Regulatory Failure Contributing to Deaths of Live Kidney Donors

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American Journal of Transplantation 2012; 12: 829–834 Wiley Periodicals Inc.

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Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/j.1600-6143.2011.03918.x

Personal Viewpoint

Regulatory Failure Contributing to Deaths of Live Kidney Donors A. L. Friedmana,∗ , T. G. Petersb and L. E. Ratnerc a Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY b Department of Surgery, University of Florida Health Sciences Center, Jacksonville, FL c Department of Surgery, Columbia University, New York, NY *Corresponding author: Amy L. Friedman, [email protected]

Hemorrhagic deaths of living kidney donors from failure of vascular clips used on the renal artery, first documented in 2006, have continued due to postoperative Hem-o-lok clip failure with sudden, massive bleeding. While the FDA issued a Class II recall of the Hem-o-lok clip for laparoscopic donor nephrectomies in 2006, two live kidney donors in the United States and one in India have since died. Compliance in timely reporting of deaths by the manufacturer and donor hospitals has not been enforced. Oversight agencies did not inform practitioners that donors died due to clip failures. A February 2011 survey disclosed that Hem-o-lok or other clips are still used by some surgeons as a sole means of arterial control in laparoscopic donor nephrectomy; thus, a practice with documented fatal outcomes persists. We conclude that systems failures by oversight-regulatory agencies in communication to active clinicians led, at least in part, to preventable deaths. Information which was disseminated was neither complete nor timely. A corrective plan, funded by oversight agencies and the Hem-olok manufacturer, is proposed. All surgeons operating on a living organ donor must select vascular control techniques that entail tissue transfixion and assure a safe operative recovery. The Hem-o-lok and other surgical clips must not be used to control the donor renal artery.

Key words: Donor, live donor, outcome, quality, regulatory, safety Abbreviations: ASTS, American Society of Transplant Surgeons; CMS, Center for Medicare and Medicaid Services; DOH, Department of Health; FDA, food and drug administration; HRSA, health resources and services administration; LODN, Living Organ Donor Network. MAUDE, manufacturer and user facility device experience database; MPSC, Membership and Professional Standards Committee.

Received 22 September 2011, revised 18 November 2011 and accepted for publication 22 November 2011

Introduction

“An extra professional burden falls on the surgeon performing the donor nephrectomy. . . .’ Joseph Murray, M.D., Nobel Laureate, 1990.

Deaths of two living kidney donors from vascular clip failure were first documented in January 2006 in our report of preventable hemorrhage after donor nephrectomy. That study stressed the mortal danger of major vessel control with hemostatic clips, and emphasized the necessity of transfixion control (suture or staple anchored within the vessel wall) of the donor renal artery. A nationwide survey of transplant surgeons further affirmed a clear professional opinion that renal arterial control with clips (nontransfixion) is unsafe (2). By June of 2006, the US Food and Drug Administration (FDA) and Teleflex, the manufacturer of the Hem-o-lok locking clip, issued a Class II recall indicating that its use on the renal artery in laparoscopic donor nephrectomy was contraindicated (3). Since the Class II recall, to our knowledge, two live kidney donors in the United States (2008 and 2011) and one in India (2008) have died, and an additional three donors have suffered severe hemorrhagic events from failure of the Hem-o-lok clip. Each of these catastrophes occurred following closure of the surgical incisions, and each surgeon apparently believed that all major vascular structures were secure as the operation ended. The donor surgeons were either unaware of, or ignored, the FDA recall or device contraindication. To better understand how system failures contributed to this pattern of preventable death from massive hemorrhage due to clip failure, we sought information from both regulatory and professional communities. There were clearly missed opportunities for effectively communicating critical information to active clinicians; thus, at least in part, regulatory failure led to donor deaths. 829

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The United States Food and Drug Administration (FDA) FDA Class II recall means that the medical device at issue may cause “temporary or medically reversible adverse health consequences, or where the probability of serious adverse health consequences is remote (4)”. Since our 2006 review documented severe risk, the Hem-o-lok recall likely should have been Class I, meaning that “there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.” Additionally, an FDA role is to “monitor recalls and assess the adequacy of a firm’s efforts in recall” (4), requiring US hospitals (facilities) to report death or serious injury to its Manufacturer and User Facility Device Experience Database (MAUDE) (5), with similar reporting to the manufacturer within 10 working days (6). Manufacturers must submit similar reports of deaths, serious injuries and malfunctions within 30 calendar days of becoming aware of an event (7). The 2006 Class II recall provided no data and did not indicate that donor fatality was associated with clip failure, although it is now apparent that three deaths were then known to both the manufacturer and the FDA. Furthermore, the Hem-o-lok clips received another unqualified approval from the FDA, devoid of any mention of the contraindicated use, in November of 2006, 5 months after the recall (8). Through a request for copies of communications between the FDA and the manufacturer under the Freedom of Information Act, we have learned that the FDA considered their recall action concluded in November 2007, though the manufacturer subsequently reported (to the agency) in March 2008 that three effectiveness checks demonstrated a level of 48% effectivity for the recall. We have interpreted this information to mean that less than one-half of those who were notified, confirmed receipt of the information. On May 5, 2011, the FDA and the Health Resources and Services Administration (HRSA) issued a joint safety communication directed to transplant and urology professionals, as well as patients, about the Hem-o-lok clip and its attendant failures to control live kidney donor postoperative hemorrhage. This first public release of data by a national regulatory entity cited 15 medical device reports of 12 injuries and three deaths between November 19, 2001 and March 20, 2005, as well as three additional kidney donor deaths since the Class II recall of 2006, a delay of over 5 years (9). While the May 2011 advisory references six-donor deaths, we found only four in MAUDE. As these events unfolded, each of us directed a US live donor kidney transplant program. Like other surgeons who might initiate system changes in transplant hospitals, we remained uninformed through official oversight channels about deaths occurring from Hem-o-lok clip failure, and must surmise that other US live donor kidney program 830

professionals were equally uninformed. Although we have a well-recognized interest in this topic (10), none of us was aware of the HRSA-FDA action until receiving a separate e-mail notification dated May 9, 2011. Finally, information regarding certain deaths (Table 1) associated with the Hem-o-lok clip failure in donor nephrectomies may vary depending upon data source and reporting body (the lay media, peer review publication, MAUDE and personal communications). Noncompliance with the reporting requirements by facilities and the manufacturer appears to have limited FDA ability to perform appropriate, timely analysis of Hem-o-lok clip failure. Yet, it is not apparent that the FDA has enforced reporting requirements upon either facilities or the manufacturer.

The Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) OPTN/UNOS Policy 12.8.4 (11) states that transplant programs must report all instances of living donor deaths within 72 h after becoming aware of the death, an outcome of HRSA’s directive in 2006 that oversight of living donor transplantation is within the OPTN’s purview (12). The UNOS Membership and Professional Standards Committee (MPSC) is charged with insuring that OPTN/UNOS transplant centers remain in compliance with this and related federal government approved policies (13). These reporting requirements likely mean that UNOS knew about the two US donor deaths (2008 and 2011), but did not disclose that fatalities had occurred. Instead, UNOS twice sent notifications by e-mail and standard mail, expressing the FDA and manufacturer’s recall, and the specific Hem-o-lok contraindications in laparoscopic donor nephrectomy implying, but not clearly stating, that deaths had occurred due to clip failure. These communications were distributed to kidney program directors, transplant administrators, kidney transplant surgeons, quality review officers, compliance officers and CEO’s of kidney hospitals. Center identification would not have been necessary to communicate these fatal events in a manner with much greater impact than simple repetition of manufacturer package insert verbiage. An example of a potential format that might have been used, is found in the MAUDE report 3003898360-2011-00048 which contains sufficient detail to impart the necessary information, yet still preserves confidentiality (Table 1). The event description states: “Weck hem-o-lok clips were utilized to ligate the renal artery. Approx 3 hours post surgery, the pt went into cardiac arrest. The pt was sent to the operating room where an exploratory laparotomy was performed. The pt was hemorrhaging and in shock. The pt expired in the operating room. It was alleged, the clips could be seen floating in the abdominal cavity which was reportedly full of blood. The clips were closed. The hospital reported an American Journal of Transplantation 2012; 12: 829–834

Live Kidney Donor Deaths Table 1: Living kidney donor deaths: seven associated with Hem-o-lok clip failure to control the renal artery in donor nephrectomy. FDA/HRSA May 5, 2011 advisory refers to six deaths, but may not include the 2005 Dekel et al. (Israel) or 2008 (India) cases. Total number of donor deaths may therefore be higher than 6. MAUDE (Manufacturer and User Facility Device Experience Database) reports obtained through searches for Manufacturer = Teleflex; Product = Hem-o-lok; Product = Hemolok; Device = Clip, Implantable; Event Type = Death. Dates = 01/01/2000 to 05/14/2011 Data source

Event date

Report date

Reporter

No. of Hem-o-lok clips

MAUDE 10444752003-00007 (22) MAUDE 10444752005-00007 (23)

7/24/2001

7/29/2003

Manufacturer

2

2/1/2005

3/28/2005

Manufacturer

Unknown

Asiaonehealth (24) Dekel et al. (25)

2/16/05 9/2005

2/28/2009 2008

Journalist Surgeon

Unknown 2

MAUDE 10444752005-00015 (26)

9/1/2005

10/14/2005

Manufacturer

Unknown

Operating surgeon

2008

2010, informal report only

Surgeon

2

MAUDE 1290403 (27)

10/27/08

1/14/09

Facility

1

MAUDE 30038983602009-00007 (28) MAUDE 30038983602011-00048 (29)

10/28/08

1/27/09

Manufacturer

1

1/13/11

3/29/11

Manufacturer

>1

autopsy confirmed the “renal artery was surgically cut and unclamped’”. This appears to be a report by the manufacturer, of a January 13, 2011 donor death that we infer generated the HRSA-FDA advisory, and that we have interpreted as the sixth of the reported fatalities. As the sole repository of center-derived donor data, UNOS could similarly have disseminated specific and timely details to avert subsequent donor risk.

Center for Medicare and Medicaid Services and the United States Department of Health (CMS/DOH) Unexpected deaths are reported to state Departments of Health, which, in turn, have served as local representatives of CMS. The New York State DOH, in March 2011, released an advisory to all transplant centers in the state indicating that Hem-o-lok clip failure was identified as the cause of the 2008 donor death. Prior to May 5, 2011 this was the only public, officially released confirmation of donor death related to clip failure. And, it would not appear timely considering a lapse of 3 years.

Other

Reports appear to represent the same case from “The National University Hospital” in Singapore Reported from Israel, unlikely to be included in FDA/HRSA May 5, 2011 advisory Unknown whether this was a “donor” nephrectomy, implied by FDA/HRSA May 5, 2011 advisory Case occurred in India, unlikely to be included in FDA/HRSA May 5, 2011 advisory Reports appear to represent the same case

artery is challenging without access to the centralized, confidential records that are available only to the manufacturer or regulatory agencies. As noted above, the HRSA-FDA advisory references six deaths, while only four are identifiable in MAUDE. One additional MDR report (10444752005-00015) described a nephrectomy that may have been known to be a donor nephrectomy to the FDA, but is not publicly disclosed to be so. Thus, we believe that there are either one or two Hem-o-lok associated donor deaths known to the FDA that have not been reported in MAUDE, but are included in the advisory. An Israeli donor death is documented in the peer review literature, but does not match any of the MAUDE reports. Similarly, a case that occurred in India and was personally reported to one of the authors does not match any of the MAUDE reports. For these reasons, we conclude that at least eight (6 HRSAFDA deaths + Israeli + Indian) or nine (6 HRSA-FDA deaths + 1 unclassified MAUDE nephrectomy + Israeli + Indian) donor deaths have occurred.

The American Society of Transplant Surgeons (ASTS)(14)

Actual Number of Donor Deaths Confirmation of the specific number of living donor deaths associated with use of the Hem-o-lok clip on the renal American Journal of Transplantation 2012; 12: 829–834

Responding to our concerns about donor deaths linked to clip failure, the ASTS leadership provided access to its membership for our initial survey in 2002 and did so again 831

Friedman et al. Table 2: Factors that prevented effective communication and/or outcome from Class II recall for Hem-o-lok clips, and contributed to additional deaths of living donors Stakeholder

Barrier (S)

Manufacturer

• Commercial self-interest

Donor surgeons (transplant surgeons, urologists, minimally invasive surgeons)

• Belief in Hem-o-lok safety

Proposed solution • Enhanced compliance with reporting requirements • Penalty for noncompliance • Publication of adverse events in the peer review literature • Publication of adverse outcomes data in the peer review literature

• Limited access to adverse outcomes data • Not regular member of transplant community

Donor hospitals

• Limited communication between professional communities (transplant surgery, urology, minimally invasive fields) • Low frequency events have limited appeal to general journals (e.g. New England Journal of Medicine, JAMA) Resistance to change • Limited access to adverse outcomes data • No precedent for effective communication within hospitals • No precedent for effective communication between hospitals and medical staffs • No precedent for model of accountability for medical devices within hospitals/operating rooms

UNOS/OPTN

• Voluntary organization

FDA

• Peer review, confidentiality issues • Concern about discoverability • Lack of QAPI live donor program with long-term review of national results • Primary clearance process for medical devices does not consistently require review of safety and effectiveness • Inadequate resources for postmarket surveillance • Lack of expertise to objectively assess adequacy of manufacturer’s analysis of adverse events

in 2011. Subsequently, follow-up warnings were sent to all ASTS members following both the 2008 and 2011 incidents emphasizing the content of the UNOS advisories, again noting that the Hem-o-lok clip was contraindicated in donor renal artery control. However, living donor nephrectomy may be performed by transplant surgeons, urologists and minimally invasive surgeons, some of whom are likely not members of the ASTS. So information disseminated solely through ASTS and other transplant organizations cannot be expected to reach all US donor surgeons. 832

• Improve mechanism of communication within hospitals • Inform urology + minimally invasive professional societies

• Publication of adverse outcomes data in the peer review literature • Enhanced compliance with reporting requirements • Penalty for noncompliance • Establish precedent of effective communication, within hospital, between hospital and medical staff • Establish precedent of hospital accountability for medical devices within hospitals/operating rooms • Establish live donor national level QAPI within UNOS/OPTN structure

• Accept and follow recommendations of Institute of Medicine report July 2011 • Impose penalties for failed compliance with reporting requirements to MAUDE on manufacturer and donor facilities • Engage independent experts in classification of medical device recalls

Failures and Proposed Remedies It is apparent that system failures occurred in oversight agencies and organizations since timely and clearly stated warnings about fatal outcomes involving donor renal artery control with clip devices were not fully effective (Table 2). We believe that the manufacturer, the FDA and UNOS did not act in a fashion which facilitated corrective action at the point of care. It appears that lack of information regarding individual deaths and a pattern of adverse events contributed to ongoing fatalities. Additionally, while these American Journal of Transplantation 2012; 12: 829–834

Live Kidney Donor Deaths

events were catastrophic in nature, their low frequency increased the challenge of pattern recognition for similar events occurring at different live donor programs. Detection would have required regular, centralized analysis of pooled data over time, an activity not feasible through all of the events recorded in this report. Current UNOS surveillance of live donor programs would seem to be a positive step, at least in so far as center awareness may be concerned. Patient confidentiality, peer review, liability issues and defensive medicine are legitimate considerations in limiting disclosure of facts concerning adverse events. The FDA’s apparent acceptance of the manufacturer’s assessment that bleeding was caused by “misapplication of the clips”, omitted an opportunity to require an independent analysis of Hem-o-lok clips, to overcome proprietary conflict of interest, and to improve patient safety. Potentially life-saving safety information must be timely disseminated to transplant teams, donor hospitals and all concerned with the safety and outcomes of living kidney donors. The vast majority of our donor–surgeon colleagues want— and need—timely, clearly stated patient safety information. Thus, we believe that a corrective action plan, funded by oversight agencies and Teleflex, should now include:

1. Reclassification of the Hem-o-lok recall to Class I: contraindicated for use in any donor nephrectomy. 2. Collaboration with the ASTS, UNOS, The American Urological Association (15), The American Association of Kidney Patients (16), the National Kidney Foundation(17) and other professional and patient organizations to disseminate data driven information about the risk of nontransfixion methods of renal artery control in donor nephrectomy. 3. Establishment of a National Quality Assurance and Performance Improvement Program for living donors, using monthly and long-term reviews of data, within the UNOS committee structure, and supplied by data provided by individual live donor programs, in order to promptly identify dangers to living donors. 4. Requirement that a donor life and medical insurance program, such as the Living Organ Donor Network (LODN) (18), be implemented in all transplant centers performing live donor procedures. 5. Investigation of Hem-o-lok safety, use and outcomes in all types of nephrectomy. Objective analysis by a multidisciplinary team, including members of the urology community, should be required by the FDA for assessment of the Hem-o-lok clip for use in nondonor nephrectomies.

Finally, we understand that some surgeons continue to have confidence that clips, including the Hem-o-lok device, provide secure renal artery closure (19). As “implantable American Journal of Transplantation 2012; 12: 829–834

clips”, they are categorized as Class II medical devices by the FDA (20). Similar to many other Class II devices, they were and have all been initially cleared for human use through the 510(k) clearance process without any review by the FDA of safety and effectiveness, on the basis of being substantially equivalent to other devices already in use. At the FDA’s own request, the Institute of Medicine (IOM) (21) has just reviewed this approach and concluded that conclusions include that (1) the process cannot be transformed into a premarket evaluation of safety and effectiveness as long as the standard for clearance is not objective review of the device itself; and (2) postmarket surveillance is inadequate. These findings by the IOM validate our observations about Hem-o-lok clips, for which basic data demonstrating safety and effectiveness have never been published or reviewed by the FDA. We also note that failure of the manufacturer and donor facilities to comply with MAUDE reporting requirements might be the source of financial penalties that would represent potential funds for enhanced analysis of MAUDE reports by the FDA. Of greatest concern is the finding that even in February 2011, 16/180 US based ASTS members responding to a new survey indicated that Hem-o-lok or other clips are always or sometimes used as a sole means of arterial control in laparoscopic donor nephrectomy at their institutions. It appears to us unclear why the 2006 recall applied only to the use of Hem-o-lok clips in laparoscopic donor nephrectomies. From a surgical perspective, there is no logical rationale for expecting that clip use on a renal artery stump will be safer simply because the incision is larger (in an open approach), or smaller (in a robotic approach), or traverses an internal organ (natural orifice approach). In fact, we wonder whether the Hem-o-lok clip is safe for use on any artery of similar caliber to the renal artery, e.g. the splenic artery. In light of the data we have assembled, and the technical nuances that distinguish a donor nephrectomy (complete skeletonization of the vessel, short stump), continued use of clips are both legally indefensible and morally intolerable. All surgeons who accept the privilege of operating on a living organ donor must honor that person by selection of a vascular control technique that entails transfixion of tissue, and that assures, to the highest degree, a safe operative recovery followed by a long and healthy life.

Acknowledgments The authors honor Ronald Herrick, Joan Hubbard and all other living kidney donors who have entrusted donor surgeons with their own lives in order to save the lives of others. We are grateful to Michael Abecassis MD, MBA, and other ASTS Past Presidents, to the outgoing Executive Director Katrina Crist, and to the ASTS Staff, Kim Gifford, Jamison Visone and Chantay Parks for facilitating the membership surveys. Finally, we wish to thank all those transplant surgeons who have trusted us to protect the confidential details about their reported adverse events and who have allowed us access to their data.

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Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

14.

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American Journal of Transplantation 2012; 12: 829–834