New Mexico Lions Sight Conservation Foundation, Inc. dba New Mexico Lions Eye Bank

During an inspection of your firm, New Mexico Lions Sight Conservation Foundation, Inc., also doing business as New Mexico Lions Eye Bank, located at 2501 Yale Boulevard SE, Suite 100, Albuquerque, NM, conducted between February 23 and February 28, 2024, the United States Food and Drug Administration (FDA) documented significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps) set forth in Title 21 Code of Federal Regulations (CFR) Part 1271 (21 CFR 1271) and issued under the authority of Section 361 of the Public Health Service Act [42 U.S.C. § 264].

The deviations documented on the Form FDA-483, List of Inspectional Observations (FDA 483), were presented to and discussed with you at the conclusion of the inspection. These items of concern include, but are not limited to, the following:

1. Failure to determine as ineligible a donor who is identified as having a risk factor for, or clinical evidence of, any of the relevant communicable disease agents or diseases for which screening is required under 21 CFR 1271.75(a)(1) [21 CFR 1271.75(d)]. You failed to determine as ineligible two donors of ocular HCT/Ps with a documented diagnosis or clinical evidence of sepsis, including two or more systemic responses to infection, documented within their available medical records during the hospital stay immediately preceding death. For example:

a. Donor (b)(6), (b)(7)(C) was determined eligible on 2/5/24, and ocular HCT/Ps from the donor were distributed on 2/1/24.

The donor was taken to the Emergency Department (ED) on (b)(6), (b)(7)(C) and was found to have altered mental status, hypothermia, hypotension, leukocytosis, and lactic acidosis, among other serious medical conditions. The donor was diagnosed with urosepsis and treated with three renally dosed antibiotics and was admitted to the Intensive Care Unit (ICU) for sepsis and septic shock. The donor continued to decline and expired on (b)(6), (b)(7)(C).

Donor (b)(6), (b)(7)(C) had a diagnosis of sepsis (urosepsis), risk factors for and clinical evidence of sepsis, and two or more systemic responses to infection documented in the medical records of the hospital stay immediately preceding death based on, but not limited to, the following:

Urinary tract infection (urine culture from 1/29/24 grew more than 100,000 cfu/mL of more than two microorganisms);

Elevated White Blood Cell (WBC) count >12,000 cells/mm3 (21,700 cells/mm3 on (b)(6), (b)(7)(C));

Respiratory rate >20 breaths/minute (26 breaths/minute on (b)(6), (b)(7)(C));

Heart rate >90 beats/minute (99 beats/minute on (b)(6), (b)(7)(C));

Altered mental status;

Lactic acidosis; and

Hypotension.

b. Donor (b)(6), (b)(7)(C) was determined eligible on 3/6/23, and ocular HCT/Ps from the donor were distributed on 3/2/23.

The donor presented in the ED on (b)(6), (b)(7)(C) with acute hypoxic respiratory failure, decreased tissue perfusion, tachycardia, tachypnea, and hypertension. Not long after arriving in the ED, the donor’s systolic blood pressure dropped in the 50s mmHg, which is described as the medical center’s “sepsis protocol.” Despite treatment with intravenous fluids, antibiotics, and norepinephrine, the donor continued to decline and expired on (b)(6), (b)(7)(C). According to documentation in the medical records, the donor’s primary cause of death is listed as septic shock, with a secondary cause of death as acute hypoxic respiratory failure.

Donor (b)(6), (b)(7)(C) had a diagnosis of sepsis and septic shock, risk factors for and clinical evidence of sepsis, and two or more systemic responses to infection documented in the medical records of the hospital stay immediately preceding death based on, but not limited to, the following:

WBC count >12,000 cells/mm3, <4,000 cells/mm3, or band forms >10% (donor had left shift of 88.3% neutrophils and 53% band forms on (b)(6), (b)(7)(C));

Respiratory rate >20 breaths/minute (36 breaths/minute on (b)(6), (b)(7)(C));

Heart rate >90 beats/minute (137 beats/minute on (b)(6), (b)(7)(C));

Elevated serum creatinine (2.4 mg/dL on 2/28/23 (0.5-1.5mg/dL reference range)) indicating acute kidney injury;

Acute hypoxic respiratory failure;

Altered mental status; and

Systolic blood pressure dropped to 50 mmHg.

The events described above are HCT/P deviations related to core Current Good Tissue Practice (CGTP) requirements and must be investigated and documented. Because these situations represent an HCT/P deviation relating to a core CGTP and to the prevention of communicable disease transmission or HCT/P contamination; and HCT/Ps were distributed, deviation reports must be submitted to FDA in accordance with 21 CFR 1271.350(b).

2. Failure to ensure procedures are in compliance with the donor eligibility requirements within Subpart C – Donor Eligibility of 21 CFR Part 1271 [21 CFR 1271.47(a)]. For example, your procedures, “T-710 Donor Screening Criteria,” “TF-710-01 Donor Screening Criteria Guide,” and “T-720 Donor Eligibility Determination,” are used to determine donor eligibility, and “TF-710-02 Sepsis Algorithm,” is used to determine a donor’s risk for sepsis and if an infectious disease consult is required. These procedures fail to include all clinical evidence and systemic responses to infection, if unexplained, of sepsis during the donor’s hospital stay immediately preceding death to appropriately evaluate a donor’s sepsis risk. Additionally, your procedures fail to include systemic responses to infection of sepsis such as a heart rate >90 beats/minute, partial pressure of carbon dioxide (PaCO2) <321, and more severe signs of sepsis, such as unexplained hypoxemia, elevated lactate, oliguria, altered mentation, and hypotension.

Both donors referenced above were evaluated for a risk of sepsis using the “TF-710-02 Sepsis Algorithm.” Documentation in the donor records included the following standard statement that failed to take into account all the clinical evidence of sepsis and systemic responses to infection as documented in the medical records during the hospital stay immediately preceding death:

“As long as these were all the clinical ID tests drawn (or the only ID studies done) (blood, sputum, urine, peritoneal fluid, CSF, AFB Cxs; viral tests; Quantiferon, etc) there was no definitive empirical evidence of sepsis or bacteremia at TOD.”

The deviations identified above are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment complies with all applicable federal regulations. You are responsible for reviewing your firm’s operations as a whole to ensure that you are in compliance with the law.

We acknowledge receipt of your letter, dated March 20, 2024, providing a response to the FDA’s inspectional observations. We have reviewed your response and we have determined that the response is inadequate to address our concerns. We have the following comments regarding your FDA 483 response.

1. In response to Observation 1, your disagreement that the donors were septic at the time of the death does not account for the donors’ medical records with documented diagnoses and clinical evidence of sepsis, including systemic responses to infection, during their hospital stay immediately preceding death. Your response states, “Quite simply, one cannot be septic and have negative blood cultures. And the practice of paper sepsis has proven over and over and over and over to be an inaccurate characterization of sepsis. At the same time the active problem list carries over “sepsis” the individual has no elevated temp and has 2 sets of no growth blood cultures. Prior to 2009, this individual would not have sepsis listed on their active problem list because the no growth blood cultures prove the patient is not septic! Fast forward to 2009 and a line has been drawn in the sand and most patients on admit are all of a sudden septic?! We respectfully challenge the FDA to please follow the logic here.”

Regardless of the year, the donors would have been diagnosed with sepsis based on clinical presentation and laboratory data. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.1-2 A diagnosis of sepsis can be made in the emergency room and positive blood cultures are not required for the diagnosis of sepsis.1-2 Positive pre-mortem blood cultures may be associated with clinical evidence of sepsis. However, negative blood cultures do not exclude a diagnosis of bacteremia or sepsis. Routine blood cultures do not identify all microbial agents that can cause sepsis and additional incubation time, or special media is sometimes needed. Previous administration of antibiotics is frequently a reason for negative blood cultures (i.e., culture negative sepsis)3. There are a myriad of reasons why blood cultures may be negative in cases of sepsis, and the absence of a positive blood culture does not exclude sepsis as a cause of death.

Additionally, in FDA’s Guidance for Industry: Eligibility Determination of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (August 2007), the Agency describes our current thinking on the risks of sepsis in deceased donors to include a review of medical records during a hospital stay immediately preceding death for diagnosis of sepsis, clinical evidence of infection, and systemic responses to infection. These risk factors for sepsis and septic shock are supported in recent medical literature.1-2

2. Your response to Observation 2 states your current written procedures meet FDA regulatory requirements for evaluating clinical signs/symptoms of sepsis. However, your procedures and algorithm do not account for the diagnosis or clinical evidence of sepsis, including systemic responses to infection, during a hospital stay immediately preceding death. They also do not include more severe signs of sepsis, for example, unexplained hypoxemia, elevated lactate, oliguria, altered mentation, and hypotension per FDA guidance referenced above. We note that a donor must be determined ineligible if there is documented diagnosis and clinical evidence of sepsis, including systemic responses to infection, documented in their medical records during a hospital stay immediately preceding death regardless of whether that information is documented within five days of death.

You should take prompt action to correct the violations addressed in this letter and prevent their recurrence. Failure to promptly correct these violations may result in regulatory action being initiated by FDA without further notice.

Your response should be sent to the following address: Young Mi Yoon, Compliance Officer, U.S. Food & Drug Administration, Office of Biological Products Operations – Division 2, 222 W. 7th Avenue, #25, Room 122, Anchorage, AK 99513 or emailed to YoungMi.Yoon@fda.hhs.gov. If you should have any questions, please contact Young Mi Yoon, Compliance Officer at (907) 248-8146 x 104 or via e-mail.