Comprehensive CSS MOrley Audit Report_25MAR2010[1]

8/21/2019 Comprehensive CSS MOrley Audit Report_25MAR2010[1]

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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 237. 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 4718. 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 6831. 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 12440. 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 13547. 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 1.1Subject Age Summary


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Figure 1.2Subject Gender Summary

Figure 1.3-Subject Location Summary


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Figure 1.4-Subject Race Summary

As noted inFigure 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 treatedwith device:

Subject Number Location Reason for Non-Treatment

83 Cincinnati unknown

85 Sacramento Subject had infection at biopsy

site89 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 issuesidentified, 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 ofcompleting 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 orUniversity 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 #82: Should have been re-consented 3 times. Subject #96: Should have been re-consented 2 times.

Subject #97: Should have been re-consented 1 time.








Subject #114: Should have been re-consented 3 times. Subject #115: Should have been re-consented 1 time.









Subject #131: Should have been re-consented 3 times. Subject #134: Should have been re-consented 3 times.

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 Risksection: Added in Each preparation ofcultured skin substitutes is tested before clinical use, and must benegative for infection. Second bullet point adds in Also, similarkinds of materials used for similar kinds of tissue repair have beenassociated with the development of auto-immune disease at a latertime in life, but this has not been seen with cultured skin substitutesin more than 15 years experience. Added in as the third bullet point:the polymer fabric, and other materials used in preparation of thecultured skin substitute are from bovine sources (cows or beef).

Also, several drugs are used for preparation and application ofcultured skin. These drugs include penicillin, streptomycin,neomycin, polymyxin B, mupirocin, ciprofloxacin, amphotericin B,hydrocortisone and insulin, If the patient is known to be allergic tothese materials or drugs; she/he should not be treated with cultured

skin substitutes. Added a fourth bullet point: It is also possible thatan allergic reaction and loss of cultured skin grafts could occurfrom the treatment of burn scars, if the original burns were treatedwith cultured skin. Specific tests will be performed to determinewhether a risk of allergic reaction may occur for treatment of burnscars. Deleted bullet point #6 referring to mouse cell preparation ofCSS.

06/22/2003

October2003

Change in Risk Bullet point #2 was changed back to match theAugust 2002 ICF version. Bullet point #3 regarding the polymerfabric from bovine sources was deleted. Bullet point #4: allergicreaction of loss of CSS was deleted.

01/27/2004

May 2004 Proceduressection: added in and/or clinical examination thatfollow the course of the healing process. And Joint range ofmotion will be recorded when applicable. Riskssection: added theallergic reaction by CSS made from the bovine cells paragraph thatwas removed in the October 2003 version.

06/23/2004

September2005

Risksection: Number of patients changed from 75 to 125 ofexperience 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

January2006

Proceduressection: changed the term debridement to removal;added on a reason of traced and photographed treated areas toevaluate whether the cultured skin is growing normally with therest of your body. Changed the range of motion recording toPassive 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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Risksection: added in first bullet point Also, antibiotics areapplied to the cultured skin for several days to reduce chances ofinfection. Deleted CSS from cadaver skin will only be used if ithas tested negative for HIV (AIDS) and hepatitis, and also hassatisfied 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 yearchanged to add andperiodically between three and five years post-grafting. Added in the wound biopsy section of procedures

routine clinic visits after your discharge. Deleted the passive inthe range of motion recorded section. Added in skin test performed

to evaluate whether CSS skin may be used for treatment of burnscars after treatment of original burns with CSS. In theExperimental Proceduressection: Deleted the skin test forallergic 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 skinsubstitute, if allogeneic cells from cadaver skin are used. Thechance of rejection of cultured allografts (cadaver skin cells) is nogreater than the chance of rejection of cadaver skin that is routinely

used as a temporary wound cover. Next bullet point added incultured skin made from cadaver skin will only be used if it hastested negative for HIV (AIDS) and hepatitis, and also has satisfiedall 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 Productssection there is a section added in perIRB instructions regarding Conflict of Interest: adds in Dr. Steve

Boyce, a sub-investigator on this study, has received paymentsfrom the company that owns the rights to the process used in thisstudy. This disclosure is made so that you can decide if thisrelationship 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 forinclusion in the clinical investigation but for whom the treating physician believes the device may providea benefit in treating and/or diagnosing their disease or condition. This provision is typically approved forindividual 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 optionavailable 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 investigationaldevice should occur.

Prior FDA approval is needed before compassionate use occurs. In order to obtain Agency approval, thesponsor should submit an IDE supplement requesting approval for a protocol deviation under section812.35(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 uninvolvedphysician, authorization from IDE sponsor)

As figure 3.1 demonstrates, the compassionate use regulations were not always followed by theSponsor/investigator. The source documentation needed to substantiate that all the above reference pointswere completed. Auditors could not locate all authorizations required by the regulations to enroll asubject 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 iscertainly 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 wereapproved. 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 3.2Compassionate 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 mannerthroughout the study. The Boston Shriners site was the only outlying site that had a record of whoattended the training session regarding the cultured skin substitute. There was no documentation on whatwas 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 Regulations312.62Investigator 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 administeredthe 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 medicalrecords


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The Code of Federal Regulations 812.140(a)(3)(i)A participating investigator shall maintain the followingaccurate, 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 thefailure 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 thefollowing 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 currentrecords 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, theindividual'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 recordsrelating 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 fora 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 formswere used within the same subject. The forms do not reflect a revision date: one form has nodate 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 formshows the numbers as 1 through 4, however the label is none under 0; the label normal is betweenthe numbers 1 and 2 and hyper is the label under number 3. The same type of variance occurredon 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 andthe label contracture goes across the number 4 and 5. By not using a consistent format for thecollection 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 collectionand only used a few of the CRFs from the sponsor. The data was combined for Post OperativeDate (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 noinitials/signatures or date given. Follow up was not done per protocol, even though the subjectdid 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 andthere 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 recordinformation regarding safety and efficacy as subject is emergency use and not an actual researchsubject. 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 formfor set one.

Subject #92:POD 81, 182, and 365 data collection was not done. Other CRFs were done a weekor more out of window with no reason why it wasnt completed on time as subject was in thehospital 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/ POD14, and Qualitative Outcome for set one/POD 28

Subject #95: CRFs not signed, incomplete, many CRF pages are marked thru with a line and thenote says to see the treatment summary in medical chart; however medical treatment summarywas not present.

Subject #96: CRFs are incomplete to include: Microbiology for set one, Qualitative Outcome forsets one, two and three.

Subject #97: CRF pages appear to be written by two different people (handwriting different anddifferent 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 forseveral years then completed in 2009. Errors marked thru with no initials, date, or reason whychange was made.

Subject #100: CRFs not completed, notes state to see patient treatment summary. Subject diedthree days after receiving CSS. No initials, signatures, dates on CRFs. Forms were filled out withheader information from POD 0 thru POD 365, forms were then marked through with a lineacross 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 dateof correction noted as August 26, 2009.

Subject #104: CRFs are incomplete-Specifically: physical exam form for Set 1/ POD 0 andseveral Qualitative Outcome and Investigator Global Assessment Forms. There are changes madeby Peggy Simpson, RN at UC Shriners on the Galveston Shriners forms. Peggy initialed but didnot date the changes. Other changes are scratched thru (e.g. PE pre study) with no initial or dateas 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 CRFsnot signed or dated. No PI review of CRF. Changes made to CRF forms several years later thanoriginal entry made. On 11/10/2005 a protocol deviation was generated for a Set 2 physical examnot 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. Notall changes are signed and dated.

Subject #107: CRFs not completed until Peggy Simpson RN at UC Shriners completed forms inJuly 2009.

Subject #108:CRFs were not completed for set 1 from POD 14 to POD 365. Set 2 and 3 had nocollection performed.

Subject #109:CRFs are typed, no signature. PE for pre study visit has a date of 10/29/2 005which 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 studysubjects, 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 CRFdocumentation was performed.

Subject #115: This was a scar contracture release and re-grafting. The CRFs were designed tocollect 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 wasreported. OR report dated 4/21/2006 contradicts what is reported in the CRF with regards to nocomparative site available.

Subject #121: The CRFs appear to have been typed up after the initial information wasgathered. The site was handwriting the information on CRFs, and the medical records weremostly 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 Shrinersin 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. Subjectrecords were completed in 2006.

Subject #130: PI review and sign off by Dr. Kagan was done on 01/29/2009 when subject wascompleted in September 2007.

Subject #131:PI reviewed and signed off on 01/29/2009 when subject was completed in Augustof 2007.

Subject #133: CRFs incomplete. This subject received CSS for scar contracture due to previousburn. The CRF was not designed to capture information for scar contracture subjects. Therefore, amajority of this information was left blank.

The case report forms were overall, very poorly designed. There were areas of data capturing that did notsync with the protocol. Additionally, there was no documentation for site personnel training, with respectto 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 theCRFs were completed.

The majority of the CRFs were completed with ink in standard pen/paper format. However, there wereseveral CRFs that were typed, and multiple cases where typed CRFs appeared even after deviations werenoted by Dr. Steve Boyce that the information had not been collected. The auditors identified PeggySimpson, RN, research nurse at the UC Shriners site as making corrections/changes to CRF documentsduring 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 orchanges 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 followingaccurate, 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 regulationwas violated in approximately half of the subjects enrolled. The investigators at the sitesdid not oversee the research protocol as follows:


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1. CRFs were not completed properly2. CRFs were improperly corrected3. CRFs were not signed off by the PI and/or sponsor4. Diagnostic Test were not signed off by the PI5. 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 dateon many of the pages.

7. CRFs that were typed in, appear to have been done at a later date, however they were signed offby 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 studymisconduct with back dating. It does appear suspicious as several subjects had deviations writtenby Dr. Boyce regarding the fact that no data was collected, and yet there was typed data, with asignature 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 ReportForm 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.


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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


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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


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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 wasnot 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


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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 Awill 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 beperformed 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.


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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 93Subject 97 Subject 98 Subject 99 Subject 103

Subject 104 Subject 105 Subject 106 Subject 109




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 comparativeset; rather it states that for each administration of CSS, a comparative site will be treated with split-

thickness skin.


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Figure 6.1- Comparative Site Summary

After selection, Site A will be defined as the right most location, the upper most location, or thefront 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).


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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 randomizedno comparative site administered




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Subject 119: Not randomizedno comparative site administeredSubject 120: Not randomizedno comparative site administered

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 therewas no source documentation available in this subjects study file in order to verify how the site

determined or completed the randomization.


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Figure 6.2-Correctly Randomized Subjects


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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 woundscovered 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.

Per CFR 812.110, investigators did not follow the investigational plan (protocol) dated November2003,

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:


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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


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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


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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


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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 EscharExcision 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 ofthe CRF sometimes differed from the actual anatomical burn estimate page. The chart listing belowindicates 11 of the 43 2nddegree burn estimates did not match. Of the 43 subjects that had 3rddegreeburns 18 of the subjects had a variance and of the total burn estimate 21 of the 43 subjects hadinconsistencies. Some of the subjects had variations in both 2ndand 3rddegree burn areas.

Several of the inconsistencies can be attributed to the fact that the area on in the CRF was left blank thuscreated a 0 in the database. There was only one or two people recording information for the CSS studysubjects. It seems intuitively obvious that someone (PI) should have been looking at these inconsistenciesand requesting a clarification for the data records. These discrepancies show a consistent lack of attentionto the details of the study which demonstrates a lack of commitment to follow the CFR section 812.40regarding RecordKeeping.

Subject 85: Treatment Indication: Giant Hairy Nevus

Subject 112: Treatment Indication: Giant Hairy Nevus


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Burn Area EstimatesHighlights difference in burn estimate data recorded in initial overall estimate and summed estimates by boIncludes treated patients only

2nd Degree Burns 3rd Degree Burns Total Burn AreaAnatomical Anatomical Anatomical

Enroll #: Initial Est. Burn Est Difference Initial Est. Burn Est Difference Initial Est. Burn Est Diff

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 -6.0

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 -0.5

91 3 3 0.00 61 51.5 -9.50 64 54.5 -9.592 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 -4.0

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.

108 35 0 -35.00 50 0 -50.00 85 0 -85.

109 5 0 -5.00 75 55.2 -19.80 80 72.2 -7.8

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.

119 72.5 70.5 -2.00 18.5 18.5 0.00 91 89 -2.0

120 10 4 -6.00 60 29.25 -30.75 70 33.25 -36.

121 1.75 1.75 0.00 89 89 0.00 91 90.75 -0.2

123 4 4 0.00 85 85 0.00 89 89 0.00124 0 0 0.00 86 83.75 -2.25 86 74.75 -11.

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


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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 BurnAreaAnatomical Anatomical Anatomical

Enroll #: Initial Est. Burn Est Difference Initial Est. Burn Est Difference Initial Est. Burn EstDifference129 1 1 0.00 80 80.25 0.25 81.25 81.25 0.00130 10 10.4 0.40 84 85.15 1.15 94 0 -94.131 0 0 0.00 90 90 0.00 90 0 -90.132 0 0 0.00 68 68 0.00 68 68 0.00133 0.75 0.5 -0.25 58.75 58.75 0.00 59.5 48.25 -11.134 7 7 0.00 65 65 0.00 72 66 -6.0

136 24.25 24.25 0.00 43.5 43.5 0.00 67.75 67.75 0.00137 12.5 12.7 0.20 58.5 58.6 0.10 70.5 71.2 0.70138 0.5 0.5 0.00 75.5 75.5 0.00 76.0 76 0.00139 0 0 0.00 69.85 69.85 0.00 69.85 69.85 0.00


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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 areadditional grafts below that separate this information.

There were forty four (44) treated subjects in this study population. It was observed that all 44 treatedsubjects had signed the Informed Consent Form (ICF), and thirteen (13) untreated subjects also signedICF. While all of the subjects reviewed in this part of the audit, did sign the ICF. There were somediscrepancies, as noted below:

Subject 129- ICF is on plain paper, no heading for Shriners Hospital or UC. ICF states that thestudy has periodic visits for the 1st year; however subject not brought back in for visits 91,182 or365. There is no documentation that the subject withdrew from the study.


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Subject 121- There is an ICF for Galveston Hospital which states received from Cincinnati May2004; revised in Galveston 12/12/04 and then revised again 02/24/06. Subjects mother signedthe 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 wasfrom Mexico and signed an English consent, there should have been a note to file stating that theperson 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 thesubjects 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 wasinitially brought into the ER facility and/or the Shriners Hospital H&P notes. The medical history oftenwas provided by the parents or guardian who accompanied the subject to the hospital.


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11.Pre-Study Physical Exam

The physical exam graph (Figure 11.1) shows that eighty six (86) percent of the subjects had a completePhysical Exam (PE) performed. The other fourteen (14) percent was incomplete. The sites werecompleting the PEs based on information located in the medical records, and usually the research nursewas 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 allcategories should have been completedper CFR 812.140(a)(3) -Records of each subject's case historyand 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, theindividual's hospital chart(s), and the nurses' notes. Such records shall include:

Figure 11.1- Pre-Study Physical Exam Completed


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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. Boycesdatabase, however could not be confirmed by auditors in the medical records. One subject did not havethe 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 ofantibodies 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 weremaintained in an extremely poor manner and not sufficiently for auditor review. Less than half of thesubjects, 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 theantibodies were to be drawn to test for allergic reaction of the cultured skin. Since less than half of thesubjects actually had results from the testing done, and there were no notes to file to explain why thesetests results were not obtained. The subjects had their blood taken twice during the study (Pre study andPOD 28) and these antibody tests were not performed.

This is a violation of CFR 812.100 Subpart E-Responsibilities of Investigators:An investigator isresponsible 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


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subjects under the investigator's care, and for the control of devices under investigation. An investigatoralso 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 appropriateprotocol mandated tracing was completed of the biopsy. The biopsy tracings could not be located forfour subjects. As the pie chart shows, the majority of subjects did have the skin biopsies for tracingsperformed 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


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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 weretracings that were completed for all pieces of CSS in the set. The following was observed with regards toCSS tracings in vitro:

Subject #105: was listed as incomplete as it was observed that a set that was not applied due tocontamination.

Subject #134: originally had a set 3; however the information regarding the CSS tracings couldnot 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.


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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:


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CFR 812.140(a)(3)(i) Documents evidencing informed consent and, for any use of a device by theinvestigator 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 foreach 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 (whetheranticipated 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 andthe results of all diagnostic tests.; 812.140(a)(3)(iii) A record of the exposure of each subject to theinvestigational 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 specificrequirement 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, POD14, 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, theissue is that these checks or PIsigned 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 requestedper the protocol and in the CRF, in the study visits following POD 28. Subjects were still in the hospitalor returning as outpatients, however there is nothing to support why the follow- up visits were notcompleted. It was observed, however, that many of the photographs were taken at or near the correctfollow 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 theoutpatient clinic. There was no viable reason why the follow up data could not have been obtained on themajority of the subjects. Per the CRFs the only data that needed to have been collected was thePhotography, the Healed Wound Biopsy (as possible), and Qualitative Outcome (QO) and at visit POD365 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 notesor any records found that could substantiate the information recorded on QO or IGA forms. The CRFforms 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 thatcompleted the QO form would know exactly how to complete this form. The instructions on how toassess the pliability (for example) should have been included on the form or given to the site in a writtenmanner so that consistency could have been maintained throughout the study and throughout personnelchanges.

The clinical scar assessments are subjective and validation is operator dependent. To use clinically, theraters 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 aquestion that asked were there any adverse events?,and was typically answered with a noand theadverse 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


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subjects were treated with the CSS, often completed the CRFs himself, compiled the data, reported thedata, and published the data.

The Physical Exam (PE) reports were completed by the research nurses, as was confirmed through theinterview 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 formswere not completed in a consistent manner. Some forms, for example, listed Sinus Tachycardia as normaland others listed it as abnormal on PE page under cardiac. The training should have been made clear tothe sites, how to complete the PE form. PE forms were often completed based on expected burn status ofburn patients. However there were subjects where the PE appeared to have completed correctly. Someforms (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 differenthandwriting, with no initials/signature or date given. Follow up not done per protocol, even thoughsubject did return to clinic for follow up visits.

Subject 132:Error corrections were not signed or initialed; Template form stating PI Dr. Kagan hasreviewed all data from beginning to end on this patient, and signed and dated 1/29/09. Pre- study PE wasdone as same day of PE for set 1. The pre study PE was noted with all no's recorded and the PE for set 1used 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 thencompleted 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 iseligible 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 yearsafter 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 withoutknowing 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 01/29/2009and Dr. Boyce 02/06/2009. CRFs have mark outs with no initials or dates. All visits have not beencompleted.

Subject 82: Consistency in documentation is not found between the sponsor and sites. SacramentoShriners made their own forms for data collection, and only used a few of the CRFs from the sponsor.


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The data for the Qualitative Outcome report switched the numbering system from the original CRF, solooking at the numbers the data would be off. The sets were combined for POD 91,182 and 365 which isin error. Sets 3 and 4 were combined. Either the sponsor did not conduct training, or there was nocommunication 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 scratchedthrough, without accompanying initials and date, in order to track the data change (for example: PhysicalExam Pre-Study). Set 1 Qualitative Outcomes report is signed and dated by Melissa Reed, research nursein Cincinnati, regarding a Galveston patient.

Subject 86:The CRF/Source was copied and sent to University of Cincinnati. The pages were typed andthere is no signature or date identifying when these were completed or who completed them. It appearsthat Steve Boyce, who at this time was the PI listed, gave approval as the sponsor, and then completedmany of the CRFs himself. Auditors question bias and accuracy as Dr. Boyce had total control of thissubject's information.

Subject 123: Many corrections were made by Peggy Simpson in July 09; three years after the initial datawas recorded. Errors previously crossed out with no initials Drawings of graft placements were done onfemale 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 nodocumentation found in subject's medical records, as well in Dr. Boyce's database to explain why subjectdid not continue in study. Additionally, there was no record of what became of the biopsy. The Sponsorhad received information, based on an email found from Cincinnati to Sacramento which states shipmentof CSS was expected for August 3, 2005. There are no CRFs completed, except for 3 lines regarding thebiopsy. No reason is noted as to why this subject did not continue on study, or if any follow- up wascompleted.

Subject 102:Corrections made after annual reports reported to FDA and major burn magazinepublications, 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 untila couple of years after the fact. Several CRFs were not signed or dated. No review by PI of case reportforms as no PI review form was present in the CRF. Changes are made to CRF forms several years laterthan 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 orinitials to indicate when additional information was written in. Other than set 1, no set was completed pastPOD 28, no PE's were done, protocol was not followed, see deviations and comments for furtherinformation.


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16.Biopsy of Recipient Sites

Figure 16.1 is showing the biopsy of recipient sites completed. This graph demonstrates that that thebiopsies were overall not completed in a protocol compliant fashion The X axis represents the number ofSets applied (Sets 1- 12) and the Y axis represents the number of biopsies completed for the total numberof 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 numberas 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 dictatedOR reports stated the biopsies were collected, however many did not. The investigators for the study didnot always document information regarding the research part of the subjects care. Auditors observed thatthe investigators relied upon the research nurses to document the biopsy; however it is ultimately theresponsibility of the principal investigator to see that the information is collected and documented. Therewere no notes to file to explain why the biopsies were not being performed and recorded in the CRFs asthe protocol required.

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


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17.Photography of Wound Bed, Pre-Surgery

Figure 17.1, below, is graphic representation of how the sites performed the required photography of thewound bed, per protocol. While the documentation reflects that the photography was done for the mostpart, when the sets 11 and 12 were documented, they were incomplete. Only sets 9 and 10 were donetotally 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 CRFphotography log (dated 02/08/08) the Photographers ID is signed by Peggy Simpson, RN.


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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 totalCSS sets applied. The graft illustrates that at POD 0, 129 photos were completed and 30 were eitherincomplete 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 completelyat POD 91, 28 were done completely at POD 182, and only 26 were done completely at POD 365. Thiswas 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 asthose photos were done on specific areas. The photos were not done in a consistent manner across allsites. There were no written instructions identified in file records informing sites of how to capture thephotos in a dependable method. Some photos were close ups of the areas grafted with CSS or AG andothers were from a distant of an entire body area or the whole body. The graph also shows that many ofthe later POD information were not captured, at all, by the sites.

Figure 18.1-Photography Post Graft


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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 beencompleted 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 thatthe 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


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

studies.

Figure 19.2Study Site Tracings for POD 28


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20.Microbial Cultures

Figure 20.1 illustrates overall that the microbial tests were performed on the subjects. Per protocol, thesemicrobial culture tests were to be completed Pre0, POD 0, POD 0, POD 7, and POD 14. For the mostpart the tests were executed and an organism was identified or not as determined through themicrobiology 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, notapplicable, 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 anda 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 themicrobial cultures done.

The data collection for the microbial cultures follows the same trend as the other information collected forthis study. The initial information, pre study and POD 0 was completed and documented fairly wellHowever, 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


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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 woundbiopsy at all protocol specified time points. The protocol states that healed wound biopsies will beobtained 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 gatheredwould 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 performedwere not evaluated by a dermatologist.

There were records that indicated subject was not in the operating room on the day that the biopsy was tohave 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 asecondary endpoint of the study under protocol section d.4.5. Out of the 159 sets of grafts applied tosubjects, 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.


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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 sitewill 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: Healedarea: donor area ratio for cultured skin substitute. The same question was asked on the same form forPOD 28. However, per the protocol schedule of events, this assessment was to be completed only at thePOD 28 time point.

Figure 22.1 shows that this information was periodically collected at POD 14, and that the majority of thehealed 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 postoperative day 28. The fact that this data was to be used as an end point for the study and the data wasnot captured as per protocol, and deviations were not reported as per protocol, raises serious questions asto how determinations were made for annual reports, presentations, and publications that were preparedby Steve Boyce, PhD during the years this CSS study has been ongoing.

Figure 22.1-Healed Area Donor Ratio Completion for POD 14


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Figure 22.2- Healed Area Donor Ratio Completion for POD 28


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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 engraftmentwas 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 casereport form pages were not completed. The POD column indicates that the entire post operative dateinformation was not done. The unable to verify column denotes that there was not enough informationprovided to val