Editor’s Note: This is the third in a series of articles “revealing” five cases of nonprofit corruption and abuse. All are examples of self-inurement at taxpayers’ expense. This is against the law.
A year ago, I was left “cognitively impaired” with memory loss after my “Peyton Manning” neck surgery went wrong. So, sorry is my writing wanders, if there are no transitions, or if I repeat myself as I continue to release 11 years of findings.
If you’re an investigator, it’s kind of like your birthday and Christmas all wrapped up with crafty paper bows made from documents.
This is part 3 of revealing the first of five cases of nonprofit abuse.
This is the PermaDerm™ scandal.
The FDA found this clinical research study so bad that they shut it down.
On the up side, there is a “smoking gun.” And one of PermaDerm(tm)'s investors was recently indicted and arrested for a “pump and dump” scheme after the FBI and SEC acted to protect investors.
We’ve already waded through thousands of words of specific audit findings in Part 2. We’ll next rollercoaster along, careening wildly toward the “smoking gun.” We will then review FDA violations point by point for the two patients used in the allegedly fraudulent DoD AFIRM grant/contract applications.
Then there are the millions in NIH, FDA and DoD grants spent on this unusable research. Worst of all? The ultimate betrayal and sad possibility that charitable donations to the Shriners might have been misspent or wasted on the failed research study at their Cincinnati burn hospital.
Red flags wave wildly here for IRS exempt organization investigation, but their bosses are kind of busy these days testifying before Congress.
All of this information needs to be presented to those with oversight over the IRS. All of these lapses of ethics, apparent episodes of willful misconduct and manipulations of our tax system mean that we bear the taxes that these groups are exempt from. For example, the properties owned by the University of Cincinnati and the Shriners are normally tax-free. Their nonprofit status means that the property owners around these properties make up the difference in taxes not paid by these groups because they are tax exempt for providing benefit to the community.
This first case begins with clinical research done for 20 years at Shriners’ Burn Hospital in Cincinnati as biologist Steven Boyce Ph.D. tried to develop a “cultured skin substitute” for burn victims. A postage stamp size piece of skin was grown to typewriter paper size. The new piece is then grafted onto the victim’s burn site to protect it and regrow the skin.
The study was conducted under “oversight” provided by an Institutional Review Board from the University of Cincinnati.
The FDA first became involved after inspecting an affiliated study site at the Sacramento Shriners’ Burn Hospital from September 2 to October 27, 2005. Then, from March 7 to June 21, 2006, FDA investigators from the Cincinnati office held a "for cause, high priority" inspection of the Shriners’ hospital. 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 spite of being shut down, Boyce next got grant money from the DoD AFIRM regenerative medicine program. Since Boyce’s data from his Shriners’ study was unreliable, he used just two patients to secure $1.3 million from the AFIRM program. Then bio pharma giant Lonza got an $18 million contract from the AFIRM program, using the same patients, to develop protocols and start the military PermaDerm™ study.
So many moving parts.
So far, we have the PermaDerm ™ study at the Shriners’ hospital, the University of Cincinnati or UC, the FDA and the DoD. A marketing company named Regenicin popped up in 2010 and helped hookup Boyce’s cultured skin substitute technology with Lonza for manufacturing purposes. Regenicin then went public to obtain funding for FDA approval.
There are layers of licensing agreements, investors and government programs interwoven into what appears to be a useless ball of rusty twisted bailing wire, rolling around randomly. Imagine this in a courtroom, then throw in a spinning sack of wild cats.
These guys are fighting over the $18 million AFIRM contract.
Today’s newshook is that one of Regenicin’s first investors was AJ Discala, CEO of the Broadmoore Group and OmniView Capital. This FBI press release reports Discala and six others were indicted on ten counts including securities fraud, wire fraud and conspiracy to commit securities fraud and mail fraud in connection with the fraudulent market manipulation of four publicly traded companies.
The SEC press release is here.
Discala states that “Regenicin is part of the portfolio of companies managed by OmniView Capital.” According to Investors Hub, Discala owns 9,223,770 shares of Regenicin while CEO Randall McCoy owns 33,727,313 shares.
It’s clear that FDA approval, even provisional approval for limited use status, means money for a few insiders.
It also means that PermaDerm™ could be sold as a treatment for both civilian and military burn patients, covered under new insurance codes for Medicare billing and payment. One doctor overseeing the PermaDerm™ study helped write new insurance codes for a white paper published by the American Burn Association. Dr. Richard Kagan, head of the Shriners’ Burn Center in Cincinnati, made sure the Shriners get paid, now that the hospitals take insurance for previously free care. They can now use new codes defined by Dr. Kagan and the other authors so Medicare and other insurances pay about $55 per square centimeter for PermaDerm™. If PermaDerm™ got provisional approval as a Humanitarian Use Device and we do the math, (4,000 patients)(6,200 cm2 established per patient) = $1.3 billion for who? If the FDA gave further provisional approval, PermaDerm™ could be worth trillions. R & D courtesy of Uncle Sam, funded by you and me.
If Regenicin stocks were worth $60, AJ Discala’s would be worth nearly half a billion at $553,426,200. Randall McCoy would be worth just over $2 billion at $2,023638,780. Or just over a billion if he’d not cut out his partner, Joe Connell.
Grants from the FDA, NIH and the Shriners have primarily funded this research since 1998.
According to a recent CV of Dr. Boyce, grants are:
Past grants are:
Total past + present = $21,247,765
If we follow the money and the means used to obtain it, we’ll find a paper trail of grant and contract applications, SEC filings, FDA submissions and other documents that use “clinical data” to prove PermaDerm™ works. The problem is that the data is unreliable and using it points to the omission of material facts and raises the possibility of clinical research fraud, fraudulent grant and contract applications to the DoD AFIRM program and inaccurate filings filed with the SEC.
It’s been interesting to read what the spin doctors and sock puppets are spewing on a Yahoo Message board for RGIN, the stock ticker abbreviation for Regenicin, the company formed to bring PermaDerm™ public. Those with a vested interest were hoping the stock would soar from $2.60 a share to $60 a share. Instead, it’s been hovering around a penny a share. Messages try to pump up investors and assure the public that things are great instead of embracing the highest standards of disclosure and transparency.
For all this to go right, the following needs to happen.
- FDA submission requires HUD applicants to disclose past clinical studies.
- SEC submissions require all material facts.
- DoD/AFIRM grant and contract applications require reliable data.
- Clinical research must prove the product is safe and reliable.
- Investigators are supposed to conduct studies with proper financial disclosure so they don’t skew the results in their favor.
PermaDerm™ was developed by biologist Steven Boyce Ph.D. at the University of Cincinnati with back deals constructed to get the cultured skin substitute through FDA approval for both civilian and military applications. The Shriners and AFIRM program provide the demand for PermaDerm™.
Dr. Kagan helped write a whitepaper published on the American Burn Association (ABA) site that differentiated burn treatments so the cultured skin substitute got its own medical billing insurance code. It appears that he failed to disclose to the ABA that he’d gotten a warning letter from the FDA before the agency shut down his study. It also appears he failed to disclose significant financial interests. A search of ABA’s disclosures fails to list Kagan or Boyce.
One of the biggest red flags is the doctor’s serious lack of financial disclosure. More on some of these incestuous relationships is here.
Next, here are excerpts from the Morley Audit and an application submitted by Lonza to the AFIRM program to fund the development and commercialization of PermaDerm(tm).
Here are facts that invalidate patients 130 and 131 as research subjects.
Here is the smoking gun.
This excerpt from a Lonza AFIRM application identifies two patients.
“Two recent cases of pediatric burns of greater than 90% TBSA were treated successfully with auto ESS. ESS were prepared from split-thickness skin biopsies collected after enrollment of the burn patients by Informed Consent into a study protocol approved by the local Institutional Review Board. Subject #130 was a 10 year-old male who sustained 94% TBSA burns, and Subject #131 was a 2 year-old female who sustained 90% TBSA burns.”
After the FDA shut down the PermaDerm™ study, an audit was ordered. It took a year. Here are two lists of discrepancies explained through excerpts from both the Morley Audit and the AFIRM application. There are two kinds of discrepancies noted. First, the audit compares what the study reported to what the auditors found and uses the Code of Federal Regulations or CFR as the primary metric. These findings are then reduced into actual FDA violations for patients 130 and 131 and are presented last.
ESS = Engineered Skin Substitute.
Problems with Informed Consent
From the Morley Audit:
Subject #130: Should have been re-consented 3 times.
Subject #131: Should have been re-consented 3 times.
Problems with Matched Pair Applications
From the AFIRM application:
The injuries were all full-thickness, and occurred in separate building fires in 2007. ESS were prepared from autologous keratinocytes and fibroblasts which were isolated from split-thickness skin, cultured, and cryopreserved for later use. Cells were combined with collagen-based sponges, and incubated at the air-liquid interface to promote formation of epidermal barrier. ESS and split-thickness skin autograft (AG) were applied in a matched-pair design with each patient serving as their own control.
From the Morley Audit:
Per CFR 812.110, investigators did not follow the investigational plan (protocol) dated November 2003, 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. 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:
The first application of ESS was compared to AG for all end points, and subsequent applications of ESS were added to the first and quantify device efficacy. Data collection consisted of photographs, area measurements of donor skin and healed wounds at postoperative days (POD) 14 and 28 after grafting, and healed tissue biopsies as available.
Problems with Photography Post Graft
From the Morley Audit:
Figure 18.1, demonstrates the consistent decline in the post graph photography from POD 0 to POD 365. There were to have been 159 photographic events for the study population. This is based on the 159 total CSS sets applied. The graft illustrates that at POD 0, 129 photos were completed and 30 were either incomplete not done, or unable to verify. The decline shows that at POD 7 only 108 photos were done completely, at POD 14 only 104 were done completely and at POD 28 only 90 were done completely.
It is noticeable that after POD 28, completed photographs were minimal. Only 29 were done completely at POD 91, 28 were done completely at POD 182, and only 26 were done completely at POD 365. This was in part to the lack of POD 91-365 completion throughout the entire subject population. The sites, especially Cincinnati, took full body photos, which made it impossible to compare previous photos as those photos were done on specific areas. The photos were not done in a consistent manner across all sites. There were no written instructions identified in file records informing sites of how to capture the photos in a dependable method. Some photos were close ups of the areas grafted with CSS or AG and others were from a distant of an entire body area or the whole body. The graph also shows that many of the later POD information were not captured, at all, by the sites.
Problems with Healed Wound Biopsies
From the Morley Audit:
Figure 21.1, illustrates an overall lack of compliance with respect to the collection of a healed wound biopsy at all protocol specified time points. The protocol states that healed wound biopsies will be obtained on postoperative dates 7, 14, 28, 91, 182, and 365, not to exceed more than six biopsies total.
There were so few actual healed would biopsies performed on the subjects, the information gathered would be negligible. The healed would biopsies were to be sent to a dermatologist for dermato-pathologic interpretation. No records were identified with any results, so the few biopsies performed were not evaluated by a dermatologist.
There were records that indicated subject was not in the operating room on the day that the biopsy was to have been performed, and that is why the biopsy was not taken. The fact that so few biopsies were performed, when up to 6 should have been done, questions the collection process.
While the protocol states the healed would biopsies would be performed as possible, this process was a secondary endpoint of the study under protocol section d.4.5. Out of the 159 sets of grafts applied to subjects, only 16 sets had the healed wound biopsies completed, but then not read by a dermatologist. There is a lack of valid data to make any assessment of this endpoint.
Problems with Healed Area/Donor Area Ratio
From AFIRM application:
Data are expressed below as mean values for these two subjects for:
A) % area closed at post-operative day (POD) 14,
B) %TBSA closed at POD 28,
C) Ratio of closed to donor areas at POD 28. Due to the small sample size, mean values were calculated, but no statistical analyses were performed.
From the Morley Audit:
The completion of this data does not follow the protocol. The protocol states in section d.2 Study Format: For each administration of cultured cell-biopolymer skin substitute to a wound site, a comparative site will be treated with meshed or unmeshed split-thickness skin.
As the CFR 812.140 (a) (4) states: A participating investigator shall maintain the following accurate, complete, and current records relating to the investigator is 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 Investigator’s Global Assessment (IGA) for POD 14 asked the question: Healed area: donor area ratio for cultured skin substitute. The same question was asked on the same form for POD 28. However, per the protocol schedule of events, this assessment was to be completed only at the POD 28 time point.
Figure 22.1 shows that this information was periodically collected at POD 14, and that the majority of the healed area donor area ratio evaluations were completed at POD 28, as outlined in the protocol schedule of events. However, there were deficiencies in the overall collection of the appropriate data point of post operative day 28.
The fact that this data was to be used as an end point for the study and the data was not captured as per protocol, and deviations were not reported as per protocol, raises serious questions as to how determinations were made for annual reports, presentations, and publications that were prepared by Steve Boyce, Ph.D. during the years this CSS study has been ongoing.
Problems with Post Operative Date Completion for all Sets
From the Morley Audit:
CFR 812.140(a)(3)(i) Documents evidencing informed consent and, for any use of a device by the investigator without informed consent, any written concurrence of a licensed physician and a brief description of the circumstances justifying the failure to obtain informed consent. The case history for each individual shall document that informed consent was obtained prior to participation in the study. 812.140(a)(3)(ii) All relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests. 812.140(a)(3)(iii) A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy. 812.140(a)(4) The protocol, with documents showing the dates of and reasons for each deviation from the protocol. 812.140(a)(5) Any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigations or a particular investigation.
Auditors observed that the sites lacked compliance in completion of the data sets for POD 0, POD 7, POD 14, and POD 28, as not one of these sets was completed in 100 % accordance with the study protocol. Overall PI or Sponsor oversight is in question.
Documentation that states the PI (Drs Boyce and Kagan) did not check the CRFs until the initial year was completed by the subject was present. However, the issue is that these checks or PI signed template sheets were signed up to 2 or 3 years after the closure of the 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 Physical Exam (PE) reports were completed by the research nurses, as was confirmed through the interview portion of the audit. According to the interviews with the Cincinnati Shriners research nurses, the nurses would go back into the computer medical records and complete the PE form from the nursing assessments of the patient. While these nurses were listed as sub investigators for the study, the PE forms were not completed in a consistent manner. Some forms, for example, listed Sinus Tachycardia as normal and others listed it as abnormal on PE page under cardiac. The training should have been made clear to the sites, how to complete the PE form. PE forms were often completed based on expected burn status of burn patients. However there were subjects where the PE appeared to have completed correctly. Some forms (especially the typed ones) were identical from previously forms with no changes except for dates. The primary factor is that the PE forms were not consistent.
Some examples of what was noted during the Morley Audit are listed below:
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 #130: PI review and sign off by Dr. Kagan was done on 01/29/2009 when subject was completed in September 2007.
Subject #131: PI reviewed and signed off on 01/29/2009 when subject was completed in August of 2007.
Problems with reporting unanticipated adverse device effects
Per CFR 812.50 (1) An investigator shall submit to the Sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.
Per the overall review of subject records, there was not adequate record of adverse event reporting to the Sponsor and to the appropriate reviewing Institutional Review Boards. The sites were not reporting adverse events per Form CSS 7.8 in the Case Report Form. Per the protocol schedule of events (version November 2003), an adverse event summary was to be collected at Post Operative Days 14 and 28. This summary was incorporated into the Investigator Global Assessment as the question Any AE’s? and was answered Yes or No. The sites should have been evaluating subjects for adverse events and possible UADE’s during the entire study duration and not only at these specific time points.
Figures 32.4 and 33.5 show the summary of AE reporting for POD 14 and POD 28 (as noted on the Investigator Global Assessment) across the 159 CSS sets applied. The majority of the reporting indicated that no adverse events were present. However, because no expected events were ever identified as part of the investigational plan, investigators and Sponsor should have been reporting events in accordance with CFR 812.3. Additionally, seventy events were noted as Unexpected Events per the reports completed and filed with the subject records. It is unclear why similar events were not consistently reported as unexpected across the subject population. For instance, there were 126 events of graft loss greater than 10% identified, yet only 26 of these events were identified as unexpected. There were no parameters on why certain events were considered unexpected.
The following reported UADE’s were not reported to, or could not be verified that they were reported the appropriate Institutional Review Board:
Subject 130: Leukopenia/ Onset date: 10/2/2007
Subject 131: Hypotension/ Onset date: 8/27/2007
Subject 131: Repeat Regrafting of same body site (>10%)/ Onset date: 1/25/2008
Subject 131: Repeat Regrafting of same body site (>10%)/ Onset date: 12/21/2007
#7 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.
Subject 130 Unable to verify if subject was not showing signs of sepsis.
#8 Per CFR 812.110, investigators did not follow the investigational plan (protocol) dated November2003, or the nursing care instructions (per IDE application Attachment 4, section f.1.4.3) with respect to the care of Cultured Skin Substitute
Per overall review of subject records, there was no consistent documentation of completion with regards to the specified requirements for treatment of CSS.
Per Protocol d.2.2: At post-operative day (POD) 5, wet dressings will be discontinued and dry dressings will be administered daily until POD 7 at which time dressing changes will be performed twice daily. The following subjects were not treated according to protocol (November 2003):
Set 6 POD 4 1 of 2 dressing changes were completed
Set 6 POD 5 1 of 2 dressing changes were completed
Set 11 POD2 0 of 1 dressing change was completed
Per IDE application, Attachment 4 (section f.1.4.3): CSS sites are to be irrigated every 8 hours with CSS solution of a specified volume (usually 30 ml/graft) beginning at POD 0 through POD 5. The following subjects were not treated according to the investigational plan, specifically regarding the completion and frequency of CSS site irrigations between POD 0 and POD 5:
Subject 130: Set 6: grafts were placed in dry dressing instead of CSS irrigation
Subject 131: Set 6: grafts were placed in dry dressing instead of CSS irrigation
Problems with Cultured Skin Substitute Solution
Per IDE application, Attachment 4 (section f.1.4.3): CSS sites are to be irrigated every 8 hours with CSS solution of a specified volume (usually 30 ml/graft) beginning at POD 0 through POD 5
There are no consistent records available identifying that CSS solution was used as specified, or recording the amount of CSS solution used per application. The CSS solution was prepared, by the Sponsor, specifically for the care of Cultured Skin Substitute. It was used because of its non-cytotoxic, antimicrobial agents for management of microbial contamination on wounds. There are no accountability records regarding the preparation, storage, transport, or dispensing of this solution.
There were no specifications regarding the contents of the CSS irrigant. The contents of this solution should have remained consistent throughout the study. There were noted substitutions and changes made to this solution during the study.
Subject 131: Double antibiotic solution was used for one (1) irrigation of CSS for Set 5 at POD 5, instead of CSS irrigation solution
From the Morley Audit:
“Microbe sensitivity tests to the CSS solution were often performed at the University of Cincinnati site, but not noted as being completed at any of the other study sites. The protocol does not specify that these sensitivity tests are to be completed, however, it was frequently noted that CSS sites were infected with microbes noted to be resistant to the antimicrobial agents in the CSS solution. There were no specified procedures given on how to treat the CSS sites that were found to have CSS solution resistant microbes. In many cases, the sites were grafted with CSS even when CSS solution resistant microbes were detected prior to grafting. Therefore, there was no non-cytotoxic, antimicrobial management available for these sites:
Subject 130: There were four (4) reported deviations (8/24/2007, 8/31/2007, 9/7/2007, and 9/14/2007) of CSS being place on contaminated wound beds whereby the organisms identified were noted as resistant to CSS nutrient solution and CSS saline solution.”
The Annual Report for period January 1 – June 2004 was reviewed by auditors. Similarly as the audit started with subject #82, the audit review comes in middle of the annual reports.
Based on the regulations cited below S. Boyce, Ph.D. did not fulfill the requirements for reporting. At the initial reporting date of January 1, 2003 Steve Boyce, Ph.D. was assuming the role of the PI/Sponsor.
Information of note in the Annual report for January 1, 2006 – December 31, 2006
II.l Summary of Study: In February 2006, the technology rights for this device were acquired by a commercial developer who will assume responsibility for filing of applications for marketing permissions.
What does not appear in the annual report, or any subsequent financial disclosure forms, is that Cutanogen Corp was founded in 1997 by Dr. Steven Boyce (per a published newspaper article ―Medical Advances Incubate in Corryville by Tim Bonfiled with the Cincinnati Enquirer (local newpaper) dated June 30, 1998. (Appendix G) The article below shows that in 2006 Cambrex BioScience Walkersville, Inc. purchased Cutanogen for $1.5 million fully paid at the closing with additional purchase price payments of up to $4.8 million subject to certain milestones.
Problems with Conflict of Interest
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 Ph.D. still indicates a ”yes” for equity, “yes” for holds patent rights, “yes” for consultant, “yes” for royalty income. No dollar amounts provided.
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. The consultant agreement was from March 2006 – February 2007, however the consulting agreement has expired. There is additional information provided that on February 5, 2007 Cutanogen and CBSW (Cambrex) was sold to Lonza Corporation, a Swiss BioPharma company. CBSW is now named Lonza Walkersville, Inc. The performance milestones of Cutanogen remain pending completion.
There was never a disclosure of any amount which Dr. Boyce may have received even though the IRB requested it. The IRB board stated that there is a perception of conflict. The IRB offered three options: 1) assign another person as PI for the study; 2) disclose in the consent form the detailed information of how the investigator is involved with the company; or 3) attend the next IRB meeting and discuss why there is no conflict. Dr. Boyce changed the PI of the study to Dr. Richard Kagan and in June of 2008 revised the ICF to state: Dr. Steven Boyce, a sub-investigator on this study, has received payments from the company that owns the rights to the process used in this study. This disclosure is made so that you can decide if this relationship will affect your willingness to participate in this study. The below article was identified that may clarify the relationship. It is not known if the payments were made solely to Dr. Boyce. However since this was a published article found on the web with little effort, it is unclear why Dr. Boyce was so resistant to disclosing a dollar amount to the IRB.
Per Code of Federal regulations section 812.43 (5): Sufficient accurate financial disclosure information to allow the sponsor to submit a complete and accurate certification or disclosure statement as required under part 54 of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study. This information shall not be submitted in an investigational device exemption application, but shall be submitted in any marketing application involving the device. . Dr. Boyce failed to comply fully with the disclosure requirements.
Adverse events were not reported
II.4.2. Adverse Events: Dr. Boyce reported only ten UADEs. The FDA sent a warning letter on January 12, 2007 and noted that there had been previously identified failure to report and accurately document unanticipated and anticipated adverse device events to the sponsor and the reviewing IRB which violates 21 CFR 812.140(a)(3)(ii) - All relevant observations, including records concerning adverse device effects (whether anticipated or unanticipated), information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant previous medical history and the results of all diagnostic tests; CFR 812.150.(a)(1) - Unanticipated adverse device effects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.
The annual report for 2006 was not sent to FDA until February 12, 2007, which was a month after the warning letter had been issued to the site. Dr. Boyce continued to disregard the FDA's 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.
Unauthorized statements made to military
From the Morley Audit:
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 ll.1 Summary of Study of this same annual report it states “The objective of the quantitative data is to determine whether treatment of full-thickness burns with cultured skin substitutes reduces the requirements for harvesting of split-thickness skin autograft.”
It is uncertain why a definitive statement was made when this cultured/engineered skin is still being studied and specifically why this presentation was made while the study was on an Integrity Hold. The initial statement referred to at the beginning of this paragraph is repeated in the Conclusions section of the presentation.
Dr. Boyce also presented this report as a poster presentation at the Advanced Technology Applications for Combat Casualty Care conference on August 12, 2008 and as an oral and poster presentation at the Armed Forces Institute for Regenerative Medicine All Hands meeting on January 14, 2009. Dr. Jane Strasser of the UC Compliance Department sent a formal notification advising Dr. Boyce to suspend any presentations, publications, and/or media relations regarding the IDE project until FDA removes the Integrity Hold. During this time period, (December 29, 2008) a media publication of UC Health News announced that UC researchers 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.
What did Lonza claim in their application for $18 million?
2. Benefits to the patient: “Completed clinical studies show a reduction in the requirement for harvesting donor skin to complete wound closure.”
3. Impacts: “Availability of autologous ESS will reduce morbidity from harvesting of donor skin autografts, and reduce mortality as previously demonstrated in pediatric populations with burns of greater than 50% TBSA 1, 26, and 27.”
From the Morley audit:
“Section V: Future Plans: Dr. Boyce states that the future plans have changed due to the complexity and indefinite timeline of the Integrity Hold. He states that at present, the procedures of cGMP manufacturing of this device are being established with a commercial developer, Lonza Walkersville, Inc., and plans for alternative pathways for clinical use of the technology are under review. This last statement may suggest that new studies will be designed for the cultured skin substitute, perhaps under the engineered skin substitute; however the fact remains that much of the data for the IDE under audit cannot be verified.
Standard Operating Procedures (SOPs) Review
From the Morley Audit:
Prior to the employment of Jane Strasser, Ph.D., with the Compliance Department, Dr. Melissa Colbert had called the Morley Research Foundation to request standard operating procedures. After discussions between Melissa Colbert and Jane Green, the University of Cincinnati purchased the Morley Foundations Standard Operating Procedures for Research Sites. UC customized these procedures and put them online for use throughout the University. Upon arrival of the audit team, JoAnne Lindwall realized that UC needed device sponsor SOPs and Institutional Review Board SOPs. The Foundation supplied UC with the SOP templates for Device Sponsors and IRBs which were then customized for UC use. Prior to this year the SOPs in place for the IRB were minimal and nothing was in place for device sponsors.
The Cincinnati Shriners Hospital provided MRF auditors with a copy of Shriners SOPs as they pertain to research. The copies supplied to MRF had an adopted date of l/5/2006 however none were signed as approved by anyone. There were some Shriners Review of documents noted but it was not consistently reviewed by Shriners each year in regard to the informed consent process as outlined in Shriners SOPs. According to the Shriners SOPs the informed consent form was to receive approval by the Corporate Office of the Director of Research Programs and then was to be followed by the IRB approval of that informed consent form. Per Shriners SOPs Revising an Informed Consent Form standard operating procedures state that revisions are necessary when the protocol is modified, new risk to subjects are identified … The Cincinnati Shriners research staff did not follow their own SOPs as none of the CSS subjects were ever re-consented. The SOP that pertains to Responsibilities of the Research Team number 13 relate to the disclosure to the IRB, SHC, sponsor, and/or subjects of all potential Conflicts of Interest of Research Team members (financial, etc.). This is addressed in detail in the report on Annual Reports.
The SOP regarding Maintaining Regulatory Files specifically identifies information to be retained in the regulatory files and as the results of the regulatory audit show this was not done as stipulated by the SOP. There were clearly Shriners SOPs that were not being followed by the site…When interviewing at each site, no one mentioned following their own or anyone’s Standard Operating Procedures.
Data Safety Monitoring Board (DSMB) Report
A Data Safety Monitoring Board (DSMB) was never implemented during the course of this study. The Sponsor did not make adequate provision for data or safety monitoring during the course of this study as required per 45 CRF 46.111(a) (6): When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
Next are actual FDA violations from the Morley Audit for patients #130 and #131, organized by the folders containing the violations.
CFR = Code of Federal Regulations
CSS = Cultured Skin Substitute
1. Regulatory folder for 09/21/07
Adverse event for subject #130.
In violation of CFR 812.140(a)(1).
The subject had an event of CSS graft loss > 10%. The Nocardia species is resistant to the CSS irrigation solution that is specified in the protocol for topical use of the CSS wound post-operatively. After consulting with the medical staff, the decision was made to apply CSS regardless of wound contamination due to patient's lack of available skin and medical condition. The patient has now received 4 sets of CSS that have been evaluated for graft loss. Each set is evaluated at POD #14 and POD #20. Graft loss for each set is as follows: Set #1 POD #28-14.6%, Set #2 POD #14-46.5%, Set #3 POD #14-24.8%, Set #4 POD#14-46.2%. Also of note, the patient has been placed open ventilatory support (09/12/07) and antibiotics (09/06/07).
The PI signed the adverse event form on 09/20/07. The date that the site was made aware of the event was 09/21/07. The PI pre-dated the signature for the adverse event. The outcome was never resolved. The adverse event was not expected.
2. Regulatory folder for 11/06/07
Adverse event for subject #131 for CSS graft loss > 10%.
In violation of CFR 812.140(a)(1).
Subject #131 had CSS graft loss >10%. Patient received a total of 3 sets of CSS grafts that have been evaluated for graft loss. Set #2 to the anterior trunk was evaluated at POD #14 to have 36.6% graft loss. Re-evaluation at POD #28 revealed graft loss of 20.8%. The cause of the event that is listed is from microbial contamination of wound bed and shearing.
The PI signed on 11/06/07. The outcome is still pending and there doesn’t appear to be any resolution.
3. Regulatory folder for 03/18/08
Adverse event for subject #130 for CSS graft loss with regrafting follow-up.
In violation of CFR 812.150(a)(1).
The patient has had contamination with mycobacterium asscessus and multiple other microorganisms throughout hospitalization. The patient has now received 12 sets of CSS that have been evaluated for graft loss and regrafting is complete. Each set is evaluated at POD# 14 and POD #28.
Files do not have a date that they were ever sent to the IRB. There is no acknowledgment form IRB. AE was not sent.
4. Regulatory folder for 07/03/08
Adverse event form from subject #131.
In violation of 812.150(a)(1).
This is a follow-up for the event of a fractured left femur. The patient was rehab through regimented schedule and the end result seems to be that the patient is full weight bearing with no abnormalities noted.
The PI signed the form on 07/02/08 which the date sent to the sponsor was on 06/02/08. This is not possible when the date of the event occurred on 06/30/08, and the reported date was on 06/02/08. A note in the regulatory folder under the email correspondence was asking the sponsor/site to clarify the reason for the mismatched dates and to explain which dates are correct.
5. Regulatory folder for 02/12/09
Copies of the adverse events that the annual report states were not reported to the UC IRB and the FDA.
In violation of 812.150(a)(1).
The following adverse events do not have a stamp from the IRB that they were ever received from the site. The records to show no IRB response will be listed as subject #, date of event, initial or follow-up #, and description.
Subject #131 - 06/30/08 Follow-up #1 Fracture of left femur post discharge.
Subject #131 - 01/18/08 Initial for sets #6, 6b and follow-up #2 for sets #4-5 CSS graft loss.
Subject #131 - 02/22/08 Initial Fracture of tibia and fibula.
Subject #131 - 03/04/08 Initial Fluctuant mass right flank without drainage.
Subject #130 - 03/10/08 Follow-up #5 for sets #1-12 Graft loss > 10% without regrafting.
Subject #131 - 04/04/08 Follow-up #1 Fluctuant mass right flank without drainage.
Subject #131 - 04/04/08 Initial Fracture of left femur post discharge
The date of event section on the IRB form is always filled out form the site as the date the form is actually completed on. The date of the event should remain unchanged from the original date of the event and the subsequent follow-up should change only.
The Morley Audit suggests that data for patients 130 and 131 violated FDA rules and regulations. Therefore, any submissions relying on these two patients are unreliable.
There is your smoking gun.
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