Press Releases

Date Issued: March 9, 2017

Audiences:

• Organ and tissue procurement organizations
• Organ and tissue transplantation centers
• Health Care Providers who conduct organ and tissue transplant procedures
• Health Care Providers who care for organ and tissue transplant recipients
• Operating Room Managers, Directors and Staff
• Risk Managers
• Patients considering organ or tissue transplantation
• Organ and tissue recipients

Medical Specialties: Transplant surgeons, Nephrologists, Hepatologists, Infection Control, Infectious Disease Physicians

Product: SPS-1 Static Preservation Solution (SPS-1), manufactured by Organ Recovery Systems, Inc., is a clear to light yellow, sterile solution intended for the flushing and cold storage of kidney, liver, and pancreas at the time of organ removal from the donor in preparation for storage, transportation, and eventual transplantation into a recipient.

Purpose:
The FDA wants to heighten awareness about the potential for bacterial contamination of SPS-1, and provide recommendations to health care facilities to help mitigate potential patient exposure to infectious bacteria.

In addition, the FDA is calling attention to Organ Recovery Systems’ recall of specific SPS-1 lots and the company’s temporary suspension of production and distribution of all SPS-1 products.

Summary of Problem and Scope:
On Dec. 14, 2016, staff at a health care facility notified the FDA of an uncharacteristic odor from SPS-1 encountered during an organ procurement operation. Laboratory results from fluid samples and cultures from the SPS-1 used for this operation confirmed contamination with Pantoea and Enterococcus (intrinsically vancomycin-resistant) bacteria.

While it is not yet known how the SPS-1 used for this operation became contaminated, Organ Recovery Systems immediately initiated a voluntary removal of two lots of SPS-1: Lot Numbers PBR-0060-392 and PBR-0074-330.

On Jan. 12, 2017, Organ Recovery Systems notified customers of another report of an uncharacteristic odor from SPS-1 from a different lot, Lot Number PBR-0074-337, suggestive of potential contamination. Additionally, SPS-1 from Lot Number PBR-0060-386 was reported as being present when an odor was noticed, although the report did not identify any odor coming directly from this product.

Since then, Organ Recovery Systems temporarily suspended production and distribution of all SPS-1 products, and added Lot Numbers PBR-0074-337 and PBR-0060-386 to their recall.

On March 8, 2017, Organ Recovery Systems updated customers on the voluntary removal of SPS-1 and stated that additional sterility testing of randomly selected bags of SPS-1 should be completed by March 31, 2017.

To date, there have been no reports to the FDA of any post-operative infections or other adverse events directly linked to the identified products.

Recommendations for Organ and Tissue Procurement Organizations and Transplant Facilities:

In addition to following the standard precautions, the FDA recommends facilities and staff:

• Be aware that Organ Recovery Systems has recalled SPS-1 Lot Numbers PBR-0060-392, PBR-0074-330, PBR-0074-337, and PBR-0060-386.
  • Inspect your shelves and immediately remove these products from your inventory.
  • Return the affected lots to Organ Recovery Systems.
  • If there are questions about this recall, contact Organ Recovery Systems at 847-824-2421.
• Consider quarantining existing lots of SPS-1 not included in the recall and use an alternative FDA-cleared product until Organ Recovery Systems provides additional assurance of product safety through additional sterility testing.
  • Be aware that while contaminated SPS-1 to date has been associated with an uncharacteristic odor, the absence of an odor does not rule out the potential for bacterial contamination.
• If your facility does not have an alternative organ preservation solution immediately available, the FDA does not believe that organs exposed to SPS-1 should be excluded from transplantation. Rather, the small risk of infection should be balanced with the benefits of transplantation in each potential recipient.
• Pay attention to the quality of any organ preservation solution used. If there are concerns about odor, cloudiness, precipitation, or any other physical characteristics that could indicate contamination, carefully consider the benefits and risks.
• Report any adverse events or suspected contamination of organ preservation solution to the FDA and the manufacturer.

Recommendations for Patients considering organ or tissue transplantation procedures:

• Be aware that there are benefits and risks associated with all medical procedures. Ask your doctor about what to expect after an organ or tissue transplantation procedure including possible complications.

Recommendations for Organ and Tissue Recipients:

• If you have already undergone an organ or tissue transplantation procedure, continue with your routine follow-up with your health care provider as recommended.

FDA Activities:
The FDA is working with the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), and state public health departments to actively investigate the potential for contamination in Organ Recovery Systems’ SPS-1.

Our ongoing activities include:

• Evaluating information about documented and potential infections from multiple sources, including medical device adverse event reports submitted to the FDA, federal partners, state public health departments, and international public health agencies.
• Collaborating with CDC and HRSA to notify all Organ Procurement Organizations and transplant centers about the potential for bacterial contamination of Organ Recovery Systems’ SPS-1.
• Working with Organ Recovery Systems to reduce the risk of release of contaminated product, confirm the sterility of previously released product, and confirm appropriate quality control procedures.

The FDA will keep the public informed as significant new information becomes available.

Reporting Problems to the FDA:
Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations.

Health care personnel employed by facilities that are subject to the FDA’s user facility reporting requirements should follow the reporting procedures established by their facilities.

Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with the use of medical devices. Health care providers should submit voluntary reports of infection transmission associated with organ preservation solutions to the Agency via the Medical Device Reporting (MDR) process. If a health care provider suspects contamination of the organ preservation solution before or following use, we encourage the health care provider to file a voluntary report through MedWatch, the FDA Safety Information and Adverse Event Reporting program. User facilities participating in the FDA’s Medical Product Safety Network (MedSun) should report all of their device-related adverse events through the MedSun reporting site, not through MedWatch.
Contact Information:
If you have questions about this communication, please contact the Division of Industry and Consumer Education (DICE) at DICE@FDA.HHS.GOV, 800-638-2041 or 301-796-7100.

The UK National Institute for Health and Care Excellence (NICE) completed a comprehensive review of the literature regarding normothermic extracorporeal preservation of hearts for transplantation following donation after brainstem death. This review comes following published and unpublished research trials using the Transmedics Organ Care System.

Heart transplantation usually involves hypothermic storage of donor heart until it is surgically implanted into the patient.  With the new Transmedics device, the donor heart is stored at normal body temperature which keeps it beating and supplied with blood and nutrients for up to 8 hours until it is implanted into the patient.

The NICE review committee was summarily advised “that normothermic extracorporeal preservation might allow more frequent use of marginal hearts, so increasing the number of hearts available for transplantation. However, the available evidence did not provide data to draw any conclusions about this potential benefit.”

Out of the five experts invited to review novel technology, two surgeons representing the Society of Cardiothoracic Surgeons of Great Britain and Ireland revealed an ongoing controversy regarding the safety of the device. Dr. John Dark commented that that two hearts were disconnected from the device and had to be discarded – as a result the hearts could not be transplanted.  This was also confirmed by Dr. Steven Tsui who added that the device could cause, “inadequate perfusion leading to donor heart ischemia. If transplanted, this can result in primary graft dysfunction or primary graft failure.  Some patients who have suffered these complications have required a period of support including inotropes, balloon pump, ECMO and/or VAD.  If donor heart function does not recover after a period of support, the recipient would either die or require re-transplantation.”

A comprehensive overview of the literature included key words such as: heart, cardiac, beating, working, normothermic, continuous perfusion, and organ preservation.

Read more about the NICE recommendations:

2015 May NICE overview IP1289

2015 Oct NICE consultation IP1289

2015 Dec NICE comments IP1289

NICE specialist questionaire IP1289

1. Cedars-Sinai Medical Center

2. Stanford University Medical Center

3. Vanderbilt University Medical Center

4. The Hospital of the University of Pennsylvania

5. UCLA Medical Center

6. New York-Presbyterian/Columbia

7. Baylor University Medical Center

8. Duke University Hospital

9. Newark Beth Israel Medical Center

10. Cleveland Clinic

*based on 2015 UNOS data.

Hibernicor’s Asporto // Heart Preservation Device has undergone a design upgrade improving the usability and functionality of the heart container. This improvement follows proof-of-concept testing done at the University of Minnesota Experimental Surgical Services laboratories. The Asporto device provides perfusion of cardioplegia to the donor heart using a computer-controlled peristaltic pump in a thermoelectrically cooled and insulated container. The device effectively improves the quality of the donor heart by removing metabolic waste produced by the cardiomyocytes. The Asporto device is undergoing development and testing toward FDA approval in a 510k pathway. Further information about Asporto’s design evolution can be found in the article published in the Journal of Extracorporeal Technology.

Docket Number: FDA-2012-N-1021

Docket Name: Food and Drug User Fee and Modernization Act; Notice to Public of Web Site Location of Fiscal Years Proposed Guidance Document

Dr. Andrew Rivard’s response to FDA invitation to comments on utilizing animal studies to evaluate the safety of organ preservation devices and solutions:

What are the potential limitations of an ex vivo model in assessing reperfusion injury, and how can these limitations be mitigated?

Reperfusion injury has been evaluated by innumerable studies over a 50 year period from the onset of cardiopulmonary bypass utilized in surgery. The primary problem in cardiopulmonary bypass is the adequate cardioplegic administration during cardiac arrest.  Generally two accepted methods of cardioplegic are accepted, normothermic and hypothermic.  Both are given intermittently due to the effluent from the coronary sinus obscuring the surgical site.  Depending upon the surgical preference, the composition of the cardioplegia can be modified to include a variety of electrolytes, sugars, proteins, and autologous whole blood.   A large meta-analysis of cold blood vs. cold crystalloid cardioplegia in 2012 found no difference in patient survival.  Similar meta-analyses of warm vs. cold cardioplegia have also been published which again show no significant differences in survival.

Is there any difference between blood and crystalloid cardioplegia for myocardial protection during cardiac surgery? A meta-analysis of 5576 patients from 36 randomized trials. Sá MP, Rueda FG, Ferraz PE, Chalegre ST, Vasconcelos FP, Lima RC. Perfusion. 2012 Nov;27(6):535-46.

Is cold or warm blood cardioplegia superior for myocardial protection? Abah U, Garfjeld Roberts P, Ishaq M, De Silva R.  Interact Cardiovasc Thorac Surg. 2012 Jun;14(6):848-55

Obviously, a clinical transplant trial whereby the donor heart is preserved in the conventional manner of hypothermic static storage vs. a new preservation method is the penultimate test of effectiveness whereby morbidity and mortality can be compared to published literature and the control results.   If we take as a corollary the meta-analysis results of the cold vs warm clinical trials; there was no significant difference in long-term post operative cardiac outcomes, however warm cardioplegia was associated with an improved cardiac index, lower troponin and creatinine kinase levels.

How clinical results correlate to an ex vivo model which is studied over a period of a few hours, days, or weeks of examination is unclear.  However, the cardiac function and cellular markers may represent the overall quality of the preservation method.  Typically in heart preservation studies, one of four evaluation methods are utilized: orthotopic transplantation, Langendorff perfusion, isolated (4 chamber) working heart, and heterotophic transplantation. When examining these methods a variety of functional assessments can be made including: LV pressures, dp/dt, cardiac output, coronary flow, endothelial function.

The traditional Langendorff perfusion setup provides only flow to the aorta and coronary arteries with venous drainage from the coronary sinus. This type of setup does not generally allow for functional assessment of the LV.  However, a balloon tipped catheter can be inserted in the LV for pressures assessments.  In comparison a 4 chamber working heart is more complex and the cannulas and pumps must be arranged to provide both pre-load, and after-load of the ventricles.

Transplantation has limitations due to the high cost of the procedure, and rejection from unmatched organs.  Whereas, an ex vivo evaluation allows examination of an isolated heart with fewer confounding factors.

Histological studies provide an insight into the ultrastructual cellular composition of the heart preservation quality.  Light microscopy is a low cost and simple evaluation method to examine the effects of both the preservation and possibly reperfusion injury by taking serial samples over time with an ex vivo method.  The obviously the heart cannot be biosied too many times. Electron microscopy is a demanding evaluation which may provide additional detail at the level of the mitochondria and outer cell membranes.  Reperfusion injury is though to be due to an excessive amount of free radical production when energy substrate is provided by restoration of normal perfusion following donor heart preservation.

Perhaps the easiest method to assess reperfusion injury is to examine lactate levels of the effluent of the coronary sinus as a surrogate of the intrinsic myocardial acidosis.  Alternatively, the pH of the myocardium can be measured directly with a needle probe.  Other methods could include measuring troponin which is a byproduct of cardiomyocyte myofibril disruption. The limitations of this method for evaluation are that the timecourse to completely demonstrate the extent of tissue damage by Troponin T or Troponin I in the clinical setting can be greater than 6 hrs and last to up to 72 hrs.  This timespan is often much greater than what can be tested in the ex vivo setting.  Fortunately the absolute amount of Troponin released is proportional to the amount of cellular damage, the peak of which occurs between 24-36 hours, again this is generally much longer than an ex vivo study lasts.

In addition to markers for cell injury and function, histology, and the use of allogeneic blood during reperfusion, what measures can be taken to improve the data generated in an ex vivo model?

The stem of the question relates to either the accuracy of the scientific apparatus measuring the heart, or falsification of data generated.  Presuming the measuring instruments are standardized, then that leaves data integrity as the remaining issue.  An audit trail of the data using GLP standards would be reasonable. Perhaps submission of the raw data for evaluation could also be considered.

In an in vivo model, what are strategies to limit confounding factors, such as immunological responses and hemodynamic instability, from affecting the assessment of device-related reperfusion injury?

Tissue matching could be done prior to transplantation, or possible utilizing leukocyte depleted blood.  Given the effort to do a transplant, the extra steps to tissue match could be considered for a long-term survival study.  Again, the cost of doing a transplant is generally prohibitive for a company trying to demonstrate effectiveness of a new preservation method with the small market of heart transplantation.  Heterotopic heart transplantation has been used in the past in small studies. This would probably be the best way to limit hemodynamic instablity due to orthotopic transplant complications.  A heterotopic transplant typically is connected to the carotid artery and vein in the neck of the animal. This type of transplant allows the researcher to assess primarily for immediate graft failure or immunological modulations in xenotransplantation.  Although, could be utilized as a method to evaluate organs preserved in novel ways with high risk for failure.

Heart Xenotransplantation: Historical Background, Experimental Progress, and Clinical Prospects. Murthy R, Bajona P, Bhama JK, Cooper DK. Ann Thorac Surg. 2016

Is there a perceived hierarchy of evidence regarding data obtained from an ex vivo model and those obtained from an in vivo model? Or rather, is itmore judicious to view the two models as complements of each other?

Certainly, a heart transplant is a tour de force and penultimate evaluation of a preservation method. Whether or not this is required prior to human use is unclear.  If the FDA requires a pre-clinical heart transplant prior to clinical approval, this will significantly limit the ability of new technologies to be adopted clinically. An ex vivo method also has limitations as elucidated above, but is generally supportive of the entire evaluation.

What role does the risk of the device play in the utilization of in vivo and ex vivo models? Regarding specific experimental parameters (e.g.,length of preservation, total ischemic time), under what circumstances is it appropriate to test the worst-case scenario?

Given the extensive history of heart preservation using the Shumway method of cold ischemic static storage, all attempts should be done to compare the risk of a new preservation method to this well-established method.  If the device is intended to preserve the heart to 24 hrs, then the experimental parameters must be extended to evaluate that situation.  Also, if the harvesting methods vary from accepted standards (such as deceased donor procurement), then additional controls numbers should be obtained to balance the higher risk of post-preservation and post-transplant organ failure.  It would not be acceptable to compare the data from a DCD donor preserved using a new method without understanding the risk of a transplant from a DCD donor preserved in the standard method.  Just to highlight, there is a massive amount of cellular death that occurs in the first few minutes following global ischemia.  The ability of a preservation method to “rescue” the heart is limited and most likely will be optimal at preserving what portion viable myocardium remains intact.

What are the organ-specific challenges in developing in vivo and ex vivo models to assess reperfusion injury?

My experience is limited to the heart, and the organ specific issues are highlighted above.

What approaches would improve the in vivo and ex vivo study designs to ensure the generation of sufficient, meaningful data while limiting the number of animals used in such studies?

Again, transplantation is a highly complex and demanding surgical procedure in the animal model and should be used sparingly.  Perhaps this would be best utilized not in a research setting, rather than in training the surgeon for receiving the preserved heart and then proceeding to transplantation.

From a literature review of comparable cardiac transplantation studies the group sizes are typically 5-6 animals.  A group size of 6, in a similarly designed study was used at the Alberts-Ludwigs-University in Freiburg, Germany.  Other investigators at the Catholic University Leuven, Belgium and at the UTHSC San Antonio, TX have used ‘n’ numbers of 5 for similar studies. Furthermore, another group in Japan used an ‘N’ number of 6 for their study titled: “Cardiac Transplantation Following a 24hr Preservation using a Perfusion Apparatus”  An ‘N’ number of 6 in each group is consistent with reports of similar research published. Our previous investigations using porcine hearts determined that an N of 9 is capable of demonstrating a pH difference with a p < .005.

A sample size calculation would be acceptable based upon prior published data for ex vivo evaluations.  This should take in account sample sizes in the literature as well as the number of sample point.  For example, taking more than one biopsy of the myocardium at a particular time point may not improve the meaningfulness of the data.  So the methodology should be based upon clinically relevant outcomes and weighted toward data that can be measured in transplant patients.

To support a clinical trial application (IDE), we would like to see results from both ex-vivo and in-vivo models. Because there is more unknown/risk, we may ask the sponsor to conduct a staged clinical study with a small lead-in group, or a small feasibility study with only a few patients. What are your thoughts on this and if this does happen, are there additional clinical strategies (additional procedures/follow-ups) to mitigate safety risks in these patients?

A small clinical feasibility study with a few patients is likely less helpful than an appropriately powered clinical study.  What if there is a death in the first patient immediately post-transplant.  Is this evaluated any differently in a feasibility study vs. an appropriately powered clinical study?  The adverse event would need to be reported to the IRB, FDA, and DSMB.  Also, if the organ is damaged prior to transplant and the transplant is cancelled, then this too could be considered an adverse event because the organ would otherwise be transplanted with a morbidity and mortality matching the national standards.  Finally a full scale randomized clinical trial would be clearly acceptable by heart transplant surgeons as evidence of safety of the new technique.

Hibernicor LLC has initiated a project with the George Mason University to analyze over a million records of nationwide heart transplant data provided by the United Network of Organ Sharing (UNOS) to determine if there are any regional differences in cold ischemia time and organ wastage.  The research is designed to identify geographical disparities that may exist in the United States regarding the supply of potential donor hearts, as compared to the actual heart transplants as measured in terms of waiting time and the likelihood of receiving a transplant.  In addition the research will examine whether or not there is direct relationship between the likelihood of donor heart declination and geographical distance from the transplant center using GIS software. The information is central to developing new algorithms for optimal donor heart allocation and transportation logistics.

Hibernicor’s Asporto heart transplant device has been selected as a finalist in the Emerging Medical Innovation Valuation Competition, as part of the Design of Medical Devices Conference at the University of Minnesota. Hibernicor was one of five finalists among 24 submissions from 10 states and four countries.

Design of Medical Devices Conference April 13-16 2015

The Emerging Medical Innovation Valuation Competition, to be held during the annual Design of Medical Devices Conference (hosted by the University of Minnesota’s Medical Devices Center, College of Science and Engineering, and Academic Health Center) will provide a way for researchers and inventors to get immediate project feedback from leaders in medical technology research, engineering, and development.

This competition is for inventors (including students, faculty, staff, and corporations) seeking investor support to reach the next stage of development. Initial submissions should be no more than 10 slides summarizing the medical innovation. Judges will review and invite six inventors to give succinct, eight-minute presentations at the DMD Conference in April 2015.

Faculty and fellows from the Medical Industry Valuation Laboratory will provide feedback and determine the top three innovations—those that hold the greatest return on investment and investment potential. The top three presenters will be awarded a full valuation, including a presentation and report, of their technologies from the University of Minnesota’s Medical Industry Valuation Laboratory, valued at $15,000 per project. Winners will be announced at the conference’s keynote luncheon.