered.
There was no
continuing review
that was in the files
regarding this IRB
memo for approval
812.150(a)(3)

198

APPENDIX A:

APPENDIX A
199

200

201

APPENDIX B:
202

APPENDIX C:
203

APPENDIX D:
204

APPENDIX E:
205

206

APPENDIX F:
207

208

APPENDIX G:
209

210

211

Comprehensive CSS MOrley Audit Report - 25MAR2010

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Comprehensive CSS MOrley Audit Report - 25MAR2010

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1

Comprehensive Audit Report

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