Update February 28, 2011: This and other articles about the Shriners' development of PermaDerm (tm) were taken offline from November 22, 2010 to today. I will publish my findings ASAP.
Thank you,
Sandy Frost, Starbucks, WA
Editor’s Note: Please visit the first comment box at the end of this article for further instructions on how to wrap your head around all of this. There you can also find a link to a document depository where you can find most of the below mentioned documents. I suggest that after finding the link in the comment box that you print out the flow chart I drew up -- > because the organizational relationships are so complicated. I know there are boxes and arrows all over the place but it might help. I also feel the need to almost apologize because this information is so very technical. A list of fact after fact. My spell check gives this a reading level of 14.8 or third year college level. Sorry about that. The J-curve has been steep in this previously unexplored world of FDA rules and regulations. I am just a journalist who has gathered and studied these documents for nearly three years and now want to share this timeline as another way to tell this story.
Thank you,
Sandy
This timeline will present as much information as possible about the development of a burn treatment or cultured skin substitute known as PermaDerm™ at Shriners Hospital for Children (SHC) in Cincinnati, Ohio. Clinical studies are generally conducted under the supervision of an Institutional Review Board or IRB. The PermaDerm ™ study at SHC Cincinnati was supposed to have been overseen by the University of Cincinnati’s IRB.
This study was conducted to develop a method of growing a burn patient’s skin into bigger sheets of skin to graft onto their burn sites. This cultured skin substitute or CSS is known today as PermaDerm™ and is being brought to market by a bio-pharma company named Lonza with marketing done by a company named Regenicin.
The University of Cincinnati is part of the U.S. Army’s regenerative medicine program (AFIRM) by sponsoring this study and commercialization of PermaDerm (tm) through SHC Cincinnati. The Army recently funded a $1.3 million grant to more quickly commercialize PermaDerm ™ so it can be used to heal burned soldiers.
This timeline documents a long history of regulatory problems associated with this study. Problems began when the Office of Human Research Protection (OHRP) issued a letter of noncompliance in November, 2002, alleging lack of informed consent. The final determination letter was sent in April, 2003 to the University of Cincinnati to make sure that the patient records were audited for unreported protocol violations. From September 2 to October 27, 2005, FDA investigators inspected the Shriners’ Hospital for Children in Sacramento. Then from March 7 to June 21, 2006, FDA investigators from the Cincinnati office held a "for cause, high priority" inspection of the Shriners’ investigational site. The Establishment Inspection Report details the “significant deficiencies that needed to be addressed.” The FDA then issued three warning letters before issuing an “Integrity Hold” letter that shut the study down in January, 2007 because of “data reliability issues” and “system wide failures in the sponsor’s methods for conducting and managing clinical trials.”
In Feb. 2007, officials from UC sent their response to the FDA, stating they’d consolidate concerns expressed in the warning letters with the Integrity Hold letter. The University committed to system and data audits before developing a Corrective Action Plan (CAP) that was sent to the FDA on July 29, 2010.
Timeline follows.
July 30, 1997 Cutanogen Corporation, Steven Boyce’s company, filed w/Ohio Secretary of State.
1998 Dr. Steven Boyce began developing a burn treatment otherwise known as a cultured skin substitute (CSS) while working at both University of Cincinnati (UC) and Shriners Hospitals for Children. The study was conducted at the Shriners Burn Hospital under the oversight of the University of Cincinnati’s School of Medicine’s Institutional Review Board or IRB. According to a Shriner fact sheet:
"The Cincinnati Shriners Cultured Skin Substitute was developed through nearly two decades of research by Dr. Steven Boyce. The process begins when a business card size piece of skin is taken from the burned child and is cultured to grow in about three weeks to the size of 100 business cards. The cultured skin substitute is then taken to surgery for application to the burn site.”
April 15, 1998 – July 17, 2000 Problems with the study come to the attention of the Office of Human Research Protection (OHRP) after the agency discovered that other informed consent documents used by the first 28 subjects enrolled between these dates that received cultured skin substitute (CSS) in this study did not have IRB approval.
July 20, 1999 Certificate of Amended Articles of Incorporation of Cutanogen Corporation filed w/ Ohio Secretary of State, signed by Steven T. Boyce, President.
October, 1999 Phase II Randomized Study of Cultured Skin Substitute V Split Thickness Skin Grafts in Patients with Severe Burn Injuries.
Nov – Dec 1999 J Burn Care Rehabilitation announces clinical research award to use cultured skin substitutes with Integra Artificial skin to replace native skin autograft and allograft for the closure of excised full thickness burns. Boyce, Kagan, Meyer, Yakuboff, Warden. Department of Research, SHC Cincinnati.
August 7, 2000 OHRP sends letter of noncompliance to Dr. Donald C. Harrison, Senior VP, UC stating that the OHRP presented SHC doctors an allegation from the Mother of a badly burned child who claimed that she was urged by a nurse to sign the informed consent document because "The Doctors need these papers signed immediately. If she has any chance at all, this is the only chance she has." It further explains "No one at any time explained the documents to her and/or that they were consent for Experimental Programs." This same OHRP letter further detailed how an otherwise excluded pregnant woman was enrolled as a research subject, to include the "collection of skin tissue for preparation of grafts as part of the research." It continues that the OHRP was presented another allegation "that the investigators continued to conduct research on a subject after the subject's family withdrew permission for her participation in research." The letter explains that though only the pregnancy allegation could be substantiated, guidance suggested changes in protocol and informed consent language so as to not inflate potential benefits to the research subjects.
September 27, 2000 UC submits report to OHRP.
March 6, 2002 Boyce, Inventor and University of Cincinnati and Shriners Hospitals for Children (Tampa, FL) apply to patent “Apparatus for preparing a biocompatible matrix.” Boyce ST. 2002. US patent pplication, publication #US2003/0170892, a Surgical device for replacement of skin. Owners: University of Cincinnati and Shriners Hospitals for Children.
November 21, 2002 OHRP replies after their review of UC’s September 27, 2000 report submitted in response to OHRP’s August 7, 2000 letter regarding Burn Wound Management and the Cultured Skin Study.
April 21, 2003 OHRP sends determination letter that matter is concluded as long as UC has investigators audit files for more unreported protocol violations. OHRP letter noted that "the University of Cincinnati has required the investigators in the above-referenced research to conduct an audit of research subjects enrolled to ensure that no additional protocol violations had occurred. In addition, OHRP notes that the investigators have been made aware of the requirement to request changes to a protocol approved by an IRB prior to the initiation of such changes, except when necessary to eliminate apparent immediate hazards to the subject. OHRP recommends that UC also consider reminding all investigators of the regulatory requirements to obtain IRB approval for changes in approved research during the period for which the IRB approval has already been given. OHRP must be notified should new information be identified which might alter this determination.”
November 7, 2003 Cincinnati Enquirer announces SHC Cincinnati burn study gets $1 million gift from Fifth Third Bank.
April, 2004 Boyce presentation, “Tissue engineering for reconstruction”; American Burn Association; breakfast session moderator; Vancouver, British Columbia, Canada.
April, 2004 Boyce presentation, “Reconstruction”; American Burn Association; correlative session moderator; Vancouver, British Columbia, Canada.
June, 2004 Richard Kagan, MD, appointed chief of staff, SHC, Cincinnati.
September, 2004 Boyce presentation, “Skin repair with cultured cells and biopolymers,” Keynote address, Australia-New Zealand Burn Association meeting; Adelaide, Australia.
September, 2004 Boyce presentation, “Tissue regeneration for wound closure,” Australia-New Zealand Burn Association meeting; Adelaide, Australia.
October, 2004 Boyce presentation, “Science and technology of skin engineering”; L’Oreal Recherche; program committee; Lausanne, Switzerland.
May 25, 2005 Cutanogen applies for PERMADERM trademark.
June 14, 2005 Boyce ST, inventor, 2005. US Patent 6,905,105, Apparatus for fabricating a biocompatible matrix. Owners: University of Cincinnati and Shriners Hospitals for Children.
Sept. 2 – Oct. 27, 2005 FDA inspects SHC Sacramento.
October, 2005 Boyce presentation, “Advances in Pediatric Burn Care”; American Academy of Pediatrics; Washington.
February 2, 2006 Cambrex acquires Cutanogen and PermaDerm ™, $1.5 million paid on closing to Boyce with another $4.8 upon meeting milestones.
March 6, 2006 FDA Warning Letter sent to Dr. Greenhalgh, SHC Sacramento. The inspection found “failure to ensure an investigation is conducted in accordance with the signed agreement with the sponsor, the investigational plan, applicable FDA regulations and any conditions of approval imposed by the FDA or the IRB…You failed to adhere to the above stated regulations. You did not conduct the study according to the investigator agreement that you signed on June 26, 1999 and you did not follow the protocol provided to you by the sponsor on November 1, 1999. Instead of conducting the study according to the protocols, you revised or removed sections of the protocol prior to obtaining approval from the sponsor.”
March, 2006 Boyce presentation, “Stem cells in wound healing”; British Society for Cell Biology; London, UK.
March 7 – June 21, 2006 FDA conducts “high priority, for cause” inspection of SHC Cincinnati.
April, 2006 J Trauma publishes “Cultured skin substitutes reduce requirements for harvesting of skin autograft for closure of excised, full-thickness burns” by Boyce, Kagan, Greenhalgh, Warner, Yakuboff, Palmieri, Warden.
May, 2006 Boyce presentation, “Tissue engineering for burn wounds”; Wound Healing Society; Tucson, AZ.
June 21, 2006 FDA issues Establishment Inspection Report for SHC Cincinnati. Hundreds of violations organized according to the inspector's observations, spelled out in a two part Establishment Inspection Report (EIR). The objectionable conditions include:
1) Failure to report unanticipated adverse device effects.
2) Unapproved informed consent documents were being used.
3) Failure to follow the investigational plan.
4) Failure to report and maintain records for all adverse events.
5) Subjects' case histories were not accurate and complete.
6) Failure to maintain or report protocol deviations.
The FDA inspector ended the EIR with this "General Discussion with Management":
"Dr. Steven Boyce and Dr. Richard Kagan stated that they did not realize the importance of following the investigational plan exactly. They misunderstood the requirements for operating the IDE. They felt that though this inspection revealed numerous deficiencies that patient safety was never put at risk. I explained the provisions that the FDA has available to them as a follow-up to the inspectional observations, which included a warning letter, disqualification or criminal prosecution. Dr. Kagan and Dr. Boyce are extremely concerned with addressing all observations and continuing to operate this IDE. They feel this trial is extremely important to the Shriner's patients and community and they will do all they can to meet all FDA concerns and regulations."
January 3, 2007 Integrity Hold Letter issued to David M. Stern, MD, Dean UC School of Medicine, shuts down PermaDerm ™ study over data integrity issues and system wide failures. It states: "We regret to inform you that we have concluded that the IDE lacks information needed to determine whether the previous annual reports submitted to this IDE are accurate and complete and we are, therefore, suspending subtantive review and placing this IDE supplement on Integrity Hold. The decision is based, in part, on the fact tha inspections of your investigational sites suggest that the clinical data and information in the above mentioned submissions may be unreliable."
January 12, 2007 FDA issues Warning Letter to Dr. Kagan, Chief of Staff, SHC. Observations include failing to obtain informed consent, failing to report and accurately document unanticipated and anticipated adverse device events and failing to maintain accurate and complete case histories for each subject.
Informed consent violations cited; on September 6, 2000, the Institutional Review Board (IRB) approved the informed consent form(ICF) to be signed by the parents enrolling their burned children in the hospital’s study. The study included data obtained from burned children enrolled from April 15, 1998 to July 17, 2000, though their parents had signed outdated and unapproved consent forms.
The study’s investigational plans revealed that post operative data as well as engraftment assessments were found to be incomplete, performed on incorrect days or not completed at all; audit of subjects’ records found that no wound cultures were obtained at the required times, nor were the grafts taken or completed within the specified time frames; failures to report and accurately document unanticipated and anticipated adverse device events.
An audit of ten burned children’s records found that none of their unanticipated adverse events or skin graft failures were listed in their case report forms (CRF) or reported to the IRB. Some of these adverse events included development of necrotic or dead tissue, pneumonia and elevated temperatures.
The FDA also questioned why the cultured skin substitute experiments were performed only in select situations in which grafting were needed.
Kagan and the Shriner's Hospital were finally warned for failing to maintain accurate and complete case histories for each subject. Audited records found incomplete and inaccurate case report forms including missing Site Biopsy Logs and blank photography logs.
January 29, 2007 FDA issues Warning Letter to Dr. David M. Stern, Dean, UC School of Medicine. It states:
“Our review of the inspection report prepared by the district office revealed serious violations of Title 21, Code of Federal Regulations (21 C.F.R.) Part 812 – Investigational Device Exemptions and Part 50 – Protection of Human Subjects. Our subsequent review of the inspection report are Failure to secure the investigator’s compliance with the signed investigator agreement, the investigational plan, applicable FDA regulations and any other conditions of approval imposed by the reviewing IRB or FDA…You failed to secure investigator compliance with the investigational plan and applicable FDA regulations. At the time of the inspection, there were no written procedures for monitoring the investigative device study and there was no documentation of monitoring the investigation…The annual reports submitted to FDA were dated June 1, 1999, July 14, 2000, November 16, 2001, January 14, 2003, September 24, 2004 and January 2, 2006. Accordingly, progress reports were not submitted to the agency at least yearly…The investigational devices did not contain labeling.”
February 2, 2007 Boyce presents at NIH Workshop “Opportunities and Obstacles with Engineered Human Skin” Boyce states Transfer of the CSS technology was accomplished by licensing from the academic sponsors to a start-up company which was acquired by an established manufacturer of biopharma products and emerging cell therapies.
February 6, 2007 Lonza acquires Cambrex bio-business, including PermaDerm ™.
February 13, 2007 UC contacts Kendle International Inc. about performing a system audit.
February 20, 2007 University of Cincinnati responds to FDA’s warning and integrity hold letters by asking for indefinite time to address the issues, namely data reliability and system-wide failures to conduct and monitor the study.
October 1, 2007 University of Cincinnati submits grant application on behalf of Steven T. Boyce for $1.3 million to “Expedite Availability of autologous engineered human skin for treatment of burned soldiers.” Links research success to duplicating results in both Lonza and Shriner’s Skin and Tissue Labs. Includes request for $400,000 to pay for Morley Foundation Audit, cites patients #130 and #131 as examples of product’s success.
November 7, 2007 FDA News reports FDA sent warning letter to Dr. Richard Kagan.
November 7, 2007 “Shriners Hospital Violated FDA Regs” published by Sandy Frost and reports that the FDA Warning Letter had been preceded by letters of noncompliance from the Office of Human Research Protection (OHRP).
December 31, 2007 “Bad Medicine?” published by Sandy Frost and sheds more light on FDA warning letter situation.
December 29, 2008 UC Health News reports Army grant of $1.3 million to fund skin research at UC and Shriners.
January 6, 2009 Kendle Audit complete. It states that “UC policies, procedures and study documentation for IDE 980023 revealed significant deviations from FDA regulations and GCP principles. The university did not have an adequate quality system in place to ensure that clinical investigations are conducted in accordance with GCPs for studies in which they are sponsor. The Office of Research and Compliance Regulatory Affairs (ORCRA) lacks a comprehensive set of procedures to govern their activities and there is inadequate documentation to demonstrate that the employees of the ORCRA have the education, training and experience to perform their job functions. Interviews with ORCRA employees reflected that the university is not fully aware of its obligations as a sponsor of clinical studies regulated by the FDA. The university appeared to be unaware of its obligation to ensue routine, periodic monitoring of clinical studies throughout the duration of the investigation. Additionally, there is an apparent lack of understanding of the university’s requirement to maintain certain study-related documentation as the sponsor of clinical research per 21 CFR 812.140 (b).”
January 14, 2009 Per the Morley audit, “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 ― CINCINNATI—University 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.”
January – December, 2009 Walter B. Morley Research Foundation audits for Comprehensive Audit Report Protocol: Burn Wound Repair with Cultured Skin Substitute, IDE Number: G980023.
February 23, 2010, “FDA Warning Letter Sent to SHC Cincinnati Still Unresolved” published by Sandy Frost.
March 25, 2010 Morley Audit submitted to FDA. The audit indicates that from pre-study through the actual audit itself, those in charge of the study continued to violate regulations though the study had received the warning letters and had been shut down. Audit includes data from patients #130 & #131 as FDA violations. These include not being reconsented, inconsistent case report forms, inability to show that #130 did not have sepsis upon admission, inconsistent comparative graft sites, too few dressing changes, grafts placed in dry dressing instead of CSS irrigation, multiple reports of deviations, CSS being placed on contaminated wound beds, no unanticipated device event reported for Leukopenia in #130 and lack of records for reporting event adverse events for #130 and 131 including graft loss. Partial list of audit findings follows timeline.
April 8, 2010 “FDA Report Details Hundreds of Violations in Shriners' Burn Treatment Study as Product Heads To Market” published by Sandy Frost.
June 8, 2010 Ten-year-old burn patient admitted to SHC Cincinnati.
June 8, 2010 Dr. Richard Kagan begins “Compassionate Use” request process that is continued by Dr. Steven Boyce as he broadcasts email requests for necessary approvals before submitting to FDA for approval.
June 15, 2010 Jane Strasser, PhD, sends request for compassionate use of PermaDerm™ to FDA.
June 16, 2010 FDA issues compassionate use denial letter and excludes the doctors’ research and publications from appeal, stating:
“We regret to inform you that your request is not approved and you may not treat this patient with the above cited investigational device… Because considerable concern exists about the validity of the data generated under this IDE, we believe that these knowledgeable clinicians should be independent from the two investigators performing this study and their understanding of the product should be derived from experience other than this IDE study or publications by Drs. Kagan or Boyce…Please be advised that FDA has considerable concern about the absence of sufficient credible scientific evidence to perform a meaningful assessment of the probable risk of using this investigational device… These observations are based on our initial inspection of your facility from March 7 to June 21, 2006, the annual reports submitted to your IDE, and a review of the Independent Third Party Audit submitted by the Morley Foundation to FDA on March 25, 2010. The latter document indicates that these failures in data collection and oversight have continued during period after the Integrity Hold Letter was issued in 2007 and while your clinical site was undergoing an Independent Audit in 2008-2009.”
June 29, 2010 University of Cincinnati submits second compassionate use request with assurances from UC vice president.
July 1, 2010 President of UC sends letter of assurance to FDA, providing oversight by two doctors with reports every two weeks. There is no disclosure or statement of conflict of interest in these compassionate use submissions that the doctor providing oversight support, Dr. Michael Edwards, was on the same board as Dr. Richard Kagan and Tipton Ford, the Director for Business Affairs, UC. Burn patient’s treatment delayed by three weeks.
July 9, 2010 “SHC Study Suspended, FDA Excludes Doctors' Research” published by Sandy Frost.
July 29, 2010 University of Cincinnati submits Corrective Action Plan to FDA.
August 18, 2010 CNW Wire reports: “Regenicin Completes Acquisition of Worldwide Exclusive Know-How Technology License from Lonza Walkersville, Lonza to Provide Exclusive Manufacturing Services to Regenicin for new proprietary Skin Production Technology…Regenicin's management team intends to use its expertise, with the assistance of Lonza Walkersville, to further enhance its capabilities and seek approval by the U.S. Food and Drug Administration for commercial sale. Regenicin plans to seek marketing approval for this revolutionary product throughout the world under the brand name PermaDerm(TM).”
August 24, 2010 CNW Wire reports “Regenicin Appoints Amgen Co-founder Dr. Joseph Rubinfeld to Board of Directors, Rubinfeld expected to assist with FDA approval process for autologous cultured skin substitute, PermaDerm(TM).”
Sept 7, 2010 PR Newswire press release announces “Pharmaceutical Industry Veteran Dr. Craig Eagle Appointed as an Independent Member to Regenicin Board of Directors, Joins Amgen Co-Founder Dr. Joseph Rubinfeld as the second independent board member; Brings another authoritative voice to Regenicin's corporate governance body.”
Sept. 10, 2010 Regenicin to Video Webcast Live From NASDAQ MarketSite, Times Square, New York City, CEO to Present New Corporate Developments and Business Opportunities at Media and Investor Conference: NYC Press and Analysts Invited to Attend in Person.
Sept. 13, 2010 PR Watch press release announces “Former Fujifilm Medical Systems USA Executive John J. Weber Agrees to Join Regenicin(TM) as a Member of Its Board of Directors and Interim CFO, Weber Brings Over 25 Years of Corporate and Financial Management Experience to the Regenicin Team.”
October 3, 2010 “FDA/SHC News & Unanswered Questions” published by Sandy Frost. Includes unanswered emails sent to UC, the Shriners and Regenicin CEO with questions about disclosures, if UC is going to revisit the potentially fraudulent grant application to U.S. Army and what did Shriners corporate boards as well as the SHC Cincinnati board of trustees do as the PermaDerm ™ research attracted letters of noncompliance?
October 5, 2010 “Regenicin Names Former U.S. Marine Corp Operations Officer, Christopher Hadsall, Chief Operating Officer” NEW YORK, Oct. 5 /PRNewswire/ -- Regenicin™, Inc. (OTC Bulletin Board:WDST.ob - News) (www.Regenicin.com), a clinical-stage biotechnology company, announced today that Mr. Christopher A. Hadsall, whose primary responsibilities will be to oversee government affairs, has agreed to join the company as Chief Operating Officer. Mr. Hadsall brings 12 years of operational management expertise to Regenicin™ and will be instrumental in working with various military groups to build the company's distribution platform for the future commercialization of PermaDerm™, its proprietary tissue - engineered skin substitute intended to restore the qualities of healthy human skin for use in the treatment of burns, chronic wounds and a variety of plastic surgery procedures.
Oct. 19, 2010 “Regenicin to Form Scientific Advisory Board” PRNewswire-FirstCall/-- Regenicin, Inc. (OTC Bulletin Board:WDST.ob- News), a development stage biotechnology company, announced today that they have begun identifying candidates for the formation of a Scientific Advisory Board. The board will include thought leaders, scientists and physicians in the fields of regenerative medicine, cellular biology, dermatology and burn and wound treatment. Appointees will play a key role in advising Regenicin on the company's current and future research and development programs as well as in corporate strategies for global expansion.
Oct. 27, 2010 “Regenicin Appoints Renowned New York Dermatologist, Dr. Gervaise Gerstner to Scientific Advisory Board” PRNewswire-FirstCall/-- Regenicin, Inc. (OTC Bulletin Board:WDST.ob - News), a development stage company focusing on next-generation tissue-engineered skin substitutes to restore the qualities of healthy human skin, announced today the appointment of Dr. Gervaise Gerstner to the company's Scientific Advisory Board. Dr. Gerstner is a board-certified dermatologist and Assistant Clinical Professor of Dermatology at Mount Sinai Hospital in New York.
October 29, 2010 Regenicin to present Live at RetailInvestorConferences.com on November 4th. PRNewswire-FirstCall/ -- Regenicin, Inc. (OTC Bulletin Board:WDST.ob- News) a biotechnology company specializing in the development of regenerative cell therapies to restore the health of damaged tissues and organs, today announced that the Company's Chief Executive Officer, Randall McCoy and Chief Financial Officer, John Weber will present at RetailInvestorConferences.com.
Nov. 2, 2010 “Regenicin to Present at Event Celebrating Advancements in Regenerative Medicine” PRNewswire/-- “Regenicin, Inc. (OTC Bulletin Board:WDST.ob- News), a biotechnology company specializing in the development of regenerative cell therapies to restore the health of damaged tissues and organs, will participate in an event to celebrate the newest advancements in regenerative medicine on November 9th, 2010 in Walkersville, MD. Regenicin will present their role in the commercialization of the therapeutic candidate, PermaDerm™, a product which could help revolutionize the way wounded warriors and civilians recover from severe burns and wounds.”
November 9, 2010 "PermaDerm (tm) Timeline, Shriner Skin Study Audit Findings" published by Sandy Frost.
End of timeline.
The Morley audit findings for the PermaDerm (tm) study include:
 There was no evidence that appropriate data safety monitoring was put into place as part of the research plan.
 Sites were grafted with Cultured Skin Substitute (CSS) even when CSS solution resistant microbes were detected prior to grafting.
 Investigators did not always document information regarding the research part of the subjects care.
 The study had no specific laboratory values consistently recorded.
 A Data Safety Monitoring Board (DSMB) was never implemented during the course of this study.
 The investigative sites did not maintain proper device disposal records.
 Of the 370 protocol deviations recorded in the audit data base, only nineteen of those can be confirmed as being received at the Institutional Review Board.
 Principal investigator S. Boyce, Ph.D. did not fulfill the requirements for reporting.
 Dr. Boyce did not demonstrate knowledge of primary function of being the sponsor PI on this study.
 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 adverse events during the time frame of this annual report but only 10 were noted by Dr. Boyce.
 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.
 The 2006 Standard Operating Procedures copies from the University of Cincinnati IRB 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.
 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 case report forms were not completed in a consistent manner throughout the study.
 There was no documentation that any of the sites received proper training on Case Report Form (CRF) completion.
 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.
 Subjects should not have been enrolled and treated with CSS, per the risk assessment information presented in the Informed Consent.
 Investigators did not follow the investigational plan (protocol) dated November 2003, with respect to pretreatment of study sites.
 There was no documentation of the process of wound irrigation to eliminate sulfamylon concentration as specified in protocol section d.2.2.
 11 of the 43 2nd degree burn estimates did not match. Of the 43 subjects that had 3rd 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 2nd and 3rd degree burn areas.
 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 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. Boyce’s 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.
 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.
 Auditors observed that the sites lacked compliance in completion of the data sets for Post Operative Date 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 subject’s 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.
 The biopsies were overall not completed in a protocol compliant fashion.
 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.
 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 POD 0, the data collection dropped off to approximately half by POD 14.
 An overall lack of compliance with respect to the collection of a healed wound biopsy at all protocol specified time points.
 There was a specific research nurse at each site that was responsible for the data collection. In addition to a specified research nurse, the PI’s responsibility is to see that the events were performed and recorded. On top of those two people, it was the sponsor’s duty to hold the sites accountable for the data collection. All of these processes that should have been in place failed.
 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.
 One hundred nineteen (119) serum antibody tests that were scheduled for POD 28, were not done. Results of the test were not documented in the case report forms or medical records.
 Investigators did not follow the investigational plan (protocol) dated November 2003 with respect to collection of the Qualitative Outcome data.
 Qualitative Outcomes were observed as not being completed beginning at POD 91 through POD 365 over the entire subject audit population.
 The FDA came to the Cincinnati site between March 16 and June 21, 2006 and cited 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 subject’s 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.
 Investigators did not follow the investigational plan (protocol) dated November 2003, or the nursing care instructions (per IDE application Attachment 4, section f.1.4.3) with respect to the care of Cultured Skin Substitute. There are no consistent records available identifying that CSS solution was used as specified, or recording the amount of CSS solution used per application.
 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.
 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.
 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.
 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 review there was no documentation of the Sponsor following up on a report of a UADE from the study sites.
 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.
 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.
 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.
 Auditors observed that the sponsor did not comply with CFR 812.25(f): The investigational plan shall include…copies 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).
 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.
 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.
 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.
 Through the course of the audit, it was noted that approximately 370 protocol deviations were identified by the sites, or thru the audit process.
 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 was not a standard operating procedure found for reporting of deviations to the UC IRB.
 Of the 370 protocol deviations recorded in the audit data base, only nineteen of those can be confirmed as being received at the IRB.
 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.
 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.
 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 January 1, 2006 – December 31, 2006
 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 newspaper) 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 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 IRB’S CONSIDERATION. INFORMATION PROVIDED IS CONSIDERED CONFIDENTIAL.
 Attached to the COI form is Dr. Boyce’s 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 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 Informed Consent Form 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.
 Monitoring of this study has not been done to date even though patients continue to be enrolled in this study under compassionate use.
 Adverse Events: Dr Boyce reported only ten UADE’s. 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).
 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 adverse events during the time frame of this annual report, of which as stated above, 10 were noted by Dr. Boyce.
 Auditors never located any minutes of the research department’s 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 UADE’s 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 Investigator’s 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.
 Neither the site nor the sponsor seems to understand the FDA’s 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.
 The adverse events reported for 2008 were 36 UADE reports by Dr. Boyce, whereas the auditors recorded 760 events.
 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 Foundation’s understanding that Mrs. Braggs-Brown was to monitor initially, then auditors were under the impression that maybe Mrs. Braggs-Brown was brought in to 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.
 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 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 ― CINCINNATI—University 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.
 The Cincinnati Shriners Hospital provided 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.
 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.
 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.
SIGNIFICANT REMARKS FROM INTERVIEWS:
 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 people’s 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 don’t 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.
 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.
 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.
 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 Peggy’s office. She was also observed in Peggy’s office when not monitoring/auditing, just talking with Peggy and both Peggy and Angela were observed more than twice going into Steve Boyce’s office shortly after the conclusion of interviews with Cincinnati Shriners staff. The MRF is not drawing any conclusions from this, however from an auditor’s 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.
 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). 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. 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.
-End-
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