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June 10, 2024

Warning Letter OBPO 24-680039

Dear Mr. Fischer:

During an inspection of your firm, Indiana Lions Eye Bank, Inc. dba VisionFirst Indiana Lions Eye Bank, located at 4745 Haven Point Blvd., Carmel, IN, conducted between January 22, 2024, and February 1, 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 (HCTPs) 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)]. Between January 2021 and January 2024, you failed to determine as ineligible five 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 1/11/24 and ocular HCT/Ps from the donor were distributed on (b)(6), (b)(7)(C).

The donor was initially hospitalized on (b)(6), (b)(7)(C) with a hospitalization that spanned (b)(4) across multiple hospitals and was complicated by multiple serious clinical conditions. Given the donor’s age, co-morbidities, deconditioned state, and protracted hospitalization, the donor was at high risk for sepsis. The donor’s health continued to decline, and the donor expired on (b)(6), (b)(7)(C) with the cause of death attributed to sepsis and septic shock.

This donor with multiple serious medical conditions had 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:

• Evidence of urinary tract infection (urine culture on 12/10/23 grew Klebsiella pneumoniae);
• Klebsiella pneumoniae aspiration pneumonia;
• Clostridioides difficile colitis
• Respiratory rate >20 breaths/minute (39 breaths/minute on 1/5/24); and
• Elevated White Blood Cell (WBC) count >12,000 cells/mm³ (16,700 cells/mm³ on 1/7/24);
• Heart rate >90 beats/minute (144 beats/minute on 1/7/24); and
• Altered mental status.

b. Donor (b)(6), (b)(7)(C) was determined eligible on 1/3/24 and ocular HCT/Ps from the donor were distributed on (b)(6), (b)(7)(C).

The donor was taken to the Emergency Department (ED) on (b)(6), (b)(7)(C) and was found to have agitation, confusion, hypotension, hypothermia, and multi-organ failure (heart, lungs, liver, kidneys). The donor was admitted to the Intensive Care Unit (ICU) for shock of mixed etiology (cardiogenic and sepsis, septic shock due to undetermined organism) and possible community acquired versus aspiration pneumonia and was treated with broad spectrum antibiotics. Despite aggressive measures, the donor continued to decline and expired on (b)(6), (b)(7)(C). The donor had a diagnosis of septic shock due to bacterial (Proteus mirabilis) and viral (Respiratory Syncytial Virus) pneumonia and clinical evidence of sepsis at the time of death. Both organisms can cause sepsis and special viral culture media, or a PCR test would be necessary to detect RSV in the blood.

Donor (b)(6), (b)(7)(C) had 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:

• Heart rate >90 beats/minute (97 beats/minute on 12/27/23)
• Sputum culture positive for Proteus mirabilis and respiratory specimen positive for RSV (12/28/23);
• Elevated procalcitonin level;
• Altered mental status;
• Lactic acidosis;
• Multi-organ failure; and
• Oliguria.

c. Donor (b)(6), (b)(7)(C) was determined eligible on 12/12/23 and ocular HCT/Ps from the donor were distributed on (b)(6), (b)(7)(C) and (b)(6), (b)(7)(C).

The donor was admitted to the ED on (b)(6), (b)(7)(C) and was noted to have systemic inflammatory response syndrome (SIRS), profound hyperglycemia, leukocytosis, thrombocytopenia, lactic acidosis, acute renal failure, “shock liver” and passive congestion of liver due to right sided heart failure, pericardial effusion, and urosepsis. The donor was given intravenous fluids and vasopressor support and was treated with Vancomycin and Zosyn for “florid septic shock.” The donor was found in asystole 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 (b)(6), (b)(7)(C) grew more than 100,000 cfu/mL of Klebsiella pneumoniae);
• Respiratory rate >20 breaths/minute (27 breaths/minute on 12/10/23 and acute hypoxic respiratory failure);
• Elevated WBC count >12,000 cells/mm³ (15,600 cells/mm3 on 12/10/23);
• Altered mental status;
• Lactic acidosis; and
• Multi-organ failure.

d. Donor (b)(6), (b)(7)(C) was determined eligible on 4/3/23 and ocular HCT/Ps from the donor were distributed on (b)(6), (b)(7)(C).

The donor was admitted to the ED from an extended care facility on 3/29/23 with a diagnosis of severe hypoxic respiratory failure, requiring supplemental oxygen, and sepsis due to bilateral pneumonia. The donor expired the same day. The ED record also describes that the donor met SIRS criteria. The discharge summary lists the primary cause of death as respiratory failure with hypoxia, with sepsis listed as a contributing factor.

Donor (b)(6), (b)(7)(C) had 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:

• Bilateral pneumonia on chest x-ray (3/29/23);
• Severe hypoxic respiratory failure;
• Heart rate >90 beats/minute (126 beats/minute on 3/29/23); and
• Respiratory rate >20 breaths/minute (31 breaths/minute on 3/29/23).

e. Donor (b)(6), (b)(7)(C) was determined eligible on 4/6/21 and ocular HCT/Ps from the donor were distributed on (b)(6), (b)(7)(C).

The donor presented in the ED on (b)(6), (b)(7)(C) and was subsequently admitted to the ICU for “undifferentiated shock” attributed to sepsis and/or hypovolemia from dehydration and third spacing of fluid. The donor was treated with multiple renally dosed broad-spectrum antibiotics between (b)(6), (b)(7)(C) and (b)(6), (b)(7)(C), had a diagnosis of undifferentiated shock initially attributed to sepsis versus hypovolemia and, on 3/26/2021, the medical record clearly states that the shock was partly due to sepsis.

While the donor also had colitis and Brevibacterium sp. bacteremia on admission, it is unclear whether the presence of this microorganism in one blood culture was a contaminant or a true pathogen. We note that Brevibacterium sp. has been reported as a cause of sepsis in cancer and immunocompromised patients.^1-2 Although follow-up blood cultures on 3/30/21 showed no growth, the specimens were obtained while the donor was still on antibiotics and the donor clinically decompensated when the antibiotics were discontinued upon withdrawal of care due to the cancer prognosis. On the day of death ((b)(6), (b)(7)(C)), the donor showed additional, more severe signs of sepsis.

Donor (b)(6), (b)(7)(C) had 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:

• Heart rate >90 beats/minute (114 beats/minute on 3/27/21)
• Diagnosis of a urinary tract infection on 3/29/21;
• Respiratory rate >20 breaths/minute (24 breaths/minute on 3/29/21);
• Elevated WBC count >12,000 cells/mm3 (24,400 cells/mm3 on 3/30/21);
• Elevated lactate (lactic acidosis);
• Altered mental status;
• Hypoxia with high FiO2 requirements;
• Oliguria; and
• Multi-organ system failure.

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 1271 [21 CFR 1271.47(a)]. For example, your procedure, “SOP-DC-1, Transplant Tissue Exclusionary Criteria” (Revision 15, Implementation Date 11/29/22), used to determine donor eligibility and “Form F-DC-25 Sepsis Consult Flowchart” (Revision 1, Implementation Date 03/14/19), used to determine if an infectious disease consult is required, 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 “Form F-DC-25 Sepsis Consult Flowchart” includes just two systemic responses to infection (fever >100.4 F and WBC >12,000 cells/mm³ or <4,000 or bands >10%) that accompany clinical evidence of infection. The flowchart fails to include a heart rate >90 beats/minute and respiratory rate >20 breaths/minute or partial pressure of carbon dioxide (PaCO₂) ˂32.³ Finally, your procedure and flowchart fail to include more severe signs of sepsis, such as unexplained hypoxemia, elevated lactate, oliguria, altered mentation, and hypotension.

All five donors referenced above were evaluated for a risk of sepsis using the “Form F-DC-25 Sepsis Consult Flowchart.” Documentation in all 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 (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 February 23, 2024, providing a response and corrective actions 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 and your firm’s corrective actions.

1. In response to Observation 1, your disagreement that the donors were septic at the time of 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, “there is still only one gold standard for the diagnosis of sepsis, and that is a positive blood culture” and that the blood cultures were negative, and sepsis was thus ruled out for all donors cited on the FDA 483.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.^3-4 A diagnosis of sepsis can be made in the emergency room and positive blood cultures are not required for the diagnosis of sepsis.^3-4 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).⁵ 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.^3-4

2. In response to Observation 3, we acknowledge that you have revised your procedure, “SOP-DC-1 Transplant Tissue Exclusionary Criteria,” to include reference to “Form F-DC-25 Sepsis Assessment Flowchart” and have revised section 6.4.11 as “Persons who have a documented medical diagnosis of sepsis immediately preceding death, or have documented clinical evidence consistent with a diagnosis of sepsis, which is not explained by other clinical conditions at the time of death.” However, your revised procedure does not account for the diagnosis or clinical evidence of sepsis, including systemic responses to infection, during a hospital stay immediately preceding death.

We also acknowledge that you have revised “Form F-DC-25 Sepsis Assessment Flowchart” to include additional systemic responses to infection such as elevated heart rate and respiratory rate. However, it fails to include additional severe signs of sepsis described above that were also missing from your revised procedure. In addition, the flowchart states, “Complete for donors, with transplant intent, that were diagnosed or had a suspicion of sepsis, or positive blood cultures noted in the donor’s available records within five (5) days of death.” 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 the FDA without further notice.

We request that you respond in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. If you believe that your products are not in violation of the law, include your reasoning and any supporting information for our consideration. Additionally, include any documentation necessary to show that correction has been achieved. If you cannot complete all corrective actions within fifteen (15) working days, please explain the reason for your delay and the timeframe within which the remaining corrections will be completed.

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.

Sincerely,
/S/

Karlton T. Watson
Program Division Director
Office of Biological Products Operations – Division 2

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1 Castagnola, E. et al. Broviac catheter-related bacteraemias due to unusual pathogens in children with cancer: case reports with literature review. J Infect. 1997 May; 34(3): 215-8.

2 Lina, B. Persistent bacteremia due to Brevibacterium species in an immunocompromised patient. Clin Infect Dis. 1994 Mar;18(3): 487-8.

3 Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810.

4 Evans, L. et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021 Nov 1;49(11): e1063-e1143

5 Scheer, CS. Impact of antibiotic administration on blood culture positivity at the beginning of sepsis: a prospective clinical cohort study. Clin Microbiol Infect. 2019 Mar; 25(3):326-331.